MS Abstracts 6c-2g1

The management of many chronic illnesses involves medications that must be injected on a frequent basis.

With fewer support resources available, patients are increasingly being obliged to manage injectable medications themselves.

Interferon-beta-1a (IFN-ß-1a), recommended for the treatment of Multiple Sclerosis (MS), must be injected intramuscularly on a weekly basis. Patients are generally advised and taught to self-inject, if possible.

This longitudinal study examined Cognitive and Affective contributions to the ability to self-inject and adherence to IFN-ß-1a over 6 months following initiation of medication.

Participants were 101 patients with a Relapsing form of MS.

Injection self-efficacy expectations, injection anxiety, adherence expectations, method of injection administration, and 6-month adherence to IFN-ß-1a were fitted to a path analytic model.

Pretreatment injection self-efficacy expectations were significantly related to 6-month adherence.

This relation was mediated by the patient's ability to self-inject. Patients 'experienced level of injection anxiety was related to adherence but not to method of injection.

A paradigm exists that Multiple Sclerosis is causally related to dysregulation of Th1 Inflammatory Cytokines and Th2 AntiInflammatory Cytokines. The Cytokine source(s) that initiate the imbalances are unknown.

In this study, delta, CD4⁺, and CD8⁺ T-Cell receptor-positive Cells (TCR⁺) were isolated from the blood.

Of 26 Definitive Relapsing/Remitting Multiple Sclerosis patients prior to Interferon-beta-1a (IFN-ß-1a) therapy and following 8-10 weeks of this therapy.

The bioactivities of Interferon-gamma (IFN-), InterLeukin-10 (IL-10), and InterLeukin-12 (IL-12) were determined.

The concentrations of IFN-, IL-10, and IL-12 from each cell type did not change significantly with IFN-ß-1a treatment.

The IL-10 secreted by delta⁺ TCR Cells strongly correlated with the IL12 secreted by the same delta⁺ TCR Cells, supporting the paradigm.

Furthermore, IFN-ß-1a therapy decreased the delta⁺ TCR Cell secretion of Th1 Cytokines after 8-10 weeks of therapy.

Myelin/Oligodendrocyte GlycoProtein (MOG) is a surface-exposed Antigen of Myelin and an important target for AutoImmune responses which mediate inflammatory DeMyelination in the Central Nervous System.

Experimentally, MOG induces strong pathogenic T-Cell responses in many strains of laboratory animals.

Immunological studies in humans also identify MOG as a surprisingly prevalent antigenic molecule among the Myelin proteins.

In addition, the Encephalitogenic properties of MOG are linked to the induction of AntiBody responses which have been demonstrated to directly promote Central Nervous System DeMyelination.

A hallmark NeuroPathological feature in disorders such as human Multiple Sclerosis.

Factors responsible for AutoImmunity to MOG likely include Genetic influences as well as other mechanisms, which are the subject of intense investigation.

This article reviews experimental data currently available on specificity and pathogenic roles of T-Cell and AntiBody responses against MOG, which have implications relevant to Multiple Sclerosis and related disorders.

Objective
To quantitatively investigate water Diffusion changes in Normal-Appearing White Matter (NAWM) and Gray Matter in patients with MS, and to evaluate whether these changes are correlated with clinical disability and disease duration.

Background
Diffusion Tensor Imaging provides quantitative information about the magnitude and directionality (Anisotropy) of water Diffusion in vivo and detects pathologic changes in MS Brain tissue.

Methods
Diffusion Tensor imaging was performed in 39 patients with MS and in 21 age-matched control subjects.

Quantitative indices, including Fractional Anisotropy, Volume Ratio, and Mean Diffusion, were obtained in 30 regions of interest located in Normal-Appearing Basal Ganglia, Cerebellar Gray Matter, and SupraTentorial and InfraTentorial NAWM.

Results
Patients with MS showed significantly reduced Anisotropy and a trend toward increased Diffusivity in the InfraTentorial and SupraTentorial NAWM, and significantly increased Anisotropy in the Basal Ganglia.

In all patients with MS, both Fractional Anisotropy and Mean Diffusivity in the Cerebral Peduncles were inversely correlated with the Expanded Disability Status Scale and Pyramidal Functional scores.

In patients with Relapsing/Remitting MS, there was a strong correlation between Expanded Disability Status Scale score and Fractional Anisotropy in both SupraTentorial and InfraTentorial NAWM.

In Primary and Secondary/Progressive MS, disease duration correlated strongly with Mean Diffusivity in InfraTentorial NAWM and Fractional Anisotropy in the Cerebral Peduncles, respectively.

Conclusion
The most striking finding of decreased Fractional Anisotropy in SupraTentorial and InfraTentorial NAWM and increased Fractional Anisotropy in Basal Ganglia may result from Axonal Degeneration due to transected Axons in remote Focal lesions.

Diffusion Tensor Imaging indices, in particular Fractional Anisotropy, appear sensitive to structural damage in NAWM that is associated with Disability and progression in MS.

Acquired Nystagmus occurs frequently in patients with Multiple Sclerosis and is often the cause of illusory motion of the environment (Oscillopsia), and blurring of vision.

Based primarily on the beneficial effect of Gabapentin on Acquired Pendular Nystagmus (APN), a GABAergic mechanism in controlling Nystagmus has been hypothesised.

If increasing GABA concentrations in the CNS are critical for the treatment of Nystagmus, then a selective GABAergic drug should be highly successful.

However, as Gabapentin is not a selective GABAergic agent, Vigabatrin, a "pure" GABAergic medication, and Gabapentin, were compared in a single blind cross over trial in eight patients with Definite Multiple Sclerosis.

Patients were randomly assigned to begin with Gabapentin (1200 mg daily) or Vigabatrin (2000 mg daily).

Neuro-Ophthalmological and Electro-OculoGraphic (EOG) evaluations were performed four and three times, respectively.

Treatment efficacy was based on improving Visual Acuity and EOG indices (amplitude or frequency of Nystagmus, or both) by at least 50% of pretreatment values. Three out of eight patients dropped out due to adverse effects.

In the remaining five patients Gabapentin improved symptomatic Pendular or Gaze Evoked Jerk Nystagmus in four. Three patients decided to continue Gabapentin therapy.

Importantly, Vigabatrin proved useful in only one out of five patients, suggesting that Gabapentin effectiveness may be related to additional non-GABAergic mechanisms of action.

Interaction with Cerebral Glutamate transmission by inhibition of NMDA receptor might be an alternative hypothesis for the therapeutic action of Gabapentin.

Expressing Leukocyte Function Antigen-1 (LFA-1; CD11a/CD18) in Relapsing/Remitting (RR) Multiple Sclerosis (MS) patients.

Blood samples were obtained from 10 RR MS patients before and after 2, 4 and 6 months of rIFN-ß-1a (Avonex) treatment.

For each sample, the percentage of CD4⁺CD45RO⁺CD11a⁺ (CD11a(dim) and CD11a⁺) T-Cells was evaluated in in vivo PBTLs.

And in untreated or rIFN-ß-1a (1000 U/ml) or recombinant soluble InterCellular Adhesion Molecule-1 (ICAM-1, the Ligand for LFA-1) (400 ng/ml) treated cultured PBTLs by triple fluorescence flow-cytometry (FACS analysis).

Soluble ICAM-1 (sICAM-1) Serum levels were evaluated by ELISA.

In vivo, the percentage of CD4⁺CD45RO⁺, CD4⁺CD45RO⁺CD11a⁺, CD4⁺CD45RO⁺CD11a^- PBTLs increased after 4 and 6 months of rIFN-ß-1a treatment compared to pretreatment and 2 months of treatment (p<0.05).

The CD11a expression per se did not change during the time course. Soluble ICAM-1 (sICAM-1) Serum levels also increased (p<0.05) after 4 and 6 months of treatment.

When T-Cells, obtained from the blood of the same patients before and during in vivo treatment, were cultured either untreated or treated with rIFN-ß-1a.

They showed an increase in the percentage of CD4⁺CD45RO⁺ T-Cells expressing CD11a⁺ (p<0.05).

The addition of recombinant sICAM-1 to untreated cultures decreased the percentage of CD4⁺CD45RO⁺ T-Cells expressing CD11a.

This last finding seems to support an indirect effect in vivo of rIFN-ß-1a via sICAM-1 on this T-Cell subset.

Since the ICAM-1 soluble form, induced in vivo in Serum by rIFN-ß-1a but lacking in in vitro conditions, keeps the percentage of CD11a⁺ unchanged within CD4⁺CD45RO⁺ T-Cells and induces their expression of CD11a^-, probably preventing T-Cells from transmigrating.

Primary cultures of murine Cerebellar Granule Neurons were exposed to CerebroSpinal Fluid from patients with subtypes of Multiple Sclerosis or acute PolyRadiculoNeuropathy (Guillain-Barre Syndrome) for 2 days.

Cells were then stained with Hoechst 33342 or terminal deoxynucleotidyl transferase-mediated dUTP nick-end labelling (TUNEL) to detect Apoptotic bodies.

The results were compared with control cultures exposed to CerebroSpinal Fluid from patients with no known Neurological Disease or deficit.

There was no significant difference in the level of Apoptosis induced between these controls and cultures not exposed to CerebroSpinal Fluid at all.

Cultures exposed to CerebroSpinal Fluid samples from patients with Relapsing/Remitting Multiple Sclerosis did not have higher levels of Apoptosis than cells exposed to controls, regardless of whether the sample was taken during relapse or remission.

However, a significant increase in Apoptosis was observed in cultures exposed to CerebroSpinal Fluid from patients with Primary/Progressive Multiple Sclerosis, and Apoptosis correlated with disease severity.

This supports the existence of biochemical differences between subgroups of Multiple Sclerosis.

A significant increase in Apoptosis was also induced by CerebroSpinal Fluid samples from patients with acute PolyRadiculoNeuropathy.

Suggesting the presence of NeuroToxic Factor(s) here also. The relevance to disease pathology is unclear.

Introduction
Multiple Sclerosis (MS) usually follows a Relapsing/Remitting course and attacks multiple areas of the Central Nervous System (CNS).

Certain Rheumatic Diseases, including Sjogren's Syndrome (SS), can present with a similar clinical picture.

Results
Two patients out 67 of 100 with MS exhibited Xerophthalmia and Xerostomia and positive Ro AntiBodies, thus fulfilling 55 diagnostic criteria.

Case 1. A 62-year-old woman developed several episodes of numbress and weakness in her left extremity and Ataxia. MRI demonstrated a high-intensity areas in PeriVentricular White Matter.

Initial laboratory studies failure to demonstrate AntiNuclear AntiBodies. Xerostomia and Xerophthalmia were apparent.

Follow-up laboratory examinations showed elevated ANA, Anti-SSA and anti-SSB.

Case 2. A 58-year-old woman was diagnosed as having MS at the age of 53 years. Several high-signal foci on MRI were demonstrated in the White Matter.

Initial Serum findings including AutoAntiBodies were unremarkable.

Sicca syndrome was present. Laboratory investigations included elevated Anti-SSA, anti-SSARo52 and ANA while Anti-SSB was within normal limits.

Discussion
Primary SS is a chronic AutoImmune Inflammatory Disease of unknown etiology.

The CNS symptoms are present in 20-25% of the patients with SS. Some patients have a Relapsing/Remitting course mimicking MS.

Focal Brain lesions in SS can occur in the Cerebral White Matter.

The features of our patients sufficiently mimicked those of MS and this disorder was the diagnosis in each patient at the time of initial evaluation, SS should be considered.

Severe tissue destruction is the presumed HistoPathological correlate of HypoIntense Multiple Sclerosis (MS) lesions.

In this study we correlated changes of lesion HypoIntensity over time with initial HistoPathological features in 14 biopsied MS lesions.

The extent of HypoIntensity increased in initially DeMyelinated plaques and decreased in ReMyelinating lesions.

The initial Axonal loss determined the increase of HypoIntensity over time. In conclusion, both Axonal Loss and DeMyelinating activity determine the evolution of HypoIntensity over time.

Platelet-Derived Growth Factor (PDGF) Ligand is a potent Glial Cell Mitogen. When its cognate receptor (PDGF-R) is expressed on Oligodendroglial lineage cells.

Such cells are considered capable of division, and the receptor thus serves as a phenotypic marker for Oligodendrocyte Precursor Cells.

Here we identify using ImmunoHistoChemistry a considerably enlarged, PDGF-R-expressing Oligodendrocyte Cell population within Multiple Sclerosis (MS) White Matter lesions compared to control Brains.

Numerous PDGF-R-positive Oligodendroglia also colabel heavily with the nuclear cell proliferation marker antibody Ki-67.

Our finding of large numbers of proliferating Oligodendroglia in MS Brains expressing up-regulated PDGF-R suggests that these progenitor-like cells represent an important source of regenerating cells for the healing MS lesion.

Multiple Sclerosis (MS) is a primary Inflammatory DeMyelinating Disease of the human Central Nervous System, characterized by accumulation of MonoNuclear Cells of Hematogenous origin.

RANTES is a C-C (beta)-Chemokine family member with strong ChemoAttractant activity for Lymphocytes and Monocytes that are implicated in the PathoGenesis of MS lesions.

However, the cellular sources of RANTES message and the regulation of its secretion within diseased Brain are poorly understood.

Therefore, we carried out this study to compare the effect of Th1 Cytokines on the induction of RANTES in different human Astrocytic Cell lines.

IFN- alone had little effect on RANTES production in both U-373MG and U-105MG cells, while TNF- or IL-1ß alone had differential effects in the two cell lines.

Low levels of RANTES Chemokine were detected in culture supernatants from U-373MG cells. By contrast, TNF- or IL-1ß dramatically increased RANTES secretion in U-105MG cells.

Interestingly, different combination treatments of cells with the three Cytokines synergistically induced RANTES release from both U-373MG and U-105MG cells.

Consistent with these results, we found similar expression patterns for RANTES at the comparable steady-state mRNA levels in both cell lines.

Furthermore, we showed that U-105MG cells treated with TNF- and IL-1ß alone or in combination markedly induced increases in the rate of transcription of the RANTES Chemokine gene.

Our results indicate that these cell lines may be good model systems for studying the regulation of RANTES expression by Cytokines in human Glial Cells.