MS Abstracts 01d-2g7

To analyze the in vivo biological effect of Anti-Interferon beta (IFN-ß) Neutralizing AntiBodies (NABs), blood concentrations of Neopterin, beta2MicroGlobulin (ß2-MG), mRNA-dependent MyxoVirus-resistant Protein A (MxA) and dsRNA-dependent Protein Kinase (PKR) were measured.

Before (pre-dose) and 24 hours after (post-dose) IFN-ß administration in 49 patients with Multiple Sclerosis (MS) with (n = 25) and without (n = 24) NABs.

The results indicated that pre-dose levels of MxA-mRNA and PKR-mRNA were highly variable [coefficient of variation (CV) > 100%] among patients.

A lower inter-individual variability was observed for pre-dose levels of #223;2-MG and Neopterin (CVs of 29% and 44%, respectively).

Significantly lower pre- and post-dose blood levels of IFN-ß induced markers, except for post-dose PKR-mRNA (p = 0.09), were seen in NAB⁺ compared with NAB^- patients and between patients with high (> 200 t(1/10)) and low (< /= 200 t(1/10)) NAB titers.

A significant inverse correlation between NAB titer and pre-dose levels of the above IFN-ß-induced markers was found.

In summary, our findings confirm that NABs affect absolute concentrations of IFN-ß induced markers and suggest that such an effect occurs in a Titer-dependent manner.

Purpose Of Review
The aim of this review is to summarize the current literature on the NeuroPsychiatry of Multiple Sclerosis (MS).

Recent Findings
Data from community samples have supported earlier findings from tertiary referral centres of high rates of Depression in MS patients.

NeuroImaging offers important clues as to the pathogenesis of Depression, but PsychoSocial factors cannot be ignored and emerge as equally important predictors.

Cognitive-behavioural therapy is an effective treatment, rivalling standard dosing of Sertraline in patients with Depression.

An allied disorder - Pseudobulbar Affect - occurs in up to 10% of MS patients and responds well to a combination of Dextromethorphan and Quinidine.

Cognitive Dysfunction affects approximately 40% of MS patients. Markers of Cerebral Atrophy have emerged as more important correlates of impaired Cognition than lesion volume.

Moreover, functional MRI studies have demonstrated the Brain's ability to compensate, in part, for damage.

Should the disease burden be too severe, however, compensatory mechanisms fail and Cognitive deficits increase accordingly.

Summary
NeuroPsychiatric abnormalities are common in MS patients. No aspect of mentation is spared. Advances in NeuroImaging are increasing our understanding of the pathogenesis of these disorders.

Translating these findings into improved methods of treatment for patients presents researchers with pressing challenges.

Sixty-two patients with Multiple Sclerosis (MS) were imaged monthly over a six-month (ie, seven monthly Magnetic Resonance Images [MRI]) Natural History Period (NHP).

Thereafter, patients were randomized to receive 11 or 33 mug of subcutaneously injected Interferon-beta-1a (IFN-ß-1a) with imaging monthly for nine months and at months 12, 18 and 24 of Therapy Phase (TP).

In the present exploratory post hoc analysis, the authors evaluated IFN-ß-1a dose effect on reducing the size of Contrast-Enhancing Lesions (CELs). MRIs performed at months 0, 3 and 6 of NHP and at months 3, 6, 9, 18 and 24 of TP were analyzed.

While a significant reduction in mean number of CELs was observed in both treatment groups of patients, the mean total volume and size of CELs was reduced only in patients undergoing therapy with 33 mug of IFN-ß-1a.

The latter suggests a significant dose effect exerted by IFN-ß-1a in the evolution of CELs' dimensions during therapy.

Purpose
Balance rehabilitation is an important component of the retraining program in people with Multiple Sclerosis (MS).

Measuring balance is fundamental for an accurate assessment and therapy selection.

The aim of this study was to compare interrater and test-retest reliability of the Berg Balance Scale, the Dynamic Gait Index, the Dizziness Handicap Inventory and the Activities-specific Balance Confidence.

Method
A group of 25 persons were enrolled in the study. The group consisted of 8 males and 17 females, mean age 41.7 years (12.5 years, SD).

The onset of pathology was 8.7 years (8.8 years SD) before the beginning of the study.

To assess the test-retest reliability two consecutive assessments were collected by the same rater. To assess the inter-rater reliability persons were concurrently assessed by two raters.

Results
The Intraclass Correlation Coefficients (ICCs) for interrater reliability ranged between 0.94 and 0.96. The ICCs for test-retest reliability ranged between 0.85 and 0.96.

Conclusion
The inter-rater reliability of the instruments proved to be satisfactory. Lower but acceptable results were obtained for the test-retest paradigm.

The data obtained in this study suggest that these scales are reliable tools for assessing balance function in persons suffering from MS.

Multiple Sclerosis is the most common potential cause of Neurological disability in young adults.

The disease has two distinct clinical phases, each reflecting a dominant role for separate pathological processes: inflammation drives activity during the Relapsing/Remitting stage.

And, Axon Degeneration represents the principal substrate of progressive disability.

Recent advances in disease-modifying treatments target only the inflammatory process. They are ineffective in the Progressive stage, leaving the science of disease progression unsolved.

Here, the requirement is for strategies that promote ReMyelination and prevent Axonal Loss.

Pathological and experimental studies suggest that these processes are tightly linked, and that ReMyelination or Myelin repair will both restore structure and protect Axons.

This review considers the basic and clinical biology of ReMyelination and the potential contribution of Stem and Precursor Cells to enhance and supplement spontaneous ReMyelination.

Objective
To examine the effects of Natalizumab on Low-Contrast Letter Acuity as a prespecified tertiary endpoint in two randomized clinical trials.

And, to evaluate the usefulness of Low-Contrast Letter Acuity Testing as a candidate test of visual function in Multiple Sclerosis (MS).

Methods
AFFIRM and SENTINEL were randomized, double-blind, placebo-controlled, multicenter, phase 3 clinical trials of Natalizumab in Relapsing MS.

Natalizumab was evaluated as monotherapy in AFFIRM and as add-on to Interferon-ß-1a in SENTINEL.

Vision testing was performed at 100% contrast (visual acuity) and low-contrast (2.5% and 1.25%).

Results
The risk of clinically significant Visual Loss (predefined as a two-line worsening of Acuity sustained over 12 weeks) at the lowest contrast level (1.25%) was reduced in the Natalizumab treatment arms by 35%,

In AFFIRM (hazard ratio = 0.65; 95% CI: 0.47 to 0.90; p = 0.008) and by 28% in SENTINEL (hazard ratio = 0.72; 95% CI: 0.54 to 0.98; p = 0.038, Cox proportional hazards models).

Mean changes in vision scores from baseline were also significantly different, reflecting worsening in non-Natalizumab groups.

Conclusions
Natalizumab reduces Visual Loss in patients with Relapsing Multiple Sclerosis.

Low-contrast acuity testing has the capacity to demonstrate treatment effects and is a strong candidate for assessment of Visual outcomes in future Multiple Sclerosis trials.

Common disability scales in Multiple Sclerosis (MS) are often weighted towards physical disability. Non-motor symptoms such as Depression, Fatigue and Pain substantially influence wellbeing in MS.

Health-Related Quality of Life (HRQoL) measures the broader impact of MS and might indicate less obvious disease burdens.

We analyzed HRQoL, using the Nottingham Health Profile Part I (NHP-I), among 345 Secondary/Progressive MS (SPMS) patients participating in a randomized trial of Interferon-beta-1a (IFN-ß-1a), 22 mug subcutaneously weekly, or matching placebo.

The results did not reveal any beneficial effect of IFN-ß-1a in any outcome measure.

NHP-I sub- and sum scores were compared for 217 population controls and correlated with demographic and clinical disease variables.

SPMS patients had lower NHP-I sum and all subscores than the controls. Patients experiencing disease progression reported worse NHP-I sum scores.

Increased Fatigue, Expanded Disability Status Scale (EDSS) and Arm Index scores were independently associated with reduction in several NHP-I subscores.

SPMS patients had significantly lower HRQoL than controls and physical disability (EDSS and Arm Index), disease progression and Fatigue strongly influenced this. MS.

Proposed Interferon-beta (IFN-ß) treatment failure criteria for patients with Relapsing/Remitting Multiple Sclerosis (RRMS) have not been validated in clinical practice.

This study aimed to establish whether:
1. IFN-ß attenuated accumulation of fixed disability in comparison to a cohort of matched historical control subjects from the Sylvia Lawry Center for MS research, and
2. Relapse-based treatment failure criteria or clinical and demographic variables had predictive value for the accumulation of fixed disability

Of the 175 IFN-ß-treated RRMS patients, 60 (34%) developed accumulation of fixed disability over a median of five years follow-up, which was significantly less than the rate of accumulation of fixed Disability in the control group (P< 0.0001).

Any relapse in the treatment period predicted accumulation of fixed disability with a sensitivity of 80% and specificity of 43%; patients totally relapse free were less likely to develop accumulation of fixed disability (P < 0.002).

Multivariate analysis confirmed that a greater risk of accumulation of fixed disability was conferred by a higher Expanded Disability Status Scale (EDSS) score starting IFN-ß (P=0.02), and by failure of IFN-beta to completely suppress relapses (P=0.004).

In conclusion, IFN-ß therapy reduced the accumulation of fixed disability in a cohort of RRMS patients, followed for a median of five years.

Higher baseline EDSS and failure of complete relapse suppression were associated with a significantly greater likelihood of accumulation of fixed Disability.

There is increasing appreciation that Multiple Sclerosis (MS) can begin in childhood or adolescence.

But pediatric MS continues to be a rare entity, with an estimated 2 to 5% of patients with MS experiencing their first clinical symptoms before age 16.

A prompt diagnosis of pediatric MS is important to optimize overall management of both the physical and social impact of the disease.

The widespread use of disease-modifying therapies (DMTs) for MS in adults, as early as following an initial isolated episode, has led to the use of DMTs in children and adolescents with MS.

However, it is imperative to distinguish pediatric MS from other childhood CNS Inflammatory DeMyelinating Disorders such as Acute Disseminated EncephaloMyelitis.

Although increasing evidence suggests a slower disease course in children with MS compared to adults, significant disability can still accumulate by early adulthood.

Furthermore, associated NeuroCognitive deficits can impair both academic and PsychoSocial function at a critical juncture in a young person's life.

This article reviews the clinical characteristics, NeuroImaging, ParaClinical findings, disease course, Epidemiology, Genetics, and PathoPhysiology of pediatric MS vis-a-vis adult MS.

Further research of pediatric MS may advance our understanding of MS PathoPhysiology in general, as well as improve the long-term health care outcomes of children and adolescents diagnosed with MS.

Background And Purpose
HypoPerfusion of the Normal-Appearing White Matter in Multiple Sclerosis (MS) may be related to Ischemia or secondary to HypoMetabolism from Wallerian Degeneration (WD).

This study evaluated whether correlating Perfusion and Diffusion Tensor Imaging (DTI) metrics in Normal-Appearing Corpus Callosum could provide support for an Ischemic mechanism for HypoPerfusion.

Materials And Methods
Fourteen patients with Relapsing/Remitting MS (RRMS) and 17 control subjects underwent Perfusion MR imaging and DTI.

Absolute measures of Cerebral Blood Volume (CBV), Cerebral Blood Flow (CBF), and Mean Transit Time (MTT) were calculated.

Mean Diffusivity (MD) and Fractional Anisotropy (FA) maps were computed from DTI data.

After visual coregistration of Perfusion and DTI images, regions of interest were placed in the Genu, Central Body, and Splenium of Normal-Appearing Corpus Callosum.

Pearson product-moment correlation coefficients were calculated using mean DTI and Perfusion measures in each region.

Results
In the RRMS group, CBF and CBV were significantly correlated with MD in the Splenium (r = 0.83 and r = 0.63, respectively; both P < .001) and in the Central Body (r = 0.86 and r = 0.65, respectively.

Both P < .001), but not in the Genu (r = 0.23 and 0.25, respectively; both P is nonsignificant).

No significant correlations were found between MTT and DTI measures or between FA and any Perfusion measure in the RRMS group.

No significant correlations between Diffusion and Perfusion metrics were found in control subjects.

Conclusion
In the Normal-Appearing Corpus Callosum of patients with RRMS, decreasing perfusion is correlated with decreasing MD.

These findings are more consistent with what would be expected in primary Ischemia than in secondary HypoPerfusion from WD.

We analyzed HLA haplotypes in pairs of 78 sporadic Multiple Sclerosis (MS) patients and 78 healthy siblings.

The presence of 2 OligoClonal IgG Bands, detected by Immunoblotting of the CerebroSpinal Fluid in healthy siblings, has previously been defined as MS Immunopathic Trait (MSIT).

Based on a cut-off derived from healthy unrelated volunteers. The frequency of MSIT was 17.9% (n=14/78 siblings).

The HLA-DR(15)2 allelle was present in:
1. 21.4% (n=3/14) of the siblings with MSIT
2. 40.6% (n =26/64) of the siblings without MSIT
3. 59% (n =46/78) of the patients with clinically-definite (CD) MS

The distribution of zero, one or two HLA-DR(2)15 alleles was significantly skewed towards a lower allelle count in the siblings with MSIT.

Compared with the group of unrelated siblings with MS (P=0.002), and also lower than their related siblings with MS (P=0.1).

These results suggest that the MS susceptibility gene, HLA-DR(2)15 type, does not induce MSIT, and conceivably these are two separate risk factors in the development of MS.

The effect of HLA-DR(2)15 and MSIT in sporadic MS appears to be synergistic.

Background
Brain Atrophy, as assessed by Magnetic Resonance Imaging (MRI), has been correlated with disability in patients with Multiple Sclerosis (MS).

Recent evidence indicates that both White Matter (WM) and Gray Matter (GM) are subject to Atrophy in patients with MS.

Although Neurological deficiencies in MS are primarily due to loss of WM, the clinical significance of GM Atrophy has not been fully explored in MS.

Methods
We have undertaken a three-year, open-label study, comparing 26 patients who elected to receive intramuscular Interferon-beta-1a (IFN-ß ) therapy, with 28 patients who elected not to receive therapy.

Both groups had quantitative Cranial MRI scans at study entry and after three years, and standardized clinical assessments every six months.

Brain Parenchymal Fraction (BPF), GM Fraction (GMF), and WM Fraction (WMF) percent changes were calculated, and T₂- and T₁-lesion volumes (LVs) assessed.

Results
After three years, mean percent (%) change in BPF favored the IFN-ß-1a treatment group (IFN-ß -1.3% versus the control group -2.5%, P=0.009).

As did the mean percent change in GMF (+0.2 versus -1.4%, P=0.014), and the mean percent change in T₁-LV (-9.3 versus +91.6%, P=0.011).

At the end of the study, there was a significant within-patient decrease in BPF for both groups (P=0.02 for the IFN-ß-1a treatment group, and P < 0.001 for the control group).

A significant within-patient decrease in WMF for the IFN-ß-1a treatment group (P=0.01), and a significant decrease in GMF for the control group (P=0.013) when compared with baseline.

Conclusion
Over a three-year period, treatment with IFN-ß significantly slowed the progression of Whole-Brain and GM Atrophy, and of T₁-HypoIntense LV accumulation, when compared with the control group.