MS Abstracts 01a-2g6

Fatigue is a significant factor in the lives of many MS patients and the most commonly reported symptom in many studies.

Fatigue is an important symptom to consider because it affects patients' social lives, occupations, and activities of daily living.

Efforts to predict Fatigue have been mixed, but it appears to be related to overall quality of life and mood.

From a pathophysiologic perspective, Fatigue in MS is multifactorial and complex, involving:
1. Dysregulation of the Immune System
2. Changes in the Nervous System related to the disease process
3. NeuroEndocrine and NeuroTransmitter changes
4. Other factors such as physical deconditioning, sleep disturbance, pain, and medication side effects

Various attempts to assess Fatigue have been made, and many measures are now available for use in clinical practice and research. In clinical practice, these measures help guide treatment considerations.

Recent research has provided valuable strategies to ameliorate Fatigue in MS, and although many patients continue to experience Fatigue despite interventions, many receive substantial relief.

Nonpharmacologic approaches-considered the first step in treatment-include exercise programs, cooling, dietary considerations, and energy conservation strategies.

For patients who continue to experience significant Fatigue, several medications (although not specifically approved for use in the reduction of MS-related Fatigue) have proved effective in this regard.

The first-line agents include Amantadine for mild Fatigue and Modafinil for more severe cases. Second-line agents include Pemoline and AntiDepressant medications. Other pharmacologic agents have also shown some promise.

Background
The annual relapse rate has been commonly used as a primary efficacy endpoint in phase III Multiple Sclerosis (MS) clinical trials.

The aim of this study was to determine the relative contribution of different possible prognostic factors available at baseline to the on-study relapse rate in MS.

Methods
A total of 821 patients from the placebo arms of the Sylvia Lawry Centre for Multiple Sclerosis Research (SLCMSR) database were available for this analysis.

The univariate relationships between on-study relapse rate and the baseline demographic, clinical, and MRI-based predictors were assessed.

The multiple relationships were then examined using a Poisson regression model. Two predictor subsets were selected.

Subset 1 included age at disease onset, disease duration, sex, Expanded Disability Status Scale (EDSS) at baseline, number of relapses in the last 24 months prior to baseline.

And the disease course (Relapsing/Remitting [RR] and Secondary/Progressive [SP]). Subset 2 consisted of Subset 1 plus gadolinium enhancement status in MRI.

The number of patients for developing the models with no missing values was 727 for Subset 1 and 306 for Subset 2.

Results
The univariate relationships show that the on-study relapse rate was higher for younger and for female patients, for RR patients than for SP patients, and for patients with positive enhancement status at entry (Wilcoxon test, p < 0.05).

A higher on-study relapse rate was associated with a shorter disease duration, lower entry EDSS, more pre-study relapses, and more enhancing lesions in T₁ at entry.

The fitted Poisson model shows that disease duration (estimate = -0.02) and previous relapse number (estimate = 0.59 for one, 0.91 for two, and 1.45 for three or more relapses vs no relapses) remain.

The authors were able to confirm these findings in a second, independent dataset.

Conclusions
The relapse number prior to entry into clinical trials together with disease duration are the best predictors for the on-study relapse rate.

Disease course did not contribute independently because its effect is covered by the pre-study relapse rate.

Gadolinium enhancement status, given the other covariates, has no significant influence on the on-study relapse rate.

Tumor Necrosis-related Apoptosis-inducing ligand (TRAIL) induces Apoptosis of Oligodendrocytes, target cells of Immune attack in Multiple Sclerosis (MS).

TRAIL-induced human Oligodendrocyte (hOL) death depends on TRAIL ligation with its receptor 1 (TRAIL-R1). However, the IntraCellular signaling initiated with ligation of TRAIL-R1 in hOLs is unknown.

We defined that IntraCellular transduction signaling involved in TRAIL-induced death of hOLs is associated with strong activation of c-jun NH2-terminal kinase (JNK) and a dominant negative mutant of MKK4/SEK1, MAP kinase upstream of JNK, inhibited TRAIL-induced Apoptosis of hOLs.

The ImmunoPrecipitation experiments showed that JNK3 isoform was predominantly activated upon hOLs exposure to TRAIL and JNK-3 activation occurred before Mitochondrial membrane dysfunction.

The other mitogen-activated protein kinase p38 and ERK, as well as Calpains and Serine proteases, were not activated during TRAIL-induced hOL death.

Accordingly, the Calpain Inhibitor, ZLLY.FMK, p38 kinase inhibitor, SB 203580, and Serine Proteases Inhibitor, TPCK, did not protect hOLs from TRAIL-induced Apoptosis.

These results demonstrate that JNK pathway is critically involved in hOL death induced by TRAIL and might have significant importance in designing new molecules to protect Immune-mediated hOLs demise.

2005 Wiley-Liss, Inc.

Experimental Autoimmune Encephalomyelitis (EAE) is an animal model of the human Autoimmune Disease Multiple Sclerosis (MS) and is primarily driven by T-Helper type-1 (Th-1) cells.

InterLeukin-12 (IL-12) and Interferon-gamma (IFN-γ) are important Cytokines involved in the differentiation and amplification of Th1 cells, however mice deficient in either IFN-γ or IL-12 still develop EAE.

We have used microarray analysis of EAE-affected CNS tissues in wild-type, IFN-γ -/- and IL-12 -/- animals to identify genes critical for development of EAE.

Over 500 genes were regulated in at least one genotype and over 94 genes were regulated in all three. Of those, 17 were also upregulated in Spleen during the disease.

We show that a majority of the genes regulated in EAE are also regulated in diseased regions of human MS tissues.

The genes in the pool of 94 are more likely to be found regulated in MS patients than the genes regulated in only one or two of the mouse strains suggesting that analyzing gene expression under these multiple genetic conditions may lead to better identification of the genes critical for disease development.

Relapses, exacerbations or attacks of Multiple Sclerosis are the dominating feature of Relapsing/Remitting Multiple Sclerosis (MS), but are also observed in patients with Secondary/Progressive MS.

High-dose MethylPrednisolone is the routine therapy for relapses at present, but other treatments are also in current use.

The objective of the task force was to review the literature on treatment of MS relapses to provide evidence-based treatment recommendations.

Review was carried out on the literature with classification of evidence according to the EFNS guidelines for scientific task forces.

Short-term, high-dose MethylPrednisolone treatment should be considered for the treatment of relapses of MS (level A recommendation).

The optimal GlucoCorticoid treatment regimen, in terms of clinical efficacy and adverse events, remains to be established.

A more intense, interdisciplinary rehabilitation programme should be considered as this probably further improves recovery after treatment with MethylPrednisolone (level B recommendation).

Plasma Exchange is probably efficacious in a subgroup of patients with severe relapses not responding to MethylPrednisolone therapy, and should be considered in this patient subgroup (level B recommendation).

There is a need for further randomized, controlled trials in order to establish the optimal treatment regimen for relapses of MS.

Two methods were used to estimate the long-term impact of Disease-Modifying Drug Therapy (DMDT) in patients with Relapsing Multiple Sclerosis (MS) who completed a placebo-controlled, randomized clinical trial of Interferon-beta-1a (IFN-ß-1a).

The study cohort consisted of patients with ambulatory Relapsing MS who had previously participated in a placebo-controlled clinical trial for two years.

At its end, patients were managed in an unstructured fashion by their Neurologists and re-evaluated at an average of 6.1 years after the end of the trial.

Follow-up evaluation was obtained for 93% of the 172 eligible patients.

Because study inclusion criteria required that all patients have an Expanded Disability Status Scale (EDSS) score of < or = 3.5 at entry, disability progression at follow-up was defined as EDSS > or = 6.0.

Two methods were used to estimate the expected proportions that reached EDSS > or = 6.0 at follow-up. Estimates were compared with observed proportions.

Method 1 used progression rates observed during the two-year phase III clinical trial and the percentage of time that patients were on DMDT during the follow-up period.

Method 2 used progression rates from a natural history comparison group of Relapsing/Remitting MS patients.

At the eight-year follow-up, 42.0% of the original placebo patients and 29.1% of the original IFN-ß-1a patients reached an EDSS > or = 6.0, an observed treatment effect of approximately 30%.

Using method 1, it was estimated that 36.3% of the original placebo patients and 27.6% of the original IFN-ß-1a patients should have reached an EDSS > or = 6.0. Use of the natural history control group (method 2) predicted less plausible outcomes.

Estimated proportions of patients reaching the endpoint were 63.3% for the original placebo group and 55.8% for the original IFN-ß-1a group.

Treatment effect sizes of 75-90% would be required to match estimates from method 2 with the observed outcome.

The paucity of data on the long-term treatment of patients with MS may be aided by applying these or similar methods to vigorously followed cohorts of patients.

FTY720 is the first of a new ImmunoModulator class: Sphingosine 1-Phosphate (S1P) Receptor Agonist.

In 1994, an ImmunoSuppressive natural product, ISP-I (myriocin), was isolated from the culture broth of Isaria sinclairii, a type of vegetative wasp.

The chemical modification of ISP-I yielded a new compound, FTY720, which has more potent ImmunoSuppressive activity and less toxicity than ISP-I does.

FTY720 has been shown to be highly effective in experimental AlloTransplantation models and Autoimmune Disease models.

A striking feature of FTY720 is the induction of a marked decrease in peripheral blood T- and B-Cells at doses that show ImmunoSuppressive activity in these models.

Reportedly, FTY720 is rapidly converted to FTY720-phosphate (FTY720-P) by sphingosine kinase 2 in vivo, and FTY720-P acts as a potent agonist at S1P receptors.

Recently, it has been suggested that FTY720-P internalizes S1P1 on Lymphocytes and thereby inhibits the migration of Lymphocytes toward S1P.

Thus, it is likely that the reduction of circulating Lymphocytes by FTY720 is due to the inhibition of S1P/S1P1-dependent Lymphocyte egress from Secondary Lymphoid tissues and Thymus.

Because FTY720 displays a novel mechanism of action that has not been observed with other ImmunoSuppressive agents and shows a synergism with Cyclosporin A (CsA) and Tacrolimus.

It is presumed that FTY720 provides a useful tool for the prevention of transplant rejection and a new therapeutic approach for Autoimmune Diseases including Multiple Sclerosis and Rheumatoid Arthritis.

Patients with Clinically Isolated Syndromes suggestive of Multiple Sclerosis have evidence for abnormality in Normal-Appearing Gray Matter detected using the Magnetization Transfer Ratio (MTR), a quantitative MRI measure.

One potential mechanism for the decreased Gray Matter MTR (GM MTR) observed is trans-synaptic morphological abnormality secondary to DeMyelinating lesions that are in an anatomically linked pathway but remote location.

We investigated this potential association by studying the location of abnormalities using voxel-based analysis of GM MTR maps in a group of 80 patients studied within 6 months of presenting with isolated Optic Neuritis and compared the findings with those seen in 50 age- and sex-matched healthy controls.

Occipital Cortex and whole Brain analysis comparing all Optic Neuritis patients and controls revealed a selective decrease of MTR bilaterally in the Visual Cortex in patients [Brodmann area (BA) 17].

Whole Brain analysis of patients fulfilling the McDonald criteria for Multiple Sclerosis (n = 20) showed a lower MTR compared to controls bilaterally in the Visual Cortex (BA 17/18), left Hippocampus, bilateral superior Temporal Gyrus, bilateral Lenticular Nuclei and the right Cerebellum.

There was no significant difference in the percentage of Gray Matter between patients and controls in the regions of abnormal MTR detected in the Visual Cortex.

The intrinsic MTR decrease seen in patients suggests that there are structural changes in the Visual Cortex following an attack of Optic Neuritis.

Potential mechanisms for this include Trans-Synaptic Neuronal Degeneration and Cortical Synaptic morphological changes; such abnormalities may also contribute to MTR abnormalities observed in the Normal-Appearing Gray Matter in Multiple Sclerosis.

Interferon-beta (IFN-ß) reduces the number and load of new Contrast-Enhancing Lesions (CELs) in patients with Multiple Sclerosis (MS).

However, the ability of IFN-ß to reduce lesion sizes and re-enhancements of pre-existing CELs has not been examined extensively.

Activity of Contrast Re-Enhancing Lesions (Re-CELs) and contrast single-enhancing lesions (S-CELs) were monitored in ten patients with Relapsing/Remitting (RR) MS.

These patients underwent monthly post-contrast Magnetic Resonance Imaging (MRIs) for an 18-month natural history phase and an 18-month therapy phase with subcutaneous IFN-ß-1b, totaling 37 images per patient.

The activity was analyzed using the first image as a baseline and registering subsequent active monthly images to the baseline. There was a 76.4% reduction in the number of CELs with IFN-ß therapy.

The decrease was greater (P = 0.003) for S-CELs (82.3%) than for Re-CELs (57.4%). S-CELs showed no changes in durations of enhancement and maximal lesion sizes with treatment.

Exclusively for Re-CELs, IFN-ß-1b significantly decreased maximal lesion sizes, total number of enhancement periods and total months of enhancement.

Thus, IFN-ß appears to be effective in reducing the degree of severity of inflammation among Re-CELs, as reflected by their reduced maximal lesion sizes and durations of enhancement.

The aim of this outcome study was to evaluate the effectiveness and prognostic factors of inpatient multidisciplinary rehabilitation treatment in patients with Multiple Sclerosis (MS).

We analyzed 230 consecutive inpatients with MS admitted to an MS rehabilitation ward who followed an individualized, goal-oriented, multidisciplinary rehabilitation program.

Every patient was submitted to a Neurological Examination and evaluated by means of Kurtzke's Expanded Disability Status Scale (EDSS), with its Functional Systems (FS), Barthel Index (BI) and the Rivermead Mobility Index (RMI).

We observed an effectiveness (percentage of potential improvement achieved during rehabilitation) of nearly 16% on BI and 8% on RMI, corresponding to an improvement in 124 patients (54%) on BI and 113 patients (49%) on RMI.

Basal EDSS (beta = -0.32, P < 0.001), Cognitive status (beta = -0.15, P < 0.05) and disease duration (beta = -0.13, P < 0.05) were negatively associated with effectiveness of treatment on BI (adjusted R2 = 0.176).

Whereas effectiveness on RMI was correlated only with the EDSS score (beta = -0.34, P < 0.001, adjusted R2 = 0.113).

In the logistic regression analysis, the absence of severe Sphincteric disturbances was correlated with the probability of improvement on BI that was nearly twice as high (OR =2.25, 95% CI 1.24-4.08) as that of other patients.

Moreover, patients without severe Cognitive deficits showed a similar probability (OR =2.37, 95% CI 1.05-5.33) of improvement on RMI.

The results of this study provide further evidence that intensive multidisciplinary rehabilitation in MS is effective in the majority of MS patients and that early treatment may favor functional recovery.

AntiCholinergics and intermittent catheterization are the cornerstones of Bladder management in early Multiple Sclerosis (MS).

In advanced MS however, Bladder management is based more on tradition than on evidence. Nurses seem to deal with catheter problems and chronic incontinence.

Despite the abundant use of indwelling catheters, there is a lack for guidelines on catheter-induced problems. The psychosexual and social impact of Bladder problems in advanced MS is often neglected.

The international multidisciplinary special interest group on Sexual, Urological and Bowel Dysfunction in MS (SUBDIMS) as a special interest group of the Rehabilitation in Multiple Sclerosis (RIMS) was confronted with a high variability in practice and a lack of guidelines.

A literature review was prepared during three multidisciplinary expert meetings. This review will be the basis of further initiatives to improve the Urological treatment of patients with advanced MS.

Biomarkers that allow the identification of patients with Multiple Sclerosis (MS) with an insufficient response to ImmunoModulatory treatment would be desirable, as currently available treatments are only incompletely efficacious.

Previous studies have shown that the expression of CD25, CD26 and CCR5 on T-Cells is altered in patients with active MS.

We studied the expression of these molecules by flow cytometry in patients followed for six months during ImmunoModulatory treatment.

In Interferon-beta (IFN-ß)-treated patients, we found that the hazard ratio for developing an attack was 28 in patients with CD26⁺ CD4⁺ T-Cell counts above median.

And, this risk was independent of the risk conferred by Neutralizing Anti-IFN-ß AntiBodies.

CD26⁺ CD4⁺ T-Cell counts may identify patients with MS at increased risk of attack during treatment with IFN-ß.