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MS Abstracts 8b-2g1

  1. T1 lesion load and Cerebral Atrophy as a marker for clinical progression in Multiple Sclerosis: A prospective 18 months follow-up study
    Eur J Neurol 2001 Jan;8(1):37-42

  2. Multiple Sclerosis: altered Glutamate homeostasis in lesions correlates with Oligodendrocyte and Axonal damage
    Ann Neurol 2001 Aug;50(2):169-80

  3. Costs, quality of life and disease severity in Multiple Sclerosis: a cross-sectional study in Sweden
    Eur J Neurol 2001 Jan;8(1):27-35

  4. Fibroblast growth factor-II Gene therapy reverts the clinical course and the pathological signs of chronic Experimental AutoImmune EncephaloMyelitis in C57BL/6 mice
    Gene Ther 2001 Aug;8(16):1207-13

  5. Diagnosis of Myelopathy
    Rev Prat 2001 Jun;51(11):1187-90

  6. Combination of Cyclophosphamide and Interferon-beta halts progression in rapidly Transitional Multiple Sclerosis
    J Neurol NeuroSurg Psychiatry 2001 Sep;71(3):404-7

  7. Systematic review of Vertigo in primary care
    Br J Gen Pract 2001 Aug;51(469):666-71

  8. Prevention of EAE in Callithrix Jacchus: a chimeric antagonist MonoClonal AntiBody against human CD40 is associated with altered B-Cell responses
    J Immunol 2001 Sep 1;167(5):2942-2949

  9. MRI characteristics of the MLF in MS with chronic InterNuclear Ophthalmoparesis
    Neurology 2001 Sep 11;57(5):762-8

  10. Association between the endogenous RetroVirus HRES-1 and Multiple Sclerosis in the United Kingdom - evidence of Genetically different disease subsets?
    Dis Markers 2000;16(3,4):101-4

  11. Overview of Imaging in Multiple Sclerosis and White Matter Disease
    NeuroImaging Clin N Am 2000 Nov;10(4):669-687

  12. Continuous InterLeukin-6 application in vivo via MacroEncapsulation of InterLeukin-6-expressing COS-7 cells induces massive Gliosis
    Glia 2001 Sep;35(3):234-45


T1 Lesion Load And Cerebral Atrophy As A Marker For Clinical Progression In Multiple Sclerosis: A Prospective 18 Months Follow-Up Study

Sailer M, Losseff NA, Wang L, Gawne-Cain ML, Thompson AJ, Miller DH
Eur J Neurol 2001 Jan;8(1):37-42
Otto-von-Guericke-University, Dept of Neurology II, Magdeburg, Leipzigerstrasse 44, 39120 Magdeburg, Germany; and NMR Research Unit, The Institute of Neurology and National Hospital for Neurology and NeuroSurgery, Queen Square, London WC1N 3BG, UK
PMID# 11509079; UI# 21400575

We investigated the relationship between local tissue destruction, diffuse Cerebral Atrophy and clinical progression in patients with established Multiple Sclerosis (MS).

Twenty-nine patients with MS (13 patients with Relapsing/Remitting and 16 with Secondary/Progressive disease) were included in a prospective serial study.

Cerebral volumes, T1 HypoIntense lesion volumes, T2 HyperIntense lesion volumes at baseline and at 18 months follow-up.

And the volume of monthly enhancing lesions from month 0 to month 9 were assessed on Magnetic Resonance Imaging (MRI) Brain scans using highly reproducible semi-automated quantitative techniques.

The main outcome measures were the MRI parameters and Disability on Kurtzkes' Expanded Disability Status Scale.

There was a significant correlation between the change (increase) in T1 lesion volume and progressive Cerebral Atrophy.

Whereas no correlation between the T2 lesion volume and Atrophy was seen over the same follow-up period.

The change in T1 lesion volume correlated more strongly than did T2 lesion volume change with the change in Disability.

We conclude that HypoIntense abnormalities detected in T1-weighted Brain scans and Cerebral Atrophy may be directly linked.

Although one should bear in mind some potential for reversibility due to Inflammatory, Edematous lesions.

These MR measures are a useful marker of progressive tissue damage and clinical progression in established MS.


Multiple Sclerosis: Altered Glutamate Homeostasis In Lesions Correlates With Oligodendrocyte And Axonal Damage

Werner P, Pitt D, Raine CS
Ann Neurol 2001 Aug;50(2):169-80
Albert Einstein College of Medicine, Dept of Neurology, Bronx, NY 10461, USA
PMID# 11506399; UI# 21397219

Glutamate ExcitoToxicity, recently demonstrated in an animal model of Multiple Sclerosis (MS), is evoked by altered Glutamate homeostasis.

In the present study, we investigated the major regulating factors in Glutamate ExcitoToxicity by ImmunoHistoChemistry in MS and control White Matter.

With markers for Glutamate production (Glutaminase), Glutamate transport (GLAST, GLT-1 and EAAT-1), Glutamate metabolism (Glutamate DeHydrogenase [GDH] and Glutamine Synthetase [GS]), Axonal damage (SMI 32) and CNS cell types.

Active MS lesions showed high-level Glutaminase expression in Macrophages and Microglia in close proximity to DysTrophic Axons.

Correlation between Glutaminase expression and Axonal Damage was confirmed experimentally in animals.

White Matter from Other Inflammatory Neurologic Diseases displayed Glutaminase reactivity, whereas normals and noninflammatory conditions showed none.

All three Glutamate transporters were expressed robustly, mainly on Oligodendrocytes, in normal, control and MS White Matter, except for GLT-1, which showed low-level expression around active MS Lesions.

GS and GDH were present in Oligodendrocytes in normal and Non-MS White Matter but were absent from both active and chronic silent MS lesions, suggesting lasting metabolic impediments.

Thus, imbalanced Glutamate homeostasis contributes to Axonal and Oligodendroglial pathology in MS. Manipulation of this imbalance may have therapeutic import.


Costs, Quality Of Life And Disease Severity In Multiple Sclerosis: A Cross-Sectional Study In Sweden

Henriksson F, Fredrikson S, Masterman T, Jonsson B
Eur J Neurol 2001 Jan;8(1):27-35
Karolinska Institutet, Huddinge Hospital, 14186 Huddinge, Sweden; and
Stockholm School of Economics, Centre for Health Economics, Divison of Neurology, Stockholm, Sweden
PMID# 11509078; UI# 21400574

This study assessed the cost to society of Multiple Sclerosis (MS) in Sweden in 1998. The cost-of-illness method, based on the human capital theory, was used as the theoretical framework.

The study used a cross-sectional approach, in which resource utilization data and quality-of-life data (utilities) were collected at a single time point.

The total cost of MS was estimated at 4868 MSEK, or 586 MEUR, giving an annual cost of 442 500 SEK, or 53 250 EUR, per patient (1USD = 9.73 SEK, 1 EUR = 8.31 SEK, as of 21 September 2000).

Direct costs accounted for about 67% of total cost, and they were dominated by the cost of personal assistants and drugs.

Indirect costs (loss of production) accounted for about 33% of total costs. To these economic costs, intangible costs of 2702 MSEK (325 MEUR) should be added as well.

Direct, indirect and informal care costs all rose significantly with increased disability and were higher during a relapse.

Quality of life declined substantially with increased disability and was lower during a relapse.

Multiple Sclerosis was found to be associated with much higher costs to society than has been ascertained by former studies.

The study also revealed a strong correlation between severity of the disease and quality of life.

These results are crucial for further studies on the cost-effectiveness of new treatments aimed at preventing relapses and reducing progression of the disease.


Fibroblast Growth Factor-II Gene Therapy Reverts Clinical Course And Pathological Signs Of Chronic Experimental AutoImmune EncephaloMyelitis In C57BL/6 Mice

Ruffini F, Furlan R, Poliani PL, Brambilla E, Marconi PC, Bergami A, Desina G, Glorioso JC, Comi G, Martino G
Gene Ther 2001 Aug;8(16):1207-13
DIBIT-San Raffaele Scientific Institute, NeuroImmunology Unit, Dept of NeuroScience, Milano, Italy
PMID# 11509953; UI# 21400613

The development of therapies aimed to promote ReMyelination is a major issue in chronic Inflammatory DeMyelinating Disorders of the Central Nervous System (CNS).

Such as Multiple Sclerosis (MS), where the permanent Neurological impairment is due to the Axonal loss resulting from recurrent episodes of Immune-mediated DeMyelination.

Here, we show that the Intrathecal injection of a Herpes Simplex Virus (HSV) type-1 replication-defective multigene vector, engineered with the human Fibroblast Growth Factor (FGF)-II Gene (TH:bFGF vector).

Was able to significantly revert in C57BL/6 mice the ClinicoPathological signs of chronic Experimental AutoImmune EncephaloMyelitis (EAE), the animal model of MS.

The treatment with the TH:bFGF vector was initiated within 1 week after the clinical onset of EAE and was effective throughout the whole follow-up period (ie 60 days).

The disease-ameliorating effect in FGF-II-treated mice was associated with:

  1. CNS production of FGF-II from vector-infected cells which were exclusively located around the CSF space (Ependymal, Choroidal and LeptoMeningeal Cells)

  2. Significant decrease (P < 0.01) of the number of MyelinoToxic cells (T-Cells and Macrophages) both in the CNS Parenchyma and in the LeptoMeningeal space

  3. Significant increase (P < 0.01) of the number of Oligodendrocyte precursors and of Myelin-forming Oligodendrocytes in areas of DeMyelination and Axonal Loss

Our results indicate that CNS Gene therapy using HSV-1-derived vector coding for NeuroTrophic Factors (ie FGF-II) is a safe and non-toxic approach.

That might represent a potential useful 'alternative' tool for the future treatment of Immune-mediated DeMyelinating Diseases.


Diagnosis Of Myelopathy

Labauge P
Rev Prat 2001 Jun;51(11):1187-90
CHU de Montpellier-Nimes Hopital, Service de Neurologie, Caremeau 30029 Nimes
PMID# 11503487; UI# 21395555

Diagnosis of Myelopathy whatever its cause, is based on clinical findings: Paraparesis, loss of Sensibility, Sphincterian disturbance.

Diagnosis of Myelopathy requires Magnetic Resonance Imaging, which rules out Compressive and Vascular Disorders.

Main causes of Inflammatory Myelopathies are Multiple Sclerosis, MultiSystemic Disorders, Infectious and Post-Infectious Diseases.

Absence of identifiable causes in one quarter of the cases leads to the diagnosis of Idiopathic Myelitis.


Combination Of Cyclophosphamide And Interferon-ß Halts Progression In Rapidly Transitional Multiple Sclerosis

Patti F, Cataldi ML, Nicoletti F, Reggio E, Nicoletti A, Reggio A
J Neurol NeuroSurg Psychiatry 2001 Sep;71(3):404-7
Univ of Catania, Dept of Neurological Sciences, Via S Sofia 78, 95123 Catania, Italy
PMID# 11511721; UI# 21403166

The effects of combined treatment with Cyclophosphamide (CTX) and Interferon-beta (IFN-ß) are described in selected patients with "rapidly Transitional" Multiple Sclerosis.

This form of Multiple Sclerosis is extremely active with very frequent and severe attacks which produce a dramatic increase on the Expanded Disability Status Scale (EDSS).

Ten patients with rapidly Transitional Multiple Sclerosis were previously treated with Interferon-ß, but none benefited by this treatment.

Monthly treatment with intravenous CTX, from 500 mg/m(2) to 1500 mg/m(2) to obtain a chronic LymphoCytopenia (600/mm(3) to 900/mm(3)) produced a marked and significant reduction in the number of relapses (p<0.0001), disability previously accumulated (p<0.0001).

And a reduction of T2 MRI burden of lesion. This particular group of patients benefited by combining Cyclophosphamide and IFN-ß.

The possibility is considered of carrying out further studies to test the efficacy of the association between the two drugs for patients who are not responsive to IFN-ß or other active disease modifying therapies.


Systematic Review Of Vertigo In Primary Care

Hanley K, O'Dowd T, Considine N
Br J Gen Pract 2001 Aug;51(469):666-71
Trinity College, Dublin, Ireland
PMID# 11510399; UI# 21402208

The symptom of Vertigo is usually managed in primary care without further referral. This review examines the evidence on which general practitioners can base clinical diagnosis and management of this relatively common complaint.

Research in this area has in the main been from secondary and tertiary centers and has been of variable quality.

Indications are that the conditions that present in general practice are most likely to be Benign Positional Vertigo, acute Vestibular Neuronitis, and Meniere's Disease.

However, Vascular incidents and Neurological causes, such as Multiple Sclerosis, must be kept in mind. An important practice point is that Vestibular sedatives are not recommended on a prolonged basis for any type of  Vertigo.

There is a need for basic Epidemiological and clinical management research of  Vertigo in general practice.


Prevention of EAE In Callithrix Jacchus: A Chimeric Antagonist MonoClonal AntiBody Against Human CD40 Is Associated With Altered B-Cell Responses

Boon L, Brok HP, Bauer J, Ortiz-Buijsse A, Schellekens MM, Ramdien-Murli S, Blezer E, van Meurs M, Ceuppens J, de Boer M, 't Hart BA, Laman JD
J Immunol 2001 Sep 1;167(5):2942-2949
Biomedical Primate Research Center, Tanox Pharma B.V., Amsterdam, The Netherlands; Institute of Brain Research, Univ of Vienna, Dept of ImmunoBiology, Rijswijk, The Netherlands; Dept of NeuroImmunology, Vienna, Austria; Netherlands Central Organization for Applied Scientific Research Prevention and Health, Division of Immunological and Infectious Diseases, Leiden, The Netherlands; Univ, Medical Center, Imaging Science Institute, Utrecht, The Netherlands; Catholic Univ of Leuven, Division of Experimental Immunology, Faculty of Medicine, Belgium; Erasmus University, Dept of Immunology, Rotterdam, The Netherlands; and Academic Hospital Dijkzigt, Dijkzigt, The Netherlands
PMID# 11509643

Inhibition of CD40-CD40 Ligand interaction is a potentially effective approach for treatment of AutoImmune Diseases, such as Multiple Sclerosis.

We have investigated this concept with a chimeric antagonist anti-human CD40 mAb (ch5D12) in the marmoset monkey Experimental AutoImmune EncephaloMyelitis (EAE) model.

Marmosets were immunized with recombinant human Myelin Oligodendrocyte Glycoprotein (rMOG) and treated from the day before immunization (day -1) until day 50 with either ch5D12 (5 mg/kg every 2-4 days) or placebo.

On day 41 after the induction of EAE, four of four placebo-treated monkeys had developed severe clinical EAE, whereas all animals from the ch5D12-treated group were completely free of disease symptoms.

High Serum levels of ch5D12 associated with complete coating of CD40 on circulating B-Cells were found.

At necropsy placebo- and ch5D12-treated animals showed similar MOG-specific LymphoProliferative responses in vitro.

But ch5D12 treatment resulted in strongly reduced Anti-MOG IgM Ab responses and delayed Anti-MOG IgG responses.

Most importantly, treatment with ch5D12 prevented intramolecular spreading of Epitope recognition.

Postmortem Magnetic Resonance Imaging and ImmunoHistologic analysis of the CNS showed a markedly reduced lesion load after ch5D12 treatment.

In conclusion, the strong reduction of clinical, pathological, and radiological aspects of EAE by ch5D12 treatment in this preclinical model points to a therapeutic potential of this engineered antagonist Anti-CD40 mAb for Multiple Sclerosis.


MRI Characteristics Of The MLF In MS With Chronic InterNuclear Ophthalmoparesis

Frohman EM, Zhang H, Kramer PD, Fleckenstein J, Hawker K, Racke MK, Frohman TC
Neurology 2001 Sep 11;57(5):762-8
Univ of Texas Southwestern Medical Center, Depts of Neurology, and Radiology, Dallas, Texas
PMID# 11552000; UI# 21436210

The authors imaged the Medial Longitudinal Fasciculus (MLF) in 58 patients with MS and chronic InterNuclear Ophthalmoparesis (INO).

To determine which MRI technique best shows the characteristic lesion associated with this Ocular Motor Syndrome.

Using quantitative infrared Oculography, the authors determined the ratios of abduction to adduction for velocity and acceleration.

To confirm the presence of INO and to determine the severity of MLF dysfunction in 58 patients with MS and INO.

Conventional MRI techniques, including Proton Density Imaging (PDI), T2-weighted imaging, and Fluid-Attenuated Inversion Recovery (FLAIR) imaging, were used to ascertain which technique best shows MLF lesions within the BrainStem Tegmentum.

T1-weighted imaging was performed to determine the frequency of BrainStem Tegmentum HypoIntensities.

All patients studied had evidence of an MLF lesion HyperIntensity on PDI, whereas T2-weighted imaging and FLAIR imaging showed these lesions in 88% and 48% of patients, respectively.

With PDI, DorsoMedial Tegmentum lesions were seen in the Pons in 93% of patients and in the MidBrain of 66% of patients.

Lesions were observed at both locations in 59% of patients. One patient had an MLF Lesion with a corresponding T1 HypoIntensity.

PDI best shows the MLF lesion in patients with MS and INO.


Association Between The Endogenous RetroVirus HRES-1 And Multiple Sclerosis In The United Kingdom - Evidence Of Genetically Different Disease Subsets?

Rasmussen HB, Kelly MA, Francis DA, Clausen J
Dis Markers 2000;16(3,4):101-4
Roskilde University, Dept of Life Sciences and Chemistry, PO Box 260, DK-4000 Roskilde, Denmark
PMID# 11381188; UI# 21275382

In the present study we determined the frequencies of four HaploTtypes of the human T-Cell LymphoTropic Virus-related endogenous sequence, HRES-1, in 110 Multiple Sclerosis (MS) patients and 100 healthy control subjects from the United Kingdom.

We found evidence of an association between this endogenous RetroVirus and MS (p < 0.01), in particular reflecting an increased frequency of HRES-1 HaploTtype 1 in the group of patients.

There was no significant difference in the distribution of HRES-1 HaploTtypes between Relapsing/Remitting MS and the Primary/Progressive form of the disease.

The odds ratio for HRES-1 HaploTtype 1 and MS did not differ significantly between individuals positive for HLA-DR2 and DR2-negative individuals.

Comparison of the observations from the present study with previous results implicated HRES-1 as a marker of Genetic heterogeneity in MS.


Overview Of Imaging In Multiple Sclerosis And White Matter Disease

Butman JA, Frank JA
NeuroImaging Clin N Am 2000 Nov;10(4):669-687
National Institutes of Health, Imaging Sciences Program, Clinical Center, Dept of Diagnostic Radiology, Bethesda, Maryland
PMID# 11359718

MR imaging is the dominant paraclinical test for evaluating Multiple Sclerosis (MS) because of its exquisite sensitivity to White Matter pathology.

Knowledge of the signal characteristics of MS lesions, anatomic distribution of lesions, differential diagnosis, and most important, the clinical context, markedly improve the specificity of the MR examination.

MR imaging findings can be used to predict future conversion to Clinically Definite MS before a second clinical exacerbation.


Continuous InterLeukin-6 Application In Vivo Via MacroEncapsulation of InterLeukin-6-Expressing COS-7 Cells Induces Massive Gliosis

Tilgner J, Volk B, Kaltschmidt C
Glia 2001 Sep;35(3):234-45
Univ of Freiburg, Dept of Neuropathology, Freiburg, Germany
PMID# 11494414; UI# 21385056

The inflammatory Cytokine InterLeukin-6 (IL-6) was found in senile plaques of Alzheimer's patients and might be involved in the pathology of Parkinson's Disease and Multiple Sclerosis.

Interestingly, an AstoCytosis is also found in these NeuroDegenerative Disorders. To evaluate the direct effects of IL-6 in vivo on Glial Cells, we created a new in vivo model.

IL-6 and mock-transfected (control group) COS-7 cells were encapsulated in a Poly-Acryl-Nitril membrane for implantation into the rat Striatum.

Afterward, the host Immune reaction to the membrane without encapsulated cells and the biological action of IL-6-producing capsules was evaluated.

Animals with an implanted membrane without cells, showed a moderate AstroCytosis 5 days after the operation. Furthermore, Microglia and T-Cells could be detected and after 30 days the AstroCytosis decreased to a small layer around the membrane.

In comparison to the control group, which received a sham operation, our results demonstrate that the response of Glial Cells is caused by the mechanical damage of the surgical procedure itself, rather than due to the introduced membrane material.

In contrast, we found a massive proliferation and activation of Astrocytes and Microglia after 10 days by IL-6-secreting capsules, indicating that IL-6 is involved in the induction of Gliosis.

Control animals that received encapsulated mock-transfected COS-7 cells showed only a weak response.

These data point to an involvement of IL-6 in the proliferation and activation of Glial Cells as seen in NeuroDegenerative Disorders.

Copyright 2001 Wiley-Liss, Inc.

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