MS Abstracts 02d-2g5

Background
Subcutaneous IFN-ß-1b (Betaferon((R))) is an established Immunomodulatory treatment for Relapsing/Remitting MS and active Secondary/Progressive Multiple Sclerosis (SPMS).

It modulates Cytokine and Adhesion Molecule expression but long term in vivo effects of IFN-ß-1b on the Immune System are not known in Multiple Sclerosis.

Objective
To address the effects of IFN-ß-1b on Serum levels for soluble Adhesion Molecules and Cytokine Receptors from MS patients.

Methods
Serial blood samples were obtained from 40 patients of the frequent MRI subgroup (20 patients each from the placebo and the IFN-ß-1b treatment group).

Participating in the European multi-center clinical trial with IFN-ß-1b for Secondary/Progressive MS, at regular intervals for up to 36 months.

Soluble Adhesion Molecules (sVCAM-1, sICAM-1, sL-Selectin), as well as TNF-Receptor I and II were analyzed in the Serum of patients by Enzyme Linked Immunosorbent Assays (ELISAs).

Monthly Brain MRI was performed in 34 of these patients (16 patients from the placebo and 18 from the IFN-ß-1b group) during months 1-6 and 19-24 to monitor disease activity as assessed by newly occurring Gadolinium (Gd) enhancing lesions.

Results
An early and significant increase in sVCAM and sTNF-RII Serum levels was detected in 16 out of 20 patients (80 %) treated with subcutaneous IFN-ß-1b already at month 1 but was absent in all but one patient during placebo treatment (p < 0.01).

Raised sVCAM and TNF RII Serum levels during months 1-6 inversely correlated with less MRI activity in the 19-24 months treatment interval in the IFN-a-1b treatment group ( p=0.0093 for TNF-RII; p=0.047 for VCAM).

Conclusions
VCAM and sTNF RII levels in the Serum of SPMS patients are increased during IFN-ß-1b therapy and may at least in part explain some of the treatment effects, like reduced Immune Cell transmigration.

Multiple Sclerosis (MS) plaques and age related White Matter Lesions (WML) are of similar morphological appearance on T₂ weighted MRI. Therefore their differentiation is sometimes crucial.

Proton Magnetic Resonance Spectroscopy ((1)H-MRS) adds metabolic information to conventional imaging and may help to distinguish inflammatory MS plaques from Vascular related WML.

This study was performed to evaluate the metabolite pattern in MS plaques and WML. 15 MS patients, 14 elderly individuals with WML and 16 controls were investigated by conventional MRI and short echo quantitative (1)H-MRS (TE: 30ms, TR: 3000ms).

The mean metabolite concentrations in Normal Control White Matter (NCWM), MS plaques and WML were:
1. t-NAA:8.96 mmol/l (SD:0.93) vs6.79 mmol/l (SD: 1.99) vs7.18 mmol/l (SD: 1.41)
2. Cho: 1.66 mmol/l (SD: 0.4) vs 1.49 mmol/l (SD: 0.45) vs1.46 mmol/l (SD: 0.34)
3. PCr:5.64 mmol/l (SD: 0.83) vs4.9mmol/l (SD: 1.3) vs 4.95 mmol/l (SD: 0.86)
4. Myo-Ins: 4.57 mmol/l (SD:1.05) vs 6.34 mmol/l (SD: 2.03) vs 4.5 mmol/l (SD: 0.96)

t-NAA reduction in MS plaques and WML was significant compared with controls (p < /= 0.001).

MS plaques showed significantly elevated Myo-Ins concentrations compared with controls (p = 0.002) and to WML (p = 0.003).

In summary MS plaques and WML show a decrease in their t-NAA concentrations compared with controls. Elevated concentrations of Myo-Ins in MS plaques but not in WML makes this metabolite of special interest for their differentiation.

Objective
To identify factors that impact on the ability of patients with Multiple Sclerosis (MS) to remain in work in order to make recommendations for future clinical management.

Methods
Cross-sectional studies using qualitative (phase one) and quantitative (phase two) methods.

In phase one, 62 patients were interviewed and completed an exploratory questionnaire regarding the impact of MS on employment.

In phase two, 100 patients attending an MS outpatient clinic completed an impact on work questionnaire, the self-report Barthel index, and the General Health Questionnaire (GHQ-28).

Results
In phase one, 17 areas were identified as impacting on MS patients' ability to remain in work, either relating to MS or environment.

In phase two, both MS related factors and environmental factors were reported to have a major impact on ability to work. Only 20% of patients had received any advice about work retention.

Unemployed patients (N = 64) had greater disability than employed patients on the Barthel index (difference 5.1; p < 0.001), but similar psychological wellbeing on the GHQ-28.

Conclusion
The issues that prevent people with MS from working tend to be disease-related, as well as work-related. Many patients are isolated, as they are unaware of sources of help.

Effective management by healthcare professionals has a potentially important role in helping people with Multiple Sclerosis to remain employed.

Multiple Sclerosis (MS) and Vitamin B12 deficiency share common Inflammatory and NeuroDegenerative PathoPhysiological characteristics.

Due to similarities in the clinical presentations and MRI findings, the differential diagnosis between vitamin B12 deficiency and MS may be difficult.

Additionally, low or decreased levels of Vitamin B12 have been demonstrated in MS patients.

Moreover, recent studies suggest that Vitamin B12, in addition to its known role as a co-factor in Myelin formation, has important ImmunoModulatory and NeuroTrophic effects.

These observations raise the questions of possible causal relationship between the two disorders, and suggest further studies of the need to close monitoring of Vitamin B12 levels.

As well as the potential requirement for supplementation of Vitamin B12 alone or in combination with the ImmunoTherapies for MS patients.

Spontaneous ReMyelination occurs in Multiple Sclerosis (MS) patients. However, this process is not robust enough to promote a functional and stable recovery of the Myelin architecture in DeMyelinated areas of the Central Nervous System (CNS).

As a consequence of this incomplete reparative process, the disease invariably progresses.

And patchy areas of DeMyelination, in which Axonal damage and/or loss is a constant accompanying factor, increase over time and lead to the accumulation of irreversible Neurological Deficits.

Thus, the development of cell-based therapies aimed to promote multifocal ReMyelination in MS represents one of the most challenging areas of investigation. Several cell-replacement strategies have been developed in the last few years.

Although consistently able to form new Myelin Sheaths around the transplantation site.

However, most of these therapeutic approaches are unrealistic owing to the mutifocality of the DeMyelinating process and the inability to in vitro growth and differentiate large number of Myelin-forming cells.

Recently, promising cell-replacement therapies based on the use of Stem Cells have been proposed.

However, before envisaging any potential human applications of such therapies we need to confront with some preliminary and still unsolved questions:

1. The ideal stem cell source for transplantation
2. The route of cell administration
3. The differentiation and persistence of Stem Cells into the targeted tissue and
4. The functional and long-lasting integration of transplanted cells into the host tissue

Experimental Autoimmune Encephalomyelitis (EAE) in rats is a highly valuable model of Multiple Sclerosis (MS) since it mimics major hallmarks of the human disease.

EAE induced with Myelin-Oligodendrocyte-Glycoprotein (MOG) in DA rats is Relapsing/Remitting and lesions in the Central Nervous System show Inflammation, DeMyelination, Axonal and Neuronal Loss.

Recently, Bone Marrow Transplantation (BMT) was introduced as a novel strategy to treat MS but its efficiency and the underlying mechanism are debatable.

In MOG induced EAE we found that BMT at the peak of EAE but not in the chronic phase leads to disease attenuation.

In both settings Bone Marrow (BM) transplanted rats were protected from subsequently induced relapses.

These findings could be confirmed by HistoPathology in which BM transplanted rats did not have lesions compared to non-transplanted controls.

Importantly, the protective effect was achieved by allogeneic, syngeneic and grafts from diseased rats.

BMT resulted in increased numbers of CD4+CD25bright regulatory T-Cells, increased Foxp3 expression, a shift in T-Cell Epitope recognition and a strong reduction of AutoAntiBodies even after re-challenge with MOG.

Thus, our results indicate potential mechanisms of how BMT may contribute to the improvement of MS and provide a rationale for its application in patients suffering from various Autoimmune Diseases.

Using adult male C57BL/6 mice that express a yellow fluorescent protein transgene in their Motor Neurons, we induced Experimental Autoimmune Encephalomyelitis (EAE) by immunization with Myelin Oligodendrocyte Glycoprotein Peptide 35-55 (MOG Peptide) in complete Freund's adjuvant (CFA).

Control mice of the same transgenic strain received CFA without MOG Peptide. Early in the course of their illness, the EAE mice showed LumboSacral Spinal Cord Inflammation, DeMyelination and Axonal fragmentation.

By 14 weeks post-MOG peptide, these abnormalities were much less prominent, but the mice remained weak and, as in patients with Progressive Multiple Sclerosis, Spinal Cord Atrophy had developed.

There was no significant loss of Lumbar Spinal Cord Motor Neurons in the MOG Peptide-EAE mice.

However, early in the course of the illness, Motor Neuron Dendrites were disrupted and Motor Neuron expression of HypoPhosphorylated NeuroFilament-H (hypoP-NF-H) ImmunoReactivity was diminished.

By 14 weeks post-MOG Peptide, hypoP-NF-H expression had returned to normal, but Motor Neuron Dendritic abnormalities persisted and Motor Neuron Perikaryal Atrophy had appeared.

We hypothesize that these Motor Neuron abnormalities contribute to weakness in this form of EAE and speculate that similar Motor Neuron abnormalities are present in patients with Progressive Multiple Sclerosis.

Purpose Of Review
The present article reviews the currently ongoing scientific debate on the specific characteristics of Primary/Progressive Multiple Sclerosis.

Recent Findings
The most important observations come from the studies using Magnetic Resonance Imaging showing involvement of the Normal-Appearing Brain Tissue and also from the clinical and Magnetic-Resonance-Imaging descriptions in longitudinal studies.

Summary
Progress in the diagnosis of Primary/Progressive Multiple Sclerosis has been made. Long- and short-term natural history are now better known, which will allow the designing of clinical trials in the near future.

Magnetic-Resonance-Imaging studies have demonstrated damage of the Normal-Appearing Brain Tissue.

Which may explain in part the apparent clinical and radiological paradox, common to all clinical forms of Multiple Sclerosis but perhaps more evident in the Primary/Progressive form.

Preliminary results from exploratory trials seem to indicate that these patients should no longer be excluded from therapeutic trials.

Purpose Of Review
The aim of the present report is to briefly review Multiple Sclerosis therapeutic trials published or presented in 2004 to provide an up-to-date overview of the established evidence and new insights.

Recent Findings
New data have come available that help us understand how currently approved disease modifying drugs can best be used.

Nonetheless, their limited effectiveness - especially in Progressive forms of Multiple Sclerosis - as well as the inconvenience and toxicity associated with their use, emphasize the need for new treatment strategies.

A substantial number of reports on new emerging treatment modalities were published in 2004, and one of these modalities was newly approved by the US Food and Drug Administration for the treatment of Relapsing forms of Multiple Sclerosis.

Summary
Further advances have been made in the treatment of Multiple Sclerosis patients. On the one hand, we know better how and in whom to use existing medications.

On the other hand, it is exciting to witness how increased insight in the pathophysiology of the disease and its symptoms has led to a series of new, innovative treatment modalities.

Purpose Of Review
The availability of partially effective ImmunoModulatory and ImmunoSuppressive treatments for Relapsing Multiple Sclerosis (MS) opens important ethical, methodological and practical issues in the design and conduct of new clinical trials in these patients.

Recent Findings
The recommendation of the National Health Authorities to prioritize phase III clinical trials using placebo arm raises ethical questions. In addition, patients are reluctant to be involved in such trials.

Alternative clinical trial designs will be discussed. Relapses and active lesions are accepted measures of disease activity; new/enlarging T₂ lesions and/or enhancing lesions are accepted surrogate markers of disease activity in phase II clinical trials.

On the contrary, there are no accepted Magnetic Resonance Imaging (MRI) surrogate markers of disease progression and also the clinical measures to monitor the degenerative aspects of the disease are not without important limitations.

New scales of impairment, disability and quality of life will be reviewed extensively.

We will also focus on the value of modern and quantitative MRI techniques, which hold substantial promise as tools to estimate the extent of MS-related irreversible tissue loss.

Summary
The use of an active comparator in a superior clinical-trial design is becoming an attractive option for testing the efficacy of new drugs in Relapsing MS.

At present there are no fully reliable and sensitive clinical markers of the accumulation of irreversible tissue damage in MS.

Although additional extensive application in longitudinal studies is needed, modern MRI techniques are promising tools to monitor the NeuroDegenerative aspects of MS.

Purpose Of Review
The aim of this article is to describe recent observations regarding the basis for the initiation and disease evolution of Multiple Sclerosis.

Recent Findings
A current debate is where and what initiates the NeuroInflammatory reaction that characterizes the acute Multiple Sclerosis lesion.

Immune sensitization to Neural Antigens could develop within the systemic compartment consequent to exposure to cross-reacting, possibly Viral derived, Peptides (Molecular Mimicry).

Although CD4⁺ T-Cells are considered central to initiating Central Nervous System inflammation, the actual extent and specificity of tissue injury reflects the array of Adaptive (CD8⁺ T-Cells and AntiBody) and Innate (Microglia/Macrophages) Immune constituents present in the lesions.

NeuroPathologic studies indicate that lethal changes in Neural Cells (Oligodendrocytes) could also be the initiating event.

Reflecting as yet unidentified acquired insults (e.g. exogenous Virus or reactivated endogenous RetroVirus) or intrinsic abnormalities ('NeuroDegenerative' hypothesis).

Recurrence or persistence of the disease process can reflect events occurring at multiple sites.

Including, expansion of the Immune repertoire in response to Neural Antigens transported to regional Lymph Nodes (Determinant Spreading), especially if Immune regulatory mechanisms are defective.

Alterations in Blood-Brain Barrier properties consequent to initial Cellular TransMigration.

And participation of endogenous (Microglia, Astrocytes) or long lived infiltrating cells (Macrophages, B-Cells in ectopic germinal centers) in regulating and effecting Immune functions within the Central Nervous System.

Accumulating Neurologic deficit reflects the balance between injury and repair; the latter also being negatively or positively (Trophic support and clearance of tissue debris) impacted by inflammatory processes.

Summary
Understanding the full spectrum of Multiple Sclerosis presents a continuing challenge for both Immunology and NeuroBiology.

Purpose Of Review
Despite recent progress in treating the inflammatory component of Multiple Sclerosis, current therapies have no clear impact on progression of disability, which closely relates to tissue (Myelin and Axon) injury.

Many scientists now focus their efforts on elucidating the mechanisms that lead to tissue injury, and on developing new strategies for tissue repair. We review recent breakthroughs in this field and discuss their putative applications to therapy.

Recent Findings
Several hypotheses have been raised to explain the failure of ReMyelination, including depletion of ReMyelinating Cells, quiescence of Oligodendrocyte Precursor Cells and Axonal inhibitory signals.

Success in ReMyelination therapy may be achieved either by enhancing endogenous repair or by grafting exogenous ReMyelinating Cells.

Several NeuroTrophic Factors have been shown to enhance endogenous ReMyelination, and many immature cells have been shown to induce efficient exogenous ReMyelination in animal models.

Although effective Remyelination probably represents the best way to prevent NeuroDegeneration, several alternative NeuroProtective strategies are emerging.

Statins, Cyclins and Immunophilin Ligands are orally available ImmunoModulatory agents that may protect Neurons. Other promising possibilities include the modulation of ExcitoToxicity, Nitric Oxide synthesis, or Cationic Channels.

Summary
Despite the increasing number of putative therapeutic targets, no treatment to achieve ReMyelination or NeuroProtection has yielded positive clinical results in humans.

Forging a link between basic biology and treatment of patients will require us to overcome several challenges, including assessment of efficacy of repair, improving tolerance to and delivery of NeuroTrophic Factors, and better defining the indications for and limitations of transplantation.