MS Abstracts 02a-2g6

Background
The McDonald criteria include MRI evidence for Dissemination In Space (DIS) and Time (DIT) for the diagnosis of Multiple Sclerosis in young adult patients who present with Clinically Isolated Syndromes (CIS) typical of the disease.

Although a major advance, the criteria have limited sensitivity for making an early diagnosis.

Objective
To compare the performance of McDonald criteria and modified McDonald criteria for Dissemination In Space and Time for assessing the development of clinically definite Multiple Sclerosis.

Methods
McDonald criteria were modified using the combination of a less stringent definition for Dissemination In Space and allowing a new T₂ lesion per se after three months as evidence for Dissemination In Time.

Modified and McDonald criteria were applied in 90 CIS patients at baseline and at three month follow up scans.

Results
Both criteria were highly specific (>90%) but the modified criteria were more sensitive (77% v 46%) and more accurate (86% v 73%).

Conclusions
These modified criteria should be evaluated in other CIS cohorts.

HLA-G is a non-classical Major Histocompatibility Complex (MHC) Class I Antigen with highly limited tissue distribution under non-pathological conditions.

Although capable of acting as a Peptide-presenting molecule, its strong Immune-inhibitory properties identify HLA-G as a mediator of Immune Tolerance with specific relevance at Immune-privileged sites such as Trophoblast or Thymus.

To assess the role of HLA-G in CNS immunity, we investigated its expression in Brain specimens from patients with Multiple Sclerosis (n = 11), Meningitis (n = 2) and Alzheimer's Disease (n = 2) and non-pathological CNS controls (n = 6).

Furthermore, cultured human Microglial Cells and CSF of patients with Multiple Sclerosis and controls were assessed. Furthermore, CSF from MS patients and controls, as well as cultured human Microglial Cells were assessed.

Using several HLA-G specific mAb and ImmunoHistoChemistry, HLA-G protein was found strongly expressed in Brain specimens from patients with Multiple Sclerosis while it was rarely detectable in the non-pathological control specimens.

In Multiple Sclerosis Brain specimens, HLA-G ImmunoReactivity was observed in acute plaques, in chronic active plaques, in PeriLesional areas as well as in Normal-Appearing White Matter.

In all areas Microglial Cells, Macrophages, and in part Endothelial Cells were identified as the primary cellular source of expression.

HLA-G was also found in other disease entities (Meningitis, Alzheimer's specimens) where expression correlated to activation and MHC class II expression on Microglial Cells.

Importantly, ILT2, a receptor for HLA-G, was also found in Multiple Sclerosis Brain specimens thus emphasizing the relevance of this inhibitory pathway in vivo.

HLA-G mRNA and protein expression and regulation could also be corroborated on cultured human Microglial Cells in vitro.

Further, expression of HLA-G in the CSF of Multiple Sclerosis patients and controls was analysed by flow cytometry and ELISA. Monocytes represented the main source of cellular HLA-G expression in the CSF.

Corresponding to the observations with the tissue specimens, CSF mean levels of soluble HLA-G were significantly higher in Multiple Sclerosis than in non-inflammatory controls (171 +/- 31 versus 39 +/- 10 U/ml; P = 0.0001).

The demonstration of HLA-G and its receptor ILT2 on CNS cells and in areas of Microglia activation implicate HLA-G as a contributor to the fundamental mechanisms regulating Immune reactivity in the CNS.

This pathway may act as an inhibitory feedback aimed to downregulate the deleterious effects of T-Cell infiltration in NeuroInflammation.

Objective
Our objective was to assess Brain damage in first-degree relatives of patients with Sporadic and Familial Multiple Sclerosis (MS).

Methods
Asymptomatic first-degree relatives of Sporadic (sMS, n = 152) and Familial MS (fMS, n = 88) and healthy volunteers (NC, n = 56) underwent Brain MRI and Magnetization Transfer (MT) imaging on a mobile MR scan.

On MR examinations, we visually assessed White Matter (WM) lesions and quantified WM lesion volumes, Brain volumes, and MT ratio (MTR) in lesions and Normal-Appearing WM (NAWM).

Results
A lesional MR pattern similar to that of MS patients was found in 4% sMS and 10% fMS.

In these WM lesions, MTr was lower (p < 0.0001) than in the WM of NC. In contrast, there was no difference in NAWM-MTr and Brain volume values between the three groups.

Interpretation
Focal Brain abnormalities indistinguishable from those of MS occur in asymptomatic first-degree relatives of MS patients.

These are twice more frequent in fMS than in sMS but do not lead to the widespread tissue damage commonly found in MS patients.

Although there is a genetic susceptibility to develop Brain abnormalities suggestive of focal DeMyelination in first-degree relatives of MS patients, other factors are probably critical for the development of a diffuse, clinically relevant, pathology.

Ann Neurol 2006.

Major advancements have been achieved in our ability to diagnose Multiple Sclerosis (MS) and to commence treatment intervention with agents that can favorably affect the disease course.

Although MS exacerbations and the emergence of disability constitute the more conspicuous aspects of the disease process, evidence has confirmed that most of the disease occurs on a constitutive and occult basis.

Disease-modifying therapies appear to be modest in the magnitude of their treatment effects, particularly in the Progressive stage of the disease.

Therapeutic strategies currently used for MS primarily target the inflammatory cascade. Several potential mechanisms appear to be involved in the progression of MS.

Characterizing these mechanisms will result in a better understanding of the various forms of the disorder and how to effectively treat its clinical manifestations.

It is our objective within this 2-part series on progression in MS to offer both evidence-based observations and hypothesis-driven expert perspectives on what constitutes the cause of progression in MS.

We have chosen areas of inquiry that appear to have been most productive in helping us to better conceptualize the landscape of what MS looks like Pathologically, Immunologically, NeuroScientifically, RadioGraphically, and Genetically.

We have attempted to advance hypotheses focused on a deeper understanding of what contributes to the progression of this illness.

And, to illustrate new technical capabilities that are catalyzing novel research initiatives targeted at achieving a more complete understanding of progression in MS.

Despite recent advances in the diagnosis and treatment of Multiple Sclerosis, we still lack a consensus regarding the causes, pathogenesis, and mechanisms of disease progression.

Current evidence indicates that Multiple Sclerosis is an Inflammatory NeuroDegenerative Disorder in which both Adaptive and Innate Immunity play important roles in initiation and maintenance of the disease.

Recent evidence supports the notion of molecular pathologic abnormalities beyond the plaques and dysfunction of Neurons in Normal-Appearing areas, in addition to the multifocal DeMyelination and Axonal Loss.

As important features that may underlie early reversible changes in the disease. Chronic failure of ReMyelination, Axonal regeneration, and Neuronal Dysfunction may contribute to disease progression.

This article discusses the emerging molecular evidence for the progression of Multiple Sclerosis with particular focus on alterations in the local Central Nervous System MicroEnvironment of Neural and Glial Cells.

The molecular pathways leading to structural and functional NeuroDegeneration and those that prevent regeneration need to be identified in order to design new therapeutic strategies that can halt or even reverse disease progression.

Background
Interferon-ß therapy has been shown to reduce the rate of clinical relapse and the frequency of Magnetic Resonance Imaging-defined T₂- weighted lesions in patients with Multiple Sclerosis (MS).

When given early, Interferon-ß also reduces the rate of development of Brain Atrophy and improves Axonal integrity. Nerve Growth Factor (NGF) can retard the severity and course of Experimental Allergic Encephalomyelitis.

Objective
To determine whether Interferon-ß effects on patients with MS could be related to modulation of NeuroTrophin-3 production within the Central Nervous System.

Design
We studied NeuroTrophin production by human glial and Brain Endothelial Cells in response to coculture with MS patient-derived Lymphocytes, and correlated levels of NGF secretion with clinical and Magnetic Resonance Imaging-defined markers of disease.

Results
We demonstrate that production of NGF by human Brain Microvascular Endothelial Cells is triggered by interaction with T-Lymphocytes derived from MS patients.

No such response was observed using human adult Microglia or human fetal Astrocytes.

Nerve Growth Factor production by Endothelial Cells was potentiated by pretreating Lymphocytes with Interferon-ß in vitro, and by using Lymphocytes derived from MS patients treated with Interferon-ß in vivo.

By using this assay, we show that levels of NGF induced by Lymphocytes from MS patients inversely correlate with Magnetic Resonance Imaging measures of Brain Atrophy and Axonal Injury.

Conclusion
These findings suggest that Interferon-ß-mediated production of NGF at the level of the Blood-Brain Barrier, whether acting as an ImmunoModulator or directly on Neural Cells, is another potential mechanism contributing to the Magnetic Resonance Imaging-defined effect of Interferon-ß on Brain Atrophy when given early in the course of MS.

The objective of the current study was to investigate whether minocycline improves the effect of an existing Multiple Sclerosis (MS) medication, Interferon-ß, on Experimental Autoimmune Encephalomyelitis (EAE) in mice.

When used at sub-optimal doses, neither medication affected EAE but their combination at these doses led to the significant alleviation of EAE disease severity scores and histological outcomes.

In culture, the toxicity of T-Cells to Neurons was alleviated by their prior exposure to Minocycline or Interferon-ß and their combination further attenuated Neuronal death.

Collectively, these results suggest the utility of the combination of Minocycline and Interferon-ß in MS.

Background
Low-income Medicare beneficiaries without prescription benefits have high out-of-pocket medication expenses that can discourage adherence to treatment regimens.

The Medicare Prescription Drug, Improvement, and Modernization Act (MMA) of 2003 created a temporary drug discount card program and a prescription benefit with low-income provisions to assist with medication expenditures for eligible seniors.

Objective
To determine the impact of the new drug discount card and prescription benefit on medication expenditures by low-income Medicare recipients who require pharmaceutical company assistance for obtaining medications.

Design & Setting
Retrospective, nonrandomized evaluation. Family practice physicians' office in northern Virginia.

Patients
137 Medicare recipients without prescription coverage who received assistance from pharmaceutical companies for medications.

Measurements
Patients were stratified into 3 categories according to income, household size, and the Federal Poverty Line (FPL), as defined by the new Medicare act.

Participants' long-term oral and inhaled medications, dosages, and instructions for use were obtained. The MMA criteria for low-income provisions were applied for the drug discount program and for the prescription benefit.

Medication costs under the new Medicare benefits were compared with those incurred without assistance and with the use of pharmaceutical company programs for the cohort and FPL categories.

Results
In all income categories, medication costs were lower after enrollment in all programs than those of patients without assistance. Compared with pharmaceutical company assistance, Medicare drug discount cards resulted in less savings for all income groups.

For the prescription benefit, persons with incomes less than 135% of FPL had the greatest benefit because of low-income subsidies.

Persons ineligible for low-income subsidies receiving the standard benefit had a smaller reduction in out-of-pocket costs and variable monthly expenditures; they realized a superior savings with pharmaceutical company assistance programs.

Limitations
The generalizability of these findings is limited because the authors used a discount pharmacy to determine drug costs for persons receiving no assistance, could not determine asset criteria for the MMA drug benefit low-income subsidy, and used a selected Medicare population.

Conclusions
In a low-income Medicare population without prescription coverage, pharmaceutical company programs offered considerable savings and were superior to the Medicare drug discount cards.

For the Medicare prescription plan, the greatest savings was among those eligible for low-income subsidies.

Month-to-month medication costs may vary substantially for persons ineligible for such subsidies, and pharmaceutical company assistance may be a better alternative.

Objectives
The concentration in plasma of the Brain-specific Cholesterol metabolite cerebrosterol has been proposed as a biomarker of NeuroDegeneration in Multiple Sclerosis (MS) and other Neurological Diseases.

It is unknown, however, which pathophysiological process in MS best accounts for variations in plasma cerebrosterol.

Patients And Methods
In this study, we related plasma cerebrosterol concentrations in 46 MS patients - 27 with a Relapsing/Remitting (RR) disease course and 19 with a Primary/Progressive (PP) course - to three conventional Magnetic Resonance Imaging measures:

On T₁-weighted Brain scans, volume of Gadolinium-enhanced lesions (a marker of active inflammation) and hypointense lesions (a marker of edema or axonal loss) and on T₂-weighted scans, volume of hyperintense lesions (a marker of disease extent).

Results
By multiple-regression analysis, we uncovered negative correlations between the Cerebrosterol-Cholesterol ratio in plasma and both age at sampling (beta=-0.35 and p=0.079 in RRMS; beta=-0.76 and p=0.006 in PPMS) and volume of T₂-weighted lesions (beta=-0.52 and p=0.078 in RRMS; beta=-0.50 and p=0.247 in PPMS).

Conclusion
We hypothesize that decreases in plasma Cerebrosterol may reflect the total spatiotemporal burden of MS-the cumulative effects of its dissemination in space and its duration in time.

The aims of this study were to determine and compare the sensitivity of T₂ turbo spin-echo (T₂ TSE) and Fluid-Attenuated Inversion Recovery (FLAIR) sequences at 3.0 T.

In the detection of inflammatory lesions in patients with Clinically Isolated Syndromes suggestive of Multiple Sclerosis.

Forty-nine patients were examined with a 3.0 T MRI system using 5 mm axial sections of T₂ TSE (2:19 min), FLAIR (4:00 min) and pre- and postcontrast T₁ spin-echo sequences (3:37 min).

Brain lesions were counted and categorized according to their anatomic location. Patients were classified according to Barkhof MRI criteria for FLAIR and T₂ TSE sequences.

The FLAIR sequence detected more lesions in every anatomic region except for the InfraTentorial region.

The higher sensitivity was significant for the total number of lesions (p < 0.01), the JuxtaCortical (p < 0.01), and the PeriVentricular (p=0.01) region.

A 9% increase of InfraTentorial lesions using the T₂ TSE sequence was not significant.

The higher sensitivity using the FLAIR sequence resulted in one additional MRI criterion in nine patients, whereas the better detection of InfraTentorial lesions using the T₂ TSE sequence resulted in additional MRI criteria in three patients.

In conclusion, FLAIR provides the highest sensitivity when compared with the T₂ TSE, although T₂ TSE still has a diagnostic relevance in terms of MRI criteria classification.

Background
IntraVenous Steroids are routinely used to treat disabling relapses in Multiple Sclerosis, and can be administered in an outpatient or home setting.

We developed a rating scale that allowed us to compare the two strategies formally in a trial setting.

Methods
Patients who had a clinically significant Multiple-Sclerosis relapse within 4 weeks of onset were randomly assigned administration of a 3-day regimen of IntraVenous MethylPrednisolone either in an outpatient clinic (n=69) or at home (n=69).

The MS Relapse Management Scale (MSRMS) was developed to measure patients' experiences of relapse management as the primary outcome.

Efficacy of the two treatment modalities was compared in terms of traditional measures and economic cost. A cost-minimisation analysis was also done. Analysis was by intention to treat.

Findings
Of 149 eligible patients, 138 consented to participate in the trial and were randomly assigned to a treatment group.

Coordination of care was significantly better in the home-treatment group (median score 4.5 [IQR 3.0-11.4]) than in the hospital-treatment group (12.1 [3.0-18.6]; p=0.024).

The other dimensions of the MSRMS did not differ between groups (p>0.10).

Administration of Steroids was equally safe and effective in either location, and cost was either the same or cheaper when delivered at home than when delivered in hospital.

Interpretation
Treatment of relapses in Multiple Sclerosis with Intravenous Steroids can be effectively and safely administered at home, from both patient and economic perspectives.

Moreover, the trial indicates the importance of explicit and valid outcome measures of all aspects of service delivery when making decisions about health policy.

This finding has implications for complex service delivery care models for long-term diseases.

Objectives
The aim of this study was to assess the motor function of upper extremity and its relation with Fatigue, Cognitive function and quality of life in Multiple Sclerosis (MS) patients.

Design, Setting, & Subjects
Cross-sectional and controlled study. Outpatient clinic in a university hospital.

Thirty-one patients with MS (25 women, 6 men; mean age 39.74 +/- 10.10 years; mean EDSS, 2.56 +/- 1.91) and 30 healthy subjects (20 women, 10 men; mean age 33.56 +/- 8.85 years) were enrolled into the study.

Main Measures
Nine-hole peg test (9-HPT) and Valpar Component Work Sample Test (VCWS-4), Upper Extremity Index (UEI), Paced Auditory Serial Addition Test (PASAT), Fatigue Severity Scale (FSS), and the Multiple Sclerosis Quality of Life-54 (MSQOL-54).

Results
MS patients showed significant impairment in upper extremity motor functions, Cognitive function and excessive Fatigue compared to controls (p < 0.05).

9-HPT in MS group correlated with EDSS, UEI and MSQOL-54 physical health and Cognitive function, whereas VCWS-4 scores (assembly right, assembly left and disassembly) correlated only with EDSS and UEI.

No correlation was found between the VCWS-4 and Cognitive function and Fatigue in both of the groups. Compared to control group, a strong correlation existed between the 9-HPT and VCWS-4 in MS patients (p < 0.05).

Conclusion
The results indicate that disability level (EDSS), UEI and Cognitive function in MS patients are related with impairment in upper extremity motor function.

This again contributes to an impairment in physical domain of quality of life.

A strong correlation of the 9-HPT with VCWS-4 supports the use of the 9-HPT as a measure of manual dexterity and gross motor functions.