MS Abstracts 7e-2g1

  1. Predicting Secondary/Progression in Relapsing/Remitting Multiple Sclerosis: a Bayesian analysis
    J Neurol Sci 2001 Aug 15;189(1-2):13-21

  2. Transcriptional ChanneloPathies: an emerging class of disorders
    Nat Rev NeuroSci 2001 Sep;2(9):652-659

  3. Increased Nitric Oxide products in CSF in Primary/Progressive MS may reflect Brain atrophy
    Neurology 2001 Sep 11;57(5):895-896

  4. T1 HypoIntensity of the Spinal Cord in Multiple Sclerosis
    J Neurol 2001 Jun;248(6):517-21

  5. Thyroid function and AutoImmunity during Interferon-beta-1b treatment
    J Clin Endocrinol Metab 2001 Aug;86(8):3525-32

  6. Serum inflammatory markers and clinical/MRI markers of disease progression in Multiple Sclerosis
    J Neurol 2001 Jun;248(6):487-95

  7. Sex Hormones in Experimental AutoImmune EncephaloMyelitis: implications for Multiple Sclerosis
    NeuroScientist 2001 Jun;7(3):258-70

  8. Balo's Concentric Sclerosis: clinical and radiologic features of five cases
    AJNR Am J NeuroRadiol 2001 Aug;22(7):1362-7

  9. No association of three polymorphisms in the alpha-2-MacroGlobulin and Lipoprotein related receptor Genes with Multiple Sclerosis
    J NeuroImmunol 2001 Aug 30;118(2):300-3

  10. Active MRI lesion appearance in MS is preceded by fluctuations in circulating T-Helper 1 and 2 Cells
    J NeuroImmunol 2001 Aug 30;118(2):286-94

  11. Fc receptors for ImmunoGlobulin G - a role in the PathoGenesis of Guillain-Barre Syndrome and Multiple Sclerosis
    J NeuroImmunol 2001 Aug 30;118(2):187-93


Predicting Secondary/Progression In Relapsing/Remitting Multiple Sclerosis: A Bayesian Analysis

Bergamaschi R, Berzuini C, Romani A, Cosi V.
J Neurol Sci 2001 Aug 15;189(1-2):13-21
Neurological Institute, "Fondazione C. Mondino", via Palestro 3, 27100, Pavia, Italy
PMID# 11535229

With the aid of a Bayesian statistical model of the natural course of Relapsing/Remitting Multiple Sclerosis (MS), we identify short-term clinical predictors of long-term evolution of the disease.

With particular focus on predicting onset of Secondary/Progressive course (failure event) on the basis of patient information available at an early stage of disease.

    The model specifies the full joint probability distribution for a set of variables:
  1. Early indicator variables
    • Observed during the early stage of disease
  2. Intermediate indicator variables
    • Observed throughout the course of disease, prefailure
  3. Time to failure

Our model treats the intermediate indicators as a surrogate response event, so that in right-censored patients, these indicators provide supplementary information pointing towards the unobserved failure times.

Moreover, the full probability modelling approach allows the considerable uncertainty which affects certain early indicators, such as the early relapse rates, to be incorporated in the analysis.

With such a model, the ability of early indicators to predict failure can be assessed more accurately and reliably, and explained in terms of the relationship between early and intermediate indicators.

Moreover, a model with the aforementioned features allows us to characterize the pattern of disease course in high-risk patients.

And to identify short-term manifestations which are strongly related to long-term evolution of disease, as potential surrogate responses in clinical trials.

Our analysis is based on longitudinal data from 186 MS patients with a Relapsing/Remitting initial course.

    The following important early predictors of the time to progression emerged:
  1. Age
  2. Number of Neurological Functional Systems (FSs) involved
  3. Sphincter, or Motor, or Motor-Sensory symptoms
  4. Presence of Sequela after onset

During the first 3 years of follow up, to reach EDSS  >/=4  outside relapse, to have Sphincter or Motor relapses and to reach moderate Pyramidal involvement were also found to be unfavorable prognostic factors.


Transcriptional ChanneloPathies: An Emerging Class Of Disorders

Waxman SG
Nat Rev NeuroSci 2001 Sep;2(9):652-659
Yale Univ, School of Medicine, Dept of Neurology LCI 707, P.O. Box 208018, 333 Cedar Street, New Haven, Connecticut 06520-8018, USA
PMID# 11533733

Two types of ChanneloPathy are now well recognized: Genetic, in which Ion Channels function abnormally or fail to function as a result of mutations, and AutoImmune, in which AntiBodies perturb Channel function.

Recent studies have provided growing evidence for the existence of a third type: Transcriptional ChanneloPathies, which result from changes in the expression of non-mutated Channel Genes, due to the dysregulated transcription of Genes that encode normal Channel proteins.

Transcription of Sodium Channel Genes is a highly dynamic process; it is regulated throughout development, and it can be affected by the availability of NeuroTrophic factors.

In addition, Sodium Channel transcription can change in response to physiological states such as changes in Osmolarity.

A well-studied example is Peripheral Nerve Injury, which causes Spinal Sensory Neurons to turn off some active Sodium Channel Genes and turn on others that were previously silent, a set of changes that can result in HyperExcitability of these cells.

There is evidence to suggest that the expression of Potassium and Calcium Channels might also change in certain DeMyelinating conditions.

Some of the signs that accompany Multiple Sclerosis, such as Cerebellar Ataxia, could be considered as Transcriptional ChanneloPathies.

Although increased expression of Sodium Channels in Multiple Sclerosis seems to be a compensatory reaction to allow normal Action Potential Conduction in DeMyelinated Nerves.

Recent studies have also shown upregulated expression of Sensory-Neuron-specific Sodium Channels in Purkinje Cells, indicating that a Transcriptional ChanneloPathy might perturb Cerebellar function in Multiple Sclerosis.

It is probable that we will soon recognize further disorders that are characterized by dysregulation of Channel Gene expression in Neurons.

A better understanding of Transcriptional ChanneloPathies might provide us with new opportunities to treat these disorders.


Increased Nitric Oxide Products In Primary/Progressive MS CSF May Reflect Brain Atrophy

Peltola J, Ukkonen M, Moilanen E, Elovaara I.
Neurology 2001 Sep 11;57(5):895-896
Tampere Univ Hospital, NeuroImmunology Unit, Dept of Neurology
PMID# 11552025; UI# 21436235

Because Nitric Oxide (NO) is a putative mediator of Oligodendrocyte damage in the Primary/Progressive form of MS (PPMS).

The authors analyzed the levels of NO oxidation products in CSF and Plasma from 25 patients with PPMS and 15 controls.

The levels of Nitrite + Nitrate (NOx) in CSF were fourfold higher in patients with PPMS than in controls (p < 0.001).

Whereas the concentrations in Plasma were similar. These data suggests involvement of NO in Nervous tissue damage in PPMS.


T1 HypoIntensity Of The Spinal Cord In Multiple Sclerosis

Losseff NA, Wang L, Miller DH, Thompson AJ
J Neurol 2001 Jun;248(6):517-21
Institute of Neurology, NMR Research Unit, London, UK
PMID# 11499644, UI# 21390482

It has recently been shown in Multiple Sclerosis (MS) that the volume of T1 HypoIntense lesions in the Brain explains more of the variance in disability among patients than T2 lesion volume.

T1 HypoIntense lesions may therefore represent areas of underlying pathology likely to be of functional significance, such as Axonal Loss.

The Spinal Cord is a common area of involvement in MS and its dysfunction is likely to be responsible for much of the motor disability seen.

Hence it serves as a useful model by which to examine the functional relevance of differing imaging sequences.

We have therefore examined the relationship between T1 signal intensity in the Spinal Cord and disability in 60 patients with MS.

We have also examined the relationship between T1 signal intensity and Atrophy of the Cord, as the latter is another potential marker of Axonal Loss.

Sixty patients with MS underwent Spinal Cord imaging with a T1 weighted sequence to acquire Axial sections of the Cord at the C2 level.

These sections were MTR Histogram matched to allow comparison of image intensity and a manual outlining technique was applied from which the mean Cord intensity was calculated.

Within the patient group there was a significant relationship between T1 signal intensity and disability as measured with the EDSS (r = -0.4, p < 0.005) and also between T1 signal intensity and Atrophy (r = 0.36, p < 0.005).

This study demonstrates that Disability and Atrophy are associated with a generalized reduction in Cord signal on T1 weighted images.

A lower T1 signal intensity in the Spinal Cord may be more pathologically specific than T2 HyperIntensity and may represent underlying Axonal Loss.

Although Gliosis and predominant White Matter Atrophy are alternative possibilities.


Thyroid Function And AutoImmunity During Interferon-ß-1b Treatment

A Multicenter Prospective Study
Durelli L, Ferrero B, Oggero A, Verdun E, Ghezzi A, Montanari E, Zaffaroni M
J Clin Endocrinol Metab 2001 Aug;86(8):3525-32
Universita di Torino, Clinica Neurologica, Dipartimento di NeuroScienze
PMID# 11502774; UI# 21394064

Thyroid Dysfunction and AutoImmunity have been reported during type I Interferon therapy, namely Interferon-alpha for chronic Hepatitis or Interferon-ß for Multiple Sclerosis.

To define the frequency of Thyroid Dysfunction and AutoImmunity during Interferon-ß treatment, 156 Multiple Sclerosis patients were prospectively followed up by 18 centers for 1 yr after starting Interferon-ß-1b treatment.

Serial clinical assessments and tests of Thyroid and Liver function and AntiThyroid AutoAntiBodies (all performed by the same centralized laboratory) were conducted every 3 months.

TSH and AntiThyroid AutoAntibodies against human TG or Thyroid microsomal Antigens were measured by ImmunoRadiometric methods; free T3 and T4 were measured by Chromatographic Assays.

Longitudinal occurrence of Thyroid or Liver alterations or of AutoAntiBodies was analyzed with the generalized estimating equations method, correcting for the correlation of repeated measurements of the same subject over time.

Pretreatment comparison with a control group of 437 healthy blood donors did not show significant differences in the frequency of Thyroid Dysfunction or AntiThyroid AutoAntiBody positivity.

During Interferon-ß treatment, the de novo frequency of Thyroid alteration was 8.3%, that of Liver alteration was 37.5%, and that of AntiThyroid AutoAntiBody was 4.5%.

Generalized estimating equations analysis demonstrated that the frequency of Liver alteration significantly increased during treatment compared with the baseline value (odds ratio, 7.03; confidence interval, 2.49-19.9).

Whereas that of Thyroid alteration or of AntiThyroid AutoAntiBodies did not.

The frequency of Thyroid Dysfunction during Interferon-ß treatment showed random, nonsignificant changes over time and, in addition, was not correlated to AntiThyroid AutoAntiBody positivity.


Serum Inflammatory Markers And Clinical/MRI Markers Of Disease Progression In Multiple Sclerosis

Giovannoni G, Miller DH, Losseff NA, Sailer M, Lewellyn-Smith N, Thompson AJ, Thompson EJ
J Neurol 2001 Jun;248(6):487-95
Univ of London, Dept of NeuroChemistry, London, UK
PMID# 11499639; UI# 21390477

The aim of this study was to assess whether mean Serum levels of inflammatory markers when measured serially correlate with disease progression.

Or, putative MRI markers of Axonal loss in a cohort of well-characterized Multiple Sclerosis (MS) patients.

Serial Serum levels of soluble Vascular Cell Adhesion Molecule-1 (sVCAM-1), soluble InterCellular Adhesion Molecule-1 (sICAM-1), Nitric Oxide metabolites Nitrate and Nitrite (NOx), C-Reactive Protein (CRP), Neopterin and Tumor Necrosis Factor-alpha (TNF-alpha) were measured.

In 29 MS patients, 13 with a Relapsing/Remitting (RR) and 16 with a Secondary/Progressive (SP) course, who were participating in a Phase II Clinical Trial of Anti-CD4 therapy.

Short-term whole blood stimulated TNF-alpha production was also measured. Patients were studied 12 times over an 18-month period.

MRI variables included the number and volume of Gd-enhancing lesions and the change in T1-HyperIntense, T2-HypoIntense lesions and Cerebral volume between the baseline and exit studies.

Disease progression required a sustained change in the EDSS. There was no correlation between mean levels of inflammatory markers over the study period and disease progression or changes in any of the MRI measures.

However, mean sICAM-1 levels from the first 6 months of the study were higher in patients who progressed during the study than in those that did not (443 (SD439) vs. 235 (SD162) ng/mL, p=0.05).

Mean levels of NOx were significantly higher in patients with RR MS than in patients with SP disease (59.1 micromol/L (SD 12.8) vs. 48.7 micromol/L (SD 11.9), p=0.02).

Patients with either a single relapse or no relapse had significantly higher NOx levels than patients with multiple relapses during the 18 month follow-up (59.0 micromol/L (SD 12.3) vs. 47.9 micromol/L (SD 12.0), p=0.02).

The mean levels of the other inflammatory markers did not correlate with disease course or relapse-rate.

Serum levels of many inflammatory markers do not correlate with short-term disease progression, some of the data suggest that the effects of inflammation on disease progression are delayed.

In addition raised levels of Serum Nitric Oxide metabolites are associated with a lower number of clinical relapses and a Non-Progressive disease course.

These findings, although preliminary, pose interesting questions on the role of Nitric Oxide in the PathoGenesis of MS. Inducible NO production in the early stages of the disease may be beneficial.


Sex Hormones In EAE: Implications For Multiple Sclerosis

Voskuhl RR, Palaszynski K
NeuroScientist 2001 Jun;7(3):258-70
Univ of California, Dept of Neurology, Los Angeles 90095, USA
PMID# 11499404; UI# 21390268

For decades, it has been known that females are more susceptible than males to Multiple Sclerosis (MS). It has also long been appreciated that during late pregnancy there is a decrease in MS disease activity.

Interestingly, these two observations have also been made in an extensively used animal model for MS, Experimental AutoImmune EncephaloMyelitis (EAE) in SJL mice.

Female mice are more susceptible to disease than male mice, and there is an improvement in disease during late pregnancy.

In this review, the role of sex Hormones in each of these two observations is characterized in this EAE model using castration and exogenous Hormone treatment strategies.

The gender difference in EAE susceptibility is due primarily to a protective effect of Testosterone in male mice.

The decrease in disease severity during late pregnancy appears to be due at least in part to high levels of Estriol, which characterize this time period.


Balo's Concentric Sclerosis: Clinical And Radiologic Features Of Five Cases

Karaarslan E, Altintas A, Senol U, Yeni N, Dincer A, Bayindir C, Karaagac N, Siva A
AJNR Am J NeuroRadiol 2001 Aug;22(7):1362-7
Intermed Medical Center (E.K.)
PMID# 11498428; UI# 21388930

Balo's Concentric Sclerosis (BCS) is a rare DeMyelinating Disease considered to be a variant of Multiple Sclerosis.

Five BCS cases were diagnosed antemortem based on their typical concentric mass patterns on MR images and based on clinical and CSF findings.

HistoPathologic investigation was also performed in one case. Our case report supports the concept that BCS may be a self-limited disease that is not always fatal.

Characteristic MR imaging findings may allow antemortem diagnosis of BCS when performed at the onset of the disease.


No Association Of Three Polymorphisms In The
alpha-2-MacroGlobulin And Lipoprotein Related Receptor Genes With Multiple Sclerosis

Schweer D, Jacobsen M, Ziegler A, Jakel S, Oertel WH, Sommer N, Hemmer B
J NeuroImmunol 2001 Aug 30;118(2):300-3
Philipps-University, Clinical NeuroImmunology Group, Dept of Neurology, Rudolf-Bultmann Str. 8, 35033, Marburg, Germany
PMID# 11498265; UI# 21389410

alpha-2-MacroGlobulin (A2M) is a Proteinase Inhibitor involved in deactivation of Cytokines and modulation of Antigen-mediated Immune Responses. Based on its role in Inflammatory and NeuroDegenerative Disorders.

We investigated the role of A2M and its receptor low-density Lipoprotein Receptor-Related Protein (LRP) for the development of Multiple Sclerosis (MS).

We analyzed the frequency of two polymorphisms in the A2M (Val 1000 Ile, Exon 18 del), and one polymorphism in the LRP (A216V) Gene.

In a case control study involving 326 MS patients, and 290 controls, all defined for the expression of HLA-DR15. No association was found for any of the three polymorphism with MS.

Furthermore, no differences in Serum A2M levels were detected between MS patients and controls. The results do not suggest a contribution of A2M and LRP to the development of MS.


Active MRI Lesion Appearance In MS Is Preceded By Fluctuations In Circulating T-Helper 1 And 2 Cells

Killestein J, Rep MH, Barkhof F, Roos MT, Ader HJ, van Lier RA, Polman CH
J NeuroImmunol 2001 Aug 30;118(2):286-94
Univ of Amsterdam, Dept of Immunobiology, CLB and Laboratory of Experimental and Clinical Immunology, Amsterdam, The Netherlands
PMID# 11498263; UI# 21389408

The role of T-Cell subpopulations and their ability to produce ImmunoRegulatory Cytokines has been extensively studied in Multiple Sclerosis (MS).

However, the exact mechanisms by which T-Cells and Cytokines contribute to disease activity remain to be clarified.

To analyze the longitudinal relation between markers of T-Cell activation and differentiation and disease activity in MS patients.

During a period of 9 months, clinical disease activity was scored, monthly MRI scans were performed, and blood was taken for Immune measurements in a group of 13 untreated Clinically Definite MS patients.

Disease activity, as measured by the occurrence of active MRI lesions, is associated with a significant transient decrease in both T-Cells producing Interferon-gamma (IFN-γ) and T-Cells producing InterLeukin-4 (IL-4).

Our results suggest that MRI-documented disease activity is associated with a transient decrease in circulating Cytokine producing T-Cells, possibly due to the migration of activated T-Cells into the CNS.


Fc Receptors For ImmunoGlobulin G - A Role In The Pathogenesis Of Guillain-Barre Syndrome And Multiple Sclerosis

Vedeler CA, Myhr K, Nyland H
J NeuroImmunol 2001 Aug 30;118(2):187-93
Haukeland Hospital, Univ of Bergen, Dept of Neurology, 5021, Bergen, Norway
PMID# 11498253; UI# 21389398

Receptors for the Fc part of IgG (FcγR) constitute a family of cell-surface molecules expressed on almost every cell of the Immune System.

They are also present on Non-Lymphoid Cells such as Schwann Cells and Endothelial Cells.

By linking Humoral and Cell-mediated Responses, FcγR are key in defending against Pathogens.

Polymorphisms in some FcγR Genes are associated with infectious and AutoImmune Diseases.

It was found recently that certain FcγRIIA and FcγRIIIB AlloTypes are correlated with the disease course of Guillain-Barre Syndrome (GBS) and Multiple Sclerosis (MS).

This may imply that clearance of circulating AutoAntibodies and Immune complexes is important in the PathoGenesis of these diseases.

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