MS Abstracts 8b-2g1

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.

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.

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.

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 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.

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.

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.

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.

Objective
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.

Methods
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.

Results
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.

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

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.

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.

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.