Magnetic Resonance Spectroscopy (MRS) provides a noninvasive means of assessing in vivo tissue biochemistry.

N-AcetylAspartate (NAA) is a major Brain metabolite, and its presence is used increasingly in clinical and experimental MRS studies as a putative Neuronal marker.

A reduction in NAA levels as assessed by in vivo 1H MRS has been suggested to be indicative of Neuronal viability.

However, temporal observations of Brain pathologies such as Multiple Sclerosis, Mitochondrial Encephalopathy with Lactic Acidosis and Stroke-like episodes (MELAS), and HypoThyroidism have shown reversibility in NAA levels, possibly reflecting recovery of Neuronal function.

A knowledge of the cellular localization of NAA is critical in interpreting these findings. The assumption that NAA is specific to Neurons is based on previous ImmunoHistoChemical studies on whole Brain using NAA-specific AntiBodies.

The Neuronal localization was further substantiated by cell culture experiments in which its presence in the Oligodendrocyte-type 2 Astrocyte progenitors and immature Oligodendrocytes, but not in the mature Oligodendrocytes, was observed.

More recently, studies on Oligodendrocyte biology have revealed the requirement for Trophic factors to promote the generation, maturation, and survival of Oligodendrocytes in vitro.

Here, we have used this new information to implement a more pertinent cell cultivation procedure and demonstrate that mature Oligodendrocytes can express NAA in vitro.

This observation brings into question whether the NAA changes observed in clinical in vivo 1H MRS studies reflect Neuronal function alone.

The data presented here support the hypothesis that Oligodendrocytes may express NAA in vivo and contribute to the NAA signal observed by 1H MRS.

Object
The ProInflammatory Cytokines InterLeukin-1beta (IL-1ß) and Tumor Necrosis Factor-alpha (TNF-) are produced IntraCerebrally in Brain disorders such as Trauma, Ischemia, Meningitis, and Multiple Sclerosis.

This investigation was undertaken to analyze the effect of IntraCerebral administration of IL-1ß and TNF- on Inflammatory response, Cell Death, and Edema development.

Methods
IntraCerebral microinjections of these Cytokines were administered to rats.

The animals were killed 24 or 72 hours after the injections, and their Brains were analyzed by using Deoxynucleotidyl Transferase-mediated Deoxyuridine Triphosphate nick-end labeling (TUNEL) with Digoxigenin-labeled Deoxyuridine Triphosphate, ImmunoHistoChemical studies, and Brain-specific gravity measurement.

The IL-1ß induced a transient Inflammatory response (p < 0.001) and TUNEL staining (p < 0.001), indicating cell death, in intrinsic Central Nervous System (CNS) cells and infiltrating Inflammatory cells.

In 73.8+/-6.77% of the TUNEL-positive cells, small, fragmented nuclei were found. All TUNEL-positive cells expressed the ProApoptotic Gene Bax, and 69.6+/-4.6% of the TUNEL-positive cells expressed the AntiApoptotic Gene Bcl-2.

The Bax expression was stronger than the Bcl-2 expression. Taken together, the data indicate that Cell death occurred via the Apoptotic Pathway.

The TNF- did not induce Inflammation or DNA fragmentation within the analyzed time period.

Both IL-1ß (p < 0.001) and TNF- (p < 0.01) caused VasoGenic Edema, as measured by specific gravity and Albumin staining.

The Edematous effect of TNF- persisted 72 hours after injection (p < 0.01), whereas the IL-1ß-treated animals had normalized by that time.

Conclusions
IntraCerebral Inflammation, death of intrinsic CNS Cells, and VasoGenic Edema can be mediated by IL-1ß, and TNF- can cause VasoGenic Edema.

Suppression of these Cytokines in the clinical setting may improve outcome.

Glutamate ExcitoToxicity mediated by the AMPA/kainate type of Glutamate receptors damages not only Neurons but also the Myelin-producing cell of the Central Nervous System, the Oligodendrocyte.

In Multiple Sclerosis, Myelin, Oligodendrocytes and some Axons are lost as a result of an Inflammatory attack on the Central Nervous System.

Because Glutamate is released in large quantities by activated Immune Cells, we expected that during Inflammation in MS, Glutamate ExcitoToxicity might contribute to the lesion.

We addressed this by using the AMPA/kainate antagonist NBQX to treat mice sensitized for Experimental AutoImmune EncephaloMyelitis, a DeMyelinating model that mimics many of the clinical and pathologic features of Multiple Sclerosis.

Treatment resulted in substantial amelioration of disease, increased Oligodendrocyte survival and reduced DePhosphorylation of Neurofilament H, an indicator of Axonal damage.

Despite the clinical differences, treatment with NBQX had no effect on lesion size and did not reduce the degree of Central Nervous System Inflammation.

In addition, NBQX did not alter the proliferative activity of Antigen-primed T-Cells in vitro, further indicating a lack of effect on the Immune System.

Thus, Glutamate ExcitoToxicity seems to be an important mechanism in AutoImmune DeMyelination, and its prevention with AMPA/kainate antagonists may prove to be an effective therapy for Multiple Sclerosis.

Multiple Sclerosis is an Immune-Mediated Disorder of the Central Nervous System leading to progressive decline of Motor and Sensory functions and permanent disability.

The therapy of Multiple Sclerosis is only partially effective, despite Anti-Inflammatory, ImmunoSuppresive and ImmunoModulatory measures.

White Matter Inflammation and loss of Myelin, the pathological hallmarks of Multiple Sclerosis, are thought to determine disease severity.

Experimental AutoImmune EncephaloMyelitis reproduces the features of Multiple Sclerosis in rodents and in nonhuman primates.

The dominant early clinical symptom of acute AutoImmune EncephaloMyelitis is progressive ascending muscle weakness.

However, DeMyelination may not be profound and its extent may not correlate with severity of Neurological decline.

Indicating that targets unrelated to Myelin or Oligodendrocytes may contribute to the PathoGenesis of acute AutoImmune EncephaloMyelitis.

Here we report that within the Spinal Cord in the course of AutoImmune EncephaloMyelitis not only Myelin but also Neurons are subject to Lymphocyte attack and may degenerate.

Blockade of Glutamate AMPA receptors ameliorated the Neurological sequelae of AutoImmune EncephaloMyelitis, indicating the potential for AMPA antagonists in the therapy of Multiple Sclerosis.

IntraThymic expression of tissue-specific self Antigens may be involved in Immunological Tolerance and protection from AutoImmune Disease.

We have analyzed the role of T-Cell Tolerance to ProteoLipid Protein (PLP), the main protein of the Myelin sheath, in susceptibility to Experimental AutoImmune EncephaloMyelitis (EAE), an animal model for Multiple Sclerosis.

IntraThymic expression of PLP was largely restricted to the shorter splice variant, DM20. Expression of DM20 by Thymic Epithelium was sufficient to confer T-Cell Tolerance to all Epitopes of PLP in EAE-resistant C57BL/6 mice.

In contrast, the major T-Cell Epitope in SJL/J mice was only encoded by the Central Nervous System-specific exon of PLP.

But not by Thymic DM20. Thus, lack of Tolerance to this Epitope offers an explanation for the exquisite susceptibility of SJL/J mice to EAE.

As PLP expression in the human Thymus is also restricted to the DM20 isoform, these findings have implications for selection of the AutoImmune T-Cell repertoire in Multiple Sclerosis.

Multiple Sclerosis results from the failure of several different regulatory mechanisms designed to protect against AutoImmunity, suggesting multiple targets for therapeutic intervention.

Three papers in this issue suggest that if Tolerance to components of the Nervous System is not maintained in the Thymus and AutoImmunity ensues.

The extent of Brain damage can be checked by blockade of Glutamate receptors on Neurons and Oligodendrocytes (pages 56-70).

Purpose
To investigate whether Anterior Uveitis (AU), which often accompanies Central Nervous System (CNS) and Systemic Inflammatory Diseases including Multiple Sclerosis (MS), also develops in a murine Relapsing model of MS.

Experimental AutoImmune EncephaloMyelitis (EAE) closely resembling Relapsing/Remitting MS, induced by immunization with Myelin Basic Protein (MBP) in mice.

Methods
(PL/J x SJL) F1 female mice were immunized with MBP in Complete Freund's Adjuvant (CFA) using Pertussis Toxin as co-adjuvant.

EAE was scored clinically on a scale of 0-5 based on the degree of Paralysis. Uveitis was assessed by slit-lamp biomicroscopy. Histolological analysis of the CNS and Eye were performed.

Results
All immunized mice developed a characteristic Relapsing Paralysis. Evidence of AU was present late in the course of EAE.

Only after the resolution of the first clinical relapse, in 4 of 5 mice (80%) (clinical evidence) and 5 of 5 (100%) (histological evidence).

AU was mild to moderate with the exception of one animal, in which it was severe. Involvement was invariably bilateral. Histology showed MonoNuclear inflitrates in the Iris and Ciliary Body.

Bilateral secondary Cataracts were observed in the animal with severe Inflammation. Paralytic episodes and the AU did not coincide.

There were no clinical or histological Eye abnormalities in control mice, either non-immunized or immunized with CFA and Pertussis Toxin only.

Conclusion
We report AU in a mouse model of EAE which strongly resembles Relapsing MS. These results further suggest shared Antigenic determinants between the CNS and the Eye.

Which likely become exposed to the Immune System late in the course of CNS Inflammation.

Several clinical trials have demonstrated that 4-AminoPyridine (4-AP), a Potassium channel-blocking agent, improves symptoms in some patients with Multiple Sclerosis.

The beneficial effects have typically been attributed to the restoration of conduction to DeMyelinated Axons, since this effect was previously demonstrated experimentally.

However, the clinical dose is ~250-1000 times lower than that used experimentally, potentially making extrapolation of the experimental findings unreliable.

To examine the action(s) of 4-AP in DeMyelinating Disorders, the drug was administered at clinical doses, both in vivo and in vitro.

To rat Dorsal Column Axons which had been experimentally DeMyelinated by the IntraSpinal injection of Ethidium Bromide.

4-AP had no consistent effect in restoring conduction to DeMyelinated Axons, even to Axons which were held just on the verge of conducting by adjusting the lesion temperature.

However, 4-AP had prominent effects that did not involve DeMyelinated Axons, including the potentiation of Synaptic Transmission and an increase in skeletal muscle twitch tension.

We propose that these latter effects may be largely responsible for the beneficial action of 4-AP in Multiple Sclerosis patients.

If so, the dominant effects of 4-AP in Multiple Sclerosis patients are independent of DeMyelination, and it follows that 4-AP may be beneficial in other Neurological Disorders in which function is diminished.

One of the hallmarks of the human DeMyelinating Disease, Multiple Sclerosis is the inability to compensate adequately for the loss of Myelin and of Oligodendrocytes, the Myelin-forming cells of the CNS.

Oligodendrocyte Precursor Cells, a potential source of Oligodendrocytes, have been identified in lesions of chronic Multiple Sclerosis, but it is not known whether they develop into new, fully differentiated Oligodendrocytes, capable of ReMyelination.

Sections of post-mortem Multiple Sclerosis tissue were therefore ImmunoLabelled with AntiBodies to GalactoCerebroside (GalC).

The first Oligodendrocyte-specific molecule to be expressed by differentiating Oligodendrocyte Precursor Cells, and Myelin Oligodendrocyte Glycoprotein (MOG), a marker for mature Oligodendrocytes.

In total, 23 lesions from 15 subjects with Chronic Progressive Multiple Sclerosis were analyzed.

The ImmunoLabelling revealed that Chronic Multiple Sclerosis lesions contain only small numbers of immature, process-bearing, GalC-positive Oligodendrocytes (0-2 cells/mm(2) in 10 mum thick sections).

They had a relatively large, pale nucleus (maximum diameter: 9.9 +/- 0.9 mum).

Although they appeared to make contact with surrounding DeMyelinated Axons, most immature Oligodendrocytes appeared not to be engaged in Myelination.

These findings suggest that Oligodendrocyte differentiation of Precursor Cells is a rare event in Chronic Multiple Sclerosis, which is consistent with the general failure of Myelin repair during the later stages of this disease.

The lesions in the collection, in particular those with recent DeMyelinating activity, contained another distinct population of Oligodendrocytes.

It consisted of small, round cells with a small, dense nucleus (maximum diameter: 6.8 +/- 0.8 mum) that expressed both GalC and MOG but lacked processes.

Suggesting that these cells were mature Oligodendrocytes that had survived the loss of their Myelin sheaths, i.e. they were DeMyelinated Oligodendrocytes.

In the most recent lesions in the collection, the DeMyelinated Oligodendrocytes were found in large numbers throughout the center of the lesion (up to 700 cells/mm(2)).

While in the older lesions they were found only at the edges.

Moreover, when the borders of these older lesions still contained numerous Macrophages, they tended to contain more DeMyelinated Oligodendrocytes than those lacking Macrophages.

These findings suggest that mature, DeMyelinated Oligodendrocytes gradually disappear from lesion areas with increasing age of the lesion.

The present study thus suggests that the failure of Myelin repair, in at least some cases of Chronic Multiple Sclerosis is due to:

1. Loss of DeMyelinated Oligodendrocytes from lesions
2. Failure of the Oligodendrocyte Precursor population to expand and generate new Oligodendrocytes

Gaining further insight into these processes may prove crucial for the development of ReMyelination promoting strategies.

Macrophage-Derived Chemokine (MDC), a potent ChemoAttractant for chronically activated Th2 Lymphocytes, is constitutively expressed by Dendritic Cells, B-Cells, Macrophages, and Thymic Medullary Epithelial Cells, whereas Monocytes, NK Cells, and T-Lymphocytes produce MDC only upon appropriate stimulation.

In this study, we show in vitro MDC production also by activated T-Cells, which preferentially associate with the production of Th2 Cytokines, IL-4, IL-5, and IL-6.

And inversely correlate with the production of the Th1 Cytokine, IFN-.

Moreover, high levels of MDC were detected in the Sera of the great majority of subjects suffering from Mycosis Fungoides / Sezary Syndrome or Atopic Dermatitis, which are considered as disorders characterized by the predominant expansion and activation of Th2 Cells, respectively.

By contrast, Serum MDC levels in subjects with Multiple Sclerosis or Crohn's Disease, which are characterized by a Th1 predominance, did not differ significantly from those of healthy controls.

Finally, MDC expression was detected in the skin biopsy specimens of subjects with Atopic Dermatitis, where it was expressed by both Dendrite Cells and T-Lymphocytes.

Taken together, these findings suggest that MDC production by activated T-Cells may occur both in vitro and in vivo.

Particularly in association with Th2 Cytokines, thus providing an important amplification circuit for Th2-mediated responses.

Currently there is no treatment available to improve a stable deficit in Multiple Sclerosis.

It was shown in animal models that IntraVenous ImmunoGlobulins (IVIg) can enhance Central Nervous ReMyelination, and the first open trials were promising.

We therefore conducted a double blind, placebo controlled pilot study to evaluate the effect of IVIg treatment in patients with Multiple Sclerosis with a stable clinical deficit.

The primary outcome parameter was the change in Central Motor Conduction Time as an indirect measure of Central Myelination.

Secondary outcome parameters were Neurological examinations including the Expanded Disability Status Scale (EDSS), Neurological Rating Scale (NRS), and Manual Muscle Testing (MMT).

Ten patients were treated first with placebo and then with IVIg (0.4 g/kg body weight on 5 consecutive days), the two treatments being separated by an interval of 6 weeks.

There was no difference in the Central Motor Conduction Times measured before and 6 weeks after each treatment.

Clinically there was a small improvement after IVIg treatment, but there was no significant difference when compared with placebo.

In conclusion, our data do not support a role for IVIg in the ReMyelination of stable Multiple Sclerosis lesions as measured by Central Conduction Time. The importance of the small clinical benefit is currently not clear.

Objective
To examine surgical findings and results of MicroVascular Decompression (MVD) for Trigeminal Neuralgia (TN), including patients with Multiple Sclerosis.

To bring new insight about the role of MicroVascular Compression in the PathoGenesis of the disorder and the role of MVD in its treatment.

Methods
Between 1990 and 1998, 250 patients affected by Trigeminal Neuralgia underwent MVD in the Dept of NeuroSurgery of the "Istituto Nazionale Neurologico C Besta" in Milan.

Limiting the review to the period 1991-6, to exclude the "learning period" (the first 50 cases) and patients with less than 1 year follow up, surgical findings and results were critically analyzed in 148 consecutive cases, including 10 patients with Multiple Sclerosis.

Results
Vascular Compression of the Trigeminal Nerve was found in all cases.

The recurrence rate was 15.3% (follow up 1-7 years, mean 38 months). In five of 10 patients with Multiple Sclerosis an excellent result was achieved (follow up 12-39 months, mean 24 months).

Patients with TN for more than 84 months did significantly worse than those with a shorter history (p<0.05).

There was no mortality and most complications occurred in the learning period. Surgical complications were not related to age of the patients.

Conclusions
AetioPathoGenesis of Trigeminal Neuralgia remains a mystery.

These findings suggest a common NeuroModulatory role of MicroVascular Compression in both patients with or without Multiple Sclerosis rather than a direct causal role.

MVD was found to be a safe and effective procedure to relieve typical TN in patients of all ages.

It should be proposed as first choice surgery to all patients affected by TN, even in selected cases with Multiple Sclerosis, to give them the opportunity of pain relief without Sensory deficits.