Multiple Sclerosis current issue

Short commentary on 'a consensus protocol for the standardization of cerebrospinal fluid collection and biobanking'

Mon, 08 Feb 2010 04:48:12 PST

Polymorphisms in vitamin D metabolism related genes and risk of multiple sclerosis

Simon, K. C., Munger, K. L, Xing Yang, , Ascherio, A. — Mon, 08 Feb 2010 04:48:12 PST

The extent to which potential genetic determinants of vitamin D levels may be related to multiple sclerosis (MS) risk has not been thoroughly explored. The objective of this study was to determine whether polymorphisms in VDR, CYP27B1, CYP24A1, CYP2R1 and DBP are associated with the risk of MS and whether these variants may modify associations between environmental or dietary vitamin D on MS risk.

A nested case-control study was conducted in two, large cohorts of US nurses, including 214 MS cases and 428 age-matched controls. Conditional logistic regression models were used to calculate relative risks (RR) and 95% confidence intervals (CIs) and to assess the significance of gene—environment interactions. No associations were observed for any of the single-nucleotide polymorphisms (SNPs) in VDR, CYP27B1, CYP24A1, CYP2R1 or DBP (p > 0.05 for all). The authors did observe an interaction (p = 0.04) between dietary intake of vitamin D and the vitamin D receptor FokI polymorphism on MS risk. The protective effect of increasing vitamin D was evident only in individuals with the ‘ff ’ genotype (RR = 0.2, 95% CI: 0.06, 0.78; p = 0.02 for 400 IU/day increase).

It was concluded that this does not support a role for the selected SNPs involved in vitamin D metabolism in the etiology of MS. The finding of a marginally significant gene—environment interaction requires replication in larger datasets, but suggests future genetic studies may benefit from considering relevant environmental context.

The cannabinoid receptor 1 gene (CNR1) and multiple sclerosis: an association study in two case-control groups from Spain

Mon, 08 Feb 2010 04:48:12 PST

Different studies point to the implication of the endocannabinoid system in multiple sclerosis (MS) and animal models of MS. The purpose of this study was to evaluate a possible association of MS with polymorphic markers at the CNR1 gene, encoding the cannabinoid 1 (CB₁) receptor. We have performed a genetic analysis of an AAT repeat microsatellite localized in the downstream region of the CNR1 gene, in two case—control groups of MS patients and healthy controls (HC) from Spain (Madrid and Bilbao). MS patients with primary progressive MS (PPMS) had more commonly long ((AAT) ≥₁₃) alleles and genotypes with a significant difference for genotype 7/8 in Madrid (p = 0.043) and in the sum of both groups (p = 0.016); short alleles were less frequently found in PPMS with a significant difference for allele 5 in the analysis of both groups together (p = 0.039). In patients with relapsing MS, no consistent differences in allele and genotype distribution were found. Disease severity and progression was unrelated to AAT repeat variations. In conclusion, long (AAT) ≥₁₃ CNR1 genotypes could behave as risk factors for PPMS.

Influence of HLA-DRB1 alleles on the susceptibility and resistance to multiple sclerosis in Japanese patients with respect to anti-aquaporin 4 antibody status

Mon, 08 Feb 2010 04:48:12 PST

Background: Epistatic interactions between human leukocyte antigen (HLA)-DRB1 alleles alter multiple sclerosis (MS) risk in Caucasians. Such interactions have never been studied in Asian MS patients.

Objective: To investigate the influence of HLA-DRB1 alleles, including epistatic interactions at this locus, in Japanese MS patients with and without the anti-aquaporin 4 (AQP4) antibody.

Methods: The HLA-DRB1 locus was genotyped in 108 MS patients and 127 healthy controls. MS patients were further classified into two groups according to anti-AQP4 antibody status (27 positive and 81 negative).

Results: HLA-DRB1*09 (adjusted odds ratio (OR) = 0.243, 95% confidence interval (CI) 0.099—0.533) and HLA-DRB1*01 (adjusted OR = 0.327, 95% CI 0.103—0.873) decreased the incidence of anti-AQP4 antibody-negative MS. By contrast, HLA-DRB1*12 increased the risk of anti-AQP4 antibody-positive MS (adjusted OR = 3.691, 95% CI 1.233—10.565). Individuals with HLA-DRB1*09/15 decreased the risk of anti-AQP4 antibody-negative MS (adjusted OR = 0.164, 95% CI 0.026—0.593), while those with HLA-DRB1*12/15 increased the risk of anti-AQP4 antibody-positive MS (adjusted OR = 10.870, 95% CI 2.004—81.752).

Conclusions: The ability of HLA-DRB1*09 to reduce the risk of anti-AQP4 antibody-negative MS may arise from an interaction with HLA-DRB1*15. By contrast, HLA-DRB1*12 increases susceptibility to anti-AQP4 antibody-positive MS, possibly via an interaction with HLA-DRB1*15.

Early MRI in optic neuritis: the risk for clinically definite multiple sclerosis

Mon, 08 Feb 2010 04:48:12 PST

MRI brain lesions at presentation with optic neuritis (ON) increase the risk for developing clinically definite (CD) multiple sclerosis (MS). More detailed early MRI findings may improve prediction of conversion.

The objectives of this study were to investigate the influence of number, location and activity of lesions at presentation, new lesions at early follow-up and non-lesion MRI measures on conversion from optic neuritis (ON) to CDMS.

142/143 ON patients, prospectively recruited into a serial MRI and clinical follow-up study, were followed-up at least once. Cox regression analysis determined independent early MRI predictors of time to CDMS from: (i) baseline lesion number, location and activity measures, (ii) three-month lesion activity measures and (iii) brain atrophy, magnetization transfer ratio and spectroscopy measures.

114/142 (80%) had abnormal baseline brain or cord MRI. 57 (40%) developed CDMS (median of 16 months from clinically isolated syndrome onset). Median follow-up of the non-converters was 62 months. Multivariate analysis of baseline parameters revealed gender, periventricular and gadolinium-enhancing lesions as independent predictors of CDMS. Considering both scans together, gender, baseline periventricular and new T2 lesions at follow-up remained significant (hazard ratios 2.1, 2.4 and 4.9, respectively). No non-conventional measure predicted CDMS.

It was concluded that new T2 lesions on an early follow-up scan were the strongest independent predictor of CDMS.

MRI of the corpus callosum in multiple sclerosis: association with disability

Mon, 08 Feb 2010 04:48:12 PST

Inflammatory demyelination and axon damage in the corpus callosum are prominent features of multiple sclerosis (MS) and may partially account for impaired performance on complex tasks. The objective of this article was to characterize quantitative callosal MRI abnormalities and their association with disability. In 69 participants with MS and 29 healthy volunteers, lesional and extralesional callosal MRI indices were estimated via diffusion tensor tractography. expanded disability status scale (EDSS) and MS functional composite (MSFC) scores were recorded in 53 of the participants with MS. All tested callosal MRI indices were diffusely abnormal in MS. EDSS score was correlated only with age (r = 0.51). Scores on the overall MSFC and its paced serial auditory addition test (PASAT) and 9-hole peg test components were correlated with callosal fractional anisotropy (r = 0.27, 0.35, and 0.31, respectively) and perpendicular diffusivity (r = —0.29, —0.30, and —0.31) but not with overall callosal volume or callosal lesion volume; the PASAT score was more weakly correlated with callosal magnetization-transfer ratio (r = 0.21). Anterior callosal abnormalities were associated with impaired PASAT performance and posterior abnormalities with slow performance on the 9-hole peg test. In conclusion, abnormalities in the corpus callosum can be assessed with quantitative MRI and are associated with cognitive and complex upper-extremity dysfunction in MS.

Multiparametric MR investigation of the motor pyramidal system in patients with 'truly benign' multiple sclerosis

Mon, 08 Feb 2010 04:48:12 PST

One possible explanation for the mismatch between tissue damage and preservation of neurological functions in patients with benign multiple sclerosis (BMS) is that the pathophysiology differs from that occurring in other multiple sclerosis (MS) phenotypes. The objective of this study was to identify pathologically specific patterns of tissue integrity/damage characteristics of patients with BMS, and markers of potential prognostic value. The pyramidal system was investigated in 10 BMS patients and 20 controls using voxel-based morphometry to assess grey matter (GM) atrophy, and diffusion tractography and quantitative magnetization transfer to quantify the microstructural damage in the corticospinal tracts (CSTs). Widespread reductions in GM volume were found in patients compared with controls, including the primary motor cortex. A significant decrease was observed in the mean macromolecular pool ratio (F) of both CSTs, with no fractional anisotropy (FA) change. GM volume of the primary motor areas was associated with clinical scores but not with the CST parameters. The mismatch between F and FA suggests the presence of extensive demyelination in the CSTs of patients with BMS, in the absence of axonal damage. The lack of correlation with GM volume indicates a complex interaction between disruptive and reparative mechanisms in BMS.

Diffusion tensor imaging abnormalities in depressed multiple sclerosis patients

Feinstein, A., O'Connor, P., Akbar, N., Moradzadeh, L., Scott, C., Lobaugh, N. — Mon, 08 Feb 2010 04:48:12 PST

Depression is common in patients with multiple sclerosis, but to date no studies have explored diffusion tensor imaging indices associated with mood change. This study aimed to determine cerebral correlates of depression in multiple sclerosis patients using diffusion tensor imaging. Sixty-two subjects with multiple sclerosis were assessed for depression with the Beck Depression Inventory (BDI-II). All subjects underwent magnetic resonance imaging. Whole brain and regional volumes were calculated for lesions (hyper/hypointense) and normal-appearing white and grey matter. Fractional anisotropy and mean diffusivity were calculated for each brain region. Magnetic resonance imaging comparisons were undertaken between depressed (Beck Depression Inventory ≥19) and non-depressed subjects. Depressed subjects (n = 30) had a higher hypointense lesion volume in the right medial inferior frontal region, a smaller normal-appearing white matter volume in the left superior frontal region, and lower fractional anisotropy and higher mean diffusivity in the left anterior temporal normal-appearing white matter and normal-appearing grey matter regions, respectively. Depressed subjects also had higher mean diffusivity in right inferior frontal hyperintense lesions. Magnetic resonance imaging variables contributed to 43% of the depression variance. We conclude that the presence of more marked diffusion tensor imaging abnormalities in the normal-appearing white matter and normal-appearing grey matter of depressed subjects highlights the importance of more subtle measures of structural brain change in the pathogenesis of depression.

Phase II study of oral fingolimod (FTY720) in multiple sclerosis: 3-year results

Mon, 08 Feb 2010 04:48:12 PST

In a 6-month, placebo-controlled trial, oral fingolimod (FTY720) 1.25 or 5.0 mg, once daily, significantly reduced MRI inflammatory activity and annualized relapse rate compared with placebo in patients with relapsing multiple sclerosis (MS). The objectives were to monitor the 36-month, interim efficacy and safety results of the ongoing extension of this study. In the extension (months 7—36), placebo-treated patients were re-randomized to either dose of fingolimod; fingolimod-treated patients continued at the same dose. During months 15—24, all patients receiving fingolimod 5.0 mg switched to 1.25 mg. Of the 250 patients who entered the extension study, 173 (69%) continued to month 36. Most patients were free from gadolinium-enhanced lesions (88—89%) or new T2 lesions (70—78%) at month 36. Patients receiving continuous fingolimod treatment had sustained low annualized relapse rates of 0.20—0.21, and 68—73% remained relapse-free at month 36. Over 36 months, nasopharyngitis (34%), headache (30%), fatigue (19%) and influenza (18%) were the most commonly reported adverse events. Pulmonary function remained stable and blood pressure was stable after an initial increase (3—5 mmHg) during the first 6 months of fingolimod treatment; serious adverse events included infections and skin cancer. The low MRI and clinical disease activity at 6 months were maintained at 36 months with fingolimod, which was generally well tolerated by most patients. The efficacy and safety of oral fingolimod are being further evaluated in a large phase III MS study programme.

Natalizumab treatment in multiple sclerosis: marked decline of chemokines and cytokines in cerebrospinal fluid

Mellergard, J., Edstrom, M., Vrethem, M., Ernerudh, J., Dahle, C. — Mon, 08 Feb 2010 04:48:12 PST

Natalizumab exerts impressive therapeutic effects in patients with multiple sclerosis (MS). The proposed main mode of action is reducing transmigration of leukocytes into the CNS, but other immunological effects may also be operative. Cytokines and chemokines are involved in the regulation of inflammatory responses and may reflect the disease process in MS. The objective of this study was to evaluate the effects of natalizumab treatment on cytokine and chemokine profiles systemically and intrathecally in multiple sclerosis. We used luminex to analyse a panel of cytokines (IL-1β, IL-2, IL-4, IL-5, IL-6, IL-8, IL-10, TNF-, IFN-, GM-CSF) and chemokines (CXCL9, CXCL10, CXCL11, CCL17, CCL22) in blood and cerebrospinal fluid (CSF) from 31 patients with relapsing MS before and after one year of natalizumab treatment. There was a marked decline in CSF levels of cytokines and chemokines, thus including pro-inflammatory cytokines (IL-1β, IL-6 and IL-8) as well as chemokines associated with both Th1 (CXCL9, CXCL10, CXCL11) and Th2 (CCL22). Circulating plasma levels of some cytokines (GM-CSF, TNF-, IL-6 and IL-10) also decreased after one year of treatment. This is the first study to show that natalizumab treatment is associated with a global decline in cytokine and chemokine levels at a protein level. This finding was most pronounced in CSF, in line with the reduced transmigration of cells into CNS, whereas reduction in plasma levels indicates other possible mechanisms of natalizumab treatment.

Renewal of the T-cell compartment in multiple sclerosis patients treated with glatiramer acetate

Mon, 08 Feb 2010 04:48:12 PST

The immunomodulating activity of glatiramer acetate on T-cells of multiple sclerosis patients has only been partially clarified. The objective of this work was to investigate whether glatiramer acetate modifies thymic release of newly produced T-cells and the peripheral composition of the T-cell repertoire. T-cell receptor excision circles, ^thymic naive (CD4⁺CD45RA⁺CCR7⁺CD31⁺) T helper cells, and central (CD4⁺CD45RA^-CCR7⁺) and effector (CD4⁺CD45RA^-CCR7^-) memory T-cells were evaluated in 89 untreated patients, 84 patients treated for at least 1 year, and 31 patients beginning treatment at the time of inclusion in the study and then followed-up for 12 months; controls were 81 healthy donors. The T-cell repertoire was analysed in selected samples. The percentage of ^thymicnaive T helper cells was diminished in untreated patients, but rose to control values in treated subjects; a decrease in central memory T-cells was also observed in treated patients. Follow-up patients could be divided into two subgroups, one showing unmodified ^thymicnaive T helper cells and T-cell diversity, the other in which the increased release of new T-cells was accompanied by modifications of the T-cell repertoire. Glatiramer acetate modifies the peripheral T-cell pool by activating a thymopoietic pathway of T-cell release that leads to a different setting of T-cell diversity and, likely, to a dilution of autoreactive T-cells.

Psychometrics and normative data for the Multiple Sclerosis Functional Composite: replacing the PASAT with the Symbol Digit Modalities Test

Mon, 08 Feb 2010 04:48:12 PST

The MS Functional Composite (MSFC) is a continuous scale of neurological disability for patients with multiple sclerosis (MS). Cognition is represented by the Paced Auditory Serial Addition Test (PASAT), although the Symbol Digit Modalities Test (SDMT) has been proposed as a promising alternative.

MSFC scores were calculated using either the PASAT or the SDMT with the following reference populations: National Multiple Sclerosis Society (NMSS) Task Force, 400 MS patients, and 100 normal controls. A subgroup of 115 patients was followed longitudinally, with a test—retest interval of 2.3 ± 1.2 years. Pearson correlations were calculated and analyses of variance (ANOVAs) were used to assess relationships among the MSFC components and composite scores, and differences in performance between patients and controls. Longitudinal changes were also assessed. Logistic regression was performed to determine which MSFC scores are most predictive of diagnosis, course, and work disability.

All MSFCs had similar test—retest reliability and correlations with other measures including neurological disability, depression, and fatigue. The SDMT showed slightly better validity with respect to predicting diagnosis, course, and work disability, although the amount of variance accounted for was similar for each version of the MSFC.

Our data, derived from a large sample of MS patients and normal controls, supports the validity of both PASAT and SDMT versions of the MSFC. Because the SDMT has slightly better predictive validity and has a relatively easier administration procedure, some clinicians and researchers may wish to replace the PASAT with the SDMT in future calculations of the MSFC using the calculation methods provided in this manuscript.

Sleep disturbance and fatigue in mild relapsing remitting multiple sclerosis patients on chronic immunomodulant therapy: an actigraphic study

Mendozzi, L., Tronci, F., Garegnani, M., Pugnetti, L. — Mon, 08 Feb 2010 04:48:12 PST

Background: poor sleep is common in MS and it contributes to fatigue. The β interferons produce systemic effects which may not adapt and may induce fatigue.

Objective: to verify whether subjective poor sleep and fatigue during chronic therapy correspond to reduced sleep efficiency obtained by actigraphy at home.

Methods: 42 ambulatory relapsing remitting MS patients with mild disability were monitored for at least 7 nights. Habitual sleep quality and fatigue were assessed with the MOS sleep measure and the Fatigue Severity Scale. Sleep logs provided daily sleep quality assessments during actigraphy at home. Patients were grouped according to their current treatment: no therapy, glatiramer acetate, IFNβ 3 times a week, and IFNβ once a week.

Results and Conclusion: sleep efficiency was reduced by an average of 5% in 2/3 of the nights following IFNβ injections compared to the other nights, and daily sleep ratings correlated with actigraphy. Patients on glatiramer acetate also showed a lower sleep efficiency than patients without therapy. Actigraphy data were only modestly correlated with MOSsm scores, not with fatigue. Long term adaptation of sleep effects of immunomodulant agents is incomplete and needs to be considered in treatment planning and assessment of sleep in MS.

A randomized trial of memantine as treatment for spasticity in multiple sclerosis

Mehta, L. R, McDermott, M. P, Goodman, A. D, Schwid, S. R — Mon, 08 Feb 2010 04:48:12 PST

We report the results of a single center randomized, double-blind, placebo-controlled, parallel group trial of memantine in adults with multiple sclerosis and spasticity conducted over 12 weeks. Eligible MS patients had to have an Ashworth spasticity rating of 2 or higher in at least one lower extremity muscle group. Subjects were randomized to receive either placebo or memantine 10 mg twice a day. The primary outcome measure for efficacy was the change in Ashworth Spasticity Scale Score. Although well tolerated, memantine treatment did not demonstrate efficacy in treatment of spasticity in this 12-week small exploratory study.

Optic neuritis incidence is increased in spring months in patients with asymptomatic demyelinating lesions

Balashov, K. E, Pal, G., Rosenberg, M. L — Mon, 08 Feb 2010 04:48:12 PST

Optic neuritis (ON) patients can be divided into two groups based on the presence or absence of asymptomatic demyelinating lesions (ADLs) on brain MRI. The presence of ADLs is associated with an increased risk of progression to clinically definite multiple sclerosis (CDMS). The clinical data and brain MRI of 110 patients with acute unilateral ON were analyzed. Patients with ADLs had a significantly higher incidence of ON in spring months as compared with patients with no ADLs (p = 0.0024). Increased incidence of ON in spring months was seen in patients with ADLs whether or not they were diagnosed with CDMS on follow-up.

Abstracts from PACTRIMS, Hong Kong, 20--21 November 2009: Oral Presentations

Mon, 08 Feb 2010 04:48:12 PST

Abstracts from PACTRIMS, Hong Kong, 20--21 November 2009: Posters

Mon, 08 Feb 2010 04:48:12 PST