MS Abstracts 6d-2g1

Starting from Babinski's original description, the author carries out a revision of semeiological value of the sign "fanning of the toes". It is considered that there are two clinical variants.

The first, present in most cases of connatal Encephalopathy, is due to involvement of the PreMotor Area, which is usually accompanied by Pyramidal, Dystonic or Athetoid Signs.

The second variant is present in cases of Multiple Sclerosis presumably attributible to involvement of the Lateral Spinal Tracts including the ReticuloSpinal one.

The author proposes the need of using modern NeuroImaging and ElectroPhysiological techniques for further PathoPhysiological investigation of both clinical variants of the sign.

CD154 (CD40-Ligand, gp39), expressed on activated T-Cells, is crucial in T-Cell-dependent Immune responses and may be involved in the PathoGenesis of Multiple Sclerosis (MS).

We studied CerebroSpinal Fluid and peripheral blood T-Cell expression of CD154 in MS by flow cytometry.

Patients with Secondary/Progressive MS (SPMS) had constitutive CD154 expression on CD4 and CD8 T-Cells in blood.

Constitutive CD154 expression was not observed in patients with Relapsing/Remitting MS (RRMS) or Clinically Isolated Syndromes (CIS) suggestive of DeMyelinating Disease.

After ex vivo activation CD154 was, however, expressed on a higher percentage of T-Cells from patients with CIS or RRMS than from healthy control subjects.

These results suggest involvement of CD154 in the PathoGenesis of MS, and the shift from a Relapsing/Remitting to a Secondary/Progressive disease course may be associated with constitutive, systemic CD154 expression.

In patients with Multiple Sclerosis (MS), conventional Magnetic Resonance Imaging (MRI) has markedly improved our ability to detect the macroscopic abnormalities of the Brain and Spinal Cord.

New quantitative Magnetic Resonance (MR) approaches with increased sensitivity to subtle Normal-Appearing White Matter (NAWM) and Gray Matter changes.

And increased specificity to the heterogeneous pathological substrates of MS may give information complementary to conventional MRI.

Magnetization Transfer Imaging (MTI) and Diffusion-Weighted Imaging (DWI) have the potential to provide important information on the structural changes occurring within and outside T₂-visible lesions.

Magnetic Resonance Spectroscopy (Spectroscopy) adds information on the biochemical nature of such changes.

Functional MRI might quantify the efficiency of Brain plasticity in response to MS injury and improve our understanding of the link between structural damage and clinical manifestations.

The present review summarizes how the application of these MR techniques to the study of MS is dramatically changing our understanding of how MS causes irreversible Neurological deficits.

The proliferative response of preparations of whole PBMC populations from 20 healthy individuals and 28 Multiple Sclerosis (MS) patients to Purified Protein Derivative (PPD) and Myelin Basic Protein (MBP) was monitored in a kinetic assay over a period of up to 10 days.

PPD produced a classical secondary response in both groups, the magnitude being significantly reduced in the MS cohort. The magnitude and pattern of response to MBP did not differ between the two populations. The kinetic profile characteristic of a primary response was observed in both groups.

Enrichment of the CD45RO+ve and CD45RA+ve T-Cell subsets in PBMC led to a secondary response to PPD in the RO+ve and primary response in the RA+ve population in both groups.

The response to MBP in both RO+ve and RA+ve populations exhibited primary kinetics in both MS patients and healthy individuals.

However, the use of T-Cell subset enriched populations allowed a finer dissection of the response to MBP which highlighted the more active role of RO-positive cells in MS patients.

The most striking difference between patients and healthy individuals occurred on day 4 of culture. When a greater response to MBP occurred in the CD45RO enriched population, paralleling the response to PPD, in the majority of patients.

Futhermore in 4/8 patients and only 1/8 healthy individuals the response in the RO+ve cultures was maintained at a higher level.

Than that seen in the corresponding RA+ve cultures throughout the culture period. This data indicates that a measurable memory response to MBP exists in MS patients implying prior activation of MBP reactive T-Lymphocytes during the course of disease.

Multiple Sclerosis (MS) is assumed to result from AutoAggressive T-Cell-mediated Immune responses. In which T-Helper type 1 (Th1) cells producing Cytokines, e.g. IFN- and LymphoToxin promote damage of Oligodendrocyte-Myelin units.

Dendritic Cells (DCs) as potent Antigen Presenting Cells initiate and orchestrate Immune responses. Whether phenotype and function of DCs with respect to Th1 cell promotion are altered in MS, are not known.

This study revealed that blood-derived DCs from MS patients expressed low levels of the costimulatory molecule CD86.

In addition, production of IFN-IFN- by blood MonoNuclear Cells (MNCs) was strongly enhanced by DCs derived from MS patients.

IFN-ß and IL-10 inhibited the costimulatory capacity of DCs in Mixed Lymphocyte Reaction (MLR) and showed additive effects on suppression of IL-12 production by DCs.

Correspondingly, DCs pretreated with IFN-ß and IL-10 significantly suppressed IFN- production by MNCs.

IFN-ß in vitro also upregulated CD80 and, in particular, CD86 expression on DCs. In vitro, anti-CD80 antibody remarkably increased, while anti-CD86 AntiBody inhibited DC-induced IL-4 production in MLR.

We conclude that DC phenotype and function are altered in MS, implying Th1-biased responses with enhanced capacity to induce Th1 Cytokine production.

In vitro modification of MS patients' DCs by IFN-ß and IL-10 could represent a novel way of ImmunoModulation and of possible usefulness for future ImmunoTherapy of MS.

Administration of Interferon-beta (IFN-ß) In Multiple Sclerosis (MS) patients provides clinical benefits, although its mechanism(s) of action are not completely understood.

We addressed the issue of whether concentrations of IFN-ß-1a close to those reached in the Serum of treated MS patients could modulate either Adhesion Molecules or adhesion of Peripheral Blood MonoNuclear Cells (PBMC).

As well as Fluid Phase Endocytosis (FPE) in Human Umbilical Vein Endothelial Cells (HUVEC) and in Brain-derived Microvascular Endothelial Cells (HBMEC).

Adhesion was assessed by flow cytometry, and FPE was evaluated by Peroxidase uptake. In our study, 200 U/ml IFN-ß-1a induced a reduction in adhesion of PBMC to HUVEC.

The information reported herein may contribute to further elucidating some of the mechanisms of action of IFN-ß on Vascular Endothelium.

Myelin Oligodendrocyte GlycoProtein (MOG), a minor Myelin component, is an important Central Nervous System specific target AutoAntigen for primary DeMyelination in AutoImmune Diseases such as Multiple Sclerosis (MS).

The native structure of MOG presents a GlycoSylation site at position 31 (Asn(31)). It has been recently described that GlycoSylation of a MOG Peptide Epitope improved the detection of specific AutoAntiBodies in Sera of MS patients.

The solution conformational behavior of two MOG derived Peptides-hMOG(30-50) (1) and the GlycoSylated analogue [Asn(31)(N-beta-Glc)]hMOG(30-50) (2)-were investigated through NMR analysis in a water/HFA solution.

Conformational studies revealed that Peptides 1 and 2 adopted similar conformations in this environment.

In particular, they showed strong propensity to assume a well-defined amphipatic structure encompassing residues 41-48. The N-terminal region resulted to be almost completely unstructured for both Peptides.

The presence in 1 of a low populated Asx-turn conformation characteristic of the Asn-Xaa-Thr GlycoSylation sites was the only conformational difference between Peptides 1 and 2.

Thus, the specific AntiBody recognition of Peptide 2 is most likely driven by direct interactions of the AntiBody binding site with the Asn-linked sugar moiety.

Background
The Multiple Sclerosis Functional Composite (MSFC) is a multidimensional clinical outcome measure that includes quantitative tests of leg function/ambulation (Timed 25-Foot Walk), arm function (9-Hole Peg Test), and cognitive function (Paced Auditory Serial Addition Test).

The MSFC is the primary outcome measure in the ongoing multinational phase 3 trial of Interferon-beta-1a (Avonex) in patients with Secondary/Progressive MS.

Objective
To assess the practice effects, reliability, and validity of the MSFC clinical outcome measure.

Design
Examining technicians underwent formal training using standardized materials.

The MSFC was performed according to a standardized protocol.

The 436 patients enrolled in the International Multiple Sclerosis Secondary/Progressive Avonex Controlled Trial underwent 3 prebaseline MSFC testing sessions before randomization.

Results
Practice effects were evident initially for the MSFC but stabilized by the fourth administration. The Paced Auditory Serial Addition Test demonstrated the most prominent practice effects.

The reliability of the MSFC was excellent, with an intraclass correlation coefficient for session 3 (final prebaseline session) vs session 4 (baseline) of 0.90.

The MSFC at baseline correlated moderately strongly with the Kurtzke Expanded Disability Status Scale. Among the MSFC components, the Timed 25-Foot Walk correlated most closely.

Correlations among the 3 MSFC components were weak, suggesting they assess distinct aspects of Neurologic function in patients with MS.

Conclusions
The MSFC demonstrated excellent intrarater reliability in this multinational phase 3 trial. Three prebaseline testing sessions were sufficient to compensate for practice effects.

The pattern of correlations among the MSFC, its components, and the Kurtzke Expanded Disability Status Scale supported the validity of the MSFC.

Recently, the clinical efficacy of Interferon-beta-1b (IFN-ß-1b) was demonstrated for Secondary/Progressive (SP) Multiple Sclerosis in a European multicenter study.

We evaluated the effect of IFN-beta-1b treatment on the rate of development of HypoIntense T₁ MRI lesions, a putative marker of Axonal damage.

Unenhanced T₁-weighted images were obtained in a subgroup of 95 Multiple Sclerosis patients from five centers at 6-month intervals.

This subgroup was similar to the total study population for all demographic, clinical and MRI parameters.

An experienced observer blinded to the clinical data and treatment allocation measured volumes.

The median baseline lesion load for HypoIntense T₁ lesions was 5.1 cm(3) for placebo-treated and 4.9 cm(3) for IFN-ß-1b-treated patients (P = 0.56).

Placebo-treated patients showed an increase in T₁ lesion load by a median of 14% per year (P = 0.0002 compared with baseline).

This was reduced to 7.7% per year in the IFN-ß-1b-treated patients (P = 0.003 versus placebo).

In the IFN-ß-1b arm there was a statistically significant correlation between absolute change in Expanded Disability Status Scale scores and T₁ lesion load by month 36 (r = 0.38, P = 0.0015).

In patients with SP Multiple Sclerosis, IFN-ß-1b treatment reduces the development of HypoIntense T₁ lesions, suggesting that reduced Axonal Damage in lesions may play a part in the beneficial effect that is observed clinically.

Levels of free Amino Acids were determined in randomized, blinded samples of CerebroSpinal Fluid (CSF).

From patients with Relapsing/Remitting or Chronic/Progressive Multiple Sclerosis (MS), all in the active phase of disease.

The levels were compared with amino acid amounts in patients with an acute PolyRadiculoNeuropathy (Guillain-Barre Syndrome (GBS)) and a control population of patients with no known Neurological disease or deficit.

The data did not indicate any significant changes in Amino Acid levels between MS subgroups.

The only significant differences between MS patients and controls were a modest reduction in Glutamate and a slight increase in Taurine, but the changes were so small that the biological relevance is dubious.

These results contrasted with the marked increases for many Amino Acids in CSF from patients with acute PolyRadiculoNeuropathy compared with controls.

The Amino Acid profile in CerebroSpinal Fluid (CSF) does not appear to provide evidence of differential pathology in Multiple Sclerosis (MS).

The increase in hydrophobic Amino Acids and Lysine in CSF from patients with acute PolyRadiculoNeuropathy is consistent with transudation over the Blood-CSF Barrier following an infection.

The increases in Glutamine and Alanine may reflect increased Nitrogen removal from Brain.

Linomide (Roquinimex, LS 2616) is a quinoline-3-carboxamide with pleiotropic Immune modulating capacity and it has therapeutic effects in several experimental animal models of AutoImmune Diseases.

Linomide has been evaluated in clinical trials for Multiple Sclerosis, and was indeed shown to have disease inhibitory effects.

However, due to unexpected side effects recorded in patients treated with Linomide, premature termination of clinical trials was required.

The basic mechanism(s) of action of Linomide in inducing beneficial effects in AutoImmune Diseases is still elusive.

Some experimental evidence indicates that Linomide influences the regulation of the Cytokine profile, resulting in the inhibition of AutoImmune and inflammation pathologies.

This review focuses on Linomide applied in models for AutoImmune and Inflammation pathologies of the Central and the Peripheral Nervous System.

And summarises its very encouraging disease inhibitory effects and their potential pharmacological basis.

The beneficial effects recorded with Linomide in both experimental and clinical trials emphasise the possible value of substances with Linomide-like activity for clinical use in AutoImmune and Inflammation pathologies in the near future.

Purpose
Review of the association between Optic Neuritis (ON) and Multiple Sclerosis (MS).

Results
MS often presents as acute unilateral ON. While it is clear that many patients with ON suffer from a generalized disease of the Central Nervous System.

That will go on to Clinically Definite MS (CDMS), it is also clear that others do not.

With more and more well-informed patients and the emerging pharmacotheraphy for MS, the distinction between those patients with ON who have MS and those who do not, has become more important than ever before.

Recently, a large randomized clinical trial found that treatment with recombinant Interferon-ß-1a is beneficial by reducing the development of CDMS.

On patients with ON or other Clinically Isolated Syndromes suggestive of MS and evidence of prior subclinical DeMyelination on Magnetic Resonance Imaging of the Brain.

Conclusion
Ophthalmologists should refer their patients with acute ON to a Neurologist for MS-directed investigations and decisions regarding early institution of disease modifying therapy.