MS Abstracts 05c-2g1

Until recently, Atrophy of the Brain and Spinal Chord was thought to occur late in the course of Multiple Sclerosis (MS) or as a result of rare, fulminant disease.

Now Atrophy is known to occur early and likely indicates destructive and irreversible pathologic change that may be SubClinical. Central Nervous System Atrophy from MS now can be measured accurately over short time intervals.

Atrophy may become an important prognostic indicator in MS and is being evaluated as a treatment outcome measure in population studies, and possibly in the future, in individuals.

Multiple Sclerosis and Experimental AutoImmune EncephaloMyelitis (EAE) are Immune-mediated diseases of the CNS.

They are characterized by:
1. Widespread Inflammation
2. DeMyelination
3. Variable degrees of Axonal Loss

Recent Magnetic Resonance Spectroscopy studies have indicated that Axonal damage and loss are a reliable correlate of permanent clinical Disability.

Accordingly, NeuroPathological studies have confirmed the presence and timing of Axonal injury in Multiple Sclerosis Lesions. The mechanisms of Axonal Degeneration, however, are unclear.

Since Calcium influx may mediate Axonal damage, we have studied the distribution of the pore-forming subunit of Neuronal (N)-type Voltage-gated Calcium Channels in the lesions of Multiple Sclerosis and EAE.

We found that alpha(1B), the pore-forming subunit of N-type Calcium Channels, was accumulated within Axons and Axonal Spheroids of actively DeMyelinating lesions.

The Axonal staining pattern of alpha(1B) was comparable with that of beta-Amyloid Precursor Protein, which is an early and sensitive marker for disturbance of Axonal transport.

Importantly, within these injured Axons, alpha(1B) was not only accumulated, but also integrated in the AxoPlasmic membrane, as shown by Immune electron microscopy on the EAE material.

This ectopic distribution of Calcium Channels in the Axonal membrane may result in increased Calcium influx, contributing to Axonal degeneration, possibly via the activation of Neutral Proteases.

Our data suggest that Calcium influx through Voltage-dependent Calcium Channels is one possible candidate mechanism for Axonal Degeneration in Inflammatory DeMyelinating Disorders.

The cause of Multiple Sclerosis is generally considered to be entirely T-Cell mediated.

However, recent reports of studies in a variety of animal models of inflammatory DeMyelinating Disease, coupled with detailed pathological analysis and NeuroImaging studies of Multiple Sclerosis patients, indicate that the events involved in the formation of the Multiple Sclerosis Lesion may be more complicated.

This complex PathoGenesis is reflected in the variable response of Multiple Sclerosis patients to ImmunoModulatory therapy.

Many patients with Multiple Sclerosis (MS) develope Tremors that may involve one or both lower and/or upper extremities, head and/or voice.

In the last few years, chronic high frequency Deep Brain Stimulation of the Ventral InterMedious (Vim) Thalamic Nucleus (Vim-DBS, Deep Brain Stimulation) seems to be gradually replacing Vim-Thalamotomy in surgical treatment of Tremor.

The Thalamotomy is a destructive procedure of the whole Neural components, whereas Vim-DBS has shown to be a selective NeuroPhysiological procedure to block a specific group of Neural components.

In particular large, fast and low threshold ones. MS is a disease of uncertain Etiology characterized by DeMyelinating in the Central Nervous System.

The NeuroPhysiological intraoperative targeting applied to this pathology identifies DeMyelinated plaques and the functional state of Vim, reduces pitfalls and increases accuracy.

Methods included spontaneous and induced multiunit activity recording, SemiMicroElectrode and TetraElectrode Thalamic Evoked Potentials recording and Micro/Macro Stimulation techniques.

The Nucleoside Adenosine has been shown to control the production of proinflammatory molecules through its actions on cell surface Purine Receptors.

Previously, we have reported that the Adenosine A1 Receptor (A1AR) regulates Tumor Necrosis Factor-alpha (Tumor Necrosis Factor-) and InterLeukin-6 (IL-6) expression and exhibits diminished function in patients with Multiple Sclerosis (MS; Mayne et al., Ann Neurol 1999;45:633-639).

In the present study, A1AR expression in both Brain and Peripheral Blood MonoNuclear cells (PBMC) from MS and control groups was characterized by Fluorescence-Activated Cell Sorting (FACS), Reverse Transcriptase-Polymerase Chain Reaction (RT-PCR), and ImmunoHistoChemical analyzes.

FACS analyzes of PBMC revealed that A1AR expression was chiefly detectable on CD14-positive cells and was reduced by 53.1% (p < 0.01) in MS patients compared to controls.

A1AR mRNA levels were reduced by 43.1% (p < 0.001) in the Brains of MS patients compared to patients with Other Neurological Diseases and controls.

A1AR protein expression in Brain was detected primarily in CD45-positive Glial Cells and was markedly diminished in MS patients.

The analysis of A1AR transcripts in the Brain revealed that the A1AR-beta transcript was diminished (49.2%) in MS patients compared to controls (p < 0.002).

These results indicate that the A1AR, expressed principally on cells of Monocyte/Macrophage lineage in both Brain and blood, is selectively diminished in MS patients.

Reduction of the A1AR-beta transcript in MS patients suggests that dysregulated splicing may influence A1AR protein levels, potentially leading to increased Macrophage activation and Central Nervous System inflammation.

The availability of partially effective therapies for some forms of Multiple Sclerosis (MS) raises practical and ethical issues for future placebo-controlled clinical trials.

An international Task Force of clinicians, statisticians, ethicists and regulators was convened to discuss these issues and develop consensus.

The Task Force concluded that placebo-controlled clinical trials in forms of MS for which partially effective therapies exist were ethical.

So long as study subjects were fully apprised of the availability of such therapies and were encouraged to pursue them outside of a clinical trial.

Patients who decline to utilize available treatments, after proper education and counseling, or those that fail all therapies can be considered to have no treatment alternatives and thus may participate in a placebo-controlled trial.

Multiple Sclerosis (MS) is believed to be an AutoImmune process occurring in Genetically susceptible individuals after an appropriate environmental exposure.

We have exploited the homogeneous Afrikaner population of European ancestry to investigate the likelihood that Iron dysregulation, in association with infectious and/or AutoImmune Disease susceptibility, may underlie the MS phenotype in a subgroup of patients.

The functional Z-DNA forming repeat polymorphism of the Natural Resistance-Associated Macrophage Protein-1 (NRAMP1) Gene was analyzed in 104 patients diagnosed with MS and 522 Caucasian controls.

A family-based control group consisting of 32 parental alleles not transmitted to MS offspring was additionally studied to exclude the likelihood of population substructures.

Statistically significant differences in allelic distribution were observed between the patient and control samples drawn from the same population (P < 0.01).

Evidence is furthermore provided that alleles considered to be detrimental in relation to AutoImmune disease susceptibility may be maintained in the population, as a consequence of improved survival to reproductive age following infectious disease challenge.

Although it remains to be determined whether the disease phenotype in MS patients with allele 5 of the NRAMP1 promoter polymorphism is directly related to dysregulation of Iron.

Or modified susceptibility to Viral infection and/or AutoImmunity, a combination of these processes most likely underlies the disease phenotype in these patients.

In view of the emerging role of polymorphic variants in complex diseases and minimizing of possible confounding factors in this association study.

We conclude that allelic variation in the NRAMP1 promoter may contribute significantly to MS susceptibility in the South African Caucasian population.

Copyright 2001 Academic Press.

Background
Autopsy studies showed Cortical and JuxtaCortical Multiple Sclerosis (MS) plaques.

Fluid-Attenuated Inversion Recovery (FLAIR) is an advanced Magnetic Resonance Imaging sequence that reveals tissue T₂ prolongation with CerebroSpinal Fluid suppression, allowing detection of superficial Brain lesions.

Objectives
To assess FLAIR, T₁-weighted, and T₂-weighted images for detecting lesions in or near the Cerebral Cortex in patients with MS and to explore the relation between Cortical lesions and Cortical Atrophy.

Design, Setting, And Patients
Cross-sectional study in a Univ MS clinic of 84 patients with MS and 66 age-matched healthy controls receiving 1.5-T fast FLAIR, T₂-weighted, and T₁-weighted images.

Main Outcome Measures
Regional Cortical Atrophy was rated vs controls. Cortical and JuxtaCortical lesions were ovoid HyperIntensities involving the Cortex and/or Gray-White junction.

Results
A total of 810 Cortical and JuxtaCortical lesions were seen by FLAIR in patients (mean, 9.6 per patient), most commonly in the Superior Frontal Lobe.

Cortical and JuxtaCortical lesions were identified in 72 patients and 6 controls. Fourteen percent of Cortical and JuxtaCortical lesions were seen on T₁-weighted images and 26% were seen on T₂-weighted images.

More Cortical and JuxtaCortical lesions were present in Secondary/Progressive than Relapsing/Remitting disease.

The total number of Cortical and JuxtaCortical lesions correlated significantly with disease duration and the regional number correlated with the degree of Regional Atrophy.

After taking into account NonCortical (White Matter) Lesions, only the Cortical and JuxtaCortical lesion count predicted Atrophy in that region.

Conclusions
FLAIR can detect many Cortical and JuxtaCortical lesions in MS, which were appreciated previously in autopsy studies but usually missed by Magnetic Resonance Imaging during life.

Cortical and JuxtaCortical plaque formation may contribute to Cortical Atrophy in MS.

People with Multiple Sclerosis, Paraplegia and Neural Tube defects typically have Neurogenic Lower Urinary Tract Dysfunction (NLUTD). This encompasses Detrusor HyperReflexia with or without Detrusor Sphincter DysSynergia and Hypo- or Acontractility.

Their effects undermine safe, effective and controlled storage and voiding of Urine and predispose to Reflux Nephropathy. Therefore, patients in these diagnostic groups with NLUTD would be expected to have increased risk of Renal failure.

The aim of this study was to quantify this risk using the General Practice Research Database (GPRD). All patients registered in the database between 1994 and 1997 and aged 10-69 were included in the study.

The prevalence and incidence of Renal failure and Renal replacement therapy in the general population was ascertained, as was the prevalence of Multiple Sclerosis, Paraplegia and Neural Tube defects.

The prevalence of Renal failure in each of the special populations was then compared with the prevalence in the unaffected general population.

The age-standardized prevalence of Renal failure in the GPRD population aged 10-69 years was 14 per 10,000.

The rate ratio of Renal failure compared with the general population in each of the years 1994-1997 for Neural Tube defects ranged between males (M) 6.8-9.0 and females (F) 9.2-11.5.

For Paraplegia M 4.1-9.0, F 4.0-7.0, and for Multiple Sclerosis M 0.4-1.3, F 0.5-2.2. As expected, people with Paraplegia or Neural Tube defects were found to have a substantially increased risk of Renal failure compared with the general population.

We could not demonstrate an increased risk of Renal failure in people with Multiple Sclerosis. We believe this finding requires further study, but may reflect a problem in the recognition of Renal failure in this group of patients.

We recommend that all three patient groups should be regularly screened so that Renal impairment may be detected prior to the development of Renal failure.

Copyright 2001 S. Karger AG, Basel

Objective
To establish prevalence and incidence of Multiple Sclerosis (MS) in Menorca (Balearic Islands, Spain; population: 67,009).

Methods
An extensive Epidemiological study was undertaken using all available information sources. Patients were classified according to Poser's Criteria.

Results
The prevalence rate of Definite and Probable MS was 68.6/100,000 (95% confidence interval 50.3-91.6).

The incidence rate was 3.4/100,000/year (95% CI 2.2-5.3).

The time lag between the first symptom and diagnosis was 10.2 years for patients with disease onset before 1987 and 2.1 years for patients with onset between 1987 and 1996.

Conclusion
Menorca's population has a moderately high MS risk, with a prevalence rate the highest reported for a Spanish region.

Copyright 2001 S. Karger AG, Basel

T₁ HypoIntensities are lesions that are HypoIntense on moderately T₁-weighted conventional Spin-Echo sequences and serve as markers of matrix destruction and Axonal loss.

They correlate better with clinical disability than T₂-weighted images, are found in patients with Progressive Multiple Sclerosis, and can be used as surrogate outcome measures in treatment trials.