MS Abstracts 8d-2g1

Objective
To determine whether quantitative whole-Brain MR Diffusion Histograms in patients with MS differ from those of normal control subjects.

Background
MRI detects macroscopic Cerebral lesions in MS, but the White Matter lesion burden on MRI correlates imperfectly to clinical disability.

Previous reports have further suggested abnormalities in White Matter of MS patients with no visible lesions on conventional MRI.

Methods
A total of 25 subjects (13 with MS [9 Relapsing/Remitting, 4 Secondary/Progressive] and 12 healthy control subjects) underwent Diffusion-weighted Echo Planar MRI encompassing the entire Brain.

The average Apparent Diffusion Coefficient (ADCave, or Diffusion Trace) was calculated on a pixel-by-pixel basis after segmentation of IntraCranial space from Calvarium and ExtraCranial soft tissues.

Whole-Brain ADCave Histograms were calculated and plotted for statistical comparison.

Results
Mean whole-Brain MR ADCave in MS patients was elevated and Histograms were shifted to higher values compared with normal control subjects.

Mean whole-Brain ADCave of Secondary/Progressive patients was shifted to higher values compared with Relapsing/Remitting patients.

Whole-Brain ADCave Histograms of Relapsing/Remitting patients showed no significant difference from normal control subjects.

Conclusion
Whole-Brain MR Diffusion Histograms may quantitate overall Cerebral lesion load in patients with MS and may be able to discern differences between clinical subgroups.

Objective
To examine the relationship between Depression, treatment of Depression, and Interferon-gamma (IFN-) production by peripheral blood MonoNuclear Cells in patients with comorbid diagnoses of Relapsing/Remitting Multiple Sclerosis (MS) and Major Depressive Disorder.

Design & Setting
A randomized comparative outcome trial of three 16-week treatments for depression.

Assessments were conducted at baseline, week 8, and treatment cessation. An academic outpatient treatment and clinical research center.

Patients & Interventions
Fourteen patients who met the criteria for Relapsing/Remitting MS and Major Depressive Disorder. Individual Cognitive Behavioral Therapy, group PsychoTherapy, or Sertraline therapy.

Main Outcome Measures
Depression was assessed using the Beck Depression Inventory.

Interferon-gamma production by peripheral blood MonoNuclear Cells was measured following stimulation with OKT3 or recombinant human Myelin Oligodendrocyte Glycoprotein (MOG).

Variability in Immune assays was controlled using 8 NonDepressed healthy subjects who were enrolled at times corresponding with the enrollment of MS patients.

Results
Results of the Beck Depression Inventory were significantly related to IFN- production stimulated with OKT3 or MOG at baseline (P< or = .03 for all).

Level of Depression, OKT3-stimulated IFN-gamma production, and MOG-stimulated IFN- production all declined significantly over the 16-week treatment period (P< or = .03 for all).

Among controls, there were no significant changes over time in OKT3- or MOG-stimulated IFN-, or in depression (P> or = .25 for all).

Conclusions
These findings suggest that the production of the proinflammatory Cytokine IFN- by AutoAggressive T-Cells in Relapsing/Remitting MS is related to Depression and that treatment of Depression may decrease IFN- production.

Thus, treatment of Depression may provide a novel disease-modifying therapeutic strategy as well as a symptomatic treatment for patients with MS.

Induced Apoptosis of AutoReactive T-Lymphocyte precursors in the Thymus is crucial for the prevention of AutoImmune Disorders.

IGF-I and Prolactin, which are Lymphocyte Growth Factors, may have the potential to suppress Apoptosis in Thymocytes and thus encourage AutoImmunity; conversely, dietary Fish Oil rich in Omega-3 Fats appears to upregulate Apoptosis in Lymphocytes.

Since whole-food Vegan Diets may downregulate systemic IGF-I activity, it is proposed that such a diet, in conjunction with Fish Oil supplementation and treatment with Dopamine Agonists capable of suppressing Prolactin secretion, may have utility for treating and preventing AutoImmune Disorders.

This prediction is consistent with the extreme rarity of AutoImmune Disorders among Sub-Saharan black Africans as long as they followed their traditional Quasi-Vegan lifestyles.

And with recent Ecologic studies correlating risks for IDDM and for Multiple Sclerosis mortality with animal product and/or saturated fat consumption.

Moreover, there is evidence that Vegan or Quasi-Vegan Diets are useful in the management of Rheumatoid Arthritis, Multiple Sclerosis, and possibly SLE.

The Dopamine agonist Bromocryptine exerts anti-inflammatory effects in rodent models of AutoImmunity, and there is preliminary evidence that this drug may be clinically useful in several human AutoImmune Diseases.

Better tolerated D2-specific Agonists such as Cabergoline may prove to be more practical for use in therapy.

The moderate clinical utility of supplemental Fish Oil in Rheumatoid Arthritis and certain other AutoImmune Disorders is documented.

It is not unlikely that ExtraThymic AntiInflammatory effects contribute importantly to the clinical utility of Vegan Diets, Bromocryptine, and Fish Oil in AutoImmunity.

The favorable impact of low latitude or high altitude on AutoImmune risk may be mediated by superior Vitamin D status.

Which is associated with decreased secretion of ParaThyroid Hormone; there are theoretical grounds for suspecting that ParaThyroid Hormone may inhibit Apoptosis in Thymocytes.

Androgens appear to up-regulate Thymocyte Apoptosis, may be largely responsible for the relative protection from AutoImmunity enjoyed by men, and merit further evaluation for the management of AutoImmunity in women.

It will probably prove more practical to prevent AutoImmune Disorders than to reverse them once established.

A whole-food Vegan Diet, coupled with Fish Oil and Vitamin D supplemention, may represent a practical strategy for achieving this prevention.

While concurrently lowering risk for many other life-threatening 'Western' diseases.

Copyright 2001 Harcourt Publishers Ltd.

The effect of Edema on metabolic changes in contrast-enhancing Multiple Sclerosis lesions was studied by combining quantification of Proton MR Spectra with segmentation of the volume-of-interest, which was based on BiExponential T₂ relaxation.

All Lesions showed a second component (s (long)) with a longer T₂ (185-450 ms), which was increased compared to healthy controls.

Regression analysis indicated that s (long) replaces the short-T₂ water fractions component and total Creatine. Since the water content was close to 100%, s (long) was used to correct for an increase in ExtraCellular Space.

This compensated for the apparent loss of Creatine and rendered Cholines markedly increased, as observed in animals with Experimental Allergic EncephaloMyelitis.

Total N-AcetylAspartate (NAA) concentration was inversely correlated with s (long) and between 34-70% of its average reduction was assigned to Edema.

Thus, NAA loss exceeded cellular loss. Assessment of varying degrees of Edema may be especially beneficial for quantitative longitudinal studies.

Copyright 2001 Wiley-Liss, Inc.

We have screened the whole genome for linkage in 40 Italian multiplex families with Multiple Sclerosis using 322 markers.

The GENEHUNTER-PLUS program was used to analyze these data and revealed eight regions of potential linkage where the lod score exceeds the nominal 5% significance level (0.7).

No region of linkage with genome-wide significance was identified and none of the markers showed evidence of statistically significant transmission disequilibrium.

Overall these results have refined the linkage data relating to this disease in Italians modestly supporting some previously identified areas of interest and helping to exclude others.

In the present study various Peptides, synthesized according to the binding motifs for both the ImmunoDominant Epitope of Myelin Basic Protein (MBP) 85-99.

A candidate AutoAntigen in MS, and Cop-1, differentially inhibited binding of these Antigens to disease-associated HLA-DR2 (DRB1*1501) molecules.

In particular, two Peptides with residue K at position P-1, as referred to MBP 85-99, inhibited effectively the binding of both biotinylated MBP 85-99 and Cop-1 to HLA-DR2 molecules as well as IL-2 production by two MBP-specific HLA-DR2-restricted T-Cell clones.

These findings suggest the possible utility of these compounds or their more stable derivatives in treatment of MS.

Purpose
To report a patient with Multiple Sclerosis and a history of sequential bilateral RetroBulbar Neuritis, who developed new onset of highly asymmetric upper Quadrantanopsia.

Design & Method
Interventional case report. A 36-year-old woman with Multiple Sclerosis and bilateral Retrobulbar Neuritis developed an acute asymmetric upper Nasal Quadrantanopsia.

Results
Magnetic Resonance Imaging of the Brain revealed a cyst that caused Chiasmal compression and bilateral Visual Field Defects.

Conclusion
New onset of bilateral Visual Field defects in a patient with diagnosed Multiple Sclerosis is likely to be caused by a new attack of the DeMyelinating Disease.

In this case, a newly diagnosed Chiasmal colloid cyst was the cause of Visual Field Defects.

Background & Setting
Patient-administered measures are needed to assess disability cost-effectively in large Epidemiological studies. An outpatient clinic in a large Multiple Sclerosis center.

Methods
A self-administered EDSS questionnaire was developed (EDSS-S). Consecutive patients with Clinically Definite Multiple Sclerosis completed the EDSS-S (n=95).

During the same visit, a physician completed an EDSS (EDSS-P). Scores below 4.0 were determined using Functional System (FS) scores.

Scores above 4.0 were calculated by two methods, using Gait alone and using gait and Functional System scores combined.

Results
EDSS-P scores ranged from 0-9.5 (mean 5.1, median 5.0, 78% female, age 17-78, mean age 45).

Mean EDSS-P, EDSS-S and intraclass correlation coefficients of agreement were:

1. EDSS using Ambulation alone (4.6, 5.1, 0.89)
2. EDSS using Ambulation and FS scores (4.6, 5.3, 0.87)
3. Bowel/Bladder FS scores (1.6, 1.7, 0.79)
4. Pyramidal FS scores (2.1, 2.4, 0.67)
5. Sensory FS scores (1.6, 2.1, 0.60)
6. Cerebellar FS scores (1.1, 1.6, 0.55)
7. BrainStem FS scores (0.5, 1.2, 0.45)
8. Vision FS scores (1.9, 1.3, 0.38)
9. Cerebral FS scores (0.6, 2.3, 0.27).

Conclusions
Very good correlation was seen between patient and physician scores for EDSS and the Bowel/Bladder FS score.

Four other FS scores correlated moderately. In general, patients scored themselves more disabled than physicians.

This paper profiles nursing home residents with Multiple Sclerosis (MS) at the time of admission, including SocioDemographic characteristics, health status measures, and treatments received.

Admission assessments from the Minimum Data Set are used to create these profiles of residents with MS.

There are 9,013 admission assessments in the MDS for residents with MS between June 22, 1998 and January 17, 2000 analyzed for this study.

Residents with MS are distinctly younger at admission than most nursing home residents, averaging 57.98 years of age.

Recently admitted residents with MS are more physically dependent than other nursing home residents and tend to have limited range of motion and loss of voluntary movement.

About one in three newly admitted residents with MS had some degree of impaired Cognitive function. Over one third of residents with MS were Depressed at admission.

Yet, only 11.7% of recently admitted residents with MS were evaluated by a licensed mental health specialist. This prompts concem about the PsychoSocial well-being of MS residents in nursing homes.

Fourteen consecutive Clinically Definite Relapsing/Remitting Multiple Sclerosis (MS) patients were treated with monthly IntraVenous CycloPhosphomide (CTX) for 6 months.

All had experienced severe clinical deterioration during the 12 months prior to treatment with CTX despite treatment with conventional ImmunoModulating agents and IntraVenous MethylPrednisolone.

Treatment with CTX led to improvement and Neurologic stability within 6 months which was sustained for at least 18 months after the onset of treatment with CTX.

Therapy with CTX was well tolerated. CTX may be of benefit in MS patients who experience rapid clinical worsening and are resistant to conventional therapy.

The present report describes ImmunoPathological, Radiologcal and Serological characteristics of AntiBody-mediated DeMyelination in a Multiple Sclerosis (MS) case with the main findings:

1. ImmunoGlobulin and Complement deposits in areas of active DeMyelination accompanied by massive Macrophage activation

2. Ring-enhancing Lesions in T₁-weighted MRI after Gadolinium application

3. High Titers of Serum Anti-Myelin AntiBodies

4. Signs of Macrophage activation in the Serum

Plasmapheresis may be a successful treatment for the type of inflammatory DeMyelination shown in the present case.

Magnetization Transfer Ratio (MTR) Histograms have the potential to characterize subtle diffuse changes in Multiple Sclerosis (MS) and Other White Matter Disease.

A new method is described which gives improved correlation with the Expanded Disability Status Scale (EDSS). Classification of individual subjects into normal and MS subgroups is shown.

Principal Component Analysis (PCA) and Multiple Discriminant Analysis (MDA) are shown to give results superior to methods of MTR Histogram analysis using traditional features such as peak height and peak location.

Scatterplots confirm the improved separation between groups achieved using the MDA score. The Histogram analysis provides a comparison of two classification approaches, based on PCA and MDA.

To recognize differences between normal controls and the four different subgroups of MS disease (and all MS patients). Multiple linear regression of these PCs vs. EDSS established an MR-based measure of disease.

Using a central 60-mm slab of Brain tissue, the success rate of binary classification between control and MS subgroups using MDA was 75-95%, depending on which two groups were being compared.

Multiple Regression Analysis of EDSS with the first three PCs as independent variables was significant (r = 0.83 for Secondary/Progressive MS, and r = 0.80 for all MS patients).

Copyright 2001 Wiley-Liss, Inc.