MS Abstracts 01c-2g6

Objective & Design
To determine the accuracy of Magnetic Resonance Imaging criteria for the early diagnosis of Multiple Sclerosis in patients with suspected disease. A systematic review.

Data Sources
12 electronic databases, citation searches, and reference lists of included studies.

Review methods Studies on accuracy of diagnosis that compared Magnetic Resonance Imaging, or diagnostic criteria incorporating such imaging, to a reference standard for the diagnosis of Multiple Sclerosis.

Results
29 studies (18 cohort studies, 11 other designs) were included.

On average, studies of other designs (mainly diagnostic case-control studies) produced higher estimated diagnostic odds ratios than did cohort studies.

Among 15 studies of higher methodological quality (cohort design, clinical follow-up as reference standard).

Those with longer follow-up produced higher estimates of specificity and lower estimates of sensitivity. Only two such studies followed patients for more than 10 years.

Even in the presence of many lesions (> 10 or > 8), Magnetic Resonance Imaging could not accurately rule Multiple Sclerosis in (likelihood ratio of a positive test result 3.0 and 2.0, respectively).

Similarly, the absence of lesions was of limited utility in ruling out a diagnosis of Multiple Sclerosis (likelihood ratio of a negative test result 0.1 and 0.5).

Conclusions
Many evaluations of the accuracy of Magnetic Resonance Imaging for the early detection of Multiple Sclerosis have produced inflated estimates of test performance owing to methodological weaknesses.

Use of Magnetic Resonance Imaging to confirm Multiple Sclerosis on the basis of a single attack of Neurological Dysfunction may lead to over-diagnosis and over-treatment.

Brain Atrophy has emerged as a clinically relevant component of disease progression in Multiple Sclerosis.

Progressive loss of Brain Tissue bulk can be detected in vivo in a sensitive and reproducible manner by MRI. Clinical studies have shown that Brain Atrophy begins early in the disease course.

The increasing amount of data linking Brain Atrophy to clinical impairments suggest that irreversible tissue destruction is an important determinant of disease progression to a greater extent than can be explained by conventional lesion assessments.

In this review, we will summarise the proposed mechanisms contributing to Brain Atrophy in patients with Multiple Sclerosis. We will critically discuss the wide range of MRI-based methods used to quantify regional and Whole-Brain-Volume loss.

Based on a review of current information, we will summarise the rate of Atrophy among phenotypes for Multiple Sclerosis, the clinical relevance of Brain Atrophy, and the effect of disease-modifying treatments on its progression.

Global Gray Matter (GM) loss has been reported in Multiple Sclerosis (MS).

We addressed the question of if and where GM loss is localized by means of optimized voxel-based morphometry, applied to MRI studies of 51 patients with clinically defined Relapsing/Remitting MS and 34 age-matched normal subjects, segmented into normal and abnormal Brain Tissues using a multiparametric approach.

Segmented GM volumes were subsequently compared on a voxel-by-voxel basis to highlight regions of relative GM loss (P < 0.05, corrected for multiple comparisons at AnCova).

Additionally, localized differences in Brain asymmetry between the MS and the control groups were assessed by comparing on a voxel-by-voxel basis maps of GM differences between the two Hemispheres (P < 0.05 corrected for multiple comparisons).

In MS patients, GM volume was significantly decreased at the level of the Left Fronto-Temporal Cortex and PreCuneus, as well as of Anterior Cingulate Gyrus and of Caudate Nuclei bilaterally.

The only Cortical region of significant GM loss in the Right Hemisphere was located in the PostCentral Area.

Furthermore, GM loss regions were colocalized with increased GM asymmetries (Left < Right) in MS, confirming a preferential left-sided GM loss.

Caudate Atrophy correlated with lesion load, while no correlation between Cortical regional GM loss and disease duration, clinical status or lesion load emerged.

Our findings suggest that in RR-MS Cortical GM reduction preferentially involves left Fronto-Temporal structures and deep GM, the latter correlating preferentially to global lesion load.

Background
A course of high-dose CorticoSteroids has been shown to hasten recovery from a relapse of Multiple Sclerosis (MS).

Some patients with Progressive MS ask for a course with CorticoSteroids outside a relapse, hoping to gain some functional improvement.

Objective
To describe 4 patients with advanced Progressive MS who experienced worsening of disability after treatment with high-dose CorticoSteroids.

Results
All 4 patients had moderate to severe disability and asked for CorticoSteroid treatment because they were slowly progressing. None of them had a relapse.

All experienced improvement by the end of the treatment course. One or 2 days after discontinuation of treatment, however, they deteriorated clinically and became more disabled than before treatment.

Conclusion
The use of high-dose CorticoSteroid therapy in Progressive forms of MS outside relapses can be detrimental and worsen disability.

Gray Matter (GM) damage is an important pathophysiological feature in Multiple Sclerosis (MS), and may be related to clinical, including Cognitive deficits.

Quantitative single-voxel (1)H-Magnetic Resonance Spectroscopy (TR/TE 6000/20 ms) was performed in 33 MS patients (11 per disease subtype; mean age 48 years, 16 females) and 10 healthy controls (mean age 43 years, 7 females).

No overall Spectroscopic changes were found in MS Cortex. In MS Thalamus, a 9% decrease of N-AcetylAspartate (NAA; P = 0.005) and a 31% increase of Myo-Inositol (Ins; P = 0.002) were found.

A 21% Ins increase was observed (P = 0.02) in MS Hippocampus. Reduced NAA and increased Ins concentrations are thought to reflect Neuro-Axonal damage or loss and Gliosis, respectively.

Significant correlations between Ins concentrations and total-Brain T₂ lesion load were found for MS Thalamus (r = 0.65, P < 0.001) and Hippocampus (r = 0.57, P = 0.001). MS Thalamic and Hippocampal Ins concentrations also correlated with each other (r = 0.68; P < 0.001).

Cortical Gln correlated with Thalamic NAA (r = -0.38; P = 0.03) in MS.

Thalamic and Hippocampal Ins increases were most prominent in Secondary/Progressive (SP) patients (37% and 34%, respectively), whereas the largest Thalamic NAA decrease (14%) was found in Primary/Progressive (PP) patients.

In conclusion, Thalamic and Hippocampal GM pathology are important features of (Progressive) MS.

Magn Reson Med, 2006. (c) 2006 Wiley-Liss, Inc.

Cortical reorganization in Multiple Sclerosis (MS) is defined as a compensatory mechanism which requires MS patients to overactivate specific Brain areas in order to perform the task as controls.

To investigate this process with the Paced Auditory Serial Addition Test (PASAT) task, we selected 15 MS patients who performed the PASAT task within-normal limits and 10 healthy controls.

Once selected, we used Functional Magnetic Resonance Imaging (fMRI) to investigate Brain areas involved in PASAT performance in both groups.

Results showed that the task activated the left Frontal (BA6 and 9) and Parietal Cortex (BA7 and 40) in both groups, but MS patients showed a stronger activation in the Left Prefrontal Cortex (BA9, 44 and 45) when compared with controls.

These results confirmed those obtained post hoc by Audoin et al. [Audoin, B., Ibarrola, D., Ranjeva, J.P., Confort-Gouny, S., Malikova, I., Ali-Cherif, A.M., Pelletier, J., Cozzone, P., et al., 2003].

Compensatory Cortical activation observed by fMRI during Cognitive task at the earliest stage of MS, and we interpreted this as showing true cortical reorganization..

Hum. Brain Mapp. 20, 51-58

Some Interferon-beta (IFN-ß)-treated patients with Multiple Sclerosis develop AntiBody-mediated decreased bioactivity with resultant loss of therapeutic effect.

The authors developed real-time multiplex reverse transcriptase PCR to measure expression of three IFN-ß-inducible genes to directly assess IFN-ß bioactivity in patients with Neutralizing AntiBodies (NAbs). The three genes responded in tandem.

Correlation of NAb level with bioactivity at low/moderate NAb levels was poor, indicating that for such patients, direct measurement of IFN-ß bioactivity is most reliable.

Aims
We studied the use of Botulinum-a toxin (BTX-A) injections into the Bladder as an alternative approach in patients with Neurogenic Detrusor overactivity due to Multiple Sclerosis (MS) with drug-refractory OverActive Bladder (OAB) symptoms.

Methods
Sixteen MS patients-11 women, 5 men; mean age 48.6 years-with refractory OAB symptoms were included in a one-center prospective study.

For outcome analysis, we used a Bladder diary, a complete Urodynamic study, and validated questionnaires for subjective assessment.

We injected 300 U of BTX-A (Botox(R)) into the Bladder and into the external sphincter muscle to reduce the probability of posttreatment urine retention.

Results
There was an increase in residual volume from 81.3 +/- 23.8 to 126.3 +/- 32.9 ml after 4 weeks. In one woman, transient self-catheterization was unavoidable.

Four weeks and 3 and 6 months after BTX-A injection, the significant results were as follows:

Daytime frequency was reduced by 29%, 44%, and 30%, respectively. Nocturia diminished by 33%, 72%, and 40%.

Use of pads was be reduced by 38% after 4 weeks and by 64% after 3 months.

Urodynamically, reflex volume and maximal cystometric Bladder capacity increased by 73%, 77%, and 58% (at 6 months, the increase was not significant) and by 36%, 27%, and 36% (not significant).

Maximal Detrusor pressure decreased by 35%, 22%, and 57%.

Subjective outcome indicated significant improvement of symptoms at 4 weeks and 3 months, but not at 6 months. Patient satisfaction with the therapy was very high.

Conclusions
BTX-A Detrusor injections are very effective in the treatment of drug-resistant OAB symptoms in MS patients as reflected in Urodynamic measurements and in patient satisfaction.

Build up of residual urine remains a problem of which patients must be informed.

NeuroUrol. Urodynam. (c) 2006 Wiley-Liss, Inc.

Multiple Sclerosis (MS) is the most frequent chronic Neurological Disease affecting young persons in developed countries. MS is, however, considered as a secondary cause, of Central origin, for Autonomic Dysfunction.

The most common Autonomic symptoms in MS are disorders of Micturation, Impotence, Sudomotor and GastroIntestinal disturbances, Orthostatic intolerance as well as sleep disorders.

The majority of the patients suffer at some period of the disease from Lower Urinary Tract symptoms and sexual dysfunction. Awareness and treatment of these conditions is vital to improving health and quality of life in patients with MS.

The increased understanding of the pathophysiological mechanisms in Autonomic Dysfunction in MS, along with technological and pharmaceutical developments has advanced our ability to treat the multiple aspects complicating Autonomic failure in MS.

Background
Successful treatment of severe Spasticity represents an imperative of symptomatic therapy of Multiple Sclerosis (MS).

Due to a significant improvement of physical, psychic and social rehabilitation of MS patients, as well as a long-term cost savings for the additional treatments of conditions arising from uncontrolled severe Spasticity.

Continuous Intrathecal administration of Baclofen (ITB), using a subcutaneously implanted programmable infusion pump, is a minimally invasive, reversible method for the treatment of severe diffuse Spasticity of the Spinal origin.

Case Report
The first two cases in our country, treated by ITB due to severe Spasticity caused by MS, were reported.

Despite the local complications of surgical wound healing above the implanted components of the ITB-system in one patient, the optimal reduction of Spasticity the with complete elimination of spastic pain was obtained in both patients.

Conclusion
Our initial experiences confirmed ITB as a safe and effective therapeutical option for the treatment of intractable Spasticity in patients with MS.

Major prerequisites for this were adequate patient selection and good control of the basic disease.

The use of the minimal invasive implantation technique and the experience in choosing of the adequate ITB-system components, could successfully prevent the occurrence of local complications related to the impaired healing of the ITB-system implantation site.

Multiple Sclerosis is a chronic inflammatory DeMyelinating disease of the Central Nervous System manifested morphologically by inflammation, Demyelination, Axonal loss and Gliosis.

The inflammatory lesions are characterized by massive infiltration by a heterogeneous population of cellular and soluble mediators of the Immune System, including T-Cells, B-Cells, Macrophages and Microglia.

As well as a broad range of Cytokines, Chemokines, AntiBodies, Complement and other toxic substances. The appearance of such lesions is associated with clinical relapses.

Recent detailed ImmunoPathological studies of early, acute lesions revealed profound heterogeneity in the patterns of DeMyelination and the factors of the Immune System involved.

During remission, resolution of inflammation is the main factor which leads to clinical improvement of patients.

However, the Immune System can play a beneficial role at this stage, promoting ReMyelination perhaps by production of Growth Factors such as BDNF.

In contrast, the progressive irreversible Neurological deficit in Multiple Sclerosis is associated with NeuroDegenerative processes resulting in Axonal and Neuronal loss.

The mechanisms behind damage to Axons in Multiple Sclerosis lesions are poorly understood.

However, the close proximity of areas with prominent Axonal loss and areas containing inflammatory infiltrates (e. g., T-Cells, Macrophages) suggest that Axonal damage is closely associated with inflammation.

Different soluble or cellular mediators of the Immune response have been shown to damage Axons in experimental systems, and these may be responsible for NeuroDegeneration in human disease.

Myelin Oligodendrocyte Glycoprotein (MOG) is an integral membrane protein expressed in CNS Oligodendrocytes and outermost Myelin lamellae.

Anti-MOG Abs cause Myelin destruction (DeMyelination) in animal models of Multiple Sclerosis (MS); however, such pathogenic Abs have not yet been characterized in humans.

Here, a method that specifically detects IgG binding to human MOG in its native, membrane-embedded conformation on MOG-transfected mammalian cells was used to evaluate the significance of these Auto Abs.

Compared with healthy controls, native MOG-specific IgGs were most frequently found in Serum of Clinically Isolated Syndromes (P < 0.001) and Relapsing/Remitting MS (P < 0.01), only marginally in Secondary/Progressive MS (P < 0.05), and not at all in Primary/Progressive MS.

We demonstrate that Epitopes exposed in this cell-based assay are different from those exposed on the refolded, ExtraCellular domain of human recombinant MOG tested by solid-phase ELISA.

In marmoset monkeys induced to develop MS-like CNS inflammatory DeMyelination, IgG reactivity against the native membrane-bound MOG is always detected before clinical onset of disease (P < 0.0001), unlike that against other Myelin constituents.

We conclude that
1. Epitopes displayed on native, glycosylated MOG expressed in vivo are early targets for pathogenic Abs;

2. These Abs, which are not detected in solid-phase assays, might be the ones to play a pathogenic role in early MS with predominant inflammatory activity; and

3. The cell-based assay provides a practical Serologic marker for early detection of CNS Autoimmune Demyelination including its preclinical stage at least in the primate MS model.