Objectives
Validation of CerebroSpinal Fluid (CSF) indexes as a measure for Intrathecal C3 and C4 production. Examination of their role in differential diagnosis of Immunological disorders of the Central Nervous System (CNS).

Material And Methods
Correlative study in controls (low back pain without disk herniation) between the CSF/Serum ratio (Q) for Albumin, and Q C3 and Q C4.

Comparative study of C3 and C4 indexes in patients with CNS dysfunction due to Relapsing/Remitting (R/R) Multiple Sclerosis (MS), Secondary/Progressive (S/P) MS, Systemic Lupus Erythematosus (SLE), and Human Immunodeficiency Virus (HIV) infection.

Results
Strong and statistically highly significant correlations between Q Albumin and Q C3 (r=0.89, P=0.0001), and Q C4 (r=0.68, P= 0.0001).

In MS patients decreased mean values for Serum (R/R, S/P) and CSF (R/R) C3, and increased C3 index mean value (R/R, S/P). In CNS SLE increase of mean C3 and C4 index values.

In CNS HIV increase of mean C3 and C4 index values, and CSF C3 and C4 concentrations. Most individual index values were within the reference range.

Conclusion
CSF index is a valid tool to detect Intrathecal C3 or C4 production.

C3 or C4 index contributes little to the differential diagnosis of Immunological CNS disorders. C3 might play a PathoGenic role in various Immunological CNS Disorders.

The mechanisms by which Type I Interferons (IFN) reduce the rate and severity of exacerbations in Multiple Sclerosis are unknown.

We utilized a model of Multiple Sclerosis to determine the extent of DeMyelination and ReMyelination in Theiler's Murine EncephaloMyelitis Virus (TMEV)-infected SJL/J mice treated with mouse IFN-/beta for a short (5 weeks) or a long (16 weeks) period.

All mice were chronically infected with TMEV to simulate the clinical situation in Multiple Sclerosis.

Short-term IFN-/ß treatment increased the percent of ReMyelinated Spinal Cord White Matter by threefold when compared with phosphate-buffered saline (PBS) treatment (P < 0.02), but it did not affect the extent of DeMyelination.

In contrast, long-term IFN-/ß treatment increased the extent of DeMyelination by twofold (P < 0.03).

Long-term treatment increased the absolute area of ReMyelination, but the percent ReMyelination as a function of area of DeMyelination was not changed because of increased DeMyelination.

An ImmunoModulatory mechanism may have contributed to the effect of IFN-/ß on White Matter Pathology because treated mice had higher anti-TMEV IgGs in Serum and demonstrated decreased numbers of B and T-Lymphocytes infiltrating the Central Nervous System (CNS).

There was no correlation between the level of anti- IFN-/ß AntiBodies and the extent of DeMyelination or ReMyelination.

These results indicate that the length of Type I IFN treatment may have paradoxical effects on DeMyelination and ReMyelination.

Copyright 2000 Wiley-Liss, Inc.

We have examined the demographics and long-term outcome of 1044 patients with sporadic and familial Multiple Sclerosis in a population-based cohort from London, Ontario.

The mean follow-up was 25 years in duration, and by this time most patients had reached the unambiguous endpoint scores of the Kurtzke Disability Status Scale (DSS), DSS 6, 8 or 10.

An affected family member was identified in 19.8% of the total population, and this subgroup was further divided arbitrarily into the following three groups by the type and number of relatives affected:

1. First degree only
   
2. First degree plus others
   
3. Second or third degree

The outcome in these groups was compared with that for those patients who, at a mean 25 year follow-up, had no relatives known to be affected.

Familial cases closely resembled those remaining sporadic in both demographics and outcome, although onset in the most heavily loaded families was earlier and male/female ratio was greater.

The times to DSS 6, 8 and 10 did not differ significantly when sporadic, familial and familial subgroups were compared.

These results provide no clinical support for viewing familial Multiple Sclerosis as distinct from the sporadic form.

The observed recurrence rate for siblings in a strictly defined epidemiological sample was 3.5%, much as projected.

These results validate the recurrence risks which have previously been derived from age-corrected data for these first-degree relatives.

Objective
The expression of InterCellular Adhesion Molecule-3 (ICAM-3), a member of the Ig supergene family, is restricted to Immune competent cells.

Expression of soluble and cell surface ICAM-3 (s- and c-ICAM-3) is preferentially seen in the state of low activation of the Immune System.

We studied the relevance of the expression levels of s- and c-ICAM-3 in CerebroSpinal Fluid (CSF) and blood.

As markers for disease activity as well as the influence of high-dose MethylPrednisolone (MP) treatment upon the expression of s- and c-ICAM-3 in blood of patients with Multiple Sclerosis (MS).

Materials & Methods
A total of 33 patients (relapses n = 25, remission n = 8) with Relapsing/Remitting MS were included into the study. CSF and blood were acquired from all of them.

Of the patients 24 were treated with high-dose MP. In those, blood was additionally collected at the 10th day of the therapy and after 3 months.

Expression of c-ICAM-3 was determined by two colour FACS analysis, whereas the concentration levels of s-ICAM-3 were measured by ELISA.

Results
In CSF we detected a significant decrease of the expression levels of c-ICAM-3 on CD3⁺ T-Cells in 25 patients suffering from an acute relapse in contrast to 8 patients with remission (P= 0.04).

In comparison to the levels before treatment and after 3 months, at the 10th day of MP treatment we obtained highly significant changes of the expression values of c-ICAM-3.

Both on CD3⁺ T-Cells (P = 0.0004; P= 0.005) and CD14⁺ Monocytes/Macrophages (P =0.0006; P=0.008) on the 10th day of high-dose MP treatment from 24 MS patients.

Conclusion
The increase of ICAM-3 levels might indicate the AntiInflammatory effect of the MP treatment. It could be interesting to search for similar effects investigating the new Immune modulatoring therapy forms of MS.

InterLeukin-1 (IL-1) is one of the major ProInflammatory Cytokines expressed consistently in Multiple Sclerosis (MS) lesions.

InterLeukin-1 receptor antagonist (IL-1ra) is the only known naturally occurring specific antagonistic Cytokine counteracting IL-1.

Thus IL-1ra may have a downregulating potential in the disease course of MS. We analyzed if circulating IL-1ra could be associated with different disease stages of MS in Sera of 84 MS patients and 18 controls.

IL-1ra showed considerable variations in MS patients and controls. Nevertheless we found significantly elevated Serum levels in active as well as in stable disease stages compared to controls.

IL-1ra levels were higher in Progressive disease courses compared to Relapsing/Remitting MS, but not statistically significant (median: 516 versus 434 pg/ml).

Further analysis with larger groups of patients and longitudinal studies will clarify if IL-1ra is useful as a prognostic Serum marker in MS.

Objectives
To compare CerebroSpinal Fluid (CSF) and Serum Transferrin (Tf) concentrations, Transferrin quotient and index in various subgroups of MS patients.

Material And Methods
CSF and Serum Transferrin concentrations, Transferrin quotient QTf (i.e. CSF Transferrin/Serum Transferrin x 10(3)) and index (QTf/QAlbumin) were determined in a group of 51 patients with Clinically Definite or Probable Multiple Sclerosis (MS).

Patients were subdivided according to the disease form (Relapsing/Remitting = R/R, Secondary/Progressive = S/P, Primary/Progressive = P/P.

Patients with R/R form were further subdivided into those in the attack and those in remission), disease severity (EDSS 0-5.5, EDSS 6.0-10.0).

Its treatment (non-treated - including patients treated with Vitamins and/ or Vasodilators only, treated - i.e. GlucoCorticoids and/or ImmunoSuppressants and/or (exceptionally) Interferon-ß), disease duration (0-2 years, >2-10 years, > 10 years) and sex.

Correlation of Transferrin values with age was also performed.

Results
Serum Transferrin was somewhat lower and significantly more frequently subnormal in P/P patients in comparison with the S/P form and the R/R form in remission.

Transferrin index was significantly higher in the P/P form than in the R/R as well as the S/P form.

Transferrin quotient was significantly more frequently subnormal in patients in remission compared to those in the attack of the R/R disease.

CSF Transferrin as well as Transferrin quotient were more frequently subnormal in patients with short disease duration (0-2 years) than in patients with longer disease duration; these parameters, however, correlated also significantly with age.

CSF Transferrin and Transferrin quotient were higher in male than in female patients.

Conclusion
The authors conclude that evaluation of Transferrin in MS patients - along with Albumin - may help to differentiate among various MS subgroups, since there are significant differences among R/R, S/P and P/P forms.

For this purpose, however, other CSF protein fractions should be evaluated in parallel in order to obtain more complex information and to establish a panel of examinations enabling multiple statistical analyzes.

Transferrin evaluation in MS may also be of significant theoretical interest, since Transferrin is known to be involved in the regulation of Iron metabolism and it may have a protective role against the Oxidative Stress.

Moreover, Transferrin is a Growth Factor important for proliferation of activated T-Lymphocytes.

By means of the use of Transferrin quotient and especially Transferrin index, it may be possible to estimate the proportion of intra-CNS-synthesized Transferrin and/or rate of specific Transferrin transport across the Blood-CSF Barrier. Further studies are, however, needed for such an evaluation.

InterLeukin-10 is a potent ImmunoModulatory Cytokine with possible implications for the PathoGenesis of Multiple Sclerosis. Increased IL-10 mRNA expression is associated with stable disease.

The InterLeukin-10 Gene is highly PolyMorphic and certain haplotypes result in differential InterLeukin-10 expression.

The presence of Guanine instead of Adenine at position -1082 in the IL10 promotor was shown to result in a higher IL-10 production.

We analyzed this diallelic PolyMorphism in patients with Multiple Sclerosis but did not find any association between a certain -1082 IL-10 genotype and susceptibility to or severity of Multiple Sclerosis.

Allelic variants of the ApolipoProtein E (APOE) Gene influence the course of several Neurological diseases.

In Multiple Sclerosis the concentration of APOE in CerebroSpinal Fluid and its Intrathecal synthesis is reduced.

Specific isoforms of APOE may also be important and it has been suggested that possession of the epsilon4 allele may be associated with a more aggressive disease process.

These data prompted us to re-examine, in a large group of patients with Multiple Sclerosis, the proposal that allelism in the ApolipoProtein Gene influences disease course.

Genotypes were determined in a well-defined group of 370 unrelated Caucasians with Clinically Definite Multiple Sclerosis and in 159 healthy controls. Age at onset, sex, disease duration, disease subtype were recorded.

Disability was measured using the Kurtzke Expanded Disability Status Score in patients with a disease duration of 10 years or greater.

There was no significant difference in APOE allele or genotype frequencies between patients and controls, between disease subtypes or between genders.

APOE genotype did not significantly influence age of onset, and no significant relationship between genotype, allele frequency and disease severity was found.

This study suggests that individual APOE alleles or genotypes do not determine disease susceptibility or the clinical course of Multiple Sclerosis.

Multiple Sclerosis (2000) 6 32 - 36