MS Abstracts 4d-2g

Background And Purpose
Various authors have developed criteria to classify MR imaging findings that suggest the possibility of Multiple Sclerosis.

The purpose of this study was to evaluate and compare the capacity of three sets of MR imaging criteria for predicting the conversion of isolated DeMyelinating syndromes to Clinically Definite Multiple Sclerosis .

Methods
Seventy patients with clinically isolated Neurologic symptoms suggestive of Multiple Sclerosis were prospectively studied with MR imaging.

The MR imaging findings were evaluated by two independent NeuroRadiologists who were blinded to clinical follow-up data.

Based on the clinical outcome at follow-up (presence of a second attack that established Clinically Definite Multiple Sclerosis), the sensitivity, specificity, accuracy, positive predictive value, and negative predictive value of the criteria proposed by Paty et al, Fazekas et al, and Barkhof et al were calculated.

Results
Clinically Definite Multiple Sclerosis developed in 22 (31%) patients after a mean follow-up time of 28.3 months.

The criteria proposed by Paty et al and those proposed by Fazekas et al showed identical results: sensitivity, 86%; specificity, 54%; accuracy, 64%; positive predictive value, 46%; and negative predictive value, 89%.

The criteria proposed by Barkhof et al showed the following: sensitivity, 73%; specificity, 73%; accuracy, 73%; positive predictive value, 55%; and negative predictive value, 85%.

Conclusion
The four dichotomized MR imaging parameters proposed by Barkhof et al are more specific and accurate than the criteria proposed by Paty et al or Fazekas et al for predicting conversion to Clinically Definite Multiple Sclerosis.

For determining the prevalence of Multiple Sclerosis (MS) in Germany, the outcomes of several Epidemiological studies are available. If these rates are transferred to Germany as a whole, figures result of 67,000 to 138,000 MS patients in all.

The differing prevalence rates may be caused by various problems in finding patients, the Epidemiological area, and different population structures.

To avoid these difficulties, a new approach for calculating the number of patients with diagnosed MS was chosen based on representative samples taken from the groups of physicians involved in MS treatment.

The disadvantage of this approach is that it does not allow any questioning of the diagnosis.

Projecting the results in this way and their subsequent compilation - taking "double treatments" into consideration - showed a total of 122,000 patients with diagnosed Multiple Sclerosis in Germany.

This figure corresponds to a prevalence rate of 149.1 per 100,000 inhabitants and is within the range found by Poser et al. [19]: 127 per 100,000 excluding the diagnostic category "Possible Multiple Sclerosis" and 170 per 100,000 including it.

Objectives
The study was carried out to assess the efficacy of megadose IntraVenous MethylPrednisolone in patients of Bilateral Simultaneous Optic Neuropathy (BSON) of unknown etiology.

Methods
Fifteen consecutive patients admitted in Neurology unit were included in the study.

These patients were subjected to various investigations including MRI and CSF exam to exclude all known causes of Optic Neuropathy including Multiple Sclerosis.

All patients were put on single dose IntraVenous MethylPrednisolone, 1 gm/day in adults and 500 mg/day in children for three days. Pre and post-treatment Visual parameters including Visual Evoked Potentials (VEP) were carried out.

Results
There was a female preponderance and the average age was 28 years. The Visual Acuity and P100 latences of Visual Evoked Potentials (VEP) improved in all cases. The improvement was statistically significant (P < 0.001).

Conclusion
Use of IntraVenous MethylPrednisolone is a prefered drug in Bilateral Simultaneous Optic Neuropathy (BSON) as compared to oral or RetroBulbar Steroids.

Objective
To define a safe and effective dose of Dysport for treating hip adductor Spasticity.

Methods
Patients with definite or probable Multiple Sclerosis, and disabling Spasticity affecting the Hip Adductor Muscles of both legs, were randomized to one of four treatment groups.

Dysport (500, 1000, or 1500 Units), or placebo was administered by intramuscular injection to these muscles. Patients were assessed at entry, and 2, 4 (primary analysis time-point), 8, and 12 weeks post-treatment.

Results
A total of 74 patients were recruited. Treatment groups were generally well matched at entry. The primary efficacy variables-passive Hip Abduction and distance between the knees-improved for all groups.

The improvement in distance between the knees for the 1500 Unit group was significantly greater than placebo (p=0.02). Spasm frequency was reduced in all groups, but muscle tone was reduced in the Dysport groups only.

Pain was reduced in all groups, but improvements in hygiene scores were evident only in the 1000 Unit and 1500 Unit groups. Duration of benefit was significantly longer than placebo for all Dysport groups (p<0.05).

Adverse events were reported by 32/58 (55%) Dysport patients, and by 10/16 (63%) placebo patients.

Compared with the two lower dose groups, twice as many adverse events were reported by the 1500 Unit group (2.7/patient).

The incidence of muscle weakness was higher for the 1500 Unit group (36%) than for placebo (6%).

The response to treatment was considered positive by two thirds of the patients in the 500 Unit group, and by about half the patients in the other groups.

Conclusion
Dysport reduced the degree of Hip Adductor Spasticity associated with Multiple Sclerosis, and this benefit was evident despite the concomitant use of oral AntiSpasticity medication and analgesics.

Although evidence for a dose response effect was not statistically significant, there was a clear trend towards greater efficacy and duration of effect with higher doses of Dysport. Dysport treatment was well tolerated, with no major side effects seen at doses up to 1500 Units.

The optimal dose for Hip Adductor Spasticity seems to be 500-1000 Units, divided between both legs.

Persistent DeMyelination, in addition to being the major pathology of Multiple Sclerosis and the LeucoDysTrophies, is also a feature of Spinal Cord trauma where there is evidence that it contributes to the functional deficit.

In experimental animals it is possible to ReMyelinate DeMyelinated CNS Axons by transplanting cultures containing central or peripheral Myelinogenic Cells.

Using functional testing we have been able to show that transplant-mediated ReMyelination results in restoration of function lost as a consequence of DeMyelination.

Glial Cell transplantation may therefore provide a therapeutic strategy for ReMyelinating areas of chronic DeMyelination.

This article reviews issues that have to be addressed before Glial transplantation can be undertaken in humans.

These include: what cells to use, where would the cells come from, and can we predict how much ReMyelination will be achieved?

It concludes that the most promising approach will be to use Neural multipotential Stem Cells isolated from embryonic CNS, expanded in vitro as neurospheres and then committed to Oligodendrocyte lineage differentiation prior to implantation.

However, even with such preparations, which have considerable Myelinating potential, the extent of ReMyelination that will be achieved cannot currently be predicted with any degree of certainty.

Activated, Cytokine-producing Lymphocytes may regulate Central Nervous System (CNS) Inflammation in Multiple Sclerosis (MS).

We utilize a novel combination of In Situ Hybridization (ISH) and ImmunoCytoChemical staining of Peripheral Blood Lymphocytes (PBLs) to identify spontaneously Interferon-gamma (IFN-) mRNA expressing cells as CD4⁺ or CD8⁺.

A major proportion of the IFN- mRNA expressing Lymphocytes belonged to the CD4⁺ lineage, which concords with the cellular composition of MS Brain lesions, findings in experimental models and the HLA Class II haplotype association in MS.

There were also significantly more CD8⁺ IFN- mRNA expressing Lymphocytes in the MS patients compared with healthy controls, further suggesting the contribution of activated cells from this lineage in the Inflammatory response in MS.

Both CD4⁺ and CD8⁺ IFN- mRNA expressing cells were enriched in the CerebroSpinal Fluid (CSF) as compared with the peripheral blood of the MS patients.

Combined with emerging Genetic data on HLA Class I influences, our data argues for a joint role of activated CD8⁺ and CD4⁺ cells in the PathoGenesis of MS.

RANTES (Regulated Upon Activation, Normal T-Cell Expressed And Secreted), a CC Chemokine, appears to play a role in the PathoGenesis of Relapsing/Remitting Multiple Sclerosis (RR-MS), enhancing the Inflammatory response within the Nervous System.

We have demonstrated that RANTES production is increased in RR-MS compared to controls. Interferon-beta-1b (IFN-ß-1b) treatment reduces RANTES production in Sera and Peripheral Blood Adherent MonoNuclear Cell (PBAM) supernatants both in relapse and remission.

IFN-ß-1b also reduces RANTES expression in PBAM. Our results suggest that RANTES modulation might represent one of the mechanisms of action of IFN-ß-1b in RR-MS.

Corticotropin-Releasing Hormone (CRH)-containing Neurons in the ParaVentricular Nucleus (PVN) in the HypoThalamus of Multiple Sclerosis (MS) patients are hyperactivated.

Since InterLeukin-1 (IL-1ß) is a powerful activator of CRH Neurons, its ImmunoHistoChemical expression was studied in the postmortem HypoThalamus of MS patients (n=11) and matched controls (n=11).

HypoThalamic tissue of 10/11 MS patients showed DeMyelinating lesions that in many cases contained IL-1ß-ImmunoReactive (ir) Macrophages and Glial Cells.

In control subjects IL-1ß-ir was only sporadically found in Glial Cells. Interestingly, abundant IL-1ß-ir was also present in HypoThalamic Neurons. Neuronal IL-1ß co-localized with Oxytocin and not with VasoPressin or CRH.

IL-1ß clearly yielded a less intense staining in Neurons and numbers of IL-1-ir Neurons in the PVN were 4.5-fold reduced in MS.

We suggest that IL-1ß produced by activated Glial Cells in the HypoThalamus of MS patients may contribute to the activation of the HypoThalamic CRH Neurons, while reduced expression of Neuronal IL-1ß in MS patients may have consequences for NeuroEndocrine, behavioral or Autonomic functioning.