MS Abstracts 8e-2g1

MonoNuclear Phagocytes (Monocytes, Macrophages, and Microglia) are considered central to Multiple Sclerosis (MS) pathogenesis.

Molecular cues that mediate MonoNuclear Phagocyte accumulation and activation in the Central Nervous System (CNS) of MS patients may include Chemokines RANTES/CCL5 and Macrophage inflammatory protein-1/CCL3.

We analyzed expression of CCR1 and CCR5, the Monocyte receptors for these Chemokines, on circulating and CerebroSpinal Fluid CD14⁺ Cells, and in MS Brain lesions.

Approximately 70% of CerebroSpinal Fluid Monocytes were CCR1⁺/CCR5⁺, regardless of the presence of CNS pathology, compared to less than 20% of circulating Monocytes.

In active MS lesions CCR1⁺/CCR5⁺ Monocytes were found in PeriVascular Cell Cuffs and at the DeMyelinating edges of evolving lesions.

MonoNuclear Phagocytes in early DeMyelinating stages comprised CCR1⁺/CCR5⁺ hematogenous Monocytes and CCR1^-/CCR5^- resident Microglial cells.

In later stages, Phagocytic Macrophages were uniformly CCR1^-/CCR5⁺. Cultured in vitro, adherent Monocytes/Macrophages up-regulated CCR5 and down-regulated CCR1 expression, compared to freshly-isolated Monocytes.

Taken together, these findings suggest that Monocytes competent to enter the CNS compartment derive from a minority CCR1⁺/CCR5⁺ population in the circulating pool.

In the presence of Ligand, these cells will be retained in the CNS. During further activation in lesions, infiltrating Monocytes down-regulate CCR1 but not CCR5, whereas Microglia up-regulate CCR5.

Aim
This study sought to obtain an estimate of the prevalence of Multiple Sclerosis (MS) in the Australian Capital Territory (ACT).

A largely urban region that differs climatically and SocioEconomically from other Australian cities examined in previous MS surveys.

Methods
Prevalence day was chosen to coincide with the 1996 National Census.

All ACT Neurologists' records for the previous 5 years were examined and cases of MS were classified according to the published diagnostic criteria of Rose et al. and Poser et al.

Results
By the criteria of Rose et al., as used in previous Australian surveys of MS, prevalence was 79.9/100,000 (95% confidence interval (CI) = 63.4-99.2) for females, 32.8 (22.7-46.2) for males and 56.7 (43.1-74.1) for all people, standardized to the 1996 population.

Standardized to the 1981 population for direct comparison with 1981 surveys in New South Wales, the prevalence of MS in the ACT was still unexpectedly high, particularly for females.

Using the criteria of Poser et al., the prevalence of MS standardized to the 1996 population was 70.6/ 100,000 (95% CI = 58.4-85.3) for females, 28.0 (20.3-37.8) for males and 49.5 (42.2-58.2) for all people.

There was evidence from a relatively short duration of disease in the ACT sample that some persons with long-standing MS had been missed in the survey and therefore that the prevalence of MS observed in the ACT was an underestimate.

Conclusions
The survey found an unexpectedly high prevalence of MS in the ACT. Possible reasons for this are discussed.

There was no evidence that the advent of Magnetic Resonance Imaging had increased the numbers of persons diagnosed with MS in the present survey.

A total of 13 patients, who were diagnosed with localized BrainStem lesions using MRI, were investigated.

The diagnoses were Multiple Sclerosis in five patients, BrainStem hemorrhage in three patients, PontoMedullary infarction in one patient and Wallenberg's Syndrome in four patients.

In addition, 42 ears of 21 normal adult volunteers were also examined.

In a patient with upper BrainStem lesions mainly affecting the MidBrain, the Auditory BrainStem Response (ABR) was abnormal but the Vestibular-Evoked Myogenic Potential (VEMP) was normal.

In four patients with middle BrainStem lesions which mainly affected the Pons, both ABR and VEMP were abnormal.

In five patients with lower BrainStem lesions which mainly affected the Medulla, the ABR was normal but the VEMP was abnormal

In those patients with middle-to-lower BrainStem lesions, a disappearance of VEMP reactions, delay of the positive-negative (PN) wave, increase in PN interpeak latency and decrease in PN amplitude on the affected side were confirmed.

In conclusion, the VEMP test comprises a useful new diagnostic method for identifying lower BrainStem lesions.

Objective
To reassess, in a cohort of patients with early-onset Multiple Sclerosis, the long-term evolution of Cognitive deficits, their relationship to the disease's clinical progression, and their effects on daily life.

Design
Ten years after our baseline assessment, we again compared the Cognitive performance of patients and control subjects on a NeuroPsychological test battery.

Clinical and demographic correlates of Cognitive Impairment and their effects on everyday functioning were determined by multiple linear regression analysis.

Setting & Participants
The research clinic of a Univ Dept of Neurology. Forty-five inpatients and outpatients with Multiple Sclerosis and 65 demographically matched healthy controls from the original sample.

Main Outcome Measures
Mean scores of both groups on the NeuroPsychological test battery in initial and 2 follow-up evaluations (about 4 and 10 years, respectively).

Number of Cognitively impaired subjects, defined by the number of subtests failed.

Regression coefficients measuring the relationship between clinical variables and Cognitive outcome and between mental decline and everyday functioning assessed by the Environmental and the Incapacity Status Scales.

Results
Previously detected Cognitive Defects in Verbal Memory, Abstract Reasoning, and Linguistic Processes were confirmed on the third testing, at which time deficits in Attention/Short-Term Spatial Memory also emerged.

Only 20 of 37 patients who were Cognitively unimpaired on initial testing remained so by the end of the follow-up, when the proportion of subjects who were Cognitively impaired reached 56%.

Degree of physical Disability, Progressive Disease course, and increasing age predicted the extent of Cognitive decline.

Disability level and degree of Cognitive Impairment were independent predictors of a patient's handicap in the workplace and in social settings.

Conclusions
In the course of a sufficiently long follow-up, Cognitive Dysfunction is likely to emerge and progress in a sizable proportion of patients.

As Multiple Sclerosis advances, Neurological and Cognitive involvement tend to converge.

Limitations in a patient's work and social activities are correlated with the extent of Cognitive decline, independent of degree of physical disability.

Early imaging investigations in Multiple Sclerosis (MS) described focal signs. Technological progress now suggests this concept should be revisited.

As more diffuse anomalies of the Central Nervous System are described, sometimes involving regions that appear normal with conventional imaging techniques.

This integrative concept results largely from the contribution of Magnetic Resonance Imaging techniques recently broadened to in vivo investigations.

Technical developments in MRI now provide new contrast images: Magnetization Transfer, Diffusion, Anisotropic Diffusion, or Functional MRI.

As well as new variants of conventional sequences designed to demonstrate specific aspects of the MS lesions:

1. FLAIR sequence - a T₁-weighted sequence
2. Black Holes - a particular aspect on T₁-weighted images
3. Cord Atrophy - quantification of the Axonal section of the Cord on T₁-weighted sequences

Together these new methods should improve diagnostic sensitivity (FLAIR) or provide prognosis information not provided by conventional sequences (T₁ or T₁ weighted images with or without Gadolinium injection).

Magnetic Resonance Imaging has revolutionized management of patients with Multiple Sclerosis.

This tool provides information on a dynamic process never visualized before, optimizing diagnostic capacities and formalizing the course of the lesion load.

Following clinical assessment and performance testing, MRI constitutes a second line tool for following the course of patients with Multiple Sclerosis in Phase II and III Trials.

We reviewed the correlations between the radiological and clinical findings and the methodology of published trials on Interferon-beta in Remitting, Secondary/Progressive and early onset Multiple Sclerosis.

Magnetic Resonance Imaging (MRI) is very sensitive in depicting Multiple Sclerosis (MS) lesions, but its specifity is poor.

New sequences such as Fast Spin Echo and FLAIR (Fluid Attenuated Inversion Recovery) improve the detection of lesions.

The exploration of the whole Central Nervous System, Brain, Optic Nerves and Spinal Cord improves sensitivity and specificity.

The existence of lesions at different ages responds to temporal dissemination.

MRI has also allowed us to better understand the natural history of MS, showing 5 to 10 times more Radiological than clinical activity.

In case of Isolated DeMyelinating Syndrome, MRI is the best predictor of the occurrence of Definite MS and of the severity of Disability in the subsequent 10 years.

However, the diagnosis of MS remains clinical, and systematic control MRI are not useful in clinical practice.

Globally, the course and prognosis of Multiple Sclerosis are heterogeneous, and generally considered to be unpredictable.

Advances in statistical techniques have made it possible to analyze representative cohorts of patients to clearly delineate the overall prognosis of the disease, beyond individual variations.

For each individual however, there appears to be a steady progression as shown by serial quantified Neurological Examinations. At the present time early prediction of outcome remains impossible.

In the near future, new imaging techniques may provide a solution to this problem allowing selection of patients at risk who could benefit from early treatment.

The structural and functional properties of HLA-DQ and -DR molecules that confer susceptibility to several common AutoImmune Diseases, such as Type 1 Diabetes, Rheumatoid Arthritis and Multiple Sclerosis, have been defined.

The relevant polymorphisms directly affect interaction with Peptides, which provides strong support for the hypothesis that these diseases are Peptide-Antigen driven.

Several studies indicate that structural modifications of Peptides can affect MHC Class II binding and/or TCR recognition and should be considered in the analysis of T-Cell responses in AutoImmune Diseases.

We describe a novel imaging technique that yields all of the observable properties of the Binary Spin-Bath model for Magnetization Transfer (MT) and demonstrate this method for in vivo studies of the human head.

Based on a new model of the steady-state behavior of the Magnetization during a pulsed MT-weighted imaging sequence, this approach yields parametric images of the Fractional Size of the restricted pool.

The Magnetization Exchange Rate, the T₂ of the restricted pool, as well as the Relaxation Times in the free pool.

Validated experimentally on agar gels and samples of uncooked beef, we demonstrate the method's application on two normal subjects and a patient with Multiple Sclerosis.

Magn Reson Med 46:923-931, 2001. Copyright 2001 Wiley-Liss, Inc.

Kinins are among the most potent autacoids involved in Inflammatory, Vascular and Pain processes. These short-lived Peptides, including Bradykinin, Kallidin and T-Kinin, are generated during tissue injury and noxious stimulation.

However, emerging evidence also suggests that Kinins are stored in Neuronal elements of the Central Nervous System (CNS) where they are thought to play a role as NeuroMediators in various Cerebral functions.

Particularly in the control of Nociceptive information. Kinins exert their biological effects through the activation of two transmembrane G-protein-coupled receptors, denoted BradyKinin B(1) and B(2).

Whereas the B(2) receptor is constitutive and activated by the parent molecules, the B(1) receptor is generally underexpressed in normal tissues and is activated by Kinins deprived of the C-terminal Arg (des-Arg(9)-Kinins).

The induction and increased expression of B(1) receptor occur following tissue injury or after treatment with Bacterial EndoToxins or Cytokines such as InterLeukin-1beta and Tumor Necrosis Factor-alpha.

This review summarizes the most recent data from various animal models which convey support for a role of B(2) receptors in the acute phase of the inflammatory and pain response, and for a role of B(1) receptors in the chronic phase of the response.

The B(1) receptor may exert a strategic role in inflammatory diseases with an Immune component (Diabetes, Asthma, Rheumatoid Arthritis and Multiple Sclerosis).

New information is provided regarding the role of Sensory mechanisms subserving Spinal Hyperalgesia and IntraPleural Neutrophil migration that occur upon B(1) receptor activation in streptozotocin-treated rats.

A model of Insulin-dependent Diabetes Mellitus in which the B(1) receptor seems to be rapidly overexpressed.

Although it is widely accepted that the blockade of Kinin receptors with specific antagonists could be of benefit in the treatment of Somatic and Visceral Inflammation and Pain.

Recent molecular and functional evidence, suggests that the activation of B(1) receptors with an agonist, may afford a novel therapeutic approach in the CNS Inflammatory DeMyelinating Disorder encountered in Multiple Sclerosis by reducing Immune cell infiltration (T-Lymphocytes) into the Brain.

Hence, the B(1) receptor may exert either a protective or detrimental effect depending on the Inflammatory Disease. This dual function of the B(1) receptor deserves to be investigated further.

Purpose
To evaluate the effect of treatment with Interferon-beta-1a (Avonex) initiated at the time of a first episode of Optic Neuritis in patients at high risk for Multiple Sclerosis (MS).

Design, Methods & Setting
Randomized clinical, prospective trial in fifty clinical centers throughout the US and Canada.

Study Population
After the onset of a first episode of Optic Neuritis treated with intravenous and oral CorticoSteroids, 192 patients with Brain Magnetic Resonance Imaging (MRI) evidence of SubClinical DeMyelination were randomly assigned to receive weekly intramuscular injections of 30 microg Interferon-beta-1a or placebo.

Main Outcome Measure
The study outcomes were the development of Clinically Definite MS within 3 years of follow-up and Brain MRI changes at 6, 12, and 18 months.

Results
The rates of Clinically Definite MS and of a combined MS/MRI outcome were lower in the Interferon-beta-1a group than in the placebo group (adjusted rate ratios 0.58, 95% confidence interval 0.34 to 1.00; and 0.50, 95% confidence interval 0.34 to 0.73, respectively).

Compared with the placebo group, on the 18-month Brain MRI the Interferon-beta-1a group had a smaller change from baseline in T₂ lesion volume (P =.02), fewer new or enlarging T₂ lesions (P < .001), and a lower frequency of Gd-enhancing lesions (P < .001).

Conclusion
The clinical and Brain MRI results of this trial support initiating Interferon-beta-1a treatment at the time of a first episode of Optic Neuritis occurring in patients at high risk for MS based on the presence of SubClinical Brain MRI lesions.