MS Abstracts 04f-2g1

  1. High dose IVIG in the post partum period for prevention of exacerbations in MS
    Mult Scler 2000 Oct;6 Suppl 2:S18-20; discussion S33

  2. ESIMS - an ongoing clinical trial in Secondary/Progressive Multiple Sclerosis
    Mult Scler 2000 Oct;6 Suppl 2:S27-32

  3. Treatment of Chronic Progressive Multiple Sclerosis with intravenous ImmunoGlobulins
    Mult Scler 2000 Oct;6 Suppl 2:S21-3

  4. Acute stress increases permeability of the Blood-Brain-Barrier through activation of Brain Mast Cells
    Brain Res 2001 Jan 5;888(1):117-127

  5. Multiple Sclerosis with Caudate lesions on MRI
    Intern Med 2001 Apr;40(4):358-62

  6. IFN-ß-1a may increase Serum levels of TIMP-1 in Relapsing/Remitting Multiple Sclerosis
    J Interferon Cytokine Res 2001 Mar;21(3):181-5

  7. IFN-ß-1b augments GlucoCorticoid-induced suppression of Tumor Necrosis Factor-alpha production by increasing the number of GlucoCorticoid receptors on a human Monocytic cell line
    J Interferon Cytokine Res 2001 Mar;21(3):133-5

  8. Conversion to Clinically Definite Multiple Sclerosis after isolated Spinal Cord syndrome: value of Brain and Spinal MRI
    Med Clin (Barc) 2001 Feb 17;116(6):214-216

  9. Autonomic regulation of NeuroImmunological responses: implications for Multiple Sclerosis
    J Clin Immunol 2001 Mar;21(2):61-73

  10. The NeuroImmunology of Multiple Sclerosis: possible roles of T and B-Lymphocytes in ImmunoPathogenesis
    J Clin Immunol 2001 Mar;21(2):81-92

  11. Regulation by IFN-ß of Inducible Nitric Oxide Synthase and InterLeukin-12/p40 in Murine Macrophages Cultured in the Presence of Chlamydia Pneumoniae Antigens
    J Interferon Cytokine Res 2001 Mar;21(3):137-46


High Dose IVIG In The Post Partum Period For Prevention Of Exacerbations In MS

Haas J
Mult Scler 2000 Oct;6 Suppl 2:S18-20; discussion S33
Abteilung fur Neurologie, Dept of Neurology, Judisches Krankenhaus Berlin, Germany
PMID3 11188773; UI# 21029226

The influence of pregnancy on the course of AutoImmune Diseases is well documented. In Multiple Sclerosis the European PRIMS study confirmed an ameliorating effect during pregnancy but an increase of exacerbations after delivery.

The efficacy of IVIG in AutoImmune mediated diseases has been frequently reported. Based on the experiences of Achiron we recommend IVIG to prevent exacerbations after delivery.

Since 1995 we recommend 60 g IVIG within 3 days after delivery and 10 g monthly in patients estimated to be on high risk for exacerbation. The data were compared to the PRIMS study.

The baseline data were comparable, but the exacerbation rate after delivery in our observation was 33% lower than expected.

The lowest risk for an exacerbation within the first 3 months after delivery we observed in women treated with long-term IVIG monthly. Until now the overall tolerance was excellent.

The results with IVIG after delivery suggest that ImmunoGlobulins may be a promising therapeutical approach not only in MS but also in other AutoImmune mediated diseases with a risk of exacerbation after delivery.

A European wide study with IVIG after delivery in MS is in preparation to confirm our preliminary data.


ESIMS - An Ongoing Clinical Trial In Secondary/Progressive Multiple Sclerosis

Hommes OR, Maas-Enriquez M
Mult Scler 2000 Oct;6 Suppl 2:S27-32
European Charcot Foundation, Nijmegen, The Netherlands
PMID# 11188776; UI# 21029229

The design of a double-blind, placebo-controlled, European-Canadian Study on IVIG treatment in Multiple Sclerosis - ESIMS- is described.

Three hundred and eighteen Multiple Sclerosis patients with a Secondary/Progressive course, are treated with monthly infusions of ImmunoGlobulin 10% 1 g/kg bodyweight or with 0.1 g Albumin/vial for 27 months.

The primary efficacy parameter is the percentage of patients with a confirmed treatment failure in the EDSS scale and/or the Nine Hole Peg Test Secondary outcome measures are MRI T2 lesion load, Magnetization Transfer Imaging, and MRI Brain Atrophy measures.

Documentation of health resource utilisation and ability to work will cover socio-economic aspects. Recruitment of patients was completed in October 1998. The clinical part of the trial will be completed in April 2001.


Treatment Of Chronic Progressive Multiple Sclerosis With Intravenous ImmunoGlobulins

IVIG Study Group
Interim results on drug safety of an ongoing study
Mult Scler 2000 Oct;6 Suppl 2:S21-3
Poehlau D
Sauerlandklinik Hachen, Dept of Neurology, Sundern-Hachen, Germany
PMID# 11188774; UI# 21029227

In a blinded administrative look we analyzed the safety profile of IntraVenous ImmunoGlobulin (IVIG) treatment.

In an ongoing randomized, placebo controlled double blind study on the treatment of Multiple Sclerosis (MS) patients with Primary or Secondary Chronic Progressive MS. Up to October 1999 131 patients were included in the study.

Collectively, these patients received approximately 1,200 infusions either with IVIG (400 mg/kg bodyweight every 4 weeks) or with placebo; approximately 600 IVIG infusions were administered.

All reported serious adverse events (SAE), including reports on adverse events submitted directly to the drug safety department of the sponsor, were closely analyzed.

A total of 25 SAE's (in 25 patients) have been reported up until 15th October 1999, whereby the main criterion for 'serious' in all of these cases was hospitalization.

None of these 25 SAE were regarded as drug related. No side effects relating to liver functions, kidney functions or rheological problems have been reported.

The mean score on the EDSS-scale of the patients at the point of inclusion in the study was 5.6 (median EDSS: 6.0).

We conclude that IVIG treatment, at a dose of 400 mg/kg bodyweight every 4 weeks, is a relatively safe therapy even for severely disabled Multiple Sclerosis patients.


Acute Stress Increases Permeability Of The Blood-Brain-Barrier Through Brain Mast Cells Activation

Esposito P, Gheorghe D, Kandere K, Pang X, Connolly R, Jacobson S, Theoharides TC
Brain Res 2001 Jan 5;888(1):117-127
Tufts Univ, School of Medicine, Depts of Pharmacology and Experimental Therapeutics, 136 Harrison Avenue, Boston, MA 02111, USA
PMID# 11146058; UI# 21066574

Disruption of the Blood-Brain-Barrier (BBB) is important in the pathophysiology of various inflammatory conditions of the Central Nervous System (CNS).

Such as Multiple Sclerosis (MS), in which breakdown of the BBB precedes any clinical or pathological findings.

There is some evidence that Relapsing/Remitting MS attacks may be correlated with certain types of acute stressful episodes.

Stress typically activates the Hypothalamic-Pituitary-Adrenal (HPA) axis through the release of Corticotropin Releasing Hormone (CRH), leading to production of GlucoCorticoids that down regulate Immune Responses.

However, acute stress also has pro-inflammatory effects that appear to be mediated through activation of Mast Cells.

Here we show that acute stress by immobilization increased permeability of rat BBB to intravenous 99Technetium gluceptate (99Tc).

This effect was statistically significant in the DienCephalon and the Cerebellum, while it was absent in the Cerebral Cortex where there are not Mast Cells.

Immobilization stress also induced activation of Mast Cells in DienCephalon, the site where most Mast Cells are found in the rat Brain.

Both BBB permeability and Mast Cell activation were inhibited by the 'Mast Cell stabilizer' Disodium Cromoglycate (Cromolyn).

These results expand the pathophysiology of Mast Cells and implicate them in CNS Disorders, that may possibly be induced or exacerbated by stress.


Multiple Sclerosis With Caudate Lesions On MRI

Hashiguchi S, Ogasawara N, Mine H, Kawachi Y
Intern Med 2001 Apr;40(4):358-62
Takamatsu Red Cross Hospital, Dept of Neurology, Kagawa
PMID# 11334400; UI# 21232206

A 31-year-old woman displayed sleepiness and impairment of Recent Memory. T2-weighted MRI revealed high signal intensity lesions in the Bilateral Basal Ganglia, Thalamus, and BrainStem.

Although remission was achieved with CorticoSteroid therapy, she again displayed Memory Dysfunction and emotional disturbance one year later.

At which time MRI disclosed new lesions in the Right Caudate Nucleus and Left Frontal White Matter. CorticoSteroid therapy lead to improvement, and she suffered no recurrence on maintenance Steroid therapy.

These findings suggest that Caudate lesions do occur in Multiple Sclerosis, the manifestations of which can be abulia and Memory Dysfunction, as in the present case.


IFN-ß-1a May Increase Serum Levels Of TIMP-1 In Relapsing/Remitting Multiple Sclerosis

Waubant E, Gee L, Miller K, Stabler G, Goodkin D
J Interferon Cytokine Res 2001 Mar;21(3):181-5
UCSF/Mt. Zion Multiple Sclerosis Center, San Francisco, CA 94115
PMID# 11331041; UI# 21229851

Serum levels of Matrix MetalloProtease-9 (MMP-9) and Tissue Inhibitor of MMP-1 (TIMP-1) were measured monthly in 7 patients with Relapsing/Remitting Multiple Sclerosis (MS).

6 months before and 6 months during treatment with weekly intramuscular (i.m.) injections of Interferon-beta-1a (IFN-ß-1a) 30 #mgr;g.

Within patient median MMP-9 levels were unchanged on treatment. Within-patient median TIMP-1 levels were higher during months 1-6 (771.5 ng/ml) and during months 4, 5, and 6 of treatment (793 ng/ml).

Compared with 6 months pretreatment (414 ng/ml) (respectively, p = 0.10, p = 0.047; Wilcoxon signed-rank test). These preliminary data suggest that IFN-ß-1a therapy may increase TIMP-1 levels.


IFN-ß-1b Augments GlucoCorticoid-Induced Suppression Of Tumor Necrosis Factor-alpha Production By Increasing The Number Of GlucoCorticoid Receptors On A Human Monocytic Cell Line

Uitdehaag BM, Hoekstra K, Koper JW, Polman CH, Dijkstra CD
J Interferon Cytokine Res 2001 Mar;21(3):133-5
Free University, Dept of Neurology, Amsterdam, The Netherlands
PMID# 11331035; UI# 21229845

We studied the effect of recombinant Interferon-beta-1b (IFN-ß-1b) on the sensitivity to GlucoCorticoids (GC) and on the number of GC receptors (GCR) in the human Monocytic cell line THP-1.

We found that IFN-ß-1b augments the suppressive effect that Dexamethasone has on the stimulated production of Tumor Necrosis Factor-alpha (TNF-alpha).

Most likely related to the increased number of GCR observed after exposure to IFN-ß-1b, this provides a possible clue to the mechanism of action of IFN-ß in Multiple Sclerosis.


Conversion To Clinically Definite Multiple Sclerosis
After Isolated Spinal Cord Syndrome:
Value Of Brain And Spinal MRI

Pericot I, Tintoré M, Grive E, Briev L, Rovira A, Montalban X
Med Clin (Barc) 2001 Feb 17;116(6):214-216
Unitat de NeuroImmunologia Clinica, Servei de Neurologia, Servei de Radiologia, Hospital Vall d'Hebron, Barcelona
PMID# 11333719

Isolated Spinal Cord Syndrome might be due to a first episode of Multiple Sclerosis.

The aim of the study was to determine the clinical usefulness and paraclinical characteristics and of Spinal and Brain MR imaging predicting conversion to Clinically Definite Multiple Sclerosis (CDMS) in patients with an Isolated Spinal Cord Syndrome.

Patients And Methods
We have evaluate thirty-eight patients with Isolated Spinal Cord Syndrome. A clinical protocol, Lumbar Puncture, Evoked Potential and Brain-Spinal Cord MRI were performed.

Twenty two percent of the patients fulfilling Brain MRI Paty's Criteria (p < 0.01), 54.5% Fazekas (p = 0.007) and 80% of patients fulfilling Barkhof's Criteria (p = 0.009) presented CDMS.

The Spinal MR imaging from CDMS patients was always abnormal, showing Cervical and marginal location with a diameter < 2 cm.

Brain MRI is strongly predictive of the risk of developing CDMS and Spinal Cord MRI may increase the sensitivity to detect conversion to CDMS.


Autonomic Regulation Of NeuroImmunological Responses: Implications For Multiple Sclerosis

Frohman EM, Monson NL, Lovett-Racke AE, Racke MK
J Clin Immunol 2001 Mar;21(2):61-73
Univ of Texas Southwestern Medical Center at Dallas, Dept of Neurology, Dallas, Texas 75235, USA
PMID# 11332655; UI# 21230168

The expression of Neural regulatory molecules by Immune Cells that infiltrate the Nervous System upon injury may be a mechanism for cross regulation between the Nervous System and the Immune System.

Several lines of evidence implicate nerve growth factor signaling through its receptors as a potential source of communication between the two systems.

The expression of ß-Adrenergic Receptors and Sympathetic innervation of Lymphoid Organs represents another example of communication between the Immune and the Nervous System.

In this review, we discuss mechanisms of how factors in common between the Nervous System and the Immune System may result in regulatory circuits which are important in both healthy and diseased states.

These studies may have relevance for a number of inflammatory conditions in humans, including Multiple Sclerosis.


The NeuroImmunology Of Multiple Sclerosis: Possible Roles Of T And B-Lymphocytes In ImmunoPathogenesis

O'Connor KC, Bar-Or A, Hafler DA
J Clin Immunol 2001 Mar;21(2):81-92
Center for Neurologic Diseases, Brigham and Women's Hospital, Harvard Medical School, Laboratory of Molecular Immunology, Boston, Massachusetts 02115, USA
PMID# 11332657; UI# 21230170

Multiple Sclerosis (MS) is an inflammatory disease of the Central Nervous System White Matter. The association of the disease with MHC Genes, the inflammatory White Matter infiltrates, similarities with animal models.

And the observation that MS can be treated with ImmunoModulatory and ImmunoSuppressive therapies support the hypothesis that AutoImmunity plays a major role in the disease pathology.

Evidence supports activated CD4+ Myelin-reactive T-Cells as major mediators of the disease. In addition, a renewed interest in the possible contribution of B-Cells to MS ImmunoPathology has been sparked by nonhuman primate and MS pathological studies.

This review focuses on the ImmunoPathology of MS, outlining the hypothetical steps of Tolerance breakdown and the molecules that play a role in the migration of AutoReactive cells to the CNS.

Particular focus is given to AutoReactive T-Cells and Cytokines as well as B-Cells and AutoAntibodies and their role in CNS PathoGenesis in MS.


Regulation By IFN-ß Of Inducible Nitric Oxide Synthase And InterLeukin-12/p40 In Murine Macrophages Cultured In The Presence Of Chlamydia Pneumoniae Antigens

Yao SY, Ljunggren-Rose A, Stratton CW, Mitchell WM, Sriram S
J Interferon Cytokine Res 2001 Mar;21(3):137-46
Vanderbilt Univ, School of Medicine, Dept of Neurology, Nashville, TN 37212
PMID# 11331036; UI# 21229846

Chlamydia Pneumoniae has been demonstrated in the CerebroSpinal Fluid (CSF) of patients with Multiple Sclerosis (MS). Interferon-beta (IFN-ß) has favorable effects on the clinical course of MS.

We investigated whether the beneficial effects of IFN-ß in MS may involve its role in regulating Nitric Oxide (NO) and InterLeukin-12 (IL-12) in Macrophages, as these Immune modulators form part of the Innate Immune response to IntraCellular pathogens, such as C. Pneumoniae.

Murine Macrophages in cultures exposed to elementary body antigens or recombinant Major Outer Membrane Protein (rMOMP) of C. Pneumoniae demonstrate a significant increase in NO as well as production of IL-12/p40 in culture supernatants compared with basal levels.

Addition of murine IFN-ß increased NO activity in murine Macrophages cultured with Chlamydial antigens. Addition of Neutralizing Anti-IFN-ß AntiBody prevented the NO increase.

In contrast to its effect on inducible NO Synthase (iNOS), IFN-ß reduced induction of IL-12/p40 following culture with either elementary body antigens or rMOMP. Inhibition was reversed with Anti-IFN-ß AntiBody.

If C. Pneumoniae infection is responsible for the inflammatory response in the PathoGenesis of MS, the beneficial effects of IFN-ß in MS may be due to its enhancing IntraCellular NO activity while inhibiting secretion of the proinflammatory Cytokine, IL-12.

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