MS Abstracts 03a-2g5

Purpose Of Review
Multiple Sclerosis (MS) is the most common chronic Inflammatory Neurological Disease. Despite major advances the Etiology of this disease it is still not completely understood.

In the post-genome era, advances in global screening technologies offer an opportunity to accelerate the search of new pathological pathways and to identify new therapeutic targets.

Some recent publications using novel global screening methods at the genome, transcriptome, proteome and metabolome levels are discussed.

Recent Findings
The genetic association of susceptibility to MS with loci outside the MHC has been reconfirmed. Evidence of parent-of-origin and seasonal effects on disease susceptibility add further complexity to the genetics of MS.

The search for MS susceptibility genes continues using the candidate-gene approach as well as large-scale single-nucleotide-polymorphism association studies and novel cross-species synteny analysis.

Genome-wide expression profiling using microarrays produced numerous therapeutic targets and is progressing towards profiling of rare cells.

Advances in classical proteomics methods paved the way to new initiatives aiming at determining the proteome of the Nervous System in normal and diseased states. Although progress is still slow, array-based methods are making an impact on the MS field.

Summary
The complexity of MS is clearly reflected in the latest findings using global profiling methods.

Nevertheless, these new technologies are confirming some of the basic aspects of the disease pathophysiology, i.e. its PolyGenicity, the central role of NeuroInflammation and the emerging NeuroDenegerative processes.

These data are primarily the results of genomic approaches, yet promising attempts are also made using proteomics and metabolomics.

Purpose Of Review
This review will focus on recent developments in Multiple Sclerosis (MS) pathology with particular emphasis on the patterns and mediators of lesion formation in MS, the mechanisms of Oligodendrocyte and Axon damage and the Magnetic Resonance Imaging-pathological correlation of MS lesions.

Recent Studies
The inflammatory cascade in the MS plaque has been characterized in more detail, and other factors such as Hypoxia-like injury or ExcitoToxicity, besides Immunological Effector Mechanisms, have been found to play a role in MS pathogenesis.

Cortical DeMyelination and mechanisms of NeuroAxonal damage are discussed in detail. The Radiological correlate of basic HistoPathologic findings is being approached with quantitative methods.

Similar quantitative approaches are used in MS-gene expression studies that compare patterns of gene expression in different lesion areas.

Summary
These studies will lead to better understanding of the pathogenesis of MS lesions and will hopefully identify new therapeutic targets to modulate inflammation, support ReMyelination and protect Axons and Neurons in MS.

Purpose Of Review
This review focuses on novel aspects of the pathogenesis and advances in the therapy of Multiple Sclerosis (MS).

Recent Findings
Recent observations suggest that early lesion development in MS may start in some forms with Oligodendrocyte death and that inflammation appears as a secondary phenomenon only.

The lack of sufficient ReMyelination in MS may be the result of a disturbed function of basic helix-loop-helix transcription factors.

Clinically the identification of patients with a Clinically Isolated Syndrome at high risk to develop Clinically Definite MS remains difficult; the predictive value of Serum AntiBodies against Myelin proteins remains controversial.

The role of Neutralizing AntiBodies in Interferon therapy is discussed. New therapeutic approaches in MS are emerging.

Summary
The existing view on the pathogenesis of MS is still changing. The original assumption that cell-mediated DeMyelination is the key event in lesion development dictating clinical disability is critically reviewed and alternative pathways have been suggested.

Oligodendrocyte death, Axonal loss, the role of CD8⁺ T-Lymphocytes, T-Regulatory Cells, and B-Lymphocytes have come into the focus of newly evolving concepts in MS pathogenesis.

A deepened understanding of the ImmunoPathogenesis of this disease translates into innovative therapeutic approaches, such as blockade of alpha4 Integrins by a humanized MonoClonal AntiBody.

In various animal models cell-replacement strategies yield promising results; however, turning these findings into an effective therapy in MS patients has a long way to go.

A total of 308 patients with Relapsing/Remitting Multiple Sclerosis (RRMS) documented in a clinical database have been analyzed for comparison of treatment effects of first line ImmunoModulating therapies.

During follow up for 24 months the reduction of relapse rates was evaluated in a retrospective and open-label clinical study.

By comparing the efficacy of Interferon-beta-1a (IFN-ß-1a) i.m. (Avonex), IFN-ß-1b s.c. (Betaferon), IFN-ß-1a 22 microg s.c. (Rebif 22) and Glatiramer Acetate (GA; Copaxone) in patients with RRMS (Enhanced Disability Status Score (EDSS) < 3.5) who have been treated for at least 6 months.

Compared with baseline, relapse rate was reduced to a comparable extend after 6 month treatment with all regimen. For all drugs the effect on the relapse rate was sustained over 24 months.

There was no superiority of one of the IFN-ß preparations concerning reduction of relapse rate after 12 and 24 months

However, reduction was significantly higher for patients treated with GA compared with all ß-Interferons (-0.71, P < 0.001). In addition, the discontinuation rate within 24 months was significantly lower for GA.

Despite some limitations of the study design, the results provide helpful clinical information regarding the efficacy of ImmunoModulatory therapies in early stages of RRMS patients in a clinical setting.

Objectives
The current review evaluates the safety and efficacy of Desmopressin in patients with Multiple Sclerosis (MS) who suffer from both daytime and nocturnal voiding frequency and from Incontinence.

Materials And Methods
A literature search was carried out looking for studies published between 1990 and 2003 which evaluated Desmopressin in MS patients with Bladder Dysfunction.

Results
The grand total mean effect sizes show the following estimates of clinical relevant differences: Desmopressin has a moderate effect on the number of voids during the day or during the night over a period of 6 h after taking the drug.

A large effect associated with the use of Desmopressin was detected by the mean difference in urine volume (ml) in 6 h. A small effect was detected in the mean 24-h urine volume.

Serum Sodium levels were combined with Plasma Osmolality in some studies and were found to be not significantly affected by Desmopressin treatment.

Fatigue is a common symptom of Multiple Sclerosis (MS) that is purported to cause significant distress and have detrimental effects on daily functioning, social and occupational obligations, and overall well-being.

The prevalence of Fatigue in MS is high, with 53-87% of patients reporting significant problems with Fatigue across different studies reported in the literature. The cause of Fatigue in MS is still poorly understood.

Some researchers have suggested that fatigue is a direct consequence of the MS disease process, but several studies have failed to find a relationship between disease severity and MS fatigue.

A number of investigations have reported that Depression and Sleep are significantly related to Fatigue in MS, as well as to one another.

The purpose of the present investigation was to examine the relationships among disease severity, Depression, and Sleep Disturbance in MS, and their possible role in predicting Fatigue. Four models were proposed to explore these relationships.

The best fitting model showed that all three were significant independent contributors to Fatigue in MS, accounting for 43% of the variance, with sleep disturbance reigning as the largest contributor.

Furthermore, although disease severity predicted Fatigue in our sample, both Depression and Sleep Disturbance emerged as stronger predictors.

These findings suggest that, beyond core Physical/Neurological MS symptomatology, there are other factors that contribute to Fatigue in MS, namely, Depression and Sleep Disturbance.

Background
Viruses and Virus-induced Lymphokines may have an important role in the pathogenesis of AutoImmunity (Schattner A. Clin Immunol Immunopathol; 1994). The occurrence and significance of AutoImmune manifestations after the administration of Viral vaccines remain controversial.

Methods
Medline search of all relevant publications from 1966 through June 2004 with special emphasis on search of each individual AutoImmune manifestation and vaccination.

As well as specifically searching each Viral vaccine for all potential Autoimmune syndromes reported. All relevant publications were retrieved and critically analyzed.

Results
The most frequently reported Autoimmune manifestations for the various vaccinations, were: Hepatitis A Virus (HAV) - none; Hepatitis B Virus (HBV) - Rheumatoid Arthritis, Reactive Arthritis, Vasculitis, Encephalitis, Neuropathy, Thrombocytopenia; Measles, Mumps and Rubella vaccine (MMR) - acute Arthritis or Arthralgia, chronic Arthritis, Thrombocytopenia; Influenza - Guillain-Barre Syndrome (GBS), Vasculitis; Polio - GBS; Varicella - mainly Neurological Syndromes.

Even these 'frequent' associations relate to a relatively small number of patients. Whenever controlled studies of AutoImmunity following Viral vaccines were undertaken, no evidence of an association was found.

Conclusions
Very few patients may develop some Autoimmune Diseases following Viral vaccination (in particular - Arthropathy, Vasculitis, Neurological Dysfunction and Thrombocytopenia).

For the overwhelming majority of people, vaccines are safe and no evidence linking Viral vaccines with type 1 Diabetes, Multiple Sclerosis (MS) or Inflammatory Bowel Disease can be found.

Theiler's Murine Encephalomyelitis Virus-Induced DeMyelinating Disease (TMEV-IDD) is a well-characterized murine model of human Multiple Sclerosis (MS) that closely resembles the Chronic and Progressive clinical form of the disease.

Recent studies have described the involvement of the Cannabinoid System in the progression of the disease and the benefits associated with the administration of Cannabinoid Agonists.

With the objective to study whether "indirect" agonists, that is, compounds able to reinforce the physiological EndoCannabinoid transmission and, therefore, devoid of the Psychotropic effects of "direct" Agonists, could be suitable agents for the amelioration of MS Neurological deficits.

We administered the potent and selective Anandamide uptake inhibitor UCM707 to TMEV-infected mice. Our results indicate that treatment during established disease significantly improves the Motor Function of the diseased mice.

At the Histological level, UCM707 is able to reduce Microglial activation, diminish Major Histocompatibility Complex Class II Antigen expression, and decrease cellular infiltrates in the Spinal Cord.

Additionally, in Microglial Cells, UCM707 decreases the production of the ProInflammatory Cytokines: Tumor Necrosis Factor-alpha (TNF-), InterLeukin-1beta (IL-1ß), and IL-6; reduces Nitric Oxide levels and Inducible Nitric Oxide Synthase expression.

And is able to potentiate the action of a subeffective dose of the EndoCannabinoid Anandamide. Overall, these results suggest that agents able to activate the EndoCannabinoid System could constitute a new series of drugs for the treatment of MS.

The aim of the present study was to evaluate the efficacy of the combination of Cyclophosphamide (CTX) and Interferon-beta (IFN-ß) in a group of Relapsing/Remitting (RR) Multiple Sclerosis (MS) patients who experienced treatment failure during IFN-ß therapy.

It is the general experience that ImmunoModulatory Agents (IMA) are only partially effective in RR patients. Recent data on the efficacy of ImmunoSuppressive therapies for these patients are encouraging.

The AntiInflammatory and ImmunoSuppressive effects of CTX have been utilized to treat selected cases of Multiple Sclerosis with a Progressive and worsening course as rescue therapy.

Thirty RR MS patients with clinically defined MS who experienced treatment failure during IFN-ß therapy (2 or more relapses per year or 1.5 EDSS point worsening in one year) were enrolled in the study.

And treated with CTX iv pulse therapy added to IFN-ß and followed up for 24 months. As primary endpoints we evaluated the yearly relapse rate.

We also evaluated the percentage of patients free of relapses and of EDSS variations. We analyzed the results at one year before entry (T0: IFN-ß alone), 12 (T1) and 24 (T2) months after entry. Brain MRI was performed at T0, at T1 and T2.

The 30 RR patients who had experienced a high number of relapses (r r =1.4) at T0 showed a significant improvement in yearly relapse rate (rr = 0.4) at T1 and a further improvement (RR = 0.17) at T2 (p < 0.001). The percentage of patients free of relapse was 70% at T2 (p < 0.0001).

EDSS score changed from 2.6+/-1.23 at T0 to 2.2 +/- 1.5 at T2, showing only a trend of improvement. No significant variation of MRI lesion load and no severe adverse events were recorded during the study.

These data showed that the combination of CTX plus IFN-ß halted the progression of disease in active and deteriorating MS patients.

Suggesting the necessity of RCTs to test the efficacy of this combination therapy in active RRMS patients or in patients who experienced treatment failure in response to Disease Modifying Drugs (DMDs).

To date there has been poor translation of ImmunoTherapies from rodent models to treatment of Progressive Multiple Sclerosis (MS).

In the robust, Relapsing Biozzi ABH mouse model of MS, using a combination of a transient deletion of T-Cells followed by IntraVenous (i.v.) Myelin Antigen administration, established Relapsing Disease in EAE can be effectively silenced.

However, when treatment was initiated in late stage Chronic-Relapsing Disease, despite inhibition of further relapses, mice demonstrated evidence of disease progression.

Shown by a deterioration in mobility and development of Spasticity and indicates that targeting Relapsing, Immunological components of MS alone is unlikely to be sufficient to control progression in the late stages of MS.

Over the last few years, increased evidence has supported the role of Iron dysregulation in the pathogenesis of Multiple Sclerosis (MS), as Iron is essential for Myelin formation and Oxidative Phosphorylation.

We studied indices of Iron metabolism, such as Serum Iron, Ferritin, Transferrin and soluble TransFerrin Receptor (sTFR) levels in 27 MS patients.

Seven patients had Chronic Progressive Active disease (CP-A), six had Chronic Progressive Stable (CP-S), ten had Relapsing/Remitting Active (RR-A) and four had Relapsing/Remitting Stable (RR-S) disease.

sTFR levels were found to be significantly higher in CP-A (P = 0.021) and RR-A (P < 0.004) patients than in controls.

sTFR levels were also elevated in CP-S patients but did not reach significance (P = 0.064). sTFR values in RR-S patients were comparable to those found in controls (P = 0.31).

Ferritin levels were significantly elevated only in CP-A patients (P < 0.002). Patients of the CP group had significantly higher Ferritin values than the RR patients (P < 0.004).

Haemoglobin values as well as Iron and Transferrin levels were within normal limits in all patients.

In conclusion, the increased Serum sTFR and Ferritin levels in NonAnaemic MS patients with active disease reflect the increased Iron turnover.

The mild elevation of sTFR levels in CP-S patients may indicate active inflammation with ongoing Oxidative damage that is not detectable by history or examination.

While there is now evidence for Thalamic abnormality in established Secondary/Progressive and Relapsing/Remitting Multiple Sclerosis (MS), it remains unclear when such abnormality begins.

This study investigated the emergence of Thalamic abnormality in relapsing-remitting MS by assessing the Thalamic Magnetization Transfer Ratio (MTR) in a cohort with clinically early disease.

Twenty-three patients with early Relapsing/Remitting MS (mean age 37; mean disease duration 1.9 years; Expanded Disability Status Scale (EDSS) range 0-3) and 19 healthy controls (mean age 34) were imaged yearly with a Magnetization Transfer Imaging sequence.

Twenty-two MS patients and 14 controls completed two-year follow-up. Regions Of Interest were placed in both Thalami and mean Thalamic MTR calculated.

At baseline, significant differences between patient and control Thalamic MTR were not observed.

However, at years one and two, the Thalamic MTR in patients was significantly lower than control MTR.

Although baseline lesion volume did not correlate with baseline Thalamic MTR, at year one, an association between baseline lesion volume and year one Thalamic MTR emerged.

There was also a significant inverse correlation between EDSS and Thalamic MTR (r = -0.47, P = 0.02). The study suggests that Thalamic involvement occurs within the first five years of MS onset, when most patients are still minimally disabled.