Multiple Sclerosis Journal

Background: Multiple sclerosis (MS) is a chronic, neurological disease characterized by targeted destruction of central nervous system (CNS) myelin. The autoimmune theory is the most widely accepted explanation of disease pathology. Circulating Th₁ cells become activated by exposure to CNS-specific antigens such as myelin basic protein. The activated Th₁ cells secrete inflammatory cytokines, which are pivotal for inflammatory responses. We hypothesize that enhanced production of inflammatory cytokines triggers cellular events within the dorsal root ganglia (DRG) and/or spinal cord, facilitating the development of neuropathic pain (NPP) in MS. NPP, the second worst disease-induced symptom suffered by patients with MS, is normally regulated by DRG and/or spinal cord.

Objective: To determine gene and protein expression levels of tumor necrosis factor-alpha (TNFα) within DRG and/or spinal cord in an animal model of MS.

Methods: Experimental autoimmune encephalomyelitis (EAE) was induced in adolescent female Lewis rats. Animals were sacrificed every 3 days post-disease induction. DRG and spinal cords were harvested for protein and gene expression analysis.

Results: We show significant increases in TNFα expression in the DRG and of EAE animals at peak disease stage, as assessed by clinical symptoms.

Conclusion: Antigen-induced production of inflammatory cytokines such as TNFα within the DRG identifies a potential novel mechanism for MS-induced NPP.

Both genetic and environmental factors contribute to multiple sclerosis, the most common neurodegenerative disorder with onset in young adults. The objective of the current study is, based on the hypothesis that environmentally predisposed individuals are at risk for multiple sclerosis, to investigate whether they also carry genetic variants within the vitamin D machinery. Using medical files and DNA samples from 583 trios (a patient and both parents) of the French Multiple Sclerosis Genetics Group as well as data from the French Statistics Bureau, we aimed to assess whether: (1) a seasonality of birth was observed in French multiple sclerosis patients; (2) three single nucleotide polymorphisms within the promoter region of the vitamin D receptor were associated with multiple sclerosis susceptibility; and (3) the combination of a high risk month of birth and vitamin D receptor polymorphisms were correlated to multiple sclerosis incidence. We observed a significantly reduced number of individuals born in November who were later diagnosed as multiple sclerosis patients. However, we found no association between the three studied vitamin D receptor polymorphisms and multiple sclerosis. In conclusion, our data suggest that high levels of vitamin D during the third trimester of pregnancy could be a protective factor for multiple sclerosis.

Background: Antibodies against aquaporin-4 (AQP4), a water channel particularly expressed on perivascular astrocytic podocytes, are proposed as a marker for the diagnosis of neuromyelitis optica (NMO). However, a consensus on seroprevalence and optimal detection method has not yet been reached.

Objectives: To investigate the performance of different assays to detect anti-AQP4 antibodies.

Methods: We set up five different assays. Two of them were capable to detect perivascular IgG reactivity on brain tissue by immunofluorescence (NMO-IgG). Other three assays have been set to detect anti-AQP4 antibodies: immunofluorescence and flow cytometry on AQP4-expressing cells, and a radioimmunoprecipitation assay. We assessed sensitivity and specificity of these assays by interrogating sera of 33 NMO patients, 13 patients at high risk to develop NMO (hrNMO), 6 patients affected by acute partial transverse myelitis (APTM), 20 patients with multiple sclerosis (MS), and 67 age- and sex-matched healthy controls.

Results: We found that the presence of serum NMO-IgG and anti-AQP4 reactivity is almost exclusively restricted to patients with NMO and hrNMO. Seroprevalence and sensitivity ranged from 30 to 47%, depending on the assay. Specificity ranged from 95 to 100%. Comparing results obtained in the five assays, we noticed lack of concordance in some samples.

Conclusions: Detection of NMO-IgG or anti-AQP4 antibodies may represent a valuable tool to assist neurologists in the differential diagnosis between patients with NMO, hrNMO, APTM, or MS. The current lack of a gold standard to detect anti-AQP4 antibodies implies the necessity to standardize the detection of these antibodies.

Background: Multiple sclerosis (MS) is often accompanied by cognitive dysfunction. A negative correlation between cerebral lesion load and atrophy and cognitive performance has been pointed out almost consistently. Further, the distribution of lesions might be critical for the emergence of specific patterns of cognitive deficits.

Objective: The current study evaluated the significance of total lesion area (TLA) and central atrophy for the prediction of general cognitive dysfunction and tested for a correspondence between lesion topography and specific cognitive deficit patterns.

Methods: Thirty-seven patients with MS underwent neuropsychological assessment and magnetic resonance imaging. Lesion burden and central atrophy were quantified. Patients were classified into three groups by means of individual lesion topography (punctiform lesions/periventricular lesions/confluencing lesions in both periventricular and extra-periventricular regions).

Results: TLA was significantly related to 7 cognitive variables, whereas third ventricle width was significantly associated with 20 cognitive parameters. The three groups differed significantly in their performances on tasks concerning alertness, mental speed, and memory function.

Conclusion: Third ventricle width as a straight-forward measure of central atrophy proved to be of substantial predictive value for cognitive dysfunction, whereas total lesion load played only a minor role. Periventricular located lesions were significantly related to decreased psychomotor speed, whereas equally distributed cerebral lesion load did not. These findings support the idea that periventricular lesions have a determinant impact on cognition in patients with MS.

Multiple sclerosis is a chronic, demyelinating disorder of the central nervous system. It is characterised by progressive neurological disability, which is likely to occur as a result of permanent axonal damage. Such damage may be reflected by brain atrophy, which can be identified early in the course of the disease. Patients who present with an initial episode of inflammatory demyelination, commonly referred to as a clinically isolated syndrome, are at high risk of developing clinically definite multiple sclerosis, especially if their magnetic resonance imaging studies suggest the presence of multi-focal disease. Treatment with disease-modifying therapies at the initial episode of demyelination may postpone this development. In this review we present an overview of evidence supporting early treatment initiation. We focus on three large placebo-controlled trials of interferon beta therapy: Controlled High-Risk Avonex^® Multiple Sclerosis Prevention Study, Early Treatment of Multiple Sclerosis and Betaferon ^® in Newly Emerging Multiple Sclerosis for Initial Treatment. Results from these early treatment studies are presented, and the impact of using interferon beta treatment in the early stages of disease is discussed with the aim of considering optimal therapeutic strategies to improve long-term patient outcome.

Minocycline is proposed as an add-on therapy to improve the efficacy of glatiramer acetate in relapsing—remitting multiple sclerosis. The effect of minocycline plus glatiramer acetate was evaluated in this double-blind, placebo-controlled study by determining the total number of T1 gadolinium-enhanced lesions at months 8 and 9 in patients who were starting glatiramer acetate and had at least one T1 gadolinium-enhanced lesion on screening magnetic resonance imaging. Forty-four participants were randomized to either minocycline 100 mg twice daily or matching placebo for 9 months as add-on therapy. They were assessed at screening and months 1, 3, 6, 8 and 9. Forty participants completed the study. Compared with glatiramer acetate/placebo, glatiramer acetate/minocycline reduced the total number of T1 gadolinium-enhanced lesions by 63% (mean 1.47 versus 2.95; p = 0.08), the total number of new and enlarging T2 lesions by 65% (mean 1.84 versus 5.14; p = 0.06), and the total T2 disease burden (p = 0.10). A higher number of gadolinium-enhanced lesions were present in the glatiramer acetate/minocycline group at baseline; this was incorporated into the analysis of the primary endpoint but makes interpretation of the data more challenging. The risk of relapse tended to be lower in the combination group (0.19 versus 0.41; p = NS). Treatment was safe and well tolerated. We conclude that efficacy endpoints showed a consistent trend favoring combination treatment. As minocycline is a relatively safe oral therapy, further study of this combination is warranted in relapsing—remitting multiple sclerosis.

Inflammation and neurodegeneration may have differential impacts on disease evolution in the different forms of multiple sclerosis. However, a beneficial effect of immunomodulatory drugs should not be ruled out in primary progressive multiple sclerosis. Our aim is to investigate the safety and efficacy of interferon beta-1b in primary progressive multiple sclerosis. We conducted a double-blind, stratified, randomized, parallel group, phase II pilot study where patients with primary progressive multiple sclerosis or ‘transitional’ forms of multiple sclerosis received interferon beta-1b at doses of 8 MIU or placebo for 24 months. The main objective of the study was to investigate the safety and tolerability of interferon beta-1b. The primary efficacy variable was the time to neurological deterioration (Expanded Disability Status Scale) confirmed at 3 months. Seventy-three patients were included and three dropped out the study. More patients in the treatment arm had at least one related adverse event (94.4% versus 45.9%; p < 0.001); no other significant differences in safety endpoints were observed. Time to neurological deterioration was not different between trial arms (log-rank test, p = 0.3135). Statistically significant differences favoring treatment were observed for the Multiple Sclerosis Functional Composite score at several timepoints, T1 and T2 lesion volume changes at 12 and 24 months, mean number of active lesions and proportion of patients with active lesions at 24 months. We conclude that interferon beta-1b is safe and well tolerated in patients with primary progressive multiple sclerosis and transitional multiple sclerosis. Positive effects of interferon beta on secondary clinical and magnetic resonance imaging outcomes were observed, but a beneficial effect on Expanded Disability Status Scale progression was not demonstrated.

Rolipram, a prototypic phosphodiesterase-4 inhibitor, is highly effective in suppressing Th1 autoimmunity in multiple animal models, including experimental autoimmune encephalomyelitis. In addition, rolipram has been extensively studied as a potential neuroprotective agent. Based on its anti-inflammatory activity, we tested the efficacy of rolipram in suppressing inflammatory disease activity in multiple sclerosis in a proof-of-principle phase I/II open-label clinical trial. Enrolled MS patients were evaluated by monthly MRI and clinical examinations during 3 months (four MRIs) of pretreatment baseline and 8 months of rolipram therapy. The primary outcome was a change in contrast-enhanced lesions between baseline and the last 4 months of rolipram therapy. Previously defined biomarkers of rolipram-mediated immunomodulation were evaluated during the study. The trial was stopped prematurely because the drug was poorly tolerated and because of safety concerns: we observed an increase, rather than decrease, in the brain inflammatory activity measured by contrast-enhanced lesions on brain MRI. At the administered doses rolipram was active in vivo as documented by immunological assays. We conclude that the reasons underlying the discrepancy between the therapeutic efficacy of rolipram in experimental autoimmune encephalomyelitis versus multiple sclerosis are at present not clear.

Background: Deficits in motor functioning, including walking, and in cognitive functions, including attention, are known to be prevalent in multiple sclerosis (MS), though little attention has been paid to how impairments in these areas of functioning interact.

Objectives: This study investigated the effects of performing a concurrent cognitive task when walking in people with MS. Level of task demand was manipulated to investigate whether this affected level of dual-task decrement.

Method: Eighteen participants with MS and 18 healthy controls took part. Participants completed walking and cognitive tasks under single- and dual-task conditions.

Results: Compared to healthy controls, MS participants showed greater decrements in performance under dual-task conditions in cognitive task performance, walking speed and swing time variability. In the MS group, the degree of decrement under dual-task conditions was related to levels of fatigue, a measure of general cognitive functioning and self-reported everyday cognitive errors, but not to measures of disease severity or duration.

Conclusions: Difficulty with walking and talking in MS may be a result of a divided attention deficit or of overloading of the working memory system, and further investigation is needed. We suggest that difficulty with walking and talking in MS may lead to practical problems in everyday life, including potentially increasing the risk of falls. Clinical tools to assess cognitive—motor dual-tasking ability are needed.

Background: The multidimensional assessment of fatigue is complicated by the interrelation of its multiple causes and effects.

Objective: The purpose of the research was to develop a unidimensional assessment of fatigue (U-FIS).

Methods: Data collected with the Fatigue Impact Scale (FIS) were subjected to Rasch analysis to identify potential problems with the scale. Additional items for the U-FIS were generated from interviews with UK MS patients. The U-FIS was tested for face and content validity in patient interviews and included in a validation survey to determine dimensionality (Rasch model), reliability and validity.

Results: The original FIS was not unidimensional when subscale items were combined. The modification of the FIS and addition of a number of items allowed the development of a 22-item unidimensional scale (U-FIS) that was reliable (Cronbach Alpha = 0.96; test-retest = 0.86,) and valid given correlations with the Nottingham Health Profile and ability to distinguish between MS severity groups. There was no significant difference in U-FIS scores according to MS type.

Conclusion: It is valid to conceptualize the functional impact of fatigue as unidimensional. The U-FIS is a reliable and valid questionnaire that will allow the measurement of this construct in clinical studies.

Addressing health-related quality of life is considered a desirable component of routine care for patients with multiple sclerosis. However, use of available health-related quality of life surveys is not part of routine multiple sclerosis care, possibly due to administration, scoring, and interpretation challenges presented by available questionnaires. The 25-item Functional Index for Living with Multiple Sclerosis (FILMS) questionnaire was developed and validated to allow providers to monitor and easily apply health-related quality of life information to the patient encounter. The development and pilot test processes and the results of the validation study are reported here. Convergent validity, internal consistency reliability, and test—retest reproducibility were evaluated. Strong correlations of Functional Index for Living with Multiple Sclerosis subscales with control questionnaires were demonstrated by Pearson’s correlation coefficients from 0.73 to 0.88. Internal consistency reliabilities ranged from 0.80 to 0.90, demonstrating that items were grouped into the appropriate subscale domains and that the subscale domains and the questionnaire as a whole exhibited good directionality. Test—retest reproducibility was 0.91.