MS Abstracts 04b-2g5

Multiple Sclerosis (MS) is characterized by Central Nervous System PeriVenular and Parenchymal MonoNuclear Cell infiltrates consisting of activated T-Cells and Macrophages.

We recently demonstrated that elevated expression of the Voltage-gated Potassium Channel, Kv1.3, is a functional marker of activated Effector Memory T (TEM) Cells in Experimental Allergic Encephalomyelitis and in Myelin-specific T-Cells derived from the peripheral blood of patients with MS.

Herein, we show that Kv1.3 is highly expressed in postmortem MS Brain inflammatory infiltrates.

The expression pattern revealed not only Kv1.3(+) T-Cells in the PeriVenular infiltrate but also high expression in the Parenchyma of DeMyelinated MS lesions and both Normal-Appearing Gray and White Matter.

These cells were uniformly Chemokine Receptor 7 negative (CCR7(-)), consistent with an Effector Memory phenotype. Using double-labeling ImmunoHistoChemistry and confocal microscopy, we demonstrated colocalization of Kv1.3 with CD3, CD4, CD8, and some CD68 Cells.

The expression patterns mirrored in vitro experiments showing polarization of Kv1.3 to the Immunological Synapse.

Kv1.3 was expressed in low to moderate levels on CCR7(+) Central Memory T-Cells from CerebroSpinal Fluid, but, when these cells were stimulated in vitro, they rapidly became Kv1.3(high)/CCR7(-) TEM.

Suggesting that a subset of CerebroSpinal Fluid Cells existed in a primed state ready to become TEM. These studies provide further rationale for the use of specific Kv1.3 antagonists in MS.

Identification of the T-Cell ImmunoGlobulin mucin-domain containing (Tim) Gene family introduced a new family of cell surface molecules that is involved in the regulation of Immune Responses.

We previously demonstrated that Tim-3 is expressed on terminally differentiated T helper (Th1) Cells, and serves to regulate Th1 Immune Responses.

Here, we describe the identification and function of Tim-2, a novel member of the Tim Gene family. In contrast with Tim-3, we demonstrate that Tim-2 is expressed preferentially in differentiated Th2 cells.

Blockade of the Tim-2/Tim-2 Ligand interaction, by administration of soluble Tim-2 fusion protein (Tim-2 ImmunoGlobulin [Ig]), results in T-Cell hyperproliferation and the production of Th2 Cytokines.

Administration of Tim-2 Ig during the induction phase reduces the severity of Experimental Autoimmune Encephalomyelitis, a Th1-mediated Autoimmune Disease model of Multiple Sclerosis.

We propose that Tim-2, an orthologue of human Tim-1, is critical for the regulation of Th2 responses during AutoImmune inflammation.

Background
Rituximab, an Anti-CD20 MonoClonal AntiBody that depletes CD20⁺ B-Cells, has demonstrated efficacy in Peripheral Neurological Diseases.

Whether this efficacy can be translated to Neurological Diseases of the Central Nervous System with possible AutoImmune B-Cell involvement remains unknown.

Objective
To determine the effect of Rituximab on CerebroSpinal Fluid B-Cells in patients with Multiple Sclerosis.

Design
Four patients with Primary/Progressive Multiple Sclerosis were treated with Rituximab.

CerebroSpinal Fluid and peripheral blood B-Cell subsets were identified by flow cytometry from each patient before and after Rituximab treatment.

Results
The B-Cells in CerebroSpinal Fluid were not as effectively depleted as their peripheral blood counterparts.

Rituximab treatment temporarily suppressed the activation state of B-Cells in CerebroSpinal Fluid. The residual B-Cells underwent expansion after Rituximab treatment.

Conclusion
The effect(s) of Rituximab on the CerebroSpinal Fluid B-Cell compartment is limited in comparison with the effect(s) on the B-Cells in the periphery, but this finding will need to be confirmed in a larger group of MS patients.

This study investigates whether the presence of Serum and Plasma Anti-Myelin Oligodendrocyte Glycoprotein (MOG) and Anti-Myelin Basic Protein (MBP) in patients presenting with a Clinically Isolated Syndrome (CIS) compatible with DeMyelination, predicts early conversion to Multiple Sclerosis (MS).

Forty-seven patients with CIS (46 with Optic Neuritis) had Anti-MOG and Anti-MBP AntiBodies analyzed at baseline, and clinical and Magnetic Resonance Imaging assessments.

There was no evidence that the MS status based on either the McDonald or Poser Criteria relates to the AntiBody status.

A prospective analysis of gait and strength parameters was performed in 100 patients diagnosed with MS and Pyramidal involvement admitted in a rehabilitation unit.

The patients were divided into two groups based on their ability to walk in daily life (nonassisted or cane-assisted gait) and into four clinical subgroups depending on associated involvements such as sensory loss or Cerebellar Ataxia.

Twenty healthy subjects were studied as a control group. Gait parameters were evaluated with a Locometre and muscle strength with an isokinetic dynamometer.

The results showed that the average velocity and strength of the hamstring and quadriceps were strongly correlated and reduced in the MS group in comparison with the control, and in the cane-assisted group compared with the nonassisted group.

Gait velocity tended to be more correlated to hamstring strength in the nonassisted group with a determination coefficient (r2) reaching a value of 0.44 in the sensory subgroup.

These findings provide evidence that a correlation between strength reduction and gait impairment is obvious whatever the clinical form in patients with MS.

This correlation is higher with hamstrings but may change depending on the disability level and the clinical form. This could be taken into account in the individual assessment of further rehabilitation programs.

Background
Central Pain in Multiple Sclerosis (MS) is common and often refractory to treatment.

Methods
We conducted a single-center, 5-week (1-week run-in, 4-week treatment), randomized, double-blind, placebo-controlled, parallel-group trial.

In 66 patients with MS and Central Pain States (59 Dysesthetic, seven painful spasms) of a whole-plant Cannabis-Based Medicine (CBM), containing delta-9-TetraHydroCannabinol:Cannabidiol (THC:CBD) delivered via an oromucosal spray, as adjunctive analgesic treatment.

Each spray delivered 2.7 mg of THC and 2.5 of CBD, and patients could gradually self-titrate to a maximum of 48 sprays in 24 hours.

Results
Sixty-four patients (97%) completed the trial, 34 received CBM.

In week 4, the mean number of daily sprays taken of CBM (n = 32) was 9.6 (range 2 to 25, SD = 6.0) and of placebo (n = 31) was 19.1 (range 1 to 47, SD = 12.9). Pain and sleep disturbance were recorded daily on an 11-point numerical rating scale.

CBM was superior to placebo in reducing the mean intensity of pain (CBM mean change -2.7, 95% CI: -3.4 to -2.0, placebo -1.4 95% CI: -2.0 to -0.8, comparison between groups, p = 0.005) and sleep disturbance (CBM mean change -2.5, 95% CI: -3.4 to -1.7, placebo -0.8, 95% CI: -1.5 to -0.1, comparison between groups, p = 0.003).

CBM was generally well tolerated, although more patients on CBM than placebo reported dizziness, dry mouth, and somnolence. Cognitive side effects were limited to long-term memory storage.

Conclusions
Cannabis-based medicine is effective in reducing pain and sleep disturbance in patients with Multiple Sclerosis related central Neuropathic Pain and is mostly well tolerated.

Background
The association between Cognitive Impairment and physical disability was examined in a larger, more representative sample of patients with Multiple Sclerosis (MS) than in previous studies.

Method
Two hundred and fifty-three patients attending an MS clinic were assessed with respect to physical disability using the Expanded Disability Status Scale and Cognitive Impairment using a battery of NeuroPsychological tests.

Results
Physical disability correlated with duration of disease; Cognitive Impairment did not. Virtually all measures derived from the Cognitive Battery were significantly correlated with physical disability.

Three measures of speeded information processing and one involving delayed recall of verbal material were unique predictors of disability status.

The relationship between Cognitive Impairment and physical disability was equivalent for patients with shorter (< 3 years) versus longer (> 10 years) disease duration.

Cognitive Impairment correlated with the rate of disability progression as reflected by the progression Index.

Conclusion
Cognitive Impairment is more closely associated with physical disability than most previous studies indicate.

This relationship appears to be stable throughout the duration of MS, although this conclusion is qualified by the cross-sectional design of the study. Further attention should be paid to Cognitive Impairment as a possible predictor of the rate of patients' physical decline.

We investigated the distribution of the Magnetic Resonance Imaging (MRI)-measured response to Glatiramer Acetate (GA) treatment in Multiple Sclerosis (MS) using data from a clinical trial of Relapsing/Remitting (RR) MS.

A fixed and a random effects model were used to quantify the between-patient heterogeneity in treatment response, expressed as new enhancing lesion percentage reduction.

In 95% of the patients, lesion reduction due to treatment was estimated to range between -20% and -54%, indicating a rather homogeneous effect of GA on MRI-measured disease activity in RRMS.

Using meta-analytic procedures, this study involved a quantitative synthesis of the difference in physical activity among individuals with Multiple Sclerosis (MS).

Compared with nondiseased and diseased populations and then examined factors (i.e., moderators) that explain variation in the overall difference in physical activity.

We searched MEDLINE, PsycINFO and Current Contents Plus using the key words physical activity, exercise and physical fitness in conjunction with Multiple Sclerosis.

Conducted a manual search of bibliographies of the retrieved papers, and contacted study authors about additional studies.

Overall, 53 effects were retrieved from 13 studies with 2360 MS participants and yielded a weighted mean effect size (ES) of -0.60 (95% CI = -0.44, -0.77). The weighted mean ES was heterogenous, Q = 1164.11, df = 52, P < 0.0001.

There were larger effects with objective versus self-report measures of physical activity, nondiseased versus diseased populations and Primary/Progressive versus Relapsing/Remitting MS.

The cumulative evidence suggests that individuals with MS are less physically active than nondiseased, but not diseased, populations.

Intention Tremor due to Multiple Sclerosis is clinically similar to Cerebellar Tremor. This study investigated, in 14 Multiple Sclerosis patients, the relationship between Intention Tremor severity and the lesion load in different InfraTentorial regions.

Tremor amplitude was quantified during step-tracking tasks. The lesion load was measured on Magnetic Resonance Images using an automated segmentation method.

Intention Tremor amplitude was significantly related to lesion load in the BrainStem but not in the Cerebellum.

Specifically, Tremor amplitude correlated with the lesion load in the ContraLateral Pons, and patients with more severe Tremor in both arms had a greater lesion load BiLaterally in the Pons.

These results support the view that Multiple Sclerosis Intention Tremor is related to dysfunction of Cerebellar inflow and/or outflow pathways.

Many Multiple Sclerosis (MS) patients treated with IFN-ß develop Anti-IFN-ß AntiBodies, which can interfere with the bioactivity of the injected Cytokine, i.e., AntiBody-mediated decreased bioactivity (ADB).

The precise levels of Anti-IFN-ß AntiBodies inducing decreased bioactivity is unknown. We repeatedly used a bioactivity measure, gene expression of MxA or GEM, and correlated bioactivity with measures of binding and Neutralizing AntiBodies.

The binding AntiBody assay was a capture ELISA, and the Neutralizing AntiBody (NAB) assay was a Cytopathic Effect (CPE) assay. 27% (17/64) of patients repeatedly sampled developed critical ADB.

Bioactivity as determined by GEM correlated negatively with NAB titer, and bioactivity that had been lost with the development of NABs returned if NAB levels diminished.

These data reveal that the GEM assay is a useful adjunct in the management of MS patients treated with IFN-ß, and that lost bioactivity returns when Anti-IFN-ß AntiBody levels diminish.

To provide a definitive linkage map for Multiple Sclerosis, we have genotyped the Illumina BeadArray linkage mapping panel (version 4) in a data set of 730 multiplex families of Northern European descent.

After the application of stringent quality thresholds, data from 4,506 markers in 2,692 individuals were included in the analysis.

Multipoint nonparametric linkage analysis revealed highly significant linkage in the Major Histocompatibility Complex (MHC) on Chromosome 6p21 (maximum LOD score [MLS] 11.66) and suggestive linkage on Chromosomes 17q23 (MLS 2.45) and 5q33 (MLS 2.18).

This set of markers achieved a mean information extraction of 79.3% across the Genome, with a Mendelian inconsistency rate of only 0.002%.

Stratification based on carriage of the Multiple Sclerosis-associated DRB1*1501 allele failed to identify any other region of linkage with Genomewide significance.

However, ordered-subset analysis suggested that there may be an additional locus on Chromosome 19p13 that acts independent of the main MHC locus.

These data illustrate the substantial increase in power that can be achieved with use of the latest tools emerging from the Human Genome Project and indicate that future attempts to systematically identify susceptibility genes for Multiple Sclerosis will have to involve large sample sizes and an association-based methodology.