MS Abstracts 03d-2g1

Objective
To evaluate disability and prognosis in an untreated population-based incidence cohort of Multiple Sclerosis (MS) patients.

Methods
The Expanded Disability Status Scale (EDSS) score was recorded in 220 MS patients. Disease progression was assessed by life table analysis with different endpoints and multivariate Cox regression analysis was performed for evaluation of prognostic factors.

Results
The probability of being alive after 15 years was 94.8 +/- 1.8% (s.e.), of managing without a wheelchair (EDSS < 7.0) 75.8 +/- 3.2%, of walking without walking assistance (EDSS<6.0) 60.3 +/- 3.6%, and of not being awarded a disability pension 46.0 +/- 3.7%.

The probability of still having a Relapsing/Remitting (R/R) course after 15 years was 62.0 +/- 4.1%.

A RR course and long interval between the initial (onset) and second episode (> 3 years) predicted favorable outcome.

There was also a trend towards favorable outcome in patients with Optic Neuritis, Sensory symptoms and low age at onset but these factors were associated with the R/R course.

Motor symptoms and high age at onset indicated unfavorable outcome, but these factors were associated with the Primary/Progressive course.

Conclusions
A RR course and long inter-episode intervals in the early phase of the disease were associated with a better outcome.

Other onset characteristics indicating a favorable outcome were associated with the R/R course while characteristics indicating an unfavorable outcome were associated with the P/P course.

Objective
To determine whether lesion evolution in Relapsing/Remitting Multiple Sclerosis (RRMS) patients is altered by treatment with Interferon-beta1b (IFN-ß-1b) or by IntraVenous MethylPrednisolone (IVMP) as measured by Magnetization Transfer Imaging.

Methods
Magnetization Transfer Ratios (MTR) of 225 Contrast Enhancing Lesions (CEL), in four RRMS patients were serially determined for 12 months before and 12-18 months after contrast enhancement in a baseline vs treatment trial with IFN-ß-1b.

During the baseline period, 185 new CEL were identified: 76 were treated with IVMP (1 g/day x 5 days) and designated Steroid CEL (S-CEL); the remaining 109 were considered baseline lesions (BCEL).

During IFN-ß-1b treatment, 40 CEL (IFN-CEL) were identified.

After image co-registration, Regions Of Interest (ROIs) defining new CEL were transferred to the MTR image set to determine the mean lesion MTR on each monthly exam.

The lesion MTR was compared to MTR of Normal-Appearing White Matter (NAWM) on the same exam.

Results
As early as 12 months prior to enhancement, the MTR of CEL was reduced compared to NAWM (mean 9.43 +/- 3.2%; P<0.001).

The further reduction in MTR (28% +/- 4.0) at the time of contrast enhancement was not significantly different for BCEL, S-CEL or IFN-CEL.

Following enhancement, Lesion recovery for IFN-CEL (P=0.02) and S-CEL (P=0.002) was significantly higher than BCEL.

Conclusion
IFN-ß-1b and IVMP reduce tissue damage and promote lesion recovery in RRMS patients. The additional benefit of IVMP compared to IFN-ß-1b may be related to its inhibitory effect on DeMyelination.

Glatiramer Acetate (GA) is an ImmunoTherapeutic drug for Multiple Sclerosis (MS). Several mechanisms of action have been demonstrated which target and affect T-Cells that are specific for Myelin Antigen Epitopes.

We measured the in vitro proliferation of GA-responsive T-Cells from untreated MS patients and from normal healthy subjects.

In addition, we determined the effect of prolonged GA therapy or Interferon-ß therapy on the in vitro proliferation of GA-responsive T-Cells of MS patients.

We found that GA induces the proliferation of T-Cells isolated from individuals who have not been previously exposed to GA, and that long-term in vivo therapy of MS patients with GA abrogates the GA-induced proliferative response of T-Cells.

In GA-treated patients, there is no evidence of generalized ImmunoSuppression; both tetanus toxoid and anti-CD3 induced proliferative responses remain unaffected.

We propose that prolonged in vivo exposure to GA may result in the eventual induction of anergy or deletion of a population of GA-responsive cells that may also be T-Cells that are pathogenic in MS.

This mechanism of action, in addition to other mechanisms that have been demonstrated, suggests that GA has pleiotropic effects on the Immune System in MS.

After the placebo-controlled extension of the pivotal US trial of Glatiramer Acetate for the treatment of Relapsing Multiple Sclerosis ended, 208 participants entered an open-label.

Long-term treatment protocol Magnetic Resonance Imaging (MRI) was added to the planned evaluations of these subjects to determine the consequences of long-term treatment on MRI-defined pathology and evaluate its clinical correlates.

Of the 147 subjects that remained on long-term follow-up, adequate images were obtained on 135 for quantitative MRI analysis.

The initial imaging sessions were performed between June 1998 and January 1999 at 2,447 +/- 61 days (mean +/- standard deviation) after the subject's original randomization.

Clinical data from a preplanned clinical visit were matched to MRI within 3 +/- 51 days.

At imaging, 66 patients originally randomized to placebo (oPBO) in the pivotal trial had received Glatiramer Acetate for 1,476 +/- 63 days, and 69 randomized to active treatment with Glatiramer Acetate (oGA) were on drug for 2,433 +/- 59 days.

The number of documented relapses in the 2 years prior to entering the open-label extension was higher in the group originally randomized to placebo (oPBO=1.86 +/- 1.78, oGA=1.03 +/- 1.28; P=0.002).

The annualized relapse rate observed during the open-label study was similar for both groups (oPBO=0.2 7, +/- 0.45 oGA=0.28 +/- 0.40).

But the reduction in rate from the placebo-controlled phase was greater for those beginning therapy with GA (oPBO reduced by 0.66 +/- 0.71, oGA reduced by 0.23 +/- 0.58; P=0.0002).

One or more Gadolinium enhancing lesions were found in 27.4% of all patients (number of distinct enhancements=1.16 +/- 2.52, total enhanced tissue volume=97 +/- 26 microl).

The risk of having an enhancement was higher in those with relapses during the open-label extension (odds ratio 4.65, 95% confidence interval (CI) 2.0 to 10.7; P=0.001).

The odds for finding an enhancement was 2.5 times higher for those patients originally randomized to placebo (CI 1.1 to 5.4; P=0.02) compared to those always on Glatiramer Acetate.

MRI-metrics indicative of chronic pathology, particularly measures of global Cerebral tissue loss (Atrophy), were uniformly worse for those originally on placebo.

These observations enrich our long-term follow up of the clinical consequences of treatment with Glatiramer Acetate to include its apparent effects on MRI-defined pathology.

They show that the effect of Glatiramer Acetate on enhancements is definite, but modest, consistent with the drug's described mechanisms of action, and that a delay in initiating treatment results in progression of MRI-measured pathology that can be prevented.

We combined the raw Genotyping data from three large Multiple Sclerosis Genome screens and performed a global meta-analysis in order to compare and summarize the linkage results from the different studies.

In alphabetical order, the screens provided data from 442 markers typed in 52 multiplex families with a total of 133 affected individuals (the American screen).

314 markers typed in 128 families with 264 affecteds (the British screen) and 257 markers typed in 61 families with a total of 139 affected subjects (the Canadian screen).

Multipoint analysis of these data was performed using the GENEHUNTER program.

The highest Non-Parametric Linkage (NPL) score in the meta-analysis was observed on chromosome 17q11 (NPL score 2.58), although this score falls short of Genome-wide significance.

A total of eight regions had NPL scores greater than 2.0. One of the regions with an NPL score greater than 2.0 was the HLA region on Chromosome 6p21 (NPL=2.2).

This region is known, from association studies, to be involved in MS susceptibility, but the modest linkage result observed here suggests the encoded susceptibility effect is not large compared with the high familial recurrence in MS (lambda approximately 20).

Overall, our linkage results suggest that MS is likely to be multigenic in its Genetic susceptibility.

Introduction
Measurement of Brain Volume on Magnetic Resonance Imaging (MRI) scans is regarded as an objective marker of Multiple Sclerosis (MS) severity with the potential to monitor treatment efficacy accurately.

This study was performed to assess the variability of Brain MRI Volume measurements.

Patients And Methods
We studied nine patients with Relapsing/Remitting MS, who were imaged on two occasions (separated by an interval of 24 h) using two different MR scanners and fast Fluid-Attenuated Inversion Recovery (fast FLAIR) sequences.

The whole Brain Volume computed from each image was measured three times by three observers using a seed-growing technique based on signal intensity thresholding.

Intra-observer, inter-observer and inter-scanner variabilities were expressed as Coefficients Of Variations (COVs).

The inter-scanner variability included not only the intra-observer variation but also the repositioning variability and the variation in observed Brain Volume caused by different scanner hardware and sequence implementations.

Results
There was no statistically significant difference in patients' Brain Volume values between observers (P=0.82) or between scanners (P=0.30).

The mean intra-observer COV was 1.2% (s.e.=0.4%), the mean inter-observer COV was 1.8% (s.e.=0.8%) and the mean inter-scanner COV was 2.4% (s.e.=1.2%).

The intra-observer variance was not statistically different from those found between observers (P=0.83) or scanners (P=0.44).

Conclusion
The intra-observer variability in Brain Volume measurements found in this study was within the range of intra-observer variability found in previous studies.

This study shows that the use of different observers and MR scanners has only a small influence on the measured Brain Volume and does not affect the reproducibility of this measurement greatly.

As short-term MRI studies are increasingly being used to monitor disease activity in Multiple Sclerosis (MS) it is vital to establish if short-term MRI activity is predictive of long term clinical outcome.

We followed up after 5 years a group of 10 Benign (Relapsing/Remitting MS with a disease duration > 10 years and EDSS < or = 3) and 10 early Relapsing/Remitting patients who previously had monthly serial MRI scans for 6 months.

In the early Relapsing/Remitting group median EDSS at entry to the initial serial study was three and in the Benign group 2.5. At 5-year follow up, five of these 20 patients had developed a definite deterioration in EDSS.

The median number of new enhancing lesions detected originally in the group that had deteriorated was 11 (7-17) compared to 0 (0-5) new enhancing Lesions, for those who had not deteriorated (P < 0.05).

There was a trend towards a higher baseline T₂ lesion load in the group with a definite change in EDSS but this was not significant.

This study suggests that short-term measurement of the number of Gadolinium enhancing lesions may predict long term outcome in Relapsing/Remitting MS.

A growing body of evidence implicates excessive generation of Nitric Oxide (NO) within the Central Nervous System (CNS) in Multiple Sclerosis (MS).

The aim of our study is to analyze Nitrite and Nitrate as end products of NO in the CerebroSpinal Fluid (CSF) from MS patients and correlate the concentrations with clinicol characteristics of the disease.

CSF nitrite and nitrate concentrations were measured after reduction of Nitrate, by Griess reaction, in 105 MS potients, 27 patients with Non-Inflammatory Neurological Disorders (NIND) and 13 individuals without Neurological Disorder (Co).

Mean CSF Nitrite and Nitrate concentrations were significantly higher in patients with MS and NIND compared with the Co patients (9.44 and 8.68, respectively, versus 6.85 microM; P=0.0001 and P=0.031, respectively).

There was no significant correlation between CSF Nitrite and Nitrate concentrations and activity, phase, severity and duration of MS.

Our data are in agreement with the results of previous studies which have demonstrated raised concentrations of CSF NO metabolites in MS patients, providing further evidence for NO involvement in MS.

The lack of correlation between NO metabolites and disease activity speaks in favor of the possible dual role of NO, as both ImmunoRegulatory and pro-inflammatory molecule, in the PathoGenesis of MS.

Humoral Immune Responses to Chlamydia Pneumoniae (C. Pneumoniae) were studied in paired Sera and CerebroSpinal Fluid (CSF) of patients with definite Multiple Sclerosis (MS) and other Inflammatory and Non-Inflammatory Neurological Diseases.

Seropositivity was not significantly different between these groups. However, C. Pneumoniae-specific IgG titers were significantly higher in CSF of MS than in controls.

Sixteen out of 52 seropositive MS patients (30.8%) showed Intrathecal synthesis of C. Pneumoniae-specific IgG but only one of 43 seropositive controls (2.3%).

In MS, this was strongly associated with Intrathecal synthesis of PolyClonal IgG in 13/16 patients.

However, these elevated C. Pneumoniae antibody titers in CSF did not significantly correlate with disease duration, disease course, clinical or MRI disease activity, disability or presence of OligoClonal IgG in MS.

In a survey of disease course, the efficacy and tolerability of 24-month Interferon-ß-1b therapy for Relapsing/Remitting Multiple Sclerosis (RRMS) were evaluated in 410 patients.

The investigation aimed at obtaining data from general practice and of possibly unknown, unexpected adverse reactions.

In the 241 patients still on therapy, efficacy was rated after 24 months as "good" or "very good" in 75% of cases. After 24 months, 36.9% of the patients had no exacerbation (baseline 0.3%).

Annual exacerbation rates dropped from 1.5 before treatment to 0.7 in the second treatment year. In the 2 years before treatment, 66.2% had worsened by at least 0.5 points on the Expanded Disability Status Scale (EDSS).

This proportion was reduced to 41.2% after 2 years of treatment. The safety profile corresponded to results from controlled trials.

This postmarketing survey supports data from the published controlled Interferon-ß-1b studies and confirms the main effects of this therapy under routine conditions in general practice.

Objective
To examine the influence of impaired Cognitive processing on measures of driving skills in persons with MS. Methods
Twenty-eight subjects with documented MS were divided into two groups-with [MS(+), n = 13] and without [MS(-), n = 15] Cognitive Impairment-based on NeuroPsychological performance.

Healthy control (HC) subjects (n = 17) matched on age and driving experience were also studied.

Driving-related skills were compared between the groups based on performance on two computerized driving tests: the Useful Field of Vision (UFOV) and the NeuroCognitive Driving Test (NDT).

Results
The MS(+) group performed significantly worse than both the MS(-) and HC groups in the latency to perform several driving-specific functions on the NDT, but no overall group differences were observed in actual errors on the NDT.

On the UFOV, when compared to MS(-) and HC subjects, the MS(+) group demonstrated poorer performance on two of the three subtests.

Additionally, a significantly higher percentage of MS(+) individuals were rated within the high risk (probability of crash involvement) category, relative to the MS(-) and HC groups.

Conclusions
Cognitive Impairment can negatively affect driving-related skills in persons with MS and should be considered in the determination of driving ability.

Recent evidence suggests that persons with Multiple Sclerosis may experience deficits in Verbal and VisuoSpatial acquisition rather than Recall.

The present study was designed to determine whether this finding generalized to a broader range of NeuroPsychological tests of Learning and Memory.

To control for group differences in information acquisition, healthy controls (HCs) and persons with Multiple Sclerosis (MS) were trained to specific learning criteria on both Verbal (i.e., paragraph learning and paired associates) and VisuoSpatial (i.e., facial recognition) Memory tasks.

Persons with MS required significantly more learning trials to meet criteria on the paragraph learning and facial recognition tasks, but not the paired associates test.

However, after learning comparable amounts of information, the MS and HC groups recalled statistically similar amounts of information at 30-minutes, 90-minutes, and up to 1-week on the paragraph learning and paired associate tests.

This suggests that persons with MS may have deficits in Acquisition rather than Recall per se. Results are discussed in terms of possible rehabilitation strategies to improve Memory functioning in persons with MS.