MS Abstracts 04c-2g5

Objective
To evaluate the effects of Mitoxantrone (Mx) in Progressive Multiple Sclerosis (MS) on MRI.

Methods
A total of 194 patients with worsening Relapsing/Remitting or Secondary/Progressive MS were treated with Mx 12 mg/m2 (n = 34), Mx 5 mg/m2 (n = 40), or placebo (n = 36) at 3-month intervals IV over a 2-year period.

In preselected MRI centers unenhanced and Gd-enhanced MRI scans were performed at month (M) 0, 12, and 24 in a non-randomized subset of 110 patients and non-selected for MRI criteria.

The primary MRI outcome measure was the total number of MRI scans with positive Gd enhancement per group.

Results
Twelve mg/m2 Mx failed to reach a significant difference from placebo as measured by the primary MRI outcome at month 12 (p = 0.431) and 24 (p = 0.065).

Secondary MRI outcome measures: 5 mg/m2 Mx influenced favorably the number of Gd-enhancing lesions only at month 24 (p = 0.004), but not at month 12 (p = 0.095).

Twelve mg/m2 Mx reduced the number of T₂-weighted lesions at month 24 (p = 0.027) and showed a positive trend at month 12 (p = 0.069), but not 5 mg/m2 Mx.

The number of active MR lesions showed a strong trend toward reduction in the 12 mg/m2 Mx group only at month 24 (p = 0.054). All comparisons are vs placebo, and unadjusted for baseline incidence.

Conclusions
In the MIMS trial 12 mg/m2 Mx does not reduce the number of MRI scans with positive Gd enhancement at month 12 and 24 vs placebo.

Results of secondary MRI outcome measures are suggestive of a positive impact of 12 and 5 mg/m2 Mx on some of the Gd enhanced and unenhanced MRI measures as expected from other Mx MRI studies in the past.

Background
Fatigue is one of the most common, yet poorly defined, disabling symptoms in patients with Multiple Sclerosis (MS). Several Fatigue Scales have been developed, but rigorous psychometric methods have not always been applied and validation was mainly based on small numbers of patients.

We therefore assembled a new fatigue scale from a set of widely used scales and assessed its psychometric properties in a large sample of MS patients.

Patients And Methods
Fatigue was assessed in 158 MS patients by four published quantitative scales: the Fatigue Severity Scale (FSS), Modified Fatigue Impact Scale (MFIS), MS-specific Fatigue Severity Scale (MFSS), and Visual Analogue Scale.

From these a new fatigue scale, the Wurzburg Fatigue Inventory for Multiple Sclerosis (WEIMuS), was assembled.

It contains 17 items with values from 0 to 4. The WEIMuS scale was validated in a subgroup of 67 patients and a control group of 68 patients.

Results
The MFIS and FSS but not the MFSS showed high internal consistency and split-half reliability.

After applying factor analysis within the scales, fairly reliable and valid items originally found in the MFIS and FSS were selected to construct the final 17-item WEIMuS scale, which showed a high degree of reliability.

In the validation study, varimax rotated factor analysis extracted two main factors corresponding to both Cognitive and physical Fatigue.

Conclusion
The new, two-dimensional WEIMuS showed good psychometric properties, is easy to use, and may therefore be a useful tool for the assessment of MS-associated fatigue.

Multiple sclerosis patients suffer from different types of fatigue which could be attributed to cognitive and physical fatigue. Thus, MS-associated fatigue is different from common tiredness.

Background
Chronic, HypoIntense Black Holes (BHs) are recognized as a sign of permanent damage in patients with Multiple Sclerosis.

Although the effects of Interferon-ß-1b in reducing the formation of new BHs are established, it is not clear whether the drug may reduce BH duration after these lesions are formed.

Objective
To analyze the effects of Interferon-ß-1b in reducing the duration of T1 BHs in patients with Multiple Sclerosis.

Design
Patients were clinically assessed and imaged monthly over a 36-month natural history phase and 36-month therapy phase. Numbers of contrast-enhanced lesions and newly formed BHs were counted on each scan. Each BH was counted until it was no longer seen.

Setting & Patients
Outpatient service of the NeuroImmunology Branch at the National Institutes of Health, Bethesda, Md. Six patients with Relapsing/Remitting Multiple Sclerosis were included.

One patient did not form any BHs during the therapy phase. Analyzes were performed on the remaining 5 individuals.

Interventions
Interferon-ß-1b at the dosage of 8 million international units every other day.

Main Outcome Measures
Number and duration (in months) of newly formed BHs.

Results
Rate of BH accumulation decreased with treatment (P = .01), but Kaplan-Meier models revealed that the duration of BHs did not shorten (chi(2)(1) = 2.47, P = .12).

Conclusions
Interferon-ß-1b reduces the frequency of new BH formation but does not appear to decrease their duration in time. Analyses with larger patient cohorts are needed to confirm these preliminary findings.

Background
Exogenous estrogens affect the onset and clinical course of Experimental Allergic Encephalomyelitis. Oral contraceptives, a frequent source of exogenous Estrogens in humans, could have a role in the development of Multiple Sclerosis (MS).

Objective
To examine whether recent oral contraceptive use and pregnancy history are associated with the risk of MS.

Design And Setting
A case-control study nested in the General Practice Research Database. This database contains prospective health information (drug prescriptions and clinical diagnoses) on more than 3 million Britons who are enrolled with selected general practitioners.

Participants
One hundred six female incident cases of MS, younger than 50 years, with at least 3 years of continuous recording in the General Practice Research Database before the date of first symptoms (index date).

Identified between January 1, 1993, and December 31, 2000, and 1001 controls matched on age, practice, and date of joining the practice.

Main Outcome Measure
Incidence of first symptoms of MS, confirmed through medical records.

Results
The incidence of MS was 40% lower (odds ratio, 0.6; 95% confidence interval, 0.4-1.0) in oral contraceptive users compared with nonusers during the previous 3 years.

The risk of MS increased in the 6 months after pregnancy (odds ratio, 2.9, 95% confidence interval, 1.2-6.6), but it was not otherwise related to parity.

Conclusions
The hormonal changes that occur during oral contraceptive use and pregnancy may be associated with a short-term reduction in the risk of MS, and the postpartum period may be associated with a short-term increase in the risk of MS

To examine a possible relationship between Chlamydia Pneumoniae infection and Multiple Sclerosis (MS), we undertook an ImmunoHistoChemical (IHC), molecular, and ultrastructural comparison of Central Nervous System (CNS) tissue and CerebroSpinal Fluid (CSF) sediment from patients with MS and control individuals with Other Neurological Diseases (ONDs).

In 7 of 20 MS cases, IHC staining was seen in association with Ependymal surfaces and PeriVentricular regions of formalin-fixed Brain tissue, by use of 3 different AntiChlamydial AntiBodies.

There was no staining with any of the 3 AntiChlamydial AntiBodies in formalin-fixed Brain tissue from OND controls (n=17). With available frozen CNS tissue, Polymerase Chain Reaction (PCR) studies for the presence of C. pneumoniae genes were performed.

The presence of a PCR signal was confirmed in 5 of 8 MS cases and in 3 of 18 OND controls.

In an examination of CSF sediment by electron microscopy, we observed electron-dense structures resembling Chlamydial organisms in CSF sediments from 11 of 20 MS cases and 2 of 12 OND controls.

The presence of immunogold-labeled electron-dense bodies was correlated with the presence of a PCR signal in 10 of 11 MS cases.

Results of studies using these different approaches support our suspicion of the presence of Chlamydial organisms in the CNS, in a subset of patients with MS.

Early, active Multiple Sclerosis lesions show four ImmunoPathological patterns of DeMyelination. Although these patterns differ between patients, multiple active lesions from a given patient have an identical pattern, which suggests pathogenic heterogeneity.

Therapeutic Plasma Exchange (TPE) has been successfully used to treat fulminant DeMyelinating attacks unresponsive to Steroids.

We postulated that patients with Patterns II would be more likely to improve after TPE than those with other patterns since Patterns II lesions are distinguished by prominent ImmunoGlobulin deposition and Complement activation.

We retrospectively studied 19 patients treated with TPE for an attack of fulminant CNS Inflammatory DeMyelinating Disease.

All patients with Patterns II (n=10), but none with Patterns I (n=3) or Patterns III (n=6), achieved moderate to substantial functional Neurological improvement after TPE (p< 0.0001).

Patients with Multiple Sclerosis with Patterns II pathology are more likely to respond favorably to TPE than are patients with Patterns I or III.

Disabling intractable Tremor occurs frequently in patients with Multiple Sclerosis (MS). There is currently no effective medical treatment available, and the results of surgical intervention have been variable.

Thalamotomy has been the mainstay of NeuroSurgical therapy for intractable MS Tremor, however the popularization of Deep Brain Stimulation (DBS) has led to the adoption of chronic Thalamic stimulation in an attempt to ameliorate this condition.

With the goal of examining the relative efficacy and adverse effects of these two surgical strategies, we studied twenty carefully selected patients with intractable MS Tremor.

Thalamotomy was performed in 10 patients, with chronic DBS administered to the remaining 10. Both Thalamotomy and Thalamic Stimulation produced improvements in postural and intention tremor.

The mean improvement in Postural Tremor at 16.2 months following surgery was 78%, compared with a 64% improvement after thalamic stimulation (14.6 month follow-up) (P>0.05).

Intention Tremor improved by 72% in the group undergoing Thalamotomy, a significantly larger gain than the 36% Tremor reduction following DBS (P< 0.05).

Early postoperative complications were common in both groups. Permanent complications related to surgery occurred in four patients overall.

Following Thalamotomy, long-term adverse effects were observed in three patients (30%), and comprised Hemiparesis and Seizures. Only one patient in the Thalamic stimulation group experienced a permanent deficit (Monoparesis).

We conclude that Thalamotomy is a more efficacious surgical treatment for intractable MS Tremor, however the higher incidence of persistent Neurological deficits in patients receiving lesional surgery may support the use of DBS as the preferred surgical strategy.

Many Multiple Sclerosis (MS) patients treated with IFN-ß develop Anti-IFN-ß AntiBodies, which can interfere with the bioactivity of the injected Cytokine, i.e., AntiBody-mediated decreased bioactivity (ADB).

The precise levels of Anti-IFN-ß AntiBodies inducing decreased bioactivity is unknown. We repeatedly used a bioactivity measure, gene expression of MxA or GEM, and correlated bioactivity with measures of binding and Neutralizing AntiBodies.

The binding AntiBody assay was a capture ELISA, and the Neutralizing AntiBody (NAB) assay was a Cytopathic Effect (CPE) assay.27% (17/64) of patients repeatedly sampled developed critical ADB.

Bioactivity as determined by GEM correlated negatively with NAB titer, and bioactivity that had been lost with the development of NABs returned if NAB levels diminished.

These data reveal that the GEM assay is a useful adjunct in the management of MS patients treated with IFN-ß, and that lost bioactivity returns when Anti-IFN-ß AntiBody levels diminish.

Although Magnetic Resonance Imaging (MRI) represents the most sensitive tool for the detection of White Matter abnormalities in patients with Multiple Sclerosis (MS), the heterogeneity of MS placques severely hampers the elucidation of specific pathophysiological processes.

In order to identify putative MRI markers for De- and ReMyelination, we employed the cuprizone mouse model which leads to a selective and reversible DeMyelination of the Corpus Callosum with little or no axonal damage.

Apart from Histopathology, animals were studied with high-resolution three-dimensional MRI in vivo using multiple contrasts.

While individual MRI findings significantly correlated with electron microscopy, the differentiation of regions with normal, DeMyelinated or ReMyelinated White Matter by one contrast alone was less specific than by Histology or electron microscopy.

However, an accurate MRI prediction of the in vivo Myelin status was achieved by a discriminant function analysis using a combination of T₁, T₂ and Magnetization Transfer contrast.

With a correct assignment of 95% of all animals examined, the procedure will allow for the survey of new therapeutic approaches aiming at improved ReMyelination.

Copyright (c) 2005 John Wiley & Sons, Ltd.

The authors sought to identify clinical and MRI predictors of outcome in Primary/Progressive Multiple Sclerosis (PPMS). Clinical and MRI assessments were performed at baseline and 2 and 5 years (clinical only).

At baseline, disease duration, Expanded Disability Status Scale (EDSS) and Brain Volume predicted outcome.

Adding short-term change variables, baseline EDSS, changes in T₂ lesion load and Cord Area, and number of new lesions were predictive. Clinical and MRI variables predict long-term outcome in PPMS.

During development of the Central Nervous System (CNS), postmitotic cells (including Neurons and Myelin-generating cells, the Oligodendrocytes) migrate from the germinal areas of the Neural Tube where they originate to their final destination sites.

The migration of Neurons during development has been extensively studied and has been the topic of detailed reviews.

The migration of Oligodendrocyte Precursor Cells (OPCs) is also an extremely complex and precise event, with a widespread migration of OPCs across many regions to colonize the entire CNS.

Different mechanisms have been shown to direct the migration of OPCs, among them contact-mediated mechanisms (Adhesion Molecules) and long-range cues (Chemotropic Molecules).

This review provides a detailed overview and discussion of the cellular and molecular basis of OPCs migration during development.

Because it has been shown that Neuronal and Oligodendroglial lineages share some of these mechanisms, we briefly summarize similarities and differences between these two types of Neural cells.

We also summarize the changes in the normal migration of OPCs during development that would be relevant for different Neurological Diseases (including DeMyelinating Diseases, such as Multiple Sclerosis, and Glial Cancers).

We also examine the relevance of these migratory properties of the Oligondendrocytic cell lineage for the repair of Neural damage.

We aimed to use Diffusion Tensor fiber tracking to identify the Pyramidal Tracts and Corpus Callosum in MS patients, measure the Apparent Diffusivity within the tracts, and evaluate whether this would correlate with relevant disability scores.

Dual-Echo and Diffusion Tensor Magnetic Resonance Imaging (DT-MRI) Brain scans were obtained from 29 patients with Relapsing/Remitting MS, and 13 age and gender matched normal controls.

Voxels from Pyramidal Tracts and Corpus Callosum were automatically identified using a tractography based algorithm. Mean Apparent Diffusion Coefficient (ADC(av)) was measured for these tracts.

Scores of Expanded Disability Status Scale (EDSS) and Paced Auditory Serial Addition Test (PASAT) were obtained.

The median EDSS score was 2.5 (inter-quartile range 2-3.25). The ADC(av) in the Pyramidal Tracts (p=0.02) and Corpus Callosum (p=0.0004) in patients was significantly higher than in controls.

Pyramidal Tracts ADC(av) was correlated with Pyramidal FSS (r=0.5, p=0.008).

Corpus Callosum ADC(av) was correlated with PASAT (r=-0.58, p=0.001). Global T(2) lesion volume did not correlate with the EDSS, but correlated with ADC(av) of the Pyramidal Tracts (r=0.6, p=0.0007) and Corpus Callosum (r=0.8, p< 0.0001).

T₂ lesion volume within the Pyramidal Tracts and Corpus Callosum correlated with ADC(av) in the Pyramidal Tracts (r=0.6, p=0.0009) and Corpus Callosum (r=0.65, p=0.0002) respectively, but not with Pyramidal FSS or PASAT score.

DT-MRI quantifies pathology in specific White Matter Tracts and may increase the specificity of MRI in monitoring progression of Motor and Cognitive deficits in MS.