MS Abstracts 01c-2g1

Background
A significant correlation exists between disability and the volume of Black Holes (BHL VOL), defined as HypoIntense lesions on T₁-weighted Cranial Magnetic Resonance Imaging.

A consistent correlation has also been reported between Urinary Myelin Basic Protein-like material (MBPLM) and the transition toward Secondary/Progression (SP) from Relapsing/Remitting (RR) Multiple Sclerosis (MS).

Objective
To improve the management of MS through a noninvasive and cost-effective test for monitoring disease activity or disease status.

Design And Methods
From 662 patients with MS (86 with RR MS, 259 with SP MS without continued attacks, and 317 with SP MS with continued attacks), 24-hour urine samples were obtained at enrollment in the phase 3 Linomide (Roquinimex) drug study.

The Urine specimens were analyzed for MBPLM and correlated with clinical features and findings on Cranial Magnetic Resonance Imaging.

Results
Significant but weak correlations existed between Urinary MBPLM and BHL VOL in all patients with MS (r = 0.114, P =.003; n = 662), patients with SP MS without attacks (r = 0.185, P =.003; n = 259), and all patients with SP MS (r = 0.122, P =.003; n = 576).

No significant correlations were detected in the RR MS group or any of the disease groups or subgroups whose Expanded Disability Status Scale score was 5.0 or lower.

In subgroup analysis, the most significant correlation was detected between Urinary MBPLM after adjustment for Creatinine and BHL VOL in patients with SP MS with an Expanded Disability Status Scale score of 5.5 or higher but without continued relapses (r = 0.417, P<.001; n = 138).

Conclusions
In patients with advanced SP MS, Urinary MBPLM may possibly serve as an indicator of failed remission and Axonal Damage.

Urinary MBPLM correlates with disease status in MS, especially the transition of RR MS to SP MS with advancing disability.

Objective
To examine the relation between the frequency of enhancing Magnetic Resonance Imaging lesions and their characteristics of enhancement and Atrophy in patients with early Relapsing Multiple Sclerosis.

Design
Analysis of number of enhancing lesions, Ventricular volumes and diameters, and lesion characteristics on monthly Magnetic Resonance Imaging scans during natural history follow-up.

Setting & Patients
A clinical research institution. Sixteen patients with confirmed early Relapsing Multiple Sclerosis.

Main Outcome Measure
Cerebral Atrophy as measured by Ventricular enlargement.

Results
Numbers of enhancing lesions correlated well with an increase of Ventricular size. This correlation was strongest for patients with a high proportion of concentric ring-enhancing lesions with central contrast pallor.

Conclusions
Inflammatory events, especially those within lesions with associated Blood-Brain Barrier breakdown, affect the ensuing loss of Brain Parenchyma.

Patients with a high proportion of lesions with central contrast pallor, which is likely associated with more extensive tissue damage, have a higher rate of Atrophic changes.

Context
HypoIntense lesions on T₁-weighted Spin-Echo Magnetic Resonance images (T₁ lesions) represent destructive Multiple Sclerosis (MS) lesions, consisting of Axonal Loss and Matrix destruction.

These lesions are being used as a secondary outcome measure in Phase III clinical trials.

Clinical determinants of T₁ lesions may differ between subgroups of patients with MS and subsequently may have implications for the selection of patients for clinical trials.

Objective
To determine if clinical characteristics of patients with MS are related to T₁ lesion volume.

Design
A survey of 138 patients with MS (52 with Relapsing/Remitting MS, 44 with Secondary/Progressive MS, and 42 with Primary/Progressive MS).

Setting
The Magnetic Resonance Center for Multiple Sclerosis Research,
Univ Hospital "Vrije Universiteit," Amsterdam, the Netherlands.

Main Outcome Measures
Type of MS, Expanded Disability Status Scale (EDSS) score, sex, age at first symptoms, and T₁ lesion volume.

Results
Patients with Secondary/Progressive MS have the highest T₁ lesion volume. Patients with Relapsing/Remitting MS have a lower T₁/T₂ ratio than patients with Secondary/Progressive MS and patients with Primary/Progressive MS.

In patients with Relapsing/Remitting MS and Secondary/Progressive MS, T₁ lesion volume relates to disease duration and EDSS score, while in patients with Primary/Progressive MS sex is important.

A trend toward higher T₁ lesion volume was shown for male patients with Primary/Progressive MS when compared with female patients with Primary/Progressive MS (1.0 cm(3) vs 0.3 cm(3), P=.03).

A trend toward higher T₁ lesion volume was found with age at onset in patients with Relapsing/Remitting MS and in patients with Primary/Progressive MS.

Conclusions
In patients with MS different clinical characteristics associate with T₂ lesion volume, suggesting a more destructive type of lesions in certain subgroups.

A possible sex difference in (destructive) lesion development on Magnetic Resonance Imaging should be evaluated in more detail, preferably in a cohort.

Background
Interferon-beta treatment is only partially effective in Multiple Sclerosis (MS) suggesting a potential role for adjunctive therapies.

Retinoids can augment the clinical efficacy of Type 1 Interferons in patients with Cancer. We reasoned that the same might hold in MS.

Interferon-ß-1b added to Peripheral blood MonoNuclear Cells in vitro partially reverses the CD8⁺ Suppressor Cell defect of patients with MS.

All-Trans Retinoic Acid added to Peripheral Blood MonoNuclear Cells from untreated patients with MS or from controls potentiates this ability of Interferon-ß-1b to augment CD8 Suppressor Cell function in vitro.

Objective
To determine whether Retinoid administration to patients with MS who are being treated with Interferon-beta-1b augments their CD8 Suppressor Cell function.

Setting & Participants
A university hospital MS clinic. Patients with MS who were being treated with Interferon-ß-1b, 14 patients with Secondary/Progressive MS and 3 patients with Relapsing/Remitting MS.

Results
Seventeen patients with MS received Etretinate treatment for up to 6 months. Planned dosing was 10 mg 3 times daily for the first month, 25 mg twice daily for the second and third months, and 10 mg twice daily thereafter.

The 25-mg twice daily dose was not well tolerated and of the 14 patients who remained in the phase 1 clinical trial through month 3 dose reduction to 10 mg thrice daily was required in 1 patient and to 10 mg twice daily in 4 patients.

Eleven patients completed the trial. Etretinate treatment significantly augmented suppressor function over baseline values at 1, 3, and 6 months.

No meaningful change was noted in Disability or quality of life over the course of the phase 1 clinical trial.

NeuroPsychological testing of completers suggested improvement on selected aspects of Verbal Memory at 6 months compared with baseline values.

Conclusions
Etretinate treatment at a dose of 10 mg twice or three times daily augments Suppressor Cell function in patients with MS receiving Interferon-ß-1b.

Higher dose Etretinate treatment (25 mg twice daily) is poorly tolerated by patients with MS.

Even at 10 mg twice daily adverse experiences involving the mucous membranes and the skin become troublesome for some, but not all, patients.

Whether pulse therapy or administration of Retinoid restricted to the day of Interferon-ß dosing will also augment Suppressor function, while being better tolerated, remains to be determined.

Background
Magnetic Resonance Imaging (MRI) is useful for demonstrating DeMyelinating lesions in patients with Multiple Sclerosis (MS).

Magnetic Resonance Imaging studies show that MS lesions are generally not uniform in shape, size, or distribution.

Linearly shaped lesions at the Trigeminal Root entry zone have been occasionally reported in single cases of MS, but, to our knowlege, the frequency and the clinical features of such patients have not been comprehensively characterized.

Objective
To describe the frequency and the clinical and laboratory features of patients with MS who had linearly shaped Lesions at the Trigeminal Root as seen on MRI.

Design And Setting
A retrospective review of medical records and MRI films of Japanese patients with MS admitted to a university hospital and its affiliated hospital in Sendai, Japan.

Patients And Methods
Brain MRI films of 74 consecutive Japanese patients with MS (51 females and 23 males) were studied retrospectively and the clinical and laboratory features of the patients with linearly shaped lesions at the Trigeminal Root were also investigated retrospectively.

Results
Five patients (6.8%) were shown to have T₁-weighted-HypoIntense, T₂-weighted-HyperIntense, nonenhanced linear lesions in the Pons on MRI, and these were uniformly localized in the IntraMedullary portion of the Trigeminal Root.

All of these patients had Clinically Definite MS and had various types of facial Sensory disturbances, such as Neuralgia (1 patient), Hypesthesia (2 patients), or Paresthesias (3 patients).

No other clinical or laboratory feature was characteristic in these 5 patients.

Conclusions
Linear Pontine Trigeminal Root lesions were common in our patients with MS.

They were associated with various Facial Sensory symptoms. Since similar lesions are formed in animal models of Herpes Simplex Virus infection, further study is needed to clarify whether these MS lesions are Virally induced.

Background
Apoptosis is supposed to contribute to the elimination of T-Cells from the inflamed Central Nervous System in the natural disease course of Multiple Sclerosis (MS).

In the animal model Experimental AutoImmune EncephaloMyelitis, T-Cell Apoptosis can be induced by high-dose GlucoCorticoid (GC) administration.

Objective
To study the effects of intravenous high-dose GC therapy in MS on T-Cell Apoptosis ex vivo.

Patients
Sixty-six patients with MS (28 with Relapsing/Remitting MS, 22 with Chronic Secondary/Progressive MS, and 16 with Primary Chronic Progressive MS) and 16 control patients receiving CorticoSteroids for other disorders were included in the study.

Methods
Blood samples were collected before and immediately after the first infusion of 500 to 1000 mg of MethylPrednisolone given during 2 hours in the early morning.

Gradient-isolated Peripheral Blood Leukocytes (PBLs) were cultured, unstimulated, with CorticoSteroids (positive control), the Mitogen PhytohemAgglutinin, or Anti-T-Cell Receptor MonoClonal AntiBody.

For investigation of Apoptosis, PBLs were cultured overnight and analyzed by immunoflow cytometry using TUNEL (terminal transferase-mediated dUTP biotin nick end labeling) or annexin labeling in combination with CD4⁺, CD8⁺, CD22, CD56, or Bcl-2 staining.

Proliferation was measured by (3)H-Thymidine incorporation. For Cytokine determination, supernatants were collected after 48 hours of culture.

Results
After in vivo CorticoSteroid treatment, Apoptosis of unstimulated PBLs was markedly and significantly augmented in all 3 MS subgroups.

Fluorescence-activated cell sorter analysis showed that Apoptosis affected predominantly CD4⁺ T-Cells.

Natural Killer Cells showed a relative increase after GC therapy without a change in the rate of Apoptotic Cells.

Expression of Bcl-2 in T-Cell subpopulations was not significantly modified by high-dose GC therapy.

Culture supernatants of T-Cell Receptor-stimulated PBLs after GC therapy contained lower concentrations of InterLeukin-2, Interferon-gamma, and Tumor Necrosis Factor- than those from PBLs taken before pulse therapy.

Similar changes in the rate of Apoptosis and Cytokine production were seen in controls.

Conclusions
CorticoSteroid pulse therapy is a strong inducer of Leukocyte Apoptosis. Induction of Apoptosis might contribute to the down-regulation of T-Cell activity and thereby terminate Inflammation in the Central Nervous System.

Objectives
To determine if Callosal Aatrophy and InterHemispheric dysfunction can be detected in the early stages of Relapsing/Remitting Multiple Sclerosis (MS).

And to evaluate their progression in relation to the disability and evolution of lesions seen on Magnetic Resonance Imaging during a 5-year period.

Methods
We compared 30 patients who had Clinically Definite Early-Onset Replasing/Remitting MS and mild disability with control subjects.

Regional and segmental Callosal size and extent of White Matter abnormalities on Magnetic Resonance Imaging, as well as performance on tasks exploring InterHemispheric transfer of Motor, Auditory, and Sensory information were assessed.

Patients with MS were evaluated at baseline and after 5 years. Physical disability was determined at both times using the Expanded Disability Status Scale score.

Results
Patients with MS were seen with significant Callosal Atrophy and functional impairment of InterHemispheric transfer at baseline that worsened during the 5-year study.

A significant correlation was found between the magnitude of disability and the severity of morphological and functional Callosal involvement at baseline.

This association persisted at year 5. Baseline clinical characteristics such as age and prestudy relapse rate were unrelated to Callosal size or InterHemispheric performance.

However, the number of baseline T₂-weighted lesions was correlated with Callosal involvement and this relation persisted at year 5.

Conclusion
Patients who had Relapsing/Remitting MS in the early stages of the disease and mild disability had significant Callosal involvement that progressed over time.

The relationship between disability, T₂-weighted lesions load, and degree of morphological and functional Callosal impairment confirm the potential value of using Callosal dysfunction as a surrogate marker of disease progression in MS.

Objective
To investigate the relationship between Magnetic Resonance Imaging regional lesion burden and Cognitive performance in Multiple Sclerosis (MS) over a 4-year follow-up period.

Design
Twenty eight patients with MS underwent Magnetic Resonance Imaging and took the Brief, Repeatable Battery of NeuroPsychological Tests in Multiple Sclerosis at baseline, 1 year, and 4 year follow-up.

An automated 3-dimensional lesion detection method was used to identify MS lesions within anatomical regions on Proton Density T₂-weighted images.

The relationship between Magnetic Resonance Imaging Regional Lesion Volumes and the Brief, Repeatable Battery of NeuroPsychological Tests in Multiple Sclerosis results was examined using regression analyzes.

Results
At all time points, Frontal lesion volume represented the greatest proportion of Total Lesion Volume, and the percentage of White Matter classified as lesion was also highest in Frontal and Parietal regions.

On NeuroPsychological testing, when compared with age and educational level matched control subjects, patients with MS showed significant impairment on tests of sustained attention, processing speed, and verbal memory (P<.001).

Performance on these measures was negatively correlated with MS lesion volume in Frontal and Parietal regions at baseline, 1 year, and 4 year follow-up (R = -0.55 to -0.73, P<.001).

Conclusions
Multiple Sclerosis lesions show a propensity for Frontal and Parietal White Matter.

Lesion burden in these areas was strongly associated with performance on tasks requiring sustained Complex Attention and Working Verbal Memory.

This relationship was consistent over a 4 year period, suggesting that disruption of FrontoParietal SubCortical networks may underlie the pattern of NeuroPsychological Impairment seen in many patients with MS.