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