MS Abstracts 02d-2g6

Multiple Sclerosis is an inflammatory disease of the Central Nervous System that leads to loss of Myelin and Oligodendrocytes and damage to Axons.

We show that daily administration (days 8 to 24) of murine Ciliary NeuroTrophic Factor (CNTF), a NeuroTrophic Factor that has been described as a survival and differentiation factor for Neurons and Oligodendrocytes, significantly ameliorates the clinical course of a mouse model of Multiple Sclerosis.

In the acute phase of Experimental Autoimmune Encephalomyelitis induced by Myelin Oligodendrocyte Glycoprotein peptide 35-55, treatment with CNTF did not change the peripheral Immune Response.

But did reduce the number of PeriVascular infiltrates and T-Cells and the level of diffuse Microglial activation in Spinal Cord.

Blood-Brain Barrier permeability was significantly reduced in CNTF-treated animals.

Beneficial effects of CNTF did not persist after it was withdrawn. After cessation of CNTF treatment, inflammation and symptoms returned to control levels.

However, slight but significantly higher numbers of Oligodendrocytes, NG2-positive cells, Axons, and Neurons were observed in mice that had been treated with high concentrations of CNTF.

Our results show that CNTF inhibits inflammation in the Spinal Cord, resulting in amelioration of the clinical course of Experimental Autoimmune Encephalomyelitis during time of treatment.

Purpose Of Review
Interferons were first known for their AntiViral action. ImmunoModulatory therapy with Interferons has been studied in various diseases.

This paper summarizes the role and presumed mechanisms of action of type 1 Interferons in the treatment of Ocular Disease.

Recent Findings
Preliminary data show beneficial effects of Interferons in Ocular disease such as Behcet Disease and Multiple Sclerosis-associated Uveitis in terms of Visual Acuity, IntraOcular inflammation activity, and chronic Macular Edema.

Another mode of application is topical as an adjuvant treatment in Viral Keratitis or Ocular surface malignancies.

Summary
Interferons are gaining a place in the treatment of Ocular Disease. Evidence is growing of their potential in Ocular Behcet Disease and Multiple Sclerosis-associated Uveitis.

Randomized, controlled clinical trials are needed to confirm this observation.

Further insights into the complex mechanisms of action of Interferons in health and disease will increase understanding of their mechanisms of action as a therapeutic substance.

Cyclooxygenase (COX) is a key enzyme of Arachidonic Acid metabolism and exists as two distinct isoforms. COX-1 is constitutively expressed in most tissues, whereas COX-2 is inducibly expressed at the site of inflammation.

Selective inhibitors of COX-2 have been developed and have been used as anti-inflammatory agents. Here, we show that a new-generation COX-2 inhibitor, Celecoxib, inhibited Experimental Autoimmune Encephalomyelitis (EAE).

Celecoxib, but not other COX-2 inhibitors such as Nimesulid, prevented Myelin Oligodendrocyte Glycoprotein (MOG) induced EAE when administrated orally on the day of disease induction.

Moreover, Celecoxib inhibited EAE in COX-2-deficient mice, indicating that Celecoxib inhibited EAE in a COX-2-independent manner.

In Celecoxib-treated mice, Interferon-gamma (IFN-) production from MOG-specific T-Cells was reduced and MOG-specific IgG1 was elevated compared with vehicle-treated mice.

Infiltration of inflammatory cells into the Central Nervous System and the expression of Adhesion Molecules, P-Selectin and InterCellular Adhesion Molecule-1 (ICAM-1), and a Chemokine, Monocyte Chemoattractant Peptide-1 (MCP-1), were inhibited when mice were treated with Celecoxib.

These results suggest that Celecoxib may be useful as a new additional therapeutic agent for Multiple Sclerosis.

In the past few years, Mesenchymal Stem Cells (MSCs) have come into the limelight because of their multi-lineage Stem Cell potential, which retains some aspects of embryonic Stem Cells, and because of their characteristic ImmunoRegulatory functions exerted on different Immune effector cells.

1. The regenerative and ImmunoModulatory potential of MSCs has been used to support hemopoietic Stem Cell engraftment
2. To repair or regenerate damaged or mutated tissues, such as bone, cartilage, myocardial or hepatic tissues
3. To interfere with neoplastic cell growth by transfecting MSCs with anti-neoplastic molecules
4. To modulate Autoimmune reactions such as Collagenopathies, Multiple Sclerosis and graft versus host disease

Thus, MSCs appear to be a very promising tool for regenerative and ImmunoRegulatory Cell therapy.

The etiology of Multiple Sclerosis (MS) is incompletely understood, and evidence suggests there may be more than one underlying cause in this disorder.

Furthermore, this complex and heterogeneous Autoimmune Disease shows a high degree of clinical variability between patients.

Therefore, in the absence of a single therapeutic target for MS, it is difficult to apply conventional drug design strategies in the search for new treatments.

We review the potential mechanisms of action of several effective therapies for MS that are currently available or in development.

The effects of each treatment are described in terms of their actions on key processes in a five-step model of MS pathogenesis.

Conventional ImmunoSuppressants targeting IntraCellular Ligands (e.g. Mitoxantrone) have broad CytoToxic effects on B-Cells, T-Cells, and Macrophages.

This suppresses the pathogenic Immune response in MS with high efficacy but is also associated with high toxicity, limiting the long-term use of these agents.

MonoClonal AntiBodies (e.g. Natalizumab and Alemtuzumab) are a new generation of ImmunoSuppressants that act on Immune-Cell surface Ligands.

These agents have narrower ImmunoSuppressive actions and different safety profiles compared with conventional ImmunoSuppressants.

ImmunoModulators (Interferon-beta and Glatiramer Acetate), which shift the Immune balance toward an AntiInflammatory response, are at the frontline of treatments for MS.

ImmunoModulators have targeted actions on the Immune System, but affect a greater number of ImmunoPathogenic processes than MonoClonal Antibodies.

Given the inherent heterogeneity of MS, such treatments, which act at many levels of the disease, may achieve the best clinical results.

Using our understanding of the interplay between mechanism of action and clinical effects in MS therapies may help us to better design and select new treatments for the future.

Activation of transcription factor NF-kappaB in the Central Nervous System (CNS) has been linked to Autoimmune DeMyelinating Disease; however, it remains unclear whether its function is protective or pathogenic.

Here we show that CNS-restricted ablation of 'upstream' NF-kappaB activators NEMO or IKK2 but not IKK1 ameliorated disease pathology in a mouse model of Multiple Sclerosis, suggesting that 'canonical' NF-kappaB activation in cells of the CNS has a mainly pathogenic function in Autoimmune DeMyelinating Disease.

NF-kappaB inhibition prevented the expression of ProInflammatory Cytokines, Chemokines and the Adhesion Molecule VCAM-1 from CNS-resident cells.

Thus, NF-kappaB-dependent gene expression in Non-Microglial Cells of the CNS provides a permissive ProInflammatory milieu that is critical for CNS inflammation and tissue damage in Autoimmune DeMyelinating Disease.

Overexpression of the major Myelin protein of the CNS, ProteoLipid Protein (PLP), leads to late-onset degeneration of Myelin and pathological changes in Axons.

Based on the observation that in White Matter tracts of these mutants both CD8⁺ T-Lymphocytes and CD11b⁺ Macrophage-like cells are numerically elevated, we tested the hypothesis that these cells are pathologically involved in the primarily genetically caused neuropathy.

Using flow cytometry of mutant Brains, CD8⁺ cells could be identified as activated effector cells, and confocal microscopy revealed a close association of the T-Cells with MHC-I⁺ (Major Histocompatibility Complex Class I positive) Oligodendrocytes.

Crossbreeding the Myelin mutants with mice deficient in the recombination activating gene-1 (RAG-1) lacking mature T- and B-Lymphocytes led to a reduction of the number of CD11b⁺ cells and to a substantial alleviation of pathological changes.

In accordance with these findings, Magnetic Resonance Imaging revealed less Ventricular enlargement in the double mutants, partially because of more preserved Corpora Callosa.

To investigate the role of CD8⁺ versus CD4⁺ T-Lymphocytes, we reconstituted the Myelin-RAG-1 double mutants with bone marrow from either CD8-negative (CD4⁺) or CD4-negative (CD8⁺) mice.

The severe Ventricular enlargement was only found when the double mutants were reconstituted with bone marrow from CD8⁺ mice, suggesting that the CD8⁺ Lymphocytes play a critical role in the Immune-related component of Myelin degeneration in the mutants.

These findings provide strong evidence that a primary Glial damage can cause secondary Immune reactions of pathological significance as it has been suggested for some forms of Multiple Sclerosis and other Leukodystrophies.

Background
Fatigue is a common complaint in Multiple Sclerosis (MS) and often interferes with daily functioning.

Both clinicians and researchers may need to detect high levels of Fatigue Impact using a time and effort efficient tool.

This study evaluates the psychometric properties of a rapid screening instrument for Fatigue Impact In Multiple Sclerosis.

Methods
Three Visual Analogue Scales (VAS) for assessing the impact of Fatigue were developed.

Sixty two subjects with definite MS (mean age 52 +/- 10.5 years; 29 women) and 24 healthy controls (mean age 52 +/- 14 years; 13 women) completed all VAS scales (range 0-100), the Fatigue Severity Scale (FSS) (range 7-63), the Modified Fatigue Impact Scale (MFIS) (range 0-84) and the Guys Neurological Disability Scale (GNDS) (range 0-5).

All tests were repeated with an interval of maximum three days.

To evaluate the reproducibility, IntraClass Correlations (ICC) were calculated, based on one-way analysis of variance for repeated measurements.

Validity was considered by means of correlation coefficients. ROC analysis was used to determine the accuracy of the VAS scales.

Results
The ICC of the VAS scales ranged from 0.68 to 0.69. VAS scales showed low to moderate correlation with FSS, MFIS and GNDS (Kendalls tau 0.23-0.45) and were not related with physical or Cognitive performance, or with Depression.

All VAS scales were able to discriminate between subjects with MS and controls.

Twenty five subjects with MS had a Fatigue Severity Scale score of 36 or more and were classified into the Fatigue group.

ROC analysis showed that VAS_1 is most useful to classify subjects in the Fatigue group. A cut-off value of VAS_1 of 59 displayed 76% sensitivity and 72% specificity.

When using the MFIS score of 40 or more to classify the groups, VAS_1 remained the strongest tool, with 81% sensitivity and 77% specificity at a cut-off value of 59.

Conclusions
The VAS for the impact of Fatigue on daily life (VAS_1) is a moderately reliable, though valid and useful tool to screen rapidly for Fatigue impact in Multiple Sclerosis.

A cut-off value of 59 satisfactorily classifies individuals having severe Fatigue with a high impact on daily life.

In clinical practice, a more comprehensive assessment of Fatigue and the impact on daily life is recommended.

Background
Gray Matter (GM) atrophy has been reported in Multiple Sclerosis (MS). However, little is known about its regional distribution.

Objective
To investigate the regional distribution of GM Atrophy in clinically early Primary/Progressive MS (PPMS).

Design And Patients
Thirty-one patients with PPMS within 5 years of symptom onset (mean age, 43.2 years; median Expanded Disability Status Scale score, 4.5) and 15 healthy control subjects (mean age, 43.7 years) were studied.

All subjects underwent a 3-dimensional inversion-recovery fast spoiled gradient-recalled echo sequence that was repeated after 1 year in patients only.

Magnetic Resonance Images underwent an optimized voxel-based morphometric analysis that segments Magnetic Resonance data volumes in a normalized space and quantifies tissue Atrophy on a voxel-by-voxel basis.

A lesion mask was created for each patient and used in normalization and segmentation steps to minimize bias from lesions.

A multisubject design was used in the cross-sectional study to compare patients with PPMS and controls. A 1-way analysis of variance (within-subjects) design was used in the longitudinal study.

Results
At baseline, patients with PPMS displayed bilateral Thalamic Atrophy compared with controls.

In addition, a significant association between lesion load and decreased GM volume was found for the Thalami.

Loss of GM in the Putamen, Caudate, Thalami, and Cortical and InfraTentorial areas was observed in patients after 1 year of follow-up.

Conclusions
Atrophy is most obvious in deep GM in clinically early PPMS. This may reflect increased sensitivity of these regions to NeuroDegeneration. Cortical and InfraTentorial Atrophic developed as the disease evolved.

Global Gray Matter (GM) loss has been reported in Multiple Sclerosis (MS).

We addressed the question of if and where GM loss is localized by means of optimized voxel-based morphometry, applied to MRI studies of 51 patients with clinically defined Relapsing/Remitting MS and 34 age-matched normal subjects, segmented into normal and abnormal Brain tissues using a multiparametric approach.

Segmented GM volumes were subsequently compared on a voxel-by-voxel basis to highlight regions of relative GM loss (P < 0.05, corrected for multiple comparisons at AnCova).

Additionally, localized differences in Brain asymmetry between the MS and the control groups were assessed by comparing on a voxel-by-voxel basis maps of GM differences between the two Hemispheres (P < 0.05 corrected for multiple comparisons).

In MS patients, GM volume was significantly decreased at the level of the Left Fronto-Temporal Cortex and PreCuneus, as well as of anterior Cingulate Gyrus and of Caudate Nuclei bilaterally.

The only Cortical region of significant GM loss in the Right Hemisphere was located in the PostCentral Area.

Furthermore, GM loss regions were colocalized with increased GM asymmetries (Left < Right) in MS, confirming a preferential left-sided GM loss.

Caudate Atrophy correlated with lesion load, while no correlation between Cortical regional GM loss and disease duration, clinical status or lesion load emerged.

Our findings suggest that in RR-MS Cortical GM reduction preferentially involves Left Fronto-Temporal structures and deep GM, the latter correlating preferentially to global lesion load.

Background:
High-dose Cyclophosphamide is active in Immune-mediated illnesses.

Objective
To describe the effects of high-dose Cyclophosphamide on severe refractory Multiple Sclerosis.

Design, Setting, and Patients
Patients with Multiple Sclerosis with an Expanded Disability Status Scale (EDSS) score of 3.5 or higher after 2 or more Food and Drug Administration-approved disease-modifying therapy regimens were evaluated.

Interventions
Patients received 200 mg/kg of Cyclophosphamide over 4 days.

Main Outcome Measures
Patients had Brain Magnetic Resonance Imaging and Neuro-Ophthalmologic evaluations every 6 months and quarterly EDSS and quality-of-life evaluations for 2 years.

Results
Twelve patients were evaluated for clinical response (median follow-up, 15.0 months; follow-up range, 6-24 months).

During follow-up, no patients increased their baseline EDSS scores by more than 1.0. Five patients decreased their EDSS scores by 1.0 or more (EDSS score decrease range, 1.0-5.0).

No patient had a new lesion on Brain Magnetic Resonance Imaging. No patient showed any enhancing lesions.

Patients reported improvement in all of the quality-of-life parameters measured. Neurologic improvement involved changes in gait, bladder control, and visual function.

Treatment response was seen regardless of the baseline presence or absence of contrast lesion activity. Patient quality-of-life improvement occurred independently of EDSS score changes.

In this small group of patients with treatment-refractory Multiple Sclerosis, high-dose Cyclophosphamide was associated with minimal morbidity and improved clinical outcomes.

Conclusions
High-dose Cyclophosphamide treatment in patients with severe refractory Multiple Sclerosis can result in disease stabilization, improved functionality, and improved quality of life.

Further studies are necessary to determine the most appropriate patients for this treatment.

Published online August 14, 2006 (doi:10.1001/archneur.63.10.noc60076).

Background And Objective
Fatigue is one of the most limiting symptoms in Multiple Sclerosis (MS) and the mechanisms underlying its origin are poorly understood.

Our aim was to test whether Fatigue in MS is associated with Endocrine markers.

Methods
We longitudinally studied 73 Progressive MS patients. Fatigue was assessed at baseline and at 3, 6, 12 and 24 months using the Fatigue Severity Scale (FSS).

Given the longitudinal design of our study, patients were labelled as sustained Fatigued when FSS scores were >5.0 at all time points, and as non-fatigued when FSS scores were < or = 5.0 at all time points.

Serum levels of DeHydroEpiaAndrosterone (DHEA), its sulphated conjugate (DHEAS) and Cortisol were measured at each time point.

Results
Twenty-nine patients scored >5.0 in the FSS at all time points, and 9 patients (12.3%) scored 5.0 at all time points.

Mean baseline levels of DHEAS and DHEA were lower in MS patients with sustained Fatigue when compared to patients without Fatigue (P = 0.01 and P = 0.03 respectively).

Analysis of DHEAS and DHEA over time showed significantly lower Hormone levels in patients with Fatigue [F(1,31) = 6.14, P=0.019 for DHEAS; F(1,32) = 6.63, P=0.015 for DHEA].

Conclusions
Fatigue in Progressive MS could be related to low serum levels of DHEA and DHEAS.

Our results suggest that these Hormones should be considered as biological markers of Fatigue in MS patients and that Hormone replacement may thus be tested as an option to treat Fatigue in MS patients.