MS - Abstracts 11d-2g

Purpose
We evaluated whether disrupting Genital Central Nervous System pathways is associated with subjective reports of Sexual Dysfunction in women with Multiple Sclerosis.

Materials And Methods
We performed Pudendal SomatoSensory Evoked Potential Testing in and had sexual questionnaires completed by 14 women with a mean age of 47 years who had Multiple Sclerosis.

Results
The mean Expanded Disability Status Scale was 5. All but 1 woman reported the desire for sexual intercourse. There was a high rate of dissatisfaction with their sex life and all study participants had concomitant Bladder and Bowel function problems.

The most common sexual complaint was difficult or no Orgasm, which was statistically associated with abnormalities or absence of 1 or both Pudendal Cortical Evoked Potentials. Fatigue and Arousal Disorders were also common.

Conclusions
Women with Multiple Sclerosis have a high self-reported rate of Sexual Dysfunction, which decreases quality of life.

ElectroDiagnostic data imply that Pudendal SomatoSensory innervation is necessary for normal female Orgasmic Function. More study is needed to confirm these findings.

We measured the InterLeukin (IL-6) and IL-10 levels in the Plasma and the CerebroSpinal Fluid (CSF) of a total of 23 Relapsing Multiple Sclerosis (MS) patients

• 18 with Conventional form of MS (C-MS)
• 5 with Optic-Spinal form of MS (OS-MS)].

Using ELISA and correlated them with the IgG indices and OligoClonal IgG Bands (OB) to determine whether these Cytokines play a role in the Intrathecal ImmunoGlobulin production.

IL-10 values in the CSF significantly correlated with the IgG indices and tended to be higher in OB-positive patients.

In contrast, IL-10 values in the Plasma and IL-6 values in the CSF and the Plasma did not correlate with the IgG indices or OB.

The CSF-IL-10 value in OS-MS were much lower than those of C-MS, but those of CSF IL-6 did not differ between C-MS and OS-MS.

The results remained unchanged even when OS-MS patients were excluded. Our results may suggest a role of IL-10 in upregulating the Intrathecal IgIgG synthesis in Relapsing MS.

Multiple Sclerosis occurs more commonly in females than males. However, the mechanisms resulting in gender differences in Multiple Sclerosis are unknown.

Activated Microglia are believed to contribute to Multiple Sclerosis pathology, perhaps in part due to production of Nitric Oxide (NO).

And TNF-, molecules which can be toxic to cells including Oligodendrocytes.

The current study demonstrates that the female sex Steroids Estriol, ß-Estradiol and Progesterone inhibit LipoPolySaccharide (LPS) induction of Nitric Oxide (NO) production by primary rat Microglia and by the mouse N9 Microglial cell line.

These Hormones act by inhibiting the production of inducible Nitric Oxide Synthase (iNOS) which catalyses the synthesis of NO. Estriol likely inhibits iNOS Gene expression since the Hormone blocks LPS induction of iNOS RNA levels.

The pro-inflammatory Cytokines IFN- and TNF- are believed to be important modulators of Multiple Sclerosis.

Here, we demonstrate that Estrogens and Progesterone also inhibit NO production by Microglial Cells activated in response to these Cytokines. Activated Microglia elicit TNF- in addition to NO.

And we further demonstrate that Estrogens and Progesterone repress Tumor Necrosis Factor- production by these cells.

Finally, Estriol and Progesterone, at concentrations consistent with late pregnancy, inhibit NO and TNF- production by activated Microglia.

Suggesting that Hormone inhibition of Microglial Cell activation may contribute to the decreased severity of Multiple Sclerosis symptoms commonly associated with pregnancy.

Systemic administration of Interferon-beta (IFN-ß) has been recently approved for the treatment of Relapsing/Remitting Multiple Sclerosis (RRMS).

The Immunological mechanism by which IFN-ß ameliorates MS is still partially unknown.

We measured the number of blood circulating CD4⁺, CD4^-, CD8⁺, and CD8^- T-Cells secreting IFN-.

And IL-4 in 26 RRMS patients followed for up to 9 months of an alternate day s.c. treatment with 8x16 IU of IFN-ß-1b.

Compared to pre-treatment values, a significant (P<0.05) reduction of CD4⁺, CD4^-, CD8⁺ and CD8^- Cells producing IFN-.

And of CD4⁺ and CD4^- Cells producing IL-4 was observed in MS patients.

The IFN-ß-associated effect was evident soon after the beginning of the treatment and persisted for the entire follow-up period.

We did not observe any effect of IFN-ß treatment on the percentage of IL-4-producing CD8⁺ and CD8^- Cells nor in that of Natural Killer (NK) Cells producing IFN-.

Our results show that IFN-ß treatment in MS patients induces a profound and persistent down-regulation of the number of circulating T-Cells secreting IFN-.

And IL-4 thus suggesting a broader rather than a specific ImmunoModulatory effect of IFN-ß in MS.

Effects on Adhesion Molecules of Immune Cells might contribute to the mode of action of Interferon-beta (IFN-ß) in Multiple Sclerosis (MS).

We have serially monitored the cell surface expression of Integrins CD49d (VLA-4) and CD11a (LFA-1) on fresh T-Lymphocyte subpopulations from 5 MS patients monthly for 2 months prior to treatment and for 3 months on treatment with IFN-ß-1b.

In parallel, we assessed inflammatory disease activity by monthly contrast-enhanced Magnetic Resonance Imaging (MRI).

IFN-ß treatment specifically downregulated CD49d expression on CD8⁺ and CD4⁺/CD45RO⁺ 'memory' T-Lymphocytes.

And differentially modulated the proportion of CD4⁺, CD8⁺ and CD27⁺ T-Cells.

These effects may play an important role in the reduction of Central Nervous System cell trafficking and inflammation in MS.

In the animal model of Multiple Sclerosis, Experimental AutoImmune EncephaloMyelitis, Encephalitogenic T-Cells differ from the non-Encephalitogenic ones in their expression of CD49d.

The disease-inducing CD49d (high) and not the CD49d (low) cells enter the Brain Parenchyma. In this context, we characterized CD4⁺ (CD45RO⁺ CD49d (high) cells in Relapsing/Remitting Multiple Sclerosis (RR-MS) patients.

These cells, showing characteristics of activated cells able to produce pro-inflammatory Cytokines, were found to be increased in peripheral blood during relapses and present in high numbers in CerebroSpinal Fluid.

These results suggest that the CD4⁺ CD45RO⁺ CD49d (high) subpopulation in RR-MS patients includes AutoReactive Cells and may be target for ImmunoTherapy.

AutoImmune T-Cells play a key role as regulators and effectors of organ-specific AutoImmune Disease.

In Multiple Sclerosis (MS), activated T-Cells specific for Myelin components produce a plethora of inflammatory Cytokines and mediators that contribute to Myelin damage.

The production of ProInflammatory and regulatory Cytokines by peripheral blood cells from patients with active and stable MS and healthy controls were examined.

The results show that TNF- production was somewhat elevated in active MS with no significant increase in the IFN- level.

Whereas in the chronic phase the anti-inflammatory Cytokines IL-10 and TGFß increased, accompanied by a reduction in IFN- when stimulated by Myelin Basic Protein.

Multiple Sclerosis (2000) 6 293 - 299

Patients presenting with isolated partial Cervical Myelopathy are at high risk for development of Multiple Sclerosis (MS), especially if lesions suggestive of DeMyelination are present on Cranial Magnetic Resonance Imaging (MRI).

This risk is lower, though not precisely known, in patients whose Cranial MRI is normal. This clinical issue was addressed by examining the role of paraclinical studies in establishing a diagnosis of MS at the time of initial presentation.

Twelve consecutive patients, mean age of 32.2 years, seen over 6.5 years were identified prospectively and included in this study.

Numbness was the presenting symptom in 11 of these patients. Symptoms completely resolved in nine patients regardless of treatment with GlucoCorticoids.

Evoked Potential (EP) and CerebroSpinal Fluid (CSF) examinations assisted in establishing a diagnosis of Laboratory-Supported Definite (LSDMS) or Clinically Probable (CPMS) MS in six patients at the time of presentation.

During a clinical follow-up period of 4.1 years, four developed recurrent Neurologic deficits leading to the establishment of a diagnosis of Clinically Definite MS (CDMS).

The presence of a solitary, non-specific lesion on Cranial MRI resulted in an increased risk for the development of Definite MS.

In patients with a clinically isolated Cervical partial Transverse Myelitis (TM) and normal Cranial MRI, an accurate diagnosis of MS can usually be made. Revision of the diagnostic criteria for LSDMS is warranted.