MS Abstracts 01d-2g5

Background
Fatigue is a common and disabling symptom in patients with Multiple Sclerosis (MS). Underlying mechanisms postulated so far have involved localization of Brain lesions and abnormalities of the NeuroEndocrine System and Cytokine regulation.

Objective
To investigate the relationship between Fatigue and the Hypothalamo-Pituitary-Adrenal (HPA) Axis in patients with MS.

Design & Setting
A prospective survey. Outpatient and inpatient study at the Max Planck Institute of Psychiatry, Munich, Germany.

Patients
Thirty-one patients with Clinically Definite MS, a Relapsing/Remitting Disease course, and without MS-specific treatment.

Interventions
Assessment of Fatigue with 3 questionnaires: the Fatigue Severity Scale (FSS), the Modified Fatigue Impact Scale (MFIS), and the Visual Analog Scale.

Assessment of HPA Axis regulation with the combined Dexamethasone-Corticotropin Releasing Hormone (Dex-CRH) test.

Results
The FSS score was significantly correlated with the MFIS score. Patients with Fatigue had significantly elevated AdrenoCorticoTropin (ACTH) levels in the combined Dex-CRH test.

Conclusions
In contrast to results for Chronic Fatigue Syndrome, where a HypoReactivity of the HPA Axis has been shown, MS patients with Fatigue exhibited a higher activity of the HPA Axis than those without Fatigue, as evidenced by significantly increased ACTH concentrations.

ProInflammatory Cytokines, known to be elevated in patients with MS, may cause both HPA Axis alterations and Fatigue.

Activated Macrophages have been shown to produce Brain-Derived Neurotrophic Factor (BDNF) in diseases such as Multiple Sclerosis (MS) or allergic Bronchial Asthma (BA).

However, there is little data on BDNF regulation in these cells. We demonstrate that unstimulated human peripheral blood Monocytes, but not Lymphocytes, constitutively secrete BDNF.

IL-6 and TNF- specifically enhanced BDNF secretion in Monocytes, whereas typical Th1- and Th2-Cytokines did not show any effect.

None of the Cytokines induced BDNF secretion in T- or B-Cells. Thus, our data provide evidence that IL-6 and TNF- represent a specific link between Monocyte infiltration and Neuronal changes in Inflammatory Diseases.

Objective
To prospectively evaluate the diagnostic significance of bifid VEP at initial presentation.

Materials And Methods
A hundred and sixteen patients (46 males and 70 females, age 15-54, mean 28.8), with a clinical suspicion of Multiple Sclerosis (MS), underwent pattern-shift VEP investigation between 1992 and 1998.

They were further followed by clinical, CSF, MRI means for at least 5 years (mean 7.2). Twenty-six patients remained healthy, while 90 developed DeMyelinating Disease (in 71 MS and in 19 Optic Neuritis was the final diagnosis).

Fifty healthy persons (20 males aged 18-51, mean 28.8 and 30 females aged 18-48, mean 26.2) represented the control group. The number of persons with bifid VEP in each group are analyzed.

Results
In the controls one out of 50 exhibited bifid VEP configuration. Of 26 patients with unconfirmed suspicion for MS again one had such responses.

Bifid VEP were significantly more frequent in patients with DeMyelinative pathology (nine out of 90, 10.0%, P (chi-squared) < 0.01).

Conclusions
Bifid VEP is rarely observed in healthy persons. Its presence should suggest the possibility of DeMyelinating disease and prompt further investigation and follow-up.

Interferon-ß-1b (IFN-ß-1b) is commonly used for Relapsing/Remitting Multiple Sclerosis (MS).

We report a 23-year-old woman with childhood onset Relapsing/Remitting MS treated with IFN-ß-1b who developed overt Chronic Inflammatory DeMyelinating PolyRadiculoNeuropathy (CIDP) immediately after therapy.

A baseline conduction study before IFN-ß-1b therapy revealed decreased motor conduction velocities and prolonged F wave latencies in several nerves, but there was no Neurological Sign indicating Neuropathy.

The existence of subclinical DeMyelinating Neuropathy before IFN-ß-1b treatment was suggested, although the clinical criteria for CIDP were unfulfilled.

Following two months of IFN-ß-1b therapy, numbness of her right upper and lower limbs progressively worsened and all tendon reflexes were depressed.

ElectroPhysiologically, F waves were not evoked in any limbs except for the left Ulnar and Tibial Nerves, which showed marked prolongation of F wave latencies.

Moreover, subclinical HyperThyroidism developed in association with high Titers of Anti-Thyroglobulin and AntiThyroid Peroxydase Antibodies, which were negative before IFN-ß-1b therapy.

These findings indicated that peripheral DeMyelination worsened at the Nerve Roots after IFN-ß-1b therapy. In addition to the development of AutoImmune Thyroid Disease, the patient now fulfilled the criteria for probable CIDP.

Along with the results of a previous report demonstrating IFN-ß-induced CIDP development in patients with childhood MS, this case underscores IFN-ß as a potential risk factor for CIDP in patients with childhood onset MS.

We conducted an open-labeled clinical trial of Interferon-ß-1b (IFN-ß) treatment in 20 patients with Primary/Progressive Multiple Sclerosis (PPMS).

And, longitudinally monitored AutoAntiBodies against double-stranded DNA (dsDNA), Thyroid Peroxidase (TPO), Myelin Basic Protein (MBP), Myelin Oligodendrocyte Glycoprotein (MOG), Synapsin and S-100B.

Before treatment, one patient had elevated TPO AntiBodies, four patients had elevated AntiBodies against S-100B, two patients against MOG or Synapsin and one patient against MBP.

In two patients we observed a continuous increase of dsDNA or TPO AntiBodies above the normal range. This rise paralleled IFN-ß treatment. In addition, 11 of 20 patients developed Neutralizing AntiBodies against IFN-ß.

There was no increase of AutoAntiBodies directed against Central Nervous System Antigens.

Like patients with Relapsing/Remitting or Secondary/Progressive Multiple Sclerosis, PPMS patients may be at risk of an AutoImmune response during IFN-ß treatment.

Objective
To compare the NeuroPsychological deficits of Primary/Progressive Multiple Sclerosis with those of Relapsing/Remitting and Secondary/Progressive Multiple Sclerosis.

Methods
Sixty five patients with different clinical courses of MS were NeuroPsychologically tested for Language, Attention, Memory and Executive functions.

Discriminant analysis was used to predict the type of clinical course either by clinical variables (age, EDSS and duration of illness) or NeuroPsychological test results.

Results
For single NeuroPsychological tests, group differences were rare between the Progressive courses and the Relapsing/Remitting course of MS or absent between the Progressive courses of MS.

However, discriminant analysis correctly identified 87.7 percent of the patients' courses in general, and about 90 percent of the patients with Chronic Progressive MS.

Conclusion
Using discriminant analysis, this study found NeuroPpsychological Impairment characteristic for Relapsing/Remitting, Secondary/Progressive and Primary/Progressive patients.

InterLeukin-4 is a Th2 Cytokine with potent anti-inflammatory properties. Protection from Autoimmune Encephalomyelitis and Multiple Sclerosis has been achieved with IL-4 therapy and IL-4 deficient mice developed a more severe form of clinical disease.

Four polymorphisms within the IL-4 gene are in strong linkage disequilibrium, including one in the promoter at -590, which controls transcriptional activity.

An MS protective role for the heterozygous genotype was confirmed in Spain (exon-1+33 C/T: p=0.003, OR [CI]=0.57 [0.38-0.84]), probably indicative of an MS protection haplotype at 5q31 locus. No difference among MS clinical forms or age at onset was detected.

Mitoxantrone is an Anti-Neoplastic Anthracenedione derivative that, based on its ImmunoSuppressive properties, is approved for the treatment of severe forms of Relapsing/Remitting or Secondary/Progressive Multiple Sclerosis (MS).

Whether the beneficial clinical effects of Mitoxantrone in MS are due to a broad ImmunoSuppression, or whether there is a specific mechanism of action remains unknown.

Peripheral Blood Mononuclear Cells (PBMCs) from untreated or Interferon-beta-treated patients with MS or from healthy donors were stimulated in the presence or absence of Mitoxantrone.

Irrespective of the source of the cells and the cellular phenotype, Mitoxantrone inhibited proliferation of activated PBMCs, B-Lymphocytes, or Antigen-specific T-Cell lines (TCLs) stimulated on Antigen-Presenting Cells (APCs) in a dose-dependent manner.

For functional analysis, TCLs or APCs were incubated separately with Mitoxantrone. Pre-incubation of APC more effectively impaired TCL proliferation than pre-incubation of TCLs.

Production of Cytokines, expression of activation markers, Matrix MetalloProteinases, and Chemokine Receptors were not influenced substantially by Mitoxantrone.

In contrast, in Dendritic Cells (DCs), Mitoxantrone interfered with the Antigen-Presenting capabilities.

For evaluation of apoptotic cell death of target cells, Annexin-V-conjugates and a DNA fragmentation assay were applied. Mitoxantrone induced apoptosis of PBMCs, Monocytes and DCs at low concentrations, whereas higher doses caused cell lysis.

Our observations suggest that the beneficial effects of Mitoxantrone in MS result (i) from its ImmunoSuppressive action based on nonspecific CytoToxic effects on Lymphocytes, (ii) by inducing programmed cell death of professional APCs, such as DCs.

Magnetic Resonance Imaging (MRI) is an established clinical tool for diagnosing Multiple Sclerosis (MS), The Archetypal Central Nervous System NeuroiInflammatory Disease. In this study, we have used a model of delayed-type hypersensitivity in the rat Brain.

Which bears many of the hallmarks of an MS lesion, to investigate the development of MRI-detectable changes before the appearance of conventional indices of lesion development.

In addition, we have correlated the MRI-detectable changes with the developing HistoPathology.

Significant increases in regional Cerebral Blood Volume (rCBV) preceded overt changes in Blood-Brain Barrier (BBB) permeability, T₂ relaxation and the Diffusion properties of tissue water.

Thus, changes in rCBV might be a more sensitive indicator of lesion onset than the conventional indices used clinically in MS patients, such as contrast enhancement.

In addition, we show that BBB breakdown, and consequent Edema formation, are more closely correlated with Astrogliosis than any other Histopathologic changes, while regions of T₁ and T₂ HypoIntensity appear to reflect HyperCellularity.

Axonal damage in Multiple Sclerosis (MS) lesions is associated with failure of FibrinoLysis because of the inhibition of the PlasMinogen Activator System.

Plasma membrane Receptors for tissue PlasMinogen Activator (tPA) and PlasMinogen concentrate ProteoLytic activity on the cell surface and provide protection from inhibitors that in turn may locally enhance the FibrinoLytic Response.

Therefore, we have investigated expression of two of these Receptors in MS lesions, Annexin II Tetramer (AIIt) and low-density Lipoprotein Receptor-related Protein (LRP).

In acute MS lesions both AIIt and LRP were ImmunoLocalized on Macrophages and Astrocytes while LRP was additionally found on Neuronal Cells in Cortical Gray Matter.

Western blot analysis confirmed a significant increase in AIIt in MS lesions and in a proportion of Normal-Appearing White Matter samples.

With a highly significant correlation between Annexin II levels, and factors associated with impeded FibrinoLysis, such as PlasMinogen Activator Inhibitor-1.

ImmunoBlotting analysis of PlasMinogen revealed increased levels of Lysine-PlasMinogen in samples expressing high AIIt protein levels.

Our results suggest that limited availability of tPA in MS lesions because of formation of tPA-PlasMinogen Activator Inhibitor-1 complexes, reduces capability of tPA receptors to generate Plasmin, which further diminishes FibrinoLytic capacity in active MS lesions and possibly leads to Axonal Damage.

Oral and Intrathecal Baclofen (ITB) have been associated with Epileptic Seizures. The authors observed a higher incidence of Epileptic Seizures in 99 patients with Multiple Sclerosis (MS) treated with ITB vs a matched control group (7% vs 1%, p < 0.05).

Three patients with MS on ITB developed status epilepticus. Seizures were often associated with additional triggering factors.

Objectives
To establish the frequency of Cognitive Impairment in a population based sample of patients with recently diagnosed Relapsing/Remitting Multiple Sclerosis (RRMS).

And, to determine the relation between Cognitive abnormalities and the extent of macroscopic and microscopic tissue damage revealed by Magnetic Resonance Imaging (MRI) and Magnetization Transfer (MT) imaging.

Methods
58 patients with RRMS consecutively diagnosed in the previous six months in Aquitaine and 70 healthy controls underwent a battery of NeuroPsychological Tests.

Lesion load and Atrophy indices (Brain Parenchymal Fraction and Ventricular Fraction) were measured on Brain MRI.

MT Ratio (MTR) Histograms were obtained from lesions, Normal-Appearing White Matter (NAWM), and Normal-Appearing Gray Matter (NAGM). Gadolinium enhanced lesions were counted.

Results
44 RRMS patients could be individually matched with healthy controls for age, sex, and education.

Patients performed worse in tests of Verbal and Spatial Memory, Attention, Information Processing Speed, Inhibition, and Conceptualization.

Measures of Attention and Information Processing Speed were correlated with lesion load, mean NAWM MTR, and the peak location of the NAGM MTR Histogram in the patients.

Multivariate regression analysis showed that lesion load and mean NAWM MTR were among the MR indices that were most significantly associated with Impairment Of Attention and Information Processing Speed in these early RRMS cases.

Conclusions
Cognitive Impairment appears to be common in the early stages of RRMS, mainly affecting Attention, Information Processing Speed, Memory, Inhibition, and Conceptualization.

The severity of these deficits reflects the extent of the lesions and the severity of tissue disorganization outside lesions.