Multiple Sclerosis Journal

Background

Cognitive impairment is increasingly being recognized as a common and disabling symptom of multiple sclerosis (MS) that contributes to poor quality of life in affected patients. Despite the high prevalence of cognitive impairment in MS, cognitive function is not assessed routinely in clinical practice or in clinical trials. The perception that cognitive assessments are costly, time-consuming, complicated, and difficult to administer and interpret has contributed, at least in part, to the failure to incorporate cognitive testing into standard clinical evaluation of patients with MS. Detailed studies of cognitive impairment in MS are rare and guidelines for the assessment of cognitive function in MS are lacking.

Treatment

How to manage cognitive decline in MS also requires further study. Licensed disease-modifying drug (DMD) treatments for MS reduce brain lesion development, and associations between brain lesions and cognitive performance have been reported, providing a rationale for DMD treatment of MS-associated cognitive impairment. There is some evidence for cognitive benefits of DMDs, but as few pivotal DMD trials included cognitive assessments, the effects of these agents on cognition are not fully understood and more studies are needed.

Conclusions

It is only through further studies that it will be possible to identify patients with, or at risk of, cognitive impairment and to provide appropriate therapy to limit the effects of this potentially devastating symptom.

Introduction

Multiple sclerosis (MS) is a chronic inflammatory disease with an as yet not fully understood etiological background. The geographical distribution of MS is striking with a prevalence that increases with latitude. For this reason, vitamin D deficiency is considered a possible pathogenic co-factor in MS.

Materials and methods

To study the role of the vitamin D metabolism in MS, blood samples were taken twice (summer and winter) from 103 patients with MS and 110 healthy controls. Serum concentrations of 25-hydroxyvitamin D (25(OH) D) and 1,25-dihydroxyvitamin D (1,25(OH)₂D) were measured, and detailed information on disease characteristics and environmental factors that might influence the vitamin D metabolite levels was collected.

Results

Mean serum 25(OH)D and 1,25(OH)₂D concentrations were significantly higher in summer compared to winter in both patients and controls. Using logistic regression methods, we found that in women for every 10 nmol/L increase of serum 25(OH)D level the odds of MS was reduced by 19% (odds ratio 0.81; 95% confidence interval: 0.69–0.95), suggesting a “protective” effect of higher 25(OH)D serum levels. In addition, also restricted to women, a negative correlation was found between Expanded Disability Status Scale and 25(OH)D levels (r = −0.29, P = 0.020).

Conclusions

Our data suggest that higher circulating levels of 25(OH)D are associated with a lower incidence of MS and MS-related disability in women. This may imply clues to the pathogenesis of the sex difference in risk and to the nature of the environmental factors involved in MS.

Quantitative magnetization transfer magnetic resonance imaging (qMT-MRI) can be used to improve detection of white matter tissue damage in multiple sclerosis (MS) and animal models thereof. To study the correlation between MT parameters and tissue damage, the magnetization transfer ratio (MTR), the parameter f* (closely related to the bound proton fraction) and the bound proton transverse relaxation time T_2B of lesions in a model of focal experimental autoimmune encephalomyelitis (EAE) were measured on a 7T animal scanner and data were compared with histological markers indicative for demyelination, axonal density, and tissue damage. A clear spatial correspondence was observed between reduced values of MTR and demyelination in this animal model. We observed two different levels of MTR and f* reduction for these lesions. One was characterized by a pronounced demyelination and the other corresponded to a more severe loss of the cellular matrix. Changes in f* were generally more pronounced than those of MTR in areas of demyelination. Moreover, a reduction of f* was already observed for tissue where MTR was virtually normal. No changes in T_2B were observed for the lesions. We conclude that MTR and qMT mapping are efficient and reliable readouts for studying demyelination in animal models of MS, and that the analysis of regional f* might be even superior to the analysis of MTR values. Therefore, quantitative mapping of f* from human brains might also improve the detection of white matter damage in MS.

Objective

1) To determine whether JC virus (JCV) DNA was present in the cerebrospinal fluid (CSF) and blood from patients with multiple sclerosis (MS) in comparison with controls and 2) to find out if our clinical material, based on presence of JCV DNA, included any patient at risk for progressive multifocal leukoencephalopathy (PML).

Methods

The prevalence of JCV DNA was analyzed in CSF and plasma from 217 patients with MS, 86 patients with clinically isolated syndrome (CIS), and 212 patients with other neurological diseases (OND). In addition, we analyzed CSF cells, the first report of JCV DNA in CSF cells in a single sample, and peripheral blood cells in a subgroup of MS (n = 49), CIS (n = 14) and OND (n = 53).

Results

A low copy number of JCV DNA was detected in one MS cell free CSF sample and in one MS CSF cell samples. None of these had any signs of PML or developed this disease during follow-up. In addition, two OND plasma samples were JCV DNA positive, whereas all the other samples had no detectable virus.

Conclusion

A low copy number of JCV DNA may occasionally be observed both in MS and other diseases and may occur as part of the normal biology of JC virus in humans. This study does not support the hypothesis that patients with MS would be at increased risk to develop PML, and consequently screening of CSF as a measurable risk for PML is not useful.

Background

Using double inversion recovery (DIR) MRI, cortical lesions can be seen in the brain of patients with multiple sclerosis (MS). The burden of such lesions seems to be well correlated with the severity of MS-related disability.

Objective

To investigate whether the extent of cortical damage in patients with benign MS (BMS) might contribute to explain their favorable clinical status.

Methods

Forty-eight patients with BMS (Expanded Disability Status Scale [EDSS] score ≤3.0 and disease duration ≥15 years) and 96 patients with non-disabling, early relapsing–remitting (RR) MS (EDSS score ≤3.0 and disease duration ≤5 years) were studied. Brain MRI, including a DIR and a fluid-attenuated inversion recovery (FLAIR) sequence, was acquired at baseline and after 12 months. On DIR images, intracortical (ICL) and cortical-subcortical lesions (CSL) were identified and their number and volume calculated. Total white matter (WM) lesion volume was quantified on FLAIR images.

Results

Compared with early RRMS, patients with BMS had lower number of ICL at both study time points (P ≤ 0.001 for both comparisons). At one-year follow-up, a significant increase of ICL and CSL number and total volume was observed only in early patients with RRMS. The number and volume of cortical lesions was not correlated with WM lesion volume. Total ICL number at baseline, total cortical lesion volume at baseline, and total cortical lesion volume change were independent predictors of MS phenotype.

Conclusion

In patients with BMS, the selective sparing of the cortex from disease-related focal pathology might be one of the factors associated to their favorable clinical status, independently of the (possible) accrual of WM lesions.

Background

A statistical distribution describing the number of new enhancing lesions seen on MRI in patients with MS is of great importance for improving the statistical methodology of clinical trials using new enhancing lesions as outcome measure. We examined whether there are superior alternatives for the currently proposed negative binomial (NB) distribution.

Objective

To determine the optimal statistical distribution describing new enhancing lesion counts from a selection of six conceivable models, and to assess the effect on the distribution of a treatment effect, varying follow-up duration and selection for activity at baseline.

Methods

The statistical NB, Poisson-Inverse Gaussian (P-IG), Poisson- Lognormal (P-LN), Neyman type A (NtA), Pólya-Aeppli (PA) and Zero Inflated Poisson (ZIP) distribution were fitted on new enhancing lesion data derived from one treated and two untreated cohorts of RRMS and relapsing SPMS patients and on subgroups of varying follow-up duration and selection for baseline activity. Measure of comparison was Akaike's information criterion (AIC).

Results

Both the subgroup analyses as well as a treatment had a noticeable effect on the distributional characteristics of new enhancing lesion counts. The NB distribution generally provided the most optimal fit, closely followed by the P-IG distribution and the P-LN distribution. Fits of the PA and NtA distribution were suboptimal, while the ZIP distribution was the least adequate for modelling new enhancing lesion counts.

Conclusion

The NB distribution is the optimal distribution for modelling new enhancing lesion counts, irrespective of the effect of treatment, follow-up duration or a baseline activity selection criterion.

Background

Options for non-responders to relapsing–remitting multiple sclerosis (RRMS) first-line disease-modifying therapies (DMT) are limited. We explored whether switching first-line DMT is effective.

Methods

Patients with RRMS who first received interferon-beta (IFNB) or glatiramer acetate (GA) were classified in three categories: DMT change because of suboptimal response, DMT change because of other reasons, and no DMT change during follow-up. Outcomes included annualized relapse rate (ARR) and relapse-free proportions.

Results

We identified 597 patients who initiated first-line DMT. For patients who did not change DMT (n = 240), pre-DMT and on-DMT median ARR were 0.50 and 0 (P < 0.0001). At 24 months, 76% (95%CI = 69–81%) of patients who did not change DMT were relapse-free. Of the 155 who switched because of suboptimal response, 101 switched to another first-line DMT. Median ARR pre-DMT, on first DMT and second DMT were: 0.50, 0.55, and 0.25 for switchers from IFNB to GA (IFNB/GA, n = 12) (pre-DMT versus first DMT: P = 0.92; first versus second DMT: P = 0.31); 0.90, 0.50, and 0 for switchers from GA to IFNB (GA/IFNB, n = 18; P = 0.19; P = 0.01); 0.50, 0.68, and 0 for switchers from an IFNB to another IFNB (IFNB/IFNB’, n = 71; P = 0.34; P = 0.02). Estimated relapse-free proportion after 24 months of treatment was 42% (95%CI=15–66%) during the period on IFNB versus 53% (95%CI = 17–80%) on GA for IFNB/GA (P = 0.21); 12% (95%CI = 0–40%) on GA versus 87% (95%CI = 59–97%) on IFNB for GA/IFNB (P = 0.001); and 41% (95%CI = 29–52%) on initial IFNB versus 67% (95%CI = 53–79%) on subsequent IFNB for IFNB/IFNB’ (P = 0.0001).

Conclusions

Switching first-line DMT in patients with RRMS failing initial therapy may be effective in many cases.

Balance disorders and falls are frequently observed in subjects with multiple sclerosis (MS). Along with motor impairment, sensory disorders and integration deficits of sensory inputs lead to inadequate motor responses. The assessment of these sensory disorders in an every day tasks, such as upright stance, increases our knowledge of postural control in this pathology, thus promoting more effective treatments. The aim of the study was to describe sensory impairments and sensory strategies in different sensory conditions. A stabilometric assessment was carried out in a consecutive convenience sample of 53 subjects. The age of the sample was 52.7 (21.1) years; the onset of pathology was 27.20 (14.5) years before the assessment. Balance was assessed in six sensory conditions. The impact of pathology on balance control was shown by the high percentage of abnormal scores: 75% of subjects with MS showed abnormal scores even in the eyes open condition. The alteration of a single sensory input led to an increase of abnormal scores in up to 82% of subjects. Almost all subjects showed abnormal scores in the vestibular conditions where 22% of them fell. The pattern of the subjects’ performance in the six sensory conditions suggests that balance control may be more correlated to the number of reliable sensory inputs than the nature of the sensory input itself.

Objective

Visual evoked potentials (VEP) may be suitable surrogate outcome measures in multiple sclerosis (MS) remyelination trials. The extent of spontaneous changes of subclinically delayed VEP is unknown, whereas VEP improve after acute optic neuritis (ON).

Methods

In all, 124 patients with three VEP recordings at least 3 months apart: 71 patients with MS who had never suffered clinical ON; 53 patients with ON (isolated ON or ON as an attack of MS at first recording). Latencies of P100 were analyzed by multivariate analysis of variance.

Results

Eyes of patients with MS had a mean P100 latency of 110.2 ms, worsening mildly over time (n = 104 eyes, P = 0.022). MS patients' eyes with subclinical demyelination (delayed P100 latency at first recording >116 ms) showed no significant evidence of remyelination (n = 24 eyes, P = 0.27). By contrast, in ON patients' affected eyes, mean P100 latency decreased (P = 0.001), whereas unaffected eyes remained stable (P = 0.26). Clinically non-affected eyes from both diagnostic groups with subclinically prolonged latencies remained stable (n = 32: mean P100 at 124.8 ± 10.7, 123.5 ± 13.6, and 122.8 ± 13.1 ms; P = 0.57), whereas non-affected eyes with normal latency at baseline deteriorated slightly (P = 0.001). A subgroup with more homogeneously defined follow-up periods confirmed this observation. Non-affected eyes selected for stability (difference <5 ms) between first and second recording deteriorated (normal baseline, n = 66 eyes, P = 0.013) or remained stable (prolonged baseline, n = 18 eyes, 95% confidence interval of change –5.42 to +6.89 ms, P = 0.805).

Conclusion

Prolonged P100 latencies in eyes never affected by clinical ON remain stable and thus can be used as surrogate outcome measure for remyelination trials.

Objective

To investigate the psychometric properties of the Multiple Sclerosis Impact Scale (MSIS-29) and to assess the relationship between the Kurtzke Expanded Disability Status Scale and the physical and psychological parts of this score.

Methods

A population-based study identified cases with definite multiple sclerosis (MS) in the north-east region of Ireland. They were examined and completed the MSIS-29. Cases were classified as mild (Expanded Disability Status Score (EDSS) 0–3.0), moderate (EDSS 3.5–5.5), or severe (6.0–9.5) MS.

Results

The 248 participants (82 male, 166 female) had a mean age of 49.1 years (SD 12.4). EDSS ranged from 0 to 9.5 (median 6.0). Data quality was excellent (0.02% missing data), physical and psychological scores spanned the entire range with low floor and ceiling effects. Internal consistency was high (Cronbach’s alpha 0.97 – physical score, 0.93 – psychological score). The convergent validity of the physical impact score of the MSIS-29 with the Kurtzke EDSS was confirmed with a high Spearman’s rank coefficient correlation of 0.63 (P = 0.01). Physical impact scores for mild, moderate, and severe disability as were statistically different at 25.9%, 48.0%, and 63.9%, respectively. Mean psychological score was non-significantly higher in the moderately disabled group at 47.4% compared with the severely disabled at 44.3% (P = 0.58).

Conclusions

The MSIS-29 is an acceptable, reliable, and valid method of recording quality of life. A significant relationship between higher physical impact scores of the MSIS-29 and higher Kurtzke EDSS values suggests that is may be of use in clinical trials to monitor progression.

Background

The 9-item, Fatigue Severity Scale (FSS-9) has been widely used as an outcome measure in multiple sclerosis (MS). Modern psychometric theory, in the form of the Rasch measurement model, has set new quality standards for outcome measures by appraising a broad range of measurement properties in addition to the reliability and validity emphasized by classical test theory.

Objective

To appraise the FSS-9 by application of the Rasch model.

Method

The FSS-9 was posted to patients with clinically definite MS in two centers in the United Kingdom. Analysis was based on 416 records (55% response).

Results

The 9-item scale failed to meet Rasch model expectations. Two items had poor discrimination across the scale, and two further items showed bias for factors such as age. Removal of these four items provided a valid 5-item Rasch scale that satisfied strict tests of unidimensionality.

Conclusion

Summating the nine items of the FSS-9 is invalid. Five items (FSS-5), which seem to be measuring the social impact of fatigue, provide a strictly unidimensional Rasch scale. Studies using the FSS-9 may need to be re-evaluated using the FSS-5, preferably using the Rasch transformed scores.

Objective

To explore and compare the use of health services in people with multiple sclerosis (MS) with and without fatigue.

Methods

Over a period of 30 months, the use of health services in 48 MS outpatients with persistent fatigue and 36 without fatigue was studied. Data were collected from a computerized register and by interviews, and analyzed with regard to disease severity categorized as mild or moderate/severe MS.

Results

Fatigued people with mild MS used more hospital outpatient care and primary care including rehabilitation, and a higher proportion had transportation service, compared with non-fatigued people with mild MS. In moderate/severe MS, the differences were that non-fatigued people used more occupational therapy in primary care and a higher proportion had salaried service. Regardless of MS severity, informal care was more common among fatigued people.

Conclusions

Overall, fatigued people with mild MS have more contacts with outpatient health care compared with non-fatigued people. There are few such differences in people with moderate/severe MS. The reasons for the differences in use between fatigued and non-fatigued people are not understood and need further exploration. Fatigued people more often receive informal care, thus support to caregivers are of particular importance if fatigue is present.

Background

Contrary to strong recommendations for high-dose intravenous corticosteroid treatment for relapses in multiple sclerosis (MS), uncertainty remains about most aspects of relapse management. Oral corticosteroids administered by physicians or patients themselves or no corticosteroids also appear justifiable.

Objective

To evaluate an education program that aims to involve patients with MS in decisions on relapse management.

Methods

In three German MS centers, 150 patients with relapsing MS were randomly assigned to a single, 4-h group session or a standard information leaflet. The primary outcome measure was the proportion of relapses with oral or no corticosteroid therapy as an indicator of patient autonomy in treatment decision making. Other outcomes included perceived decision autonomy, quality of life, and disability status.

Results

In the intervention group (IG), 108/139 (78%) relapses were treated with oral or no corticosteroids compared with 101/179 (56%) in the control group; P < 0.0001. Patients’ perceived autonomy of treatment decision making was significantly higher in the IG; P < 0.0001. Quality of life, disability status, and adverse events of corticosteroid therapies were comparable.

Conclusion

The patient education program led to more autonomous decision making in patients with relapsing MS. Relevant changes in relapse management were observed.

Background

Health behaviors influence chronic disease risks in the general population, and may influence health outcomes independently of comorbid diseases. Health behaviors receive less attention in multiple sclerosis (MS) than in the general population. We assessed health behaviors among participants in the North American Research Committee on Multiple Sclerosis (NARCOMS) Registry and the demographic characteristics associated with particular health behaviors.

Methods

In October 2006, we surveyed NARCOMS participants regarding smoking using questions from the Behavioral Risk Factor Surveillance Survey; physical activity using questions from the PEPI study, alcohol use using the AUDIT-C; and height and weight. To determine the independent demographic predictors of health behaviors, we used multivariable logistic regression, either binary or polytomous as appropriate.

Results

Of 8983 responders, 4867 (54.2%) ever smoked; 1542 (17.3%) currently smoked. On the basis of the AUDIT-C, 1632 (18.2%) were at risk for alcohol abuse or dependence. A quarter of participants were obese (n = 2269), and 2780 (31.3%) were overweight. Fewer than 25% of participants reported moderate or heavy leisure-time physical activity. Generally, lower socioeconomic status was associated with a higher frequency of adverse health behaviors accounting for other demographic factors. With increasing levels of disability, the reported intensity of physical activity was lower, and the frequency of overweight or obesity was higher.

Conclusions

Patients with MS exhibit frequent adverse health behaviors, increasing the risk of other chronic diseases. Further research is needed to determine how these behaviors influence disability progression, quality of life, and other MS-related outcomes.

Objectives

The aim of this study was to correlate the brain atrophy with serum levels of anti-GM1 antibodies in patients with relapsing–remitting multiple sclerosis (RRMS).

Methods

Plasma sample from 52 patients with RRMS and 65 healthy controls were examined for anti-GM1 antibodies. Patients with RRMS underwent to MRI study with automated method called SIENAX that calculated an estimate of gray matter (GM^V) and white matter (WM^V) volumes.

Results

The percentage of RRMS patients with increased anti-GM1 was 37.8%. Elevated levels of anti-GM1 antibodies did not correlate with brain atrophy.

Conclusions

Anti-GM1 antibodies do not represent a marker of axonal damage in patients with RRMS.

Vaccination is generally considered safe in patients with multiple sclerosis (MS). We report five patients who presented with multifocal or atypical demyelinating syndromes within 21 days of immunization with the quadrivalent human papilloma virus (HPV) vaccine, Gardasil^®. Although the target population for vaccination, young females, has an inherently high risk for MS, the temporal association with demyelinating events in these cases may be explained by the potent immuno-stimulatory properties of HPV virus-like particles which comprise the vaccine. A prospective case–control study of patients with MS or clinically isolated demyelinating syndromes receiving the Gardasil^® vaccine may provide relevant safety data in this population.

Intracellular production of TNFα and IL-2 after stimulation with phorbol myristate/ionomycin was flowcytometrically measured in CD4⁺ T cells from peripheral blood (PB) and cerebrospinal fluid (CSF) of 29 patients with multiple sclerosis (MS), and 16 with other inflammatory and 41 with other non-inflammatory neurological diseases. In CSF, the percentages of CD4⁺TNFα⁺IL-2⁻T cells were significantly higher in patients with MS than either of the controls, whereas no difference was found in CD4⁺TNFα⁺IL-2⁺T or CD4⁺TNFα⁻IL-2⁺T cells. The increase was more pronounced at relapse than in remission. No significant change was detected in PB. These findings suggested that CD4⁺TNFα⁺IL-2⁻T cells are intrathecally upregulated in MS.

Background

Synapsins are a family of neuron-specific phosphoproteins, one of whose subunits is encoded by the SYN3 gene. This gene is located close to one of the multiple sclerosis susceptibility regions (in 22q13.1). Two single-nucleotide polymorphisms (SNPs) (rs133945 and rs133946) in the promoter region of this gene have been proposed as factors protecting against MS. This relationship is not clear because another report failed to found such association.

Objectives

In an attempt to clarify this association, the frequency of these SNPs was analyzed in a population of 221 Spanish MS patients with a cluster of 72 Basque patients and in 373 controls with a cluster of 138 controls of a Basque origin.

Methods

The SNis analysis was performed by 9 PCR.

Results

According to our findings, these SNPs are differently distributed in the two populations. This significant bias should therefore be taken into account in association studies. Our data suggest that the C/C genotype in rs133946 and the G/G genotype in rs133945 could be protecting factors against MS in the Basque population.