MS Abstracts 9c-2g

  1. Surgery for Cervical Spinal Cord compression in Multiple Sclerosis
    NeuroSurgery 2000 Sep;47(3):637-42; discussion 642-3

  2. Association of two variants in IL-1beta and IL-1 receptor antagonist Genes with Multiple Sclerosis
    J NeuroImmunol 2000 Jul 1;106(1-2):220-227

  3. Oxidative damage to Mitochondrial DNA and activity of Mitochondrial enzymes in chronic active lesions of Multiple Sclerosis
    J Neurol Sci 2000 Aug 15;177(2):95-103

  4. Insulin-Like Growth Factor-1 fails to enhance Central Nervous System Myelin repair during AutoImmune DeMyelination
    Am J Pathol 2000 Sep;157(3):933-943

  5. A phase I trial of solubilized DR2:MBP84-102 (AG284) in Multiple Sclerosis
    Neurology 2000 Apr 11;54(7):1414-20

  6. Human HerpesVirus 6
    Rev Med Virol 2000 May;10(3):155-173

  7. Multiple Sclerosis treatments
    Pathol Biol (Paris) 2000 Mar;48(2):114-20

  8. Differential expression of NK T-Cell Valpha24JalphaQ invariant TCR chain in the lesions of Multiple Sclerosis and Chronic Inflammatory DeMyelinating PolyNeuropathy
    J Immunol 2000 Apr 15;164(8):4375-81

  9. Interferon-gamma modulates human Oligodendrocyte susceptibility to Fas-mediated Apoptosis
    J NeuroPathol Exp Neurol 2000 Apr;59(4):280-6


Surgery For Cervical Spinal Cord Compression In MS

Bashir K, Cai CY, Moore TA 2nd, Whitaker JN, Hadley MN
NeuroSurgery 2000 Sep;47(3):637-42; discussion 642-3
Univ of Alabama at Birmingham, Dept of Neurology, and Birmingham Veterans Medical Center, Neurology and Research Services, Birmingham, Alabama, USA
PMID# 10981751; UI# 20434630

The goal of this study was to investigate the clinical and paraclinical features, treatment, and outcomes of patients with Multiple Sclerosis (MS) and coexisting Spinal Cord Compression secondary to either Cervical Spondylosis or Cervical Disc Disease.

Patients with MS commonly experience Neurological disabilities that present as Myelopathy associated with Bladder dysfunction.

For some patients with MS, however, this Neurological deterioration may result from coexisting Spinal Cord Compression attributable to either Spondylosis or a Herniated Disc.

Overlapping symptoms of the two conditions do not allow clear clinical determination of the underlying cause of worsening.

Patients with MS who underwent Cervical Decompression Surgery were selected. Medical records were retrospectively reviewed, to collect data on their pre- and postoperative clinical courses.

Nine women and five men with definite MS were selected for Cervical decompression surgery to treat Neurological deterioration considered to be at least partially attributable to Spinal Cord Compression.

The most common symptoms were progressive Myelopathy (n = 13), neck pain (n = 11), and Cervical radiculopathy (n = 10). Bladder dysfunction was notably absent among these patients with MS with moderate disabilities.

Surgical intervention was frequently delayed because the Neurological deterioration was initially thought to be attributable to MS.

The majority of patients experienced either improvement or stabilization of their preoperative symptoms in the immediate postoperative period.

Three subjects (21%) maintained this improvement after a mean follow-up period of 3.8 years.

No MS relapses, permanent Neurological worsening, or serious complications resulting from surgery or general anesthesia were noted.

Carefully selected patients with MS and Cervical Spinal Cord compression secondary to either Spondylosis or Disc Disease may benefit from surgical decompression, with minimal associated morbidity.

Clinical features (especially Neck Pain and Cervical Radiculopathy) and Magnetic Resonance Imaging may assist clinicians in differentiating between the two conditions and may guide appropriate treatment without undue delay.


Association Of Two Variants In IL-1beta and IL-1 Receptor Antagonist Genes With Multiple Sclerosis

Kantarci OH, Atkinson EJ, Hebrink DD, McMurray CT, Weinshenker BG
J NeuroImmunol 2000 Jul 1;106(1-2):220-227
Mayo Clinic and Foundation, Dept of Neurology, 200 First Street, SW, Rochester, MN, USA
PMID# 10814801

We studied the putative association of a C-->T PolyMorphism in exon-5 of IL-1ß and an 85 bp tandem repeat in intron-4 of IL-1 Receptor antagonist (IL-1ra) Genes with susceptibility to or outcome of MS.

DNA from 122 cases from a population-based cohort in Olmsted County, MN who were previously categorized for disease severity and temporal course and 244 ethnically-matched controls were analyzed.

There was no association between either PolyMorphism and disease susceptibility. Allele-2 of IL-1ß and Allele-3 of the IL-1ra PolyMorphisms were associated with a favorable outcome (P=0.023 and P=0.030).


Oxidative Damage To Mitochondrial DNA And Activity Of Mitochondrial Enzymes In Chronic Active Lesions Of Multiple Sclerosis

Lu F, Selak M, O'Connor J, Croul S, Lorenzana C, Butunoi C, Kalman B
J Neurol Sci 2000 Aug 15;177(2):95-103
MS 406 MCP-Hahnemann University, Dept of Neurology, 245 North 15th Street, 19102, Philadelphia, PA, USA
PMID# 10980305

Soluble products of activated Immune Cells include Reactive Oxygen Species (ROS) and Nitric Oxide (NO) with a high potential to induce biochemical modifications and degenerative changes in areas of inflammation in the Central Nervous System (CNS).

Previously, we demonstrated an increased production of ROS by activated MonoNuclear Cells (MNC) of patients with Multiple Sclerosis (MS) compared to those of controls, and development of Oxidative damage to total DNA in association with inflammation in chronic active plaques.

The current study aimed to determine whether Mitochondrial (mt) DNA is affected by Oxidative damage, and whether Oxidative damage to Mitochondrial macromolecules (including mt DNA) is associated with a decline in the activity of Mitochondrial enzyme complexes.

Using molecular and biochemical methods we demonstrate a trend for impaired NADH DeHydrogenase (DH) activity and a possible compensatory increase in complex IV activity in association with Oxidative damage to mt DNA in chronic active plaques.

ImmunoHistoChemistry confirms the increase of Oxidative damage to DNA predominantly located in the Cytoplasmic compartment of cells in chronic active plaques.

These observations suggest that Oxidative damage to macromolecules develops in association with inflammation in the CNS, and may contribute to a decline of energy metabolism in affected cells.

As observed in NeuroDegenerative Diseases of non-inflammatory origin, decreased ATP synthesis can ultimately lead to cell death or degeneration.

Therefore, elucidation of this pathway in MS deserves further studies which may identify NeuroProtective strategies to prevent tissue degeneration and the associated clinical disability.


Insulin-Like Growth Factor-1 Fails To Enhance Central Nervous System Myelin Repair During AutoImmune DeMyelination

Cannella B, Pitt D, Capello E, Raine CS
Am J Pathol 2000 Sep;157(3):933-943
Albert Einstein College of Medicine, Depts of Pathology (NeuroPathology), Neurology, and NeuroScience, Bronx, New York, and Univ of Genova, Genoa, Italy
PMID# 10980132

Previous studies have shown that Insulin-like Growth Factor-1 (IGF-1) has beneficial effects, both clinically and HistoPathologically, on Experimental AutoImmune EncephaloMyelitis (EAE), although results vary depending on species and treatment regimen.

The present study investigated whether IGF-1, delivered at different time points during the acute and chronic phases of adoptively transferred EAE in SJL mice, had the ability to affect or enhance Myelin regeneration.

Central Nervous System tissue sampled at different stages of treatment was subjected to detailed NeuroPathological, ImmunoCytoChemical and molecular analysis.

The results revealed some transient clinical amelioration and low level ReMyelination after IGF-1 administration during the acute phase of EAE.

However, Central Nervous System tissue from acute phase treated animals sampled at chronic time points and from animals given IGF-1 during the chronic phase revealed no enhancing effect on ReMyelination in comparison to vehicle-treated controls.

Examination of Oligodendrocyte progenitor populations also revealed no differences between IGF-1- and vehicle-treated groups.

At the Cytokine level, the ImmunoModulatory molecules TGF-ß2 and TGF-ß3 displayed significant decreases that may have contributed to the transient nature of the effect of IGF-1 on EAE.

Together with evidence from previous studies, it appears doubtful that IGF-1 is a good candidate for treatment in Multiple Sclerosis, for which EAE serves as a major model.


A Phase I Trial Of Solubilized DR2:MBP84-102 (AG284) In Multiple Sclerosis

Goodkin DE, Shulman M, Winkelhake J, Waubant E, Andersson P, Stewart T, Nelson S, Fischbein N, Coyle PK, Frohman E, Jacobs L, Holcenberg J, Lee M, Mocci S
Neurology 2000 Apr 11;54(7):1414-20
Univ of California at San Francisco/Mt. Zion Multiple Sclerosis Center, Dept of Radiology; Anergen, Inc., Redwood City, CA.
PMID# 10751249; UI# 20215043

To assess the safety, tolerability, and biologic and clinical activity of a solubilized complex comprised of human Leukocyte Antigen-DR2 with Myelin Basic Protein84-102 (AG284)in patients with Secondary/Progressive MS.

Soluble species-specific Major Histocompatibility Complex Myelin Basic Protein91-103 complexes ameliorate disease in a dose-dependent manner when administered to SJL/J mice with Chronic Relapsing Experimental Allergic EncephaloMyelitis.

Preincubation with AG284 reduces the proliferative response of a DR2-restricted, Myelin Basic Protein84-102-reactive T-Cell clone, derived from a MS patient, to Myelin Basic Protein84-102 in the presence of autologous Antigen-Presenting Cells.

Thirty-three patients with Secondary/Progressive MS were randomly assigned to receive three alternate day IV doses of AG284 or placebo in a double-masked dose escalation study.

The Primary outcome was safety and tolerability. Secondary outcomes included a comparison of pre- and post-treatment Gadolinium-enhanced Brain MRI activity, Kurtzke Expanded Disability Status Scale, and Nine Hole Peg Test scores.

The frequency of adverse events was similar in the AG284 and placebo recipients. No significant treatment effect was detected by Expanded Disability Status Scale, Nine Hole Peg Test, or number of new Gadolinium-enhancing MRI lesions.

AG284 as administered during this study was safe and well tolerated. Further studies are warranted to determine the biologic activity and clinical efficacy of this potential treatment for MS.


Human HerpesVirus 6

Clark DA
Rev Med Virol 2000 May;10(3):155-173
Royal Free and Univ, College Medical School, Dept of Virology, Royal Free Campus, Rowland Hill Street, London, UK
PMID# 10815027

Human HerpesVirus 6 (HHV-6), a member of the beta-HerpesVirinae subfamily, is highly seroprevalent, has a worldwide distribution, and infection usually occurs within the first two years of life.

In this age group, HHV-6 causes febrile illness including Exanthem Subitum with Seizures, a recognized complication.

The Virus is predominantly T-LymphoTropic although it can infect a variety of cell types in vitro and CD46 has recently been identified as a cellular receptor.

The Virus persists in the host, with a latent state proposed in Monocytes and Bone Marrow Progenitor Cells, and chronic infection in Salivary Glands.

The Virus is PathoGenic in the post transplantation period and may be a cofactor in the progression of HIV disease.

The Virus has also been associated with Multiple Sclerosis (MS), with the Virus detected in Oligodendrocytes particularly in plaque regions.

The role of HHV-6 in MS remains controversial and a more extensive understanding of its NeuroTropism and association with disease is required.

Two variants of HHV-6 exist (A and B) and comparison of their complete nucleotide sequences shows the Genomes to be colinear, with a high degree of homology.

Variation in specific regions of the Genome is more extensive and probably accounts for biological and pathological differences.

Almost exclusively, variant B is associated with febrile illness in childhood and is the predominant variant detected in healthy individuals.

The Epidemiology of HHV-6A infection needs to be better defined, although it is significantly less prevalent. Biological, Genetic, Epidemiological and Pathological findings suggest that the two variants are divergent.

Copyright 2000 John Wiley & Sons, Ltd.


Multiple Sclerosis Treatments

Edan G, Coustans M
Pathol Biol (Paris) 2000 Mar;48(2):114-20
Clinique Neurologique Centre Hospitalier Universitaire De Rennes, Hopital de Pontchaillou, France
PMID# 10815287; UI# 20274431

In previous studies no clear demonstration was found of the efficacy of Azathioprine, Cyclophosphamide and Methotrexate as ImmunoProphylactic agents in cases of Multiple Sclerosis (MS).

Over the past five years a number of well-designed clinical trials utilizing ImmunoSuppressive and ImmunoModulatory agents have shown partial efficacy regarding the drugs involved.

But they have not been able to determine in what way these drugs can modify the natural course of this disease.

Among the ImmunoSuppressors, Mitoxanthrone is of particular interest as during the past two years three controlled trials have taken place in Europe and have demonstrated its efficacy both as regards clinical (frequency of symptoms, progression of the disease) and Magnetic Resonance Imaging (MRI) criteria.

Due to its potentially severe CardioToxicity related to total cumulative dose, Mitoxantrone is only prescribed for a limited period, and its use is limited to selected patients with a high relapse rate and incomplete remission, or to those who do not respond to ß-Interferon treatment.

The ImmunoModulatory agents have less immediate efficacy, but because they are well tolerated they can be used early in the course of the disease and over a prolonged period of time.

The Interferons (ß-1a or ß-1b) have been given market approval for use in the treatment of MS:

  • Three large, randomized, double-blind studies have demonstrated their capacity to reduce by 30% the frequency of symptoms

  • The appearance of disabilities associated with relapse and with the progression of the disease

Glatiramer Acetate or Copolymer-1, which is available in France (ATU), has been found to reduce the frequency of relapse by 30%.

It constitutes an alternative ImmunoModulatory treatment for Relapsing/Remitting patients without major functional disabilities and who suffer from severe side effects with ß-Interferon treatment.

In the future, the early use of ImmunoModulatory agents and therapeutic drug combinations may be introduced. Therapeutic trials are currently in progress to determine the viability of this approach.


Differential Expression Of NK T-Cell Valpha24JalphaQ Invariant TCR Chain In The Lesions Of Multiple Sclerosis And Chronic Inflammatory DeMyelinating PolyNeuropathy

Illes Z, Kondo T, Newcombe J, Oka N, Tabira T, Yamamura T
J Immunol 2000 Apr 15;164(8):4375-81
National Institute of NeuroScience, National Center of Neurology and Psychiatry, Dept of DeMyelinating Disease and Aging, Ogawahigashi, Kodaira, Tokyo, Japan; and Institute of Neurology, NeuroResource Dept, London, United Kingdom
PMID# 10754338; UI# 20219280

Human Valpha24+ NK T-Cells are a unique subset of Lymphocytes expressing the Valpha24JalphaQ invariant TCR chain.

Because they can rapidly produce large amounts of regulatory Cytokines, a reduction of NK T-Cells may lead to the development of certain AutoImmune Diseases.

Using a single-strand conformation PolyMorphism method, we demonstrate that a great reduction of Valpha24JalphaQ NK T-Cells in the peripheral blood is an Immunological hallmark of Multiple Sclerosis.

Whereas it is not appreciable in other AutoImmune/Inflammatory Diseases such as Chronic Inflammatory DeMyelinating PolyNeuropathy.

The Chronic Inflammatory DeMyelinating PolyNeuropathy lesions were often found to be infiltrated with Valpha24JalphaQ NK T-Cells. But Multiple Sclerosis lesions only rarely expressed the Valpha24JalphaQ TCR.

It is therefore possible that the extent of NK T-Cell alteration may be a critical factor which would define the clinical and Pathological features of AutoImmune Disease.

Although the mechanism underlying the NK T-Cell deletion remains largely unclear, a remarkable contrast between the CNS and Peripheral Nervous System Diseases allows us to speculate a role of tissue-specific elements such as the level of CD1d expression or differences in the CD1d-bound GlycoLipid.


Interferon-gamma Modulates Human Oligodendrocyte Susceptibility To Fas-Mediated Apoptosis

Pouly S, Becher B, Blain M, Antel JP
J NeuroPathol Exp Neurol 2000 Apr;59(4):280-6
Montreal Neurological Institute, NeuroImmunology Unit, Quebec, Canada
PMID# 10759183; UI# 20220933

Interferon-gamma (IFN-gamma) has been shown to be produced within Multiple Sclerosis (MS) lesions by infiltrating Lymphocytes; systemic administration of this Cytokine induces exacerbation of the disease.

The aim of the current study was to establish the contribution of IFN-gamma to Oligodendrocyte (OL) injury. Our studies utilized cultured human OLs, obtained by dissociation of surgically derived non-MS adult Brain tissue.

Neither cell survival nor Myelin Basic Protein (MBP) Gene expression were affected after 96 hours of treatment with IFN-gamma (100 U/ml), as assessed by LDH release, nucleosome enrichment assay, and RT-PCR.

Expression of the death receptor Fas (CD95, APO-1) was, however, significantly increased.

Furthermore, IFN-gamma-treated OLs became susceptible to Fas-mediated Apoptosis when compared with untreated cells, and were protected by pretreatment with the Caspase inhibitor ZVAD. TNF-alpha augmented the IFN-gamma-induced effect.

Our results thus indicate that IFN-gamma is not directly CytoToxic for human OLs in culture, but could indirectly modulate functional injury-related responses by upregulating Fas on the cell surface.

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