MS Abstracts 02b-2g6

The purpose of this study was to determine the sensitivities in the detection of inflammatory lesions in patients with Clinically Isolated Syndromes suggestive of Multiple Sclerosis at 3.0 T and 1.5 T.

MR imaging of 40 patients at both field strengths was performed in separate sessions including contiguous axial slices of T2 turbo spin-echo (T₂ TSE), Fluid-Attenuated-Inversion-Recovery (FLAIR) and pre- and postcontrast T₁ spin-echo (T₁ SE).

Inflammatory lesions >3 mm in size were counted and categorized according to their anatomic location. Lesion conspicuity was assessed on a five-point scale.

At 3.0 T, 13% more White Matter lesions could be identified on the FLAIR sequence and on the T₂ TSE sequence. Compared to 1.5 T 7.5% more contrast-enhancing lesions were detected at 3.0 T.

The higher detection rate at 3.0 T was significant for the InfraTentorial (p=0.02) and JuxtaCortical (p< 0.01) region on the FLAIR as well as for the InfraTentorial (p=0.03), JuxtaCortical (p=0.02) and PeriVentricular (p=0.03) region on the T2 TSE sequence.

The lesion conspicuity was significantly better at 3.0 T for FLAIR and T2 TSE sequences (p< 0.01; p=0.01).

In conclusion, high-field MRI at 3.0 T provides a significantly higher detection rate of inflammatory Brain lesions especially in the InfraTentorial, JuxtaCortical and PeriVentricular anatomic region.

Objective
To evaluate the relation between T₂ lesions and disease severity in Relapsing/Remitting Multiple Sclerosis (MS).

Methods
This article describes a 13-year longitudinal study in 30 patients.

Results
Patients were 36.3 +/- 6.0 years old, had MS for 6.1 +/- 5.8 years, Expanded Disability Status Scale was 2.2 +/- 0.8, and Brain Parenchymal Fraction (BPF) was 0.825 +/- 0.015 at study entry.

At last visit, Expanded Disability Status Scale was 4.4 +/- 1.95, Multiple Sclerosis Functional Composite was -0.34 +/- 1.7, and BPF was 0.774 +/- 0.037.

Baseline T₂ lesion volume correlated with the BPF of the last visit (r = -0.66; p < 0.0001), Magnetization Transfer Ratio (MTR) in Normal-Appearing Brain Tissue (r = -0.52; p = 0.004), and lesion MTR (r = -0.76; p < 0.0001).

Change in T₂ lesion volume in the first 2 years correlated with BPF of the last visit (r = -0.40; p = 0.03), Normal-Appearing Brain Tissue MTR (r = -0.44; p = 0.015), lesion MTR (r = -0.46; p = 0.018), Multiple Sclerosis Functional Composite scores (r = -0.50; p = 0.005), and Paced Auditory Serial Addition Task scores (r = -0.52; p = 0.003).

Age was a significant covariate for clinical but not Magnetic Resonance Imaging outcomes.

Interpretation
T₂ lesions in Relapsing/Remitting MS correlate strongly with Brain tissue loss and Brain Tissue integrity 13 years later, and with clinical disease severity, though age significantly impacts the clinical correlation.

The results provide direct evidence for the disability threshold hypothesis in MS and support monitoring T₂ lesions in Relapsing/Remitting MS.

Brain Atrophy measured by MRI is an important correlate with clinical disability and disease duration in Multiple Sclerosis (MS). Unfortunately, Neuropathologic mechanisms which lead to this Gray Matter Atrophy remain unknown.

The objective of this study was to determine whether Brain Atrophy occurs in the mouse model, Experimental Autoimmune Encephalomyelitis (EAE).

Postmortem high-resolution T₂-weighted Magnetic Resonance Microscopy (MRM) images from 32 mouse Brains (21 EAE and 11 control) were collected.

A minimum deformation atlas was constructed and a deformable atlas approach was used to quantify volumetric changes in NeuroAnatomical structures.

A significant decrease in the mean Cerebellar Cortex volume in mice with late EAE (48-56 days after disease induction) as compared to normal strain, gender, and age-matched controls was observed.

There was a direct correlation between Cerebellar Cortical Atrophy and disease duration. At an early time point in disease, 15 days after disease induction, Cerebellar White Matter lesions were detected by both histology and MRM.

These data demonstrate that Myelin-specific Autoimmune responses can lead to Gray Matter Atrophy in an otherwise normal CNS.

The model described herein can now be used to investigate Neuropathologic mechanisms that lead to the development of Gray Matter Atrophy in this setting.

The Diffusion properties of water are sensitive to microscopic changes in the White Matter of Multiple Sclerosis (MS) patients. Typical MRI measures of disease burden in MS demonstrate modest to poor correlation with disability.

Functional MRI and DTI-based fiber tracking were used to define the InterHemispheric White Matter pathway connecting bilateral Supplementary Motor Areas (SMA) in 16 MS patients sand 16 control subjects.

Fractional Anisotropy (FA), Mean Diffusivity (MD), longitudinal (lambda(1)) and transverse Diffusivity (lambda(2)) were measured along this pathway in all subjects.

Mean FA was 0.587 +/- 0.032 for patients and 0.608 +/- 0.020 for controls (P < 0.02). Mean MD was (0.821 +/- 0.055) x 10(-3) mm(2) s(-1) for patients and (0.770 +/- 0.020) x 10(-3) mm(2) s(-1) for controls (P < 0.004).

Mean lambda(1) values were (1.462 +/- 0.099) x 10(-3) mm(2) s(-1) for patients and (1.400 +/- 0.034) x 10(-3) mm(2) s(-1) for controls (P < 0.02).

Mean lambda(2) values were (0.500 +/- 0.047) x 10(-3) mm(2) s(-1) for patients and (0.454 +/- 0.027) x 10(-3) mm(2) s(-1) for controls (P < 0.001).

In addition, the correlation between the Multiple Sclerosis Functional Composite (MSFC) and transverse Diffusivity was -0.341 (P < 0.05).

The component test of the MSFC most related to the SMA pathway studied with our MRI method (Nine-hole Peg Test) showed significant correlation with transverse Diffusivity (r = 0.392, P < 0.02), indicating that probing functional pathways with MRI measures can lead to a better reflection of disease status.

Patients with Neurogenic Detrusor overactivity are a heterogeneous group with Voiding Dysfunction secondary to Neurologic injury or disease.

The Neurogenic Detrusor Overactivity Syndrome, which may include Urinary Frequency, Urgency, and Incontinence, frequently contributes to a loss of independence, or even institutionalization.

Urodynamic assessment provides the best method of quantifying and classifying Neurogenic Detrusor overactivity dysfunction in patients with primary diagnoses as diverse as Parkinson's Disease, Cerebral Palsy, Multiple Sclerosis, Spinal Cord Injury, and Spina Bifida.

For many patients, management of urinary symptoms includes pharmacotherapy with an AntiCholinergic agent.

Several novel approaches to managing Neurogenic Detrusor overactivity, including intravesical instillation of AntiCholinergic agents, Incontinent IleoVesicoStomy Vanilloids, and NeuroToxins, are being investigated.

For most patients, however, flexible dosing with an AntiCholinergic agent, with clean intermittent catheterization when indicated, has been shown to reduce the risks of Urologic complications, improve levels of continence, and enhance patient quality of life in both children and adults

Background And Purpose
Evaluation of the Spinal Cord is important in the diagnosis and follow-up of patients with Multiple Sclerosis.

Our purpose was to investigate Diffusion Tensor Imaging (DTI) changes in different regions of Normal-Appearing Spinal Cord (NASC) in Relapsing/Remitting Multiple Sclerosis (RRMS).

Methods
Axial DTI of the Cervical Spinal Cord was performed in 24 patients with RRMS and 24 age- and sex-matched control subjects.

Fractional Anisotropy (FA) and Mean Diffusivity (MD) were calculated in separate Regions Of Interest (ROIs) in the Anterior, Lateral, and Posterior Spinal Cord, bilaterally, and the Central Spinal Cord, at the C2-C3 level.

Patients and control subjects were compared with respect to FA and MD with the use of an exact Mann-Whitney test. Logistic regression and receiver operating characteristic (ROC) curve analysis assessed the utility of each measure for the diagnosis of RRMS.

Results
DTI metrics in areas of NASC in MS were significantly different in patients compared with control subjects:

FA was lower in the Lateral (mean +/- SD of 0.56 +/- 0.10 versus 0.69 +/- 0.09 in control subjects, P < .0001), Posterior (0.52 +/- 0.11 versus 0.63 +/- 0.10, P < .0001), and Central (0.53 +/- 0.10 versus 0.58 +/- 0.10, P = .049) NASC ROIs.

Assessing DTI metrics in the diagnosis of MS, a sensitivity of 87.0% (95% confidence interval [CI], 66.4 to 97.1) and a specificity of 91.7% (95% CI, 73.0 to 98.7) were demonstrated.

Conclusion
The NASC in RRMS demonstrates DTI changes. This may prove useful in detecting occult Spinal Cord pathology, predicting clinical course, and monitoring disease progression and therapeutic effect in MS.

Saltatory Conduction in Myelinated fibers depends on the specific molecular organization of highly specialized Axonal domains at the Nodes of Ranvier, the ParaNodal and the JuxtaParaNodal regions.

Voltage-gated Sodium Channels (Nav) have been shown to be deployed along the naked DemMyelinated Axon in experimental models of CNS DeMyelination and in Multiple Sclerosis lesions.

Little is known about aggregation of Nodal, ParaNodal and JuxtaParaNodal constituents during the repair process.

We analyzed by ImmunoHistoChemistry on free-floating sections from Multiple Sclerosis Brains the expression and distribution of Nodal (Nav channels), ParaNodal (ParaNodin/Caspr) and JuxtaParaNodal (Kv channels and Caspr2) molecules in DeMyelinated and ReMyelinated lesions.

Whereas in DeMyelinated lesions, ParaNodal and JuxtaParaNodal proteins are diffusely distributed on denuded Axons, the distribution of Nav channels is heterogeneous, with a diffuse ImmunoReactivity but also few broad Nav channel aggregates in all DeMyelinated lesions.

In contrast to the DeMyelinated plaques, all ReMyelinated lesions are characterized by the detection of aggregates of Nav channels, ParaNodin/Caspr, Kv channels and Caspr2.

Our data suggest that these aggregates precede ReMyelination, and that Nav channel aggregation is the initial event, followed by aggregation of ParaNodal and then JuxtaParaNodal Axonal proteins.

ReMyelination takes place in Multiple Sclerosis tissue but Myelin repair is often incomplete, and the reasons for this ReMyelination deficit are many.

We suggest that a defect of Nav channel aggregation might be involved in the ReMyelination failure in DeMyelinated lesions with spared Axons and Oligodendroglial Cells.

Given the heterogeneous nature of Multiple Sclerosis (MS), we applied DNA microarray technology to determine whether variability is reflected in Peripheral Blood (PB) Cells.

In this study, we studied whole-blood gene expression profiles of 29 patients with Relapsing/Remitting MS (RRMS) and 25 age- and sex-matched healthy controls. We used microarrays with a complexity of 43K cDNAs.

The data were analyzed using sophisticated pathway-level analysis in order to provide insight into the deregulated peripheral Immune Response programs in MS.

We found a remarkable elevated expression of a spectrum of genes known to be involved in Immune defense in the PB of MS patients compared to healthy individuals.

Cluster analysis revealed that the increased expression of these genes was characteristic for approximately half of the patients.

In addition, the gene signature in this group of patients was comparable with a Virus response program.

We conclude that the transcriptional signature of the PB Cells reflects the heterogeneity of MS.

And defines a sub-population of RRMS patients, who exhibit an activated Immune defense program that resembles a Virus response program, which is supportive for a link between Viruses and MS.

Genes and Immunity 13 July 2006; doi:10.1038/sj.gene.6364324.

Objective
To evaluate the literature about the role of Vitamin D in the prevention and treatment of Multiple Sclerosis (MS).

Data Sources
MEDLINE (1966-April 2006) and International Pharmaceutical Abstracts (1970-April 2006) searches were performed. In addition, pertinent references from identified articles were obtained.

Data Synthesis
Vitamin D supplementation prevented the development and progression of Experimental Autoimmune Encephalitis, an animal model of MS, in mice.

A large, prospective, cohort study found that Vitamin D supplementation was associated with a 40% reduction in the risk of developing MS.

Four small, noncontrolled studies suggested that Vitamin D supplementation may decrease exacerbation of MS symptoms.

Conclusions
Vitamin D supplementation may help prevent the development of MS and may be a useful addition to therapy.

However, current studies are in small populations and are confounded by other variables, such as additional Vitamin and Mineral supplementation.

Objective
The onset of Multiple Sclerosis (MS) is Relapsing/Remitting (RR) or Primary/Progressive (PP).

An improved understanding of the causes of early progressive disability (PPMS) could provide mechanistic targets for therapeutic intervention.

Methods
Five MRI parameters were investigated that could potentially cause progressive disability in 43 patients with early PPMS and 37 with early RRMS:

Atrophy in Brain Gray Matter and White Matter; intrinsic abnormality in Brain Gray Matter and White Matter (measured by the Magnetization Transfer Ratio [MTR]}; and Atrophy of the Upper Cervical Spinal Cord. Both groups were also compared with healthy controls.

Results
PPMS patients were older and more likely to be male. Both patient groups had Atrophy of Brain Gray Matter and White Matterr and intrinsic abnormality of Normal-Appearing Gray Matter and White Matter MTR.

Cord Atrophy was present only in the PPMS (mean Cord area:
1. PPMS=67.8mm2
2. RRMS=72.7mm2
3. controls 73.4mm2, p=0.007)

This was confirmed by multivariate analysis of all 5 MRI parameters plus age and gender.

Conclusion
Brain Gray Matter and White Matter is abnormal in both early RR and PPMS, but Cord Atrophy is present only in PPMS.

This is concordant with Myelopathy being the usual clinical presentation of PPMS. Measurement of Cord Atrophy appears clinically relevant in PPMS treatment trials.

The Intrathecal synthesis of IgM, determined at clinical onset in patients with Multiple Sclerosis, was found to correlate with the degree of disability (as evaluated by means of the Expanded Disability Status Scale) reached 15 years later (p < 0.001).

Moreover, a significant inverse correlation was observed between the value of the IgM index and time to the first relapse (p < 0.001) and the initiation of the Progressive phase of the disease (p = 0.01).

The prognostic value of IgM in the CSF is confirmed in previous reports as well as by our study.

If these findings are confirmed in patients with Multiple Sclerosis in a larger series, a helpful biological marker for selecting patients for ImmunoModulatory treatments will be available to Neurologists.

To address the Immune mechanism of the long-term beneficial effects of Interferon-beta (IFN-ß), we measured the IntraCellular Cytokine production patterns of IFN-γ, IL-4 and IL-13 in peripheral blood CD4⁺ and CD8⁺ T-Cells.

Which, previously displayed alterations during the early course of IFN-ß treatment, in 15 Japanese patients after long-term IFN-ß administration.

The patients were treated with IFN-ß-1b 8 x 10(6) units given subcutaneously every other day for a mean period of 34.5 +/- 5.5 months (range: 26-43 months).

During the follow-up period, 6 patients experienced 33 relapses, while the other 9 were relapse-free.

The results revealed the following Cytokine alterations:

(1) type 2 Cytokine, such as IL-4 and IL-13, were significantly increased in producing cell percentages in both CD4⁺ (p = 0.0356 and p = 0.0007, respectively) and CD8⁺ (p = 0.0231 and p = 0.0170, respectively). T-Cells

While IFN-γ, a representative type 1 Cytokine, was significantly decreased in the absolute producing cell numbers (p = 0.0125 in CD4⁺ T-Cells and p = 0.0022 in CD8⁺ T-Cells).

Even after approximately 3 years of IFN-ß administration;

(2) the IntraCellular IFN-γ / IL-4 ratio tended to decrease in both CD4⁺ and CD8⁺ T-Cells (p = 0.0535 and p = 0.0783, respectively), reflecting a strong downmodulation of type 1 Cytokine producing cells.

And importantly, (3) alterations such as the decreased IntraCellular IFN-γ / IL-4 ratio in CD4⁺ T-Cells and increased percentage of CD8⁺ IL-13+ T-Cells compared with the pretreatment levels were only statistically significant in MS patients without relapse during IFN-ß therapy (p = 0.0152 and p = 0.0078, respectively).

Therefore, we consider that Cytokine deviation toward the Th2 and Tc2 sides is linked to a long-term favorable response to IFN-ß.

While a higher IntraCellular IFN-γ / IL-4 ratio is associated with treatment failure.