MS Abstracts 03a-2g6

Objective
To assess efficacy, safety, and tolerability of every-other-day Interferon-ß-1b treatment in patients with a first clinical event suggestive of Multiple Sclerosis (MS) (Clinically Isolated Syndrome).

Methods
We conducted a multicenter, randomized, double-blind, placebo-controlled trial.

Patients with a first clinical DeMyelinating event and at least two clinically silent Brain MRI lesions were randomized to Interferon-beta-1b (IFN-ß-1b) 250 microg subcutaneously (SC) every other day (EOD) (n = 292) or placebo (n = 176), until Clinically Definite MS (CDMS) was diagnosed or they had been followed for 24 months.

Results
After 2 years, 45% of placebo patients had converted to CDMS (Kaplan-Meier estimate; primary outcome measure) and 85% fulfilled the McDonald Criteria (co-primary outcome measure).

Overall Interferon-ß-1b delayed the time to diagnosis of CDMS (p < 0.0001) and McDonald MS (p < 0.00001).

Hazard ratios (95% CI) were 0.50 (0.36 to 0.70) for CDMS and 0.54 (0.43 to 0.67) for McDonald MS favoring treatment with IFN-ß-1b.

Treatment was well tolerated, as indicated by the low rate of patients dropping out of the study before CDMS was reached (6.6% overall, 7.2% in the IFN-ß-1b group).

Conclusions
Interferon-ß-1b 250 microg subcutaneously every other day delayed conversion to Clinically Definite Multiple Sclerosis, and should be considered as a therapeutic option in patients presenting with a first clinical event suggestive of Multiple Sclerosis.

Oral Methotrexate is a potent ImmunoSuppressant, which could have a beneficial effect on relapse rates and delay disease progression in Multiple Sclerosis (MS).

We performed a systematic review of all randomized controlled trials of oral Methotrexate for MS.

Of the two randomized controlled trials identified, one was excluded due to its allocation concealment and definition of a relapse and time to sustained disease progression.

The other trial studied 60 participants with Progressive MS only. This trial reported a non-significant reduction in sustained Expanded Disability Status Scale (EDSS) progression and number of relapses in favor of Methotrexate therapy.

There were no data on relapse rate and no difference in time to first relapse.

Minor side-effects were reported in both Methotrexate (87.1%) and placebo groups (89.7%), but there were no major side-effects.

Further trials are required in both Relapsing/Remitting and Progressive groups to establish the role of oral Methotrexate in MS.

Objective
The primary objective of this study was to develop a quantitative test to assess ambulation in Multiple Sclerosis (MS) patients that is more accurate and sensitive than the Timed 25-foot walk (T25FW).

For this purpose, we developed the Six Spot Step Test (SSST), which besides speed includes co-ordination and balance, to be a lower limb counterpart to the 9-Hole Peg Test (9HPT).

Background
The T25FW, which is the ambulation test of the MS Functional Composite (MSFC), reflects only the speed component of walking.

The lack of sensitivity to other components of gait adds to the floor effect.

Methods And Patients
In the SSST, the patient is instructed to walk as quickly as possible from one end to the other of a rectangular field measuring 1 x 5 m, while kicking five cylinder blocks out of five circles marked on the floor.

Some 151 MS patients with the Expanded Disability Status Scale (EDSS) score 0-6.5 and 64 normal controls performed the SSST and the T25FW. In addition, 41 patients performed the tests twice.

Results
The range of the SSST (4.7-35.1 seconds) was wider than that of the T25FW (3.5-22.6 seconds).

Using control mean + 2 SD as cut off, 107 patients had abnormal SSST, while 100 patients had abnormal T25FW.

The T25FW (mean) increased 2.1 seconds over the EDSS range of 0-4.0, while the SSST increased 4.9 seconds.

The intra-class correlation between repeated tests (r) was 0.95 for the SSST and 0.96 for the T25FW. The correlation between the SSST and the T25FW was high (r=0.92).

Conclusion
The SSST seems to be superior to the T25FW in terms of dynamic range, floor effect and discriminatory power. The SSST is a relevant alternative for the T25FW as the ambulation component of the MSFC.

Detecting Cognitive Dysfunction may be clinically important during the early stages of Multiple Sclerosis (MS).

We assessed a self-report questionnaire on Cognitive complaints and individual NeuroPsychological Tests to select patients with early Relapsing/Remitting MS (RRMS) who needed comprehensive Cognitive testing.

Fifty-seven patients underwent Neurological and NeuroPsychological assessment, including Rao's Brief Repeatable Battery (BRB) and the complete SEP-59 Questionnaire, a French adaptation of the MSQOL-54, which contains four specific questions about self-perception of Cognitive functions.

Predictive values, specificity, sensitivity and accuracy of five individual NeuroPsychological Tests--Selective Reminding Test, Symbol Digit Modalities Test (SDMT), Similarities Subtest, PASAT and Stroop Test--were calculated to predict Cognitive Impairment.

Only 10.5% of patients did not report any Cognitive complaint, while most reported complaints.

On the basis of Cognitive performances, 59.7% of patients were classified as Cognitively impaired, although only one Cognitive score was correlated with Cognitive complaints.

Depressive symptoms and Fatigue were associated with more Cognitive complaints. Sensitivity of the SDMT to predict Cognitive Impairment was 74.2%, specificity was 76.9% and accuracy was 75.4%.

Since, at this stage, patients' Cognitive complaints are already influenced by Depression and Fatigue and do not accurately reflect Cognitive performances, the SDMT may help to select patients for testing with a more complete Cognitive battery.

Background
Evoked Potentials are used in the functional assessment of Sensory and Motor Pathways. Their usefulness in monitoring the evolution of Multiple Sclerosis has not been fully clarified.

Objective
The aim of this longitudinal study was to examine the usefulness of multimodal Evoked Potential in predicting paraclinical outcomes of disease severity and as a prognostic marker in Multiple Sclerosis.

Methods
Eighty four patients with clinically definite Multiple Sclerosis underwent Expanded Disability Status Scale (EDSS) and Functional System scoring at study entry and after a mean (standard deviation) follow-up of 30.5 (11.7) months.

Sensory and Motor Evoked Potentials were obtained in all patients at study entry and at follow-up in 64 of them, and quantified according to a conventional score.

Results
Cross-sectionally, the severity of each Evoked Potential score significantly correlated with the corresponding Functional System (0.32 < R < 0.60, p < 0.01, for all but follow-up Visual Evoked Potential) and with EDSS (0.34 < R < 0.61; p < 0.001 for all but BrainStem Evoked Potential).

EDSS significantly correlated with global Evoked Potential score severity (baseline R = 0.60, follow-up R = 0.46, p < 0.001).

Using longitudinal analysis, only changes in SomatoSensory Evoked Potential scores were significantly correlated with changes of Sensory Functional System (R = 0.34, p = 0.006).

However, patients with Multiple Sclerosis with disability progression at follow-up had more severe baseline Evoked Potential scores than patients who remained stable.

Patients with severe baseline global Evoked Potential score (higher than the median value) had a risk of 72.5% to progress on disability at follow-up, whereas patients with Multiple Sclerosis with lower scores had a risk of only 36.3%.

Conclusions
These results suggest that Evoked Potential is a good marker of the severity of Nervous damage in Multiple Sclerosis and may have a predictive value regarding the evolution of disability.

Objectives
To assess the risk of Multiple Sclerosis (MS) relapses, MRI activity, and T-Cell responses during Systemic Infections (SI) in patients with MS.

Methods
The authors prospectively studied 60 patients with MS. Twenty patients were evaluated with sequential MRI on initial visit, and 2 and 12 weeks later.

Blood samples were collected at first infection symptom and 2, 5, 12, and 24 weeks later, and production of IL-4, IL-10, IL-12, IFN-γ, TNF-, VLA-4, LFA-1, MMP-9, and MMP-2 were measured after infectious Antigens (Ag) stimulation.

Results
Increased risk of relapse and MRI activity were observed during SI.

Numbers of IFN-γ, TNF-, and IL-12 secreting cells, serum concentrations of MMP-9, and expression of VLA-4 and LFA-1 after PBMC Viral or bacterial Ag stimulation were higher in samples collected during exacerbations associated to SI.

Transwell analysis demonstrated that soluble factors produced during Viral stimulation have little effect on Myelin specific T-Cells activity.

In contrast, PBMC Viral stimulation in the presence of cognate Myelin Ag induces maximal effector responses at 20 to 30 times lower than the Ag alone.

Conclusions
There was a significant association between systemic infections and risk of MS relapse, increased MRI activity, and T-Cells activation. Furthermore, infectious agents increased Myelin specific T-Cells sensitivity to cognate Ag.

The link between Optic Neuritis and Multiple Sclerosis is well established, as is the increased risk of conversion to Multiple Sclerosis, with lesions seen at presentation on the Magnetic Resonance Imaging (MRI) scan of the Brain.

One or more asymptomatic lesions were present in 77% of the Optic Neuritis cohort from London, UK, a higher proportion than that reported in other large cohorts studied elsewhere, where generally lower prevalence rates for Multiple Sclerosis are also reported.

These observations may support the hypothesis that Optic Neuritis is more likely to be associated with abnormalities on MRI and to be due to Multiple Sclerosis in geographical regions where Multiple Sclerosis is more common.

Background
Gray Matter (GM) Atrophy has been reported in Multiple Sclerosis (MS). However, little is known about its regional distribution.

Objective
To investigate the regional distribution of GM Atrophy in clinically early Primary/Progressive MS (PPMS).

Design And Patients
Thirty-one patients with PPMS within 5 years of symptom onset (mean age, 43.2 years; median Expanded Disability Status Scale score, 4.5) and 15 healthy control subjects (mean age, 43.7 years) were studied.

All subjects underwent a 3-dimensional inversion-recovery fast spoiled gradient-recalled echo sequence that was repeated after 1 year in patients only.

Magnetic Resonance Images underwent an optimized voxel-based morphometric analysis that segments magnetic resonance data volumes in a normalized space and quantifies tissue Atrophy on a voxel-by-voxel basis.

A lesion mask was created for each patient and used in normalization and segmentation steps to minimize bias from lesions.

A multisubject design was used in the cross-sectional study to compare patients with PPMS and controls. A 1-way analysis of variance (within-subjects) design was used in the longitudinal study.

Results
At baseline, patients with PPMS displayed bilateral Thalamic Atrophy compared with controls.

In addition, a significant association between lesion load and decreased GM volume was found for the Thalami. Loss of GM in the Putamen, Caudate, Thalami, and Cortical and InfraTentorial areas was observed in patients after 1 year of follow-up.

Conclusions
Atrophy is most obvious in deep GM in clinically early PPMS. This may reflect increased sensitivity of these regions to NeuroDegeneration. Cortical and InfraTentorial Atrophy developed as the disease evolved.

Post-marketing surveillance studies are needed to assess the long-term safety, compliance and clinical efficacy of Interferon-beta-1a (IFN-ß-1a) therapy in Multiple Sclerosis (MS) patients.

The goals of this study were to:
1. Assess the safety, compliance and clinical efficacy of long-term intramuscular (i.m.) IFN-ß-1a therapy in a large cohort of patients
2. Suggest possible predictors of therapeutic response

A total of 255 patients were included in the study. Mean time on therapy was 31.7 +/- 19.3 months.

Within 3 years, 31% of patients discontinued treatment, mainly for disease activity. No significant sustained blood analysis alteration was observed over time, apart from a decrease of Cholesterol levels.

After 3 years of treatment, mean Expanded Disability Status Scale (EDSS) scores increased by 0.4 points compared with baseline.

The mean annual relapse rate was reduced compared with baseline. Patients with < or = 2 relapses in the previous 2 years and with baseline EDSS scores of < or = 2 had a longer estimated time to first relapse and to progression and first relapse, respectively.

These results confirm the safety and suggest a sustained effectiveness of i.m. IFN-ß-1a, extending the reported follow-up period to 6.3 years, and hypothesize the presence of possible predictors of clinical outcome.

The authors studied the safety and tolerability of subcutaneous Interferon-beta-1a at different doses in 24 children with clinically definite Multiple Sclerosis.

After a mean treatment period of 44 months, Interferon-ß-1a was well tolerated in 22 patients, although two experienced possible serious adverse events.

Although effectiveness cannot be inferred from this study, the authors did observe a significant reduction in the relapse rate at 22 mug, three times weekly, in the Relapsing/Remitting subgroup.

Although spontaneous ReMyelination does occur in Multiple Sclerosis lesions, its extent within the global population with this disease is presently unknown.

We have systematically analyzed the incidence and distribution of completely ReMyelinated lesions (so-called Shadow Plaques) or partially ReMyelinated lesions (shadow plaque areas) in 51 autopsies of patients with different clinical courses and disease durations.

The extent of ReMyelination was variable between cases. In 20% of the patients, the extent of ReMyelination was extensive with 60-96% of the global lesion area ReMyelinated.

Extensive ReMyelination was found not only in patients with Relapsing Multiple Sclerosis, but also in a subset of patients with Progressive disease.

Older age at death and longer disease duration were associated with significantly more ReMyelinated lesions or lesion areas.

No correlation was found between the extent of ReMyelination and either gender or age at disease onset.

These results suggest that the variable and patient-dependent extent of ReMyelination must be considered in the design of future clinical trials aimed at promoting CNS repair.

This study investigates the relation between the serological status of NMO (NeuroMyelitis Optica)-IgG and the clinical and MRI features in Japanese patients with Multiple Sclerosis.

Serum NMO-IgG was tested in 35 Japanese patients diagnosed with Multiple Sclerosis, including 19 with the Optic-Spinal form of Multiple Sclerosis (OSMS), three with the Spinal form of Multiple Sclerosis (SMS), and 13 with the conventional form of Multiple Sclerosis (CMS), which affects the brain.

NMO-IgG was detected in 14 patients, 12 with OSMS and 2 with CMS. In these patients, longitudinally extensive (> 3 Vertebral segments) Spinal Cord lesions (93% v 57%) and permanent, complete blindness (no perception of light) in at least one eye (50% v 0%) were the noticeable features as compared with NMO-IgG-negative OSMS.

The two patients having CMS with NMO-IgG had unusual Brain lesions, but in other respects had features suggesting OSMS. NMO-IgG was detected in more than half the number of patients with OSMS and in some patients with CMS.

This newly discovered Serum AutoAntiBody was markedly associated with longitudinally extensive Spinal Cord lesions and with complete blindness, suggesting severe Optic-Spinal disease.