MS Abstracts 01a-2g7

Background And Purpose
Conventional imaging of ex-vivo Brain at 1.5T in Multiple Sclerosis (MS) detects only a small fraction of the Gray Matter Cerebral Cortical lesions that can be detected by pathology.

Our purpose was to examine if imaging at 8T can detect plaques in Cortical Gray Matter (CGM) not evident at 1.5T.

Methods
An ex-vivo Brain obtained at autopsy from a patient with MS was formalin fixed and 1 cm Coronal slices were examined using MR imaging at 8T.

Results
Numerous Cerebral Cortical lesions not evident at 1.5T were seen at 8T. Lesions were easily identified using gradient-echo and Spin-Echo (SE) as well as Diffusion images.

MR imaging at 8T identified many of the types of plaques previously evident only by pathology. The magnitude of the Cortical involvement in this 1 patient was severe.

Lesions in the Gray Matter readily visible by high-field MR imaging were sometimes barely visible by pathology. MR imaging at 8T often facilitated the detection of such plaques by pathology.

Conclusion
This study establishes the utility of high-field imaging at 8T in the delineation of plaques in the Cerebral CGM in MS.

Objective
To evaluate disease status after 20 years in a cohort defined as "Benign Multiple Sclerosis (MS)" (Expanded Disability Status Scale [EDSS] score < /= 3) at 10 years from onset.

Methods
Patients with an EDSS score < /= 3 at 10 (+/- 1) years from onset were selected from the British Columbia MS clinic database. The 20-year EDSS score was the primary outcome.

Potential risk factors differentiating those who "continued Benign" (EDSS score < /= 3.0) from those who were "no longer Benign" (EDSS score > 3.0) at 20 years, including age at onset, onset symptoms, and 10-year EDSS score, were analyzed, and lower 10-year EDSS score cutoffs were investigated.

Results
Twenty-year EDSS scores were obtained for 169 of 200 patients (84.5%); of these, 88 (52.1%) continued Benign, but 36 (21.3%) progressed to require the use of a cane (EDSS score >/= 6).

Conversion to Secondary/Progressive MS occurred in 45 of 196 patients (23%) with a Relapsing/Remitting onset.

The only variable associated with disease progression at 20 years was the 10-year EDSS score (p < 0.0005); no 10-year EDSS score seemed ideal in predicting Benign status, and an EDSS score < /= 2 resulted in 32% becoming no longer Benign.

Discussion
At 10 years from onset, neither an Expanded Disability Status Scale (EDSS) score < /= 3 nor an EDSS score < /= 2 adequately represented "Benign Multiple Sclerosis (MS)" because an appreciable proportion of patients progressed in disease severity.

Appropriate and reliable criteria to identify which patients with MS remain with mild disability over the long term have yet to be determined.

Objective
To identify determinants visible on Magnetic Resonance Imaging of the Brain that explain the subsequent rate of Cerebral Atrophy in patients with recently diagnosed Multiple Sclerosis.

Design
Magnetic Resonance Imaging of the Brain was performed at baseline and after 2 years.

T₂ HyperIntense Lesion Load, Black Hole lesion load, presence of contrast-enhancing lesions, and normalized Brain Volume were derived from the baseline Magnetic Resonance Imaging.

And, considered as possible explanatory variables for the subsequent annualized percentage of Brain Volume change (PBVC/y) using forward stepwise multiple linear regression analysis.

Setting
MS center Amsterdam, Department of Neurology, VU University Medical Center, Amsterdam, the Netherlands.

Patients
Eighty-nine patients recently diagnosed as having Multiple Sclerosis were included at the time of diagnosis from our outpatient clinic. Main Outcome Measure Annualized percentage of Brain Volume change.

Results
The mean (SD) annualized rate of Cerebral Atrophy was -0.9 (0.8) PBVC/y.

Baseline normalized Whole Brain Volume (standardized coefficient, 0.426; P = .001) and baseline T₂ Lesion Load (standardized coefficient, -0.244; P = .02) were identified as explanatory variables.

For, subsequent PBVC/y and yielded a regression model that explained 31.2% of the variance in PBVC/y.

Conclusions
In patients with recently diagnosed Multiple Sclerosis, the extent of accumulated Brain Tissue loss and overall lesion load partly explain the subsequent rate of Cerebral Atrophy.

Natalizumab (Tysabri) is an effective therapy for Multiple Sclerosis.

Recently, 3 patients who were treated with Natalizumab developed Progressive Multifocal Leukoencephalopathy (PML), an opportunistic infection of the Brain with the PolyomaVirus JC.

The pathogenesis of Natalizumab-associated PML may be different from that of PML not associated with the drug.

We reviewed biologically feasible interventions for patients diagnosed as having PML or other infections while receiving Natalizumab therapy.

Existing interventions include AntiViral treatment, ImmunoModulatory therapies, Hematopoietic Growth Factors, Plasma Exchange, IntraVenous ImmunoGlobulins, and Leukapheresis and AutoTransfusion of Leukocytes.

In addition, we examined the feasibility of experimental therapies, including small interfering RNA, the in vivo use of AntiSerum, and recombinant Natalizumab-blocking molecules.

There is only circumstantial evidence that any of the proposed treatments will benefit patients with Multiple Sclerosis treated with Natalizumab who may develop PML.

In addition, the expected incidence of PML in this patient population will likely be too low to test any of the proposed interventions in a controlled manner.

Because it is currently impossible to identify patients at risk, and thus to prevent PML as a consequence of Natalizumab therapy, it is important that Neurologists be aware of possible therapeutic interventions.

Objectives
To assess the presence of perfusion abnormalities in the deep Gray Matter of patients with Relapsing/Remitting and Primary/Progressive Multiple Sclerosis (MS) in comparison with healthy controls and to investigate the impact of Perfusion Impairment on clinical disability and fatigue.

Design, Patients & Setting
Survey in a research-oriented hospital, twenty-two patients with MS and 11 age- and sex-matched healthy volunteers.

Intervention Absolute Cerebral blood flow, Cerebral blood volume, and mean transit time were measured in the Thalamus, Putamen, and Caudate Nuclei.

Main Outcome Measures
Decrease of Cerebral blood flow in the deep Gray Matter of patients with MS and correlation between Perfusion impairment and the severity of Fatigue.

Results
The Cerebral blood flow value averaged over the Thalamus, Putamen, and Caudate Nuclei was significantly lower in patients with Primary/Progressive MS (P< .001) and in patients with Relapsing/Remitting MS (P = .01) compared with controls.

And, there was a trend for patients with Primary/Progressive MS to have lower average Cerebral blood flow than patients with Relapsing/Remitting MS (P = .06).

With respect to Cerebral blood volume, there was a significant difference between patients with Primary/Progressive MS and controls (P< .001) and between the 2 groups of patients (P = .03) but not between patients with Relapsing/Remitting MS and controls (P>.30).

The Fatigue Score was significantly correlated with Cerebral blood flow (r = 0.4; P< .001) and Cerebral blood volume (r = 0.5; P = .004).

Conclusion
The decrease of tissue Perfusion in the deep Gray Matter of patients with MS is associated with the severity of Fatigue.

Background And Purpose
The cross-sectional rate of Whole-Brain N-AcetylAspartate (NAA, a Neuronal cell marker) loss in clinically similar Relapsing/Remitting Multiple Sclerosis (RRMS) patients has recently been shown to fall into 3 distinct decline rate strata.

Our goal was to test the reproducibility of this observation in a new cohort of RRMS patients.

Materials And Methods
Sixteen serial patients (12 women, 4 men, median age 38 [27-55] years) with clinically definite RRMS for an average of 5 (0.3-18) years' disease duration and a mean Expanded Disability Status Score of 2.0 (0-6) were studied, once each.

Their Whole-Brain NAA (WBNAA) amounts, obtained with proton MR Spectroscopy, were divided by Brain Volumes (segmented from MR imaging) to yield concentrations suitable for cross-sectional comparisons.

Results
Three distinct strata of cross-sectional NAA decline rates were found: -0.031, -0.32, and -1.71 mmol/L/y when disease duration was estimated from confirmed diagnosis, or -0.057, -0.20, and -1.38 mmol/L/y when measured from the first clinical symptom.

These rates and their corresponding fractions of the study population were indistinguishable from those reported previously in a different group of 49 clinically similar (mean Expanded Disability Status Score also 2.0) RRMS patients.

Conclusion
Reproducing the previous cohort's cross-sectional WBNAA decline characteristics in this new group of clinically similar RRMS patients indicates that 3 WBNAA loss strata may be a general attribute of MS.

Consequently, WBNAA could serve as a surrogate marker for the global load of Neuronal and Axonal dysfunction and damage in this disease.

Background And Purpose
Many studies have reported abnormal changes in Relapsing/Remitting Multiple Sclerosis (RRMS) by Histogram and region-of-interest-based methods by using Diffusion Tensor Imaging.

However, there are few studies on specific White Matter fiber tracts of RRMS.

Our study sought to use Diffusion Tensor Tractography-based group mapping to investigate the presence of abnormal Diffusion in the Normal-Appearing Pyramidal Tract (PYT) of RRMS and its possible mechanism.

Methods
A PYT probability map was first constructed from data on 20 healthy patients based on the deterministic-based Tractography method.

The PYT probability map was then applied to 29 RRMS patients to calculate Diffusion indices of the PYT.

In this study, 4 quantitative indices were used to characterize the abnormal Diffusion:
1. Fractional Anisotropy (FA)
2. Directionally averaged Diffusion Coefficient (D(av))
3. Axial Diffusion coefficient (lambda(1))
4. Radial Diffusion Coefficient (lambda(23))

Results
Compared with healthy controls, RRMS patients had a significantly higher D(av)) and lambda(23) but a lower FA and a trend toward a lower lambda(1) in the Normal-Appearing PYT.

In RRMS patients, PYT lesions had a significantly higher lambda(23) and a lower FA, but there were no differences for D(av) and lambda(1) when compared with the Normal-Appearing PYT.

Moreover, the Diffusion indices derived from the Normal-Appearing PYT were significantly correlated with PYT lesion volumes by using the Spearman correlation analysis.

Conclusion
Our findings confirm the presence of abnormal Diffusion in the Normal-Appearing PYT of RRMS patients and suggest that Wallerian Degeneration might be its mechanism.

Our previous results revealed that Igs in lesions and single chain variable fragment Abs (scFv-Abs) generated from clonal B-Cells in the CerebroSpinal Fluid (CSF) from patients with Multiple Sclerosis (MS) bind to Axons in MS Brains.

To study the Axonal Ags involved in MS, we identified the glycolytic enzymes, Triosephosphate Isomerase (TPI) and GAPDH, using Igs from the CSF and scFv-Abs generated from clonal B-Cells in the CSF and in lesions from MS patients.

Elevated levels of CSF-Abs to TPI were observed in patients with MS (46%), Clinically Isolated Syndrome (CIS) suggestive of MS (40%), Other Inflammatory Neurological Diseases (OIND; 29%), and Other NonInflammatory Neurological Diseases (ONIND; 31%).

Levels of GAPDH-reactive Abs were elevated in MS patients (60%), in patients with CIS (10%), OIND (14%), and ONIND (8%).

The coexistence of both AutoAntiBodies was detected in 10 MS patients (29%), and 1 CIS patient (3%), but not in patients with OIND/ONIND.

Two scFv-Abs generated from the CSF and from lesions of a MS Brain showed ImmunoReactivity to TPI and GAPDH, respectively.

The findings suggest that TPI and GAPDH may be candidate Ags for an autoimmune response to Neurons and Axons in MS.

Objective
To investigate differences in disability between African American and Caucasian patients with Multiple Sclerosis (MS) by comparing the relationship between current age and disability between races.

And by assessing the effect of adjustment for SocioEconomic Status (SES) on the associations.

Methods
The authors selected US participants from the North American Research Committee on Multiple Sclerosis (NARCOMS) Registry with an age at symptom onset of 10 to 60 years, who reported their race as Caucasian or African American (n = 21,557).

They classified participants as having mild, moderate, or severe disability in the domains of Mobility, Hand function, Cognition, and Vision.

Using Patient Determined Disease Steps and Performance Scales and assessed the association of disability with race using polytomous logistic regression.

Results
Disability increased more rapidly with increasing disease duration in older patients, but there was no interaction between race and age.

African Americans had increased odds of severe vs mild disability in all four domains dds ratio OR [95% CI]:

1. Hand 1.35 [1.10 to 1.64]
2. Vision 1.75 [1.37 to 2.27]
3. Cognition 1.32 [1.04 to 1.67]
4. Mobility 1.32 [1.11 to 1.56]

Adjustment for all covariates, including SES, attenuated these associations OR [95% CI]:

1. Hand 1.27 [1.00 to 1.61]
2. Vision 1.59 [1.19 to 2.08]
3. Cognition 0.98 [0.74 to 1.30]
4. Mobility 1.37 [1.11 to 1.67]

Lack of adjustment for SES produced stronger associations. After enrollment in NARCOMS, disability progression did not differ between the groups.

Conclusions
African Americans experience greater Multiple Sclerosis-associated disability than Caucasians.

Failure to account for SocioEconomic Status leads to overestimation of these differences. Disease progression is similar in African Americans and Caucasians after diagnosis.

Introduction And Aims
The aims of this study were to determine the reliability, responsiveness and minimally important change score of the MSIS-29 physical using the EDSS as an anchor measure.

Methods
214 MS patients (EDSS 0- 8.5) had concurrent MSIS-29 and EDSS assessments at baseline and at up to four years of follow-up.

Results
Stable patients. 116 patients had unchanged EDSS scores.

Stability of the MSIS-29 physical (mean change 0.1 points) was better in the 85 patients with EDSS 0 to 5.0 than in the 31 patients with EDSS 5.5 to 8.5.

In whom the MSIS-29 physical score fell by eight points, a response shift phenomenon. A floor effect for the MSIS-29 was observed in 5% of stable patients at both time points. Changed Patients.

98 patients experienced EDSS change with moderately strong statistically significant correlations between change scores in the EDSS and the MSIS-29 physical (r = 0.523, p< 0.0001).

Effect sizes for MSIS-29 physical change were moderate to large. Using ROC curves, the MSIS-29 change score which produced a combination of optimal sensitivity and specificity was chosen for both EDSS ranges.

For EDSS range 5.5- 8, a change score of eight had a sensitivity of 87% and specificity of 67%. For EDSS 0- 5.0, a change score of seven had a sensitivity of 78% and a specificity of 51%.

Conclusions
The MSIS-29 physical performs well over time, and is suitable for use in trials; a minimal change score of eight points in the MSIS-29 is clinically significant.

Gray Matter (GM) involvement is detected even in the earliest stages of Multiple Sclerosis (MS), and GM Atrophy occurs at a faster rate than White Matter (WM) Atrophy early in the disease course.

Studies published to date establish that:
1. GM involvement and in particular Cortical DeMyelination can be extensive in MS;
2. GM pathology may occur in part independently of WM lesion formation;
3. A primarily GM-related process may be the earliest manifestation of MS;
4. GM involvement is associated with Physical Disability, Fatigue, and Cognitive Impairment in MS; and
5. GM disease might help explain the observed dissociation between markers of inflammatory DeMyelination (relapses, WM Gadolinium enhancement, WM lesion burden) and disease progression.

It remains likely that GM damage is related to WM damage.

However, continued studies of GM pathology as well as Neuronal and Axonal involvement in MS and related experimental models are necessary to better understand the etiology and pathogenesis of the degenerative components.

We compared the clinical course of 96 patients with NeuroMyelitis Optica (NMO) to Multiple Sclerosis (MS) natural history data.

Based on the distribution of follow-up data (median 6.1 year), we estimated that 21 NMO patients would convert to a Secondary/Progressive course, but we observed only two conversions (p = 0.00002; relative risk = 0.08).

The disparate natural histories of MS and NMO suggest dissociation between relapses and clinical progression in CNS DeMyelinating Diseases.