Effect of interferon-beta1b on magnetic resonance imaging outcomes in secondary progressive multiple sclerosis: results of a European multicenter, randomized, double-blind, placebo-controlled trial. European Study Group on Interferon-beta1b in secondary progressive multiple sclerosis

A randomized placebo-controlled trial of interferon-beta1b was performed on 718 patients with secondary progressive multiple sclerosis with follow-up of up to 3 years. In addition to clinical variables, serial magnetic resonance imaging (MRI) studies were performed to determine the effect of treatment on the pathological evolution of the disease. All patients eligible for MRI had annual proton density/T2-weighted brain scans from which total lesion volume was measured and the number of new and enlarging lesions noted. A subgroup of 125 patients also underwent monthly gadolinium-enhanced and proton density/T2-weighted brain MRI from months 0 to 6 and 18 to 24 to determine the effect of treatment on the frequency of new lesion activity, defined as new enhancing lesions and new/enlarging T2 lesions not enhancing with gadolinium. The difference in total lesion volume between treatment groups was highly significant. In the placebo group, there was an increase of 15% from baseline to last scan, whereas in the interferon-beta1b group, a reduction of 2% was seen. Within the placebo group, there was a significant year-on-year increase in total lesion volume, with a mean increase of 16% at year 3 compared with baseline. In the treated group, there was a significant reduction at year 1 (4%) and year 2 (5%) compared with baseline; the 2% decrease at year 3 was not significant. The number of new or enlarging proton density/T2 lesions was also significantly reduced by treatment. In the frequent MRI subgroup, treatment was associated with a significant 65% reduction in new lesion activity between months 1 and 6, and 78% reduction from months 19 to 24. Interferon-beta1b has a substantial and sustained effect on reducing the accumulation of new inflammatory disease foci in secondary progressive MS. This therapeutic mechanism may contribute to the positive clinical benefits of treatment on the progression of sustained neurological disability and relapse activity that were also identified in this trial.     

MRI and clinical activity in MS patients after terminating treatment with interferon beta-1b

Monthly MRI activity and clinical disability were evaluated in two relapsing-remitting multiple sclerosis (RRMS) patients for 4 years during a cross-over treatment trial with IFNbeta-1b, and for a mean of 21 months after terminating treatment with IFNbeta-1b. Post-treatment MRI activity was compared to baseline activity in these patients. Although contrast enhancing lesions (CEL) and the bulk white matter lesion load (BWMLL) on T2-weighted images eventually returned to baseline values, there was a refractory period of 6 - 10 months after terminating treatment, before baseline MRI activity was restored. Although the mechanism for a sustained effect of IFNbeta-1b is unclear at this time, these results have important implications for enrollment of such patients into new treatment protocols that rely on contrast enhancing lesion frequency as an outcome measure.     

Whole brain volume changes in patients with progressive MS treated with cladribine

OBJECTIVE: To compare changes in whole brain volume measured using MRI scans in patients with progressive MS enrolled in a double-blind, placebo-controlled trial assessing the efficacy of two doses of cladribine (0.7 and 2.1 mg/kg) and to assess the correlations between change in whole brain volume and change in other conventional MRI measures. BACKGROUND: Measuring brain parenchymal volumes is an objective and reliable surrogate for the destructive pathologic process in MS. The dynamics and the mechanisms of tissue loss in progressive MS are unclear. METHODS: Whole brain volumes were measured using postcontrast T1-weighted scans with 3 mm slice thickness from 159 patients with progressive MS (70% secondary progressive and 30% primary progressive) enrolled in a double-blind, placebo-controlled trial of 12-month duration. RESULTS: Whole brain volumes were similar in the placebo and cladribine-treated patients on the baseline scans. A significant decrease of brain volume over time was observed both in the entire population of patients (p = 0.001) and in the placebo patients in isolation (p = 0.04). No significant treatment effect of either dose of cladribine on brain volume changes over time was found. In the 54 patients who received placebo, the change in brain volume was not significantly correlated with other MRI measures at baseline (enhancing lesion number and volume and T2-hyperintense and T1-hypointense lesion volumes) or at follow-up (cumulative number of enhancing lesions and absolute and percentage changes of enhancing T2- and T1-hypointense lesion volumes). CONCLUSIONS: This study shows in a large cohort of patients that brain parenchymal loss occurs, even over a short period of time, in progressive MS and that cladribine is not able to alter this process significantly. It also suggests that MRI-visible inflammation and new lesion formation has a marginal role in the development of brain atrophy in patients with progressive MS.     

New hypointense lesions on MRI in relapsing-remitting multiple sclerosis patients

BACKGROUND: Preliminary observational studies with multiple sclerosis (MS) patients have reported strong correlations between an increase in hypointense lesion load (black holes) on T1-weighted spin echo images, and an increase in disability. OBJECTIVE: We assessed the relationship of hypointense lesions to the clinical course of disease among 50 relapsing-remitting MS patients in the controlled setting of a randomized clinical trial. METHODS: Fifty patients with relapsing-remitting disease were enrolled in a randomized double-blind two-arm (cladribine vs. placebo) clinical trial of 1-year duration. All patients had monthly clinical evaluations and MRIs over the course of the trial. Multivariate techniques were used to identify predictors of clinical severity from information on exacerbations, MRIs, baseline clinical parameters, and demographics. RESULTS: At baseline, clinical severity is weakly related to counts of black holes, with rank correlations between counts and clinical scores (EDSS and SNRS) of absolute magnitude 0.3. Rates of appearance of new black holes over the course of the trial are higher for patients with more severe disease at baseline (EDSS > or = 4) than for the less severe patients. Changes in clinical severity over the course of the trial are best predicted by baseline neurologic scores and numbers of exacerbations, with black holes adding no further improvement in prediction. CONCLUSIONS: Numbers of exacerbations seem more critical to short-term clinical outcomes in relapsing-remitting MS, as reflected by patients' clinical scores, rather than black holes. Various imaging methods and MRI indices capture complementary information relating to MS disease processes. The determination of which processes are affected by different drugs should lead to more effective treatment of MS patients.     

Baseline MRI characteristics of patients at high risk for multiple sclerosis: results from the CHAMPS trial. Controlled High-Risk Subjects Avonex Multiple Sclerosis Prevention Study

The baseline MRI studies from the Controlled High-Risk Subjects Avonex Multiple Sclerosis Prevention Study (CHAMPS) trial, a randomized, longitudinal, double-blind trial of 383 patients with a first acute clinical demyelinating event and evidence of prior subclinical demyelination on magnetic resonance imaging (MRI) of the brain, provides a large MRI database for patients likely in the earliest stages of multiple sclerosis (MS). High-resolution baseline MRIs revealed a median of 13 T2 lesions (maximum = 103 lesions) and 2.05 cm3 of T2 lesion volume (maximum 35.04 cm3), with 30% of patients having one or more enhancing lesions despite receiving a standardized high-dose course of intravenous corticosteroids. Periventricular, discrete, and juxtacortical T2 lesions were present in 99%, 92% and 67% of the patients, respectively. Large (> 6 mm), T1-hypointense, infratentorial, and corpus callosum lesions were present in 69%, 50%, 55% and 58%, respectively. Clinical presentation groups showed differences in T2 lesion volume, and enhancing lesion number and volume. At baseline, 97%, 81% and 72% of the patients met 'Paty', 'Fazekas', and 'Barkhof' research criteria for MS, respectively, with the percentages similar according to clinical presentation group. These results support and extend those of smaller and/or retrospective series, which have shown substantial subclinical injury, based on brain MRI, at the earliest identifiable stages of disease.     

The effect of IFNbeta-1b on the evolution of enhancing lesions in secondary progressive MS.

BACKGROUND: After the resolution of contrast enhancement, the majority of new MS lesions become isointense with surrounding white matter on T1-weighted MRI. Less commonly, a hypointense T1 lesion develops, representing the development of more severe focal tissue damage. Interferon beta (IFNbeta) reduces both the number of new enhancing lesions and the duration of contrast enhancement. OBJECTIVE: To determine if IFNbeta affects the degree of tissue damage within new lesions and if its effects are related to lesion size. METHODS: One hundred twenty-five patients with secondary progressive MS from seven European sites were randomized to receive either IFNbeta-1b or placebo. Monthly, contrast-enhanced T1-weighted MR images were acquired at baseline, at months 1 to 6, and at months 19 to 24. The size of all new enhancing lesions developing between months 1 and 6 was recorded and their appearance at follow-up documented. RESULTS: In the first 6 months, fewer new enhancing lesions occurred in the IFNbeta-1b arm. This difference was greater for small (70% decrease) than for large (46% decrease) lesions. Hypointense T1 lesions were more likely to form from large (25%) than from small (9%) enhancing lesions in both treatment arms. Patients taking IFNbeta-1b developed fewer hypointense T1 lesions; however, the proportion of enhancing lesions developing into hypointense T1 lesions was similar in both arms. CONCLUSION: IFNbeta-1b reduced the number of new enhancing lesions, with a greater effect on small lesions. However, when a new enhancing lesion did become established, treatment with IFNbeta-1b did not alter its subsequent course.     

Hypointense and hyperintense lesions on magnetic resonance imaging in secondary-progressive MS patients.

Cranial magnetic resonance imaging (MRI) is widely used to monitor disease activity in clinical trials in multiple sclerosis (MS). The purpose of this study is to examine lesion burden as determined from hypointense regions on postcontrast T1-weighted scans (or black holes), and lesion burden on conventional T2-weighted scans, from a cohort of secondary progressive MS patients who participated in a placebo-controlled, randomized, double-blind cross-over trial assessing the therapeutic efficacy of cladribine. T2 lesion volumes and black hole volumes are approximately normal distributed when log-transformed, and are highly correlated (adjusted R2 = 0.63). Changes in clinical scores could be predicted with a reasonable degree of precision from baseline scores and changes in T2 lesion volumes (adjusted R2 values 0.52-0.7). Stratification schemes for clinical trials should include the acute proportion of the disease (enhancing T1 lesions), degree of permanent damage (black holes), and T2 lesion volume.     

Clinical-MRI correlations in a European trial of interferon beta-1b in secondary progressive MS.

BACKGROUND: The recently completed placebo-controlled multicenter randomized trial of interferon beta-1b (Betaferon) in 718 patients with secondary progressive MS shows significant delay of disease progression and reduction of relapse rate. This study provides an opportunity to assess the level of relationship between clinical and MRI outcomes in this cohort of patients with secondary progressive MS. METHODS: Brain T2-weighted lesion volume was measured annually in all available patients, with visual analysis to identify any new or enlarging (active) T2 lesions at each annual time point. A subgroup of 125 patients had monthly gadolinium-enhanced, T1-weighted imaging at months 0 to 6 and 18 to 24. Relapses were documented and expanded disability status scale (EDSS) was measured every 3 months. RESULTS: For the annual MRI outcomes, a significant but modest correlation was identified between the change in T2 lesion volume from baseline to the final scan and the corresponding change from baseline in EDSS (r = 0.17, p < 0.0001). There were significant correlations between the cumulative number of active T2 lesions and 1) change in EDSS (r = 0.18, p < 0.0001) and 2) relapse rate (r = 0.24, p < 0.0001). In the subgroup of 125 patients undergoing monthly imaging, MRI lesion activity was correlated with relapse rate over months 0 to 24 (r = 0.24, p = 0.006) but not with change in EDSS. CONCLUSIONS: These results confirm that the clinical-MRI relationships previously identified in relapsing-remitting MS still are apparent in the secondary progressive phase of the disease and support the use of MRI as a relevant outcome measure. In view of the relatively modest nature of the correlations, it seems unwise to rely on such MRI measures alone as primary efficacy variables in secondary progressive MS trials.     

A modified protocol to improve the detection of enhancing brain and spinal cord leasions in multiple sclerosis

By detecting focal blood-brain barier (BBB) breakdown, gadolinium (GD-DTPA) contrast-enhanced T1-weighted magnetic resonance imaging (MRI) allows assessment of inflammatory activity in multiple sclerosis (MS) and provides a sensitive means of monitoring immunomodulatory therapies in exploratory trials. Serial monthly studies were performed in eight relapsing-remitting and eight secondary progressive patients to assess new and more sensitive techniques for enhanced MRI. Brain and spine imaging was carried out at 1.5-T on two occasions 24–72 h apart using a conventional imaging protocol with T1-weighted MRI at single-dose (0.1 mmol/kg) Gd-DTPA and a potentially more sensitive “modified” protocol with T1-weighted MRI at triple-dose (0.3 mmol/kg) Gd-DTPA (with addition of delay and magnetisation transfer presaturation for brain imaging). For each MRI protocol the total numbers of enhancing lesions (97 paired studies) and new enhancing lesions (81 paired studies) were assessed. The total number of enhancing lesions seen was 347/75 on conventional brain/cord MRI respectively, and 754/123 on modified brain/cord MRI. The respective numbers of new enhancing lesions were 168/40 on conventional and 276/71 on modified scans. Smaller increases were seen in the proportion of active scans using the modified protocol. Sample size calculations showed no reduction in sample sizes required for a parallel group study but a reduced sample size for crossover studies using the modified protocol: the addition of cord to brain imaging did not improve power for either trial design. A combined modified brain and cord imaging protocol markedly improves the detection of areas of focal BBB leakage in MS and many be useful in selected natural history studies. The modified brain protocol reduces sample size requirements for crossover studies but not necessarily for parallel design trials.. Received: 23 May 2000, Received in revised form: 25 September 2000, Accepted: 19 October 2000     

Serum from interferon-β-1b-treated patients with early multiple sclerosis stabilizes the blood-brain barrier in vitro

Interferon-β (IFN-β) stabilizes the blood-brain barrier (BBB) in vitro. Here we investigated the effect of serum from 15 IFN-β-1b-treated multiple sclerosis (MS) patients on the permeability read-outs of small solutes in an in vitro BBB model consisting of human brain microvascular endothelial cells in co-culture with rat astrocytes. The addition of sera from IFN-β-treated patients resulted in a significantly (p?相似文献   

Interferon-beta-1b effects on re-enhancing lesions in patients with multiple sclerosis

Interferon-beta (IFNbeta) reduces the number and load of new contrast-enhancing lesions (CELs) in patients with multiple sclerosis (MS). However, the ability of IFNbeta to reduce lesion sizes and re-enhancements of pre-existing CELs has not been examined extensively. Activity of contrast re-enhancing lesions (Re-CELs) and contrast single-enhancing lesions (S-CELs) were monitored in ten patients with relapsing-remitting (RR) MS. These patients underwent monthly post-contrast magnetic resonance imaging (MRIs) for an 18-month natural history phase and an 18-month therapy phase with subcutaneous IFNbeta-1b, totaling 37 images per patient. The activity was analysed using the first image as a baseline and registering subsequent active monthly images to the baseline. There was a 76.4% reduction in the number of CELs with IFNbeta therapy. The decrease was greater (P = 0.003) for S-CELs (82.3%) than for Re-CELs (57.4%). S-CELs showed no changes in durations of enhancement and maximal lesion sizes with treatment. Exclusively for Re-CELs, IFNbeta-1b significantly decreased maximal lesion sizes, total number of enhancement periods and total months of enhancement. Thus, IFNbeta appears to be effective in reducing the degree of severity of inflammation among Re-CELs, as reflected by their reduced maximal lesion sizes and durations of enhancement.     

A pilot trial of combination therapy with mitoxantrone and interferon beta-1b using monthly gadolinium-enhanced magnetic resonance imaging

OBJECTIVE: To examine the safety of combination therapy with mitoxantrone (MITX) and interferon beta-1b (IFNbeta-1b) in patients with multiple sclerosis (MS) and a high on-therapy relapse rate and enhancing lesions on baseline magnetic resonance imaging (MRI) scan. METHODS: Ten patients with worsening relapsing remitting or secondary progressive MS were studied using monthly MRI with triple-dose gadolinium contrast. All patients must have been on IFNbeta-1b for at least six months, have at least one enhancing lesion on a screening MRI, at least one relapse on IFNbeta-1b in the six months prior to study entry and be neutralizing antibody negative. Monthly MRI scans using triple dose contrast and a 30-minute delay between contrast administration and scanning were carried out three times over two months to obtain baseline numbers of enhancing lesions each month. At the end of the baseline phase, MITX was administered at 12 mg/m2 (month 3), and 5 mg/m2 at months 4 and 5. Dosing was continued at 5 mg/m2 every third month. Monthly MRI scanning was continued throughout the duration of MITX dosing. The primary outcome measure was the frequency of new enhancing lesions. Secondary outcome measures included relapse rate, and T1 hypointense and T2 lesion burden. RESULTS: Following the addition of MITX to IFNbeta-1b mean enhancing lesion frequency decreased 90% at month 7 (P = 0.008) and enhancing lesion volume decreased by 96% (P = 0.01). Relapse rates decreased 64% (P = 0.004). T2 lesion burden and T1 hypointense lesion burden increased slightly during the baseline phase and decreased following MITX but the difference did not reach statistical significance. There were no serious adverse events on combination therapy and no drop-outs due to toxicity. Total white blood cell count was reduced at 14 days post-MITX infusion but returned to normal levels by day 21. There were no neutropenic fevers and there was no clinically significant elevation of liver function tests. CONCLUSIONS: While the number of patients in this study was small, the results suggest that the combination is safe and well tolerated. Disease activity was substantially reduced following the addition of MITX to IFNbeta-1b.     

Effect of interferon-β1α therapy on multiple sclerosis based on gadolinium-enhancing or active T2 magnetic resonance imaging outcomes: a meta-analysis

Objectives: Interferon-beta1alpha (IFN-β1α) is widely used to modify the course of relapsing-remitting multiple sclerosis. However, many patients have relapses. The purpose of this study was to evaluate magnetic resonance imaging (MRI) as a predictor of IFN-β1α treatment efficacy in patients with MS.

Methods: PubMed, Embase, and the Cochrane Library were searched to identify eligible studies. Manual searches were also conducted. All eligible trials included MS patients who received IFN-β1α based on gadolinium-enhancing or active T2 MRI lesions for determination of relapse rates.

Results: Of 499 identified studies, we included 10 trials reporting data on 6,037 MS patients. IFN-β1α therapy significantly reduced the risk of relapse (RR: 0.87; 95% confidence intervals (CI): 0.76–0.99; p = 0.032). Furthermore, baseline median T2 lesion volume was found to be related to IFN-β1α therapy and relapse (p = 0.018). Subgroup analysis suggested that IFN-β1α therapy was associated with reduced risk of relapse (RR: 0.82; 95%CI: 0.71–0.94; p = 0.005 versus placebo). However, there was no significant difference in the risk of relapse compared to treatment with low dose IFN-β1α (RR: 0.93; 95%CI: 0.80–1.08; p = 0.337) or glatiramer acetate (RR: 0.93; 95%CI: 0.77–1.14; p = 0.506). Finally, IFN-β1α therapy significantly increased the risk of injection-site disorders, influenza-like syndrome, and alanine transferase elevation.

Discussion: Effects of IFN-β1α therapy are associated with a statistically significant impact on baseline median T2 lesion volume. However, the safety outcomes are significantly worse in patients who receive IFN-β1α therapy.     

Effect of interferon beta-1b in MS: assessment of annual accumulation of PD/T2 activity on MRI. UBC MS/MRI Analysis Group and the MS Study Group

OBJECTIVE: To determine whether the efficacy of interferon beta-1b (IFNbeta-1b) on lesion activity could be shown with annual analysis of MRI. BACKGROUND: Clinical outcomes and MRI burden of disease changes in MS patients in a multicenter double-blind placebo-controlled 5-year trial of IFNbeta-1b have been reported, together with an analysis of 6-weekly MRI activity in a small subgroup during 2 years. MRI activity measurements based on annual scans have not been documented. METHODS: Patients were randomized into three treatment arms: placebo, 1.6 mIU, and 8 mIU IFNbeta-1b self-administered subcutaneously every other day. Active lesions were identified as new, enlarging, or recurrent on proton density and T2-weighted MRI scans. Gadolinium was not used. An annual accumulation activity index was developed as an additional analysis of lesion activity. RESULTS: During the 5 years, both high- and low-dose IFNbeta-1b groups showed a striking reduction in lesion annual accumulation activity on the activity index versus placebo (p = 0.001). Thirty-five percent of the high-dose patients and 29% of the low-dose patients were MRI inactive by this method of analysis, whereas only 16% of placebo patients were inactive (p = 0.001, placebo versus 8 mIU). CONCLUSIONS: This analysis of the annual accumulation of lesion activity shows that the previously reported treatment effect seen on MRI scanning once every 6 weeks in a subcohort of the patients can also be seen on yearly scans. This annual accumulation activity analysis provides an independent MRI confirmation of a treatment and dose effect for IFNbeta-1b.     

Multiple sclerosis: myelin basic protein induced mRNA expression of proinflammatory cytokines in mononuclear cells is suppressed by interferon-β 1b in vitro

Beta-interferon (IFN-β) is a promising treatment in multiple sclerosis (MS), reducing the exacerbation rate and MRI lesion burden, as well as the disease progression in relapsing-remitting MS. IFN-β was originally defined by its antiviral effects, but the interest has recently been focused on its immunomodulatory properties. Myelin basic protein (MBP) is one of several autoantigens considered to be the target for autoaggressive immune responses, which eventually might lead to the development of MS. To study in-vitro effects of IFN-β1b on MBP induced cytokine expression, mRNA for the Th1 cytokines IFN-γ and TNF-α, the Th2 related IL-4 and IL-6, the cytolytic perforin and the immune response downregulating TGF-β was measured with in situ hybridization after culture of blood mononuclear cells (MNC) in the presence and absence of MBP. Numbers of cells expressing IFN-γ, TNF-α, perforin and IL-4 mRNA were significantly suppressed after culture with 10 U/ml IFN-β1b. No such effect was seen on MBP induced IL-6 or TGF-β mRNA expression. These observations suggest that one of the major effects of IFN-β1b is the induction of a shift in the cytokine mRNA profile towards a more immunosuppressive pattern. In parallel in vitro tests, the control substance dexametasone (40 μg/ml) reduced the numbers of cells expressing mRNA for all cytokines under study with the exception of TGF-β, to an extent equal to or even more pronounced than IFN-β1b.     

Open trial of the effectiveness of interferon beta 1a (Avonex) in the treatment of multiple sclerosis in Poland: MRI results

OBJECTIVE: To assess the effect of interferon-beta 1A (IFNb 1A, Avonex) treatment on magnetic resonance (MR) image in patients with remitting-relapsing multiple sclerosis (RR MS) who participated in the Polish Avonex trial. PATIENTS AND METHODS: RR MS patients (N = 126) participated in a two-year randomized open trial of Avonex treatment administered in the dose of 30 mcg once a week. MRI was performed twice in each case: shortly before the patient's enrollment in the study and within a month from the study completion. Changes in T2-weighted lesion volume and T1-weighted gadolinium-enhanced lesion volume, as well as the number of new T2-weighted and T1-weighted gadolinium-enhanced lesions were measured. RESULTS: Over the two-year treatment period the mean volume of T2-weighted lesions decreased by 3.9% (p = 0.83) while that of T1-weighted gadolinium-enhanced lesions decreased by 79% (p = 0.084%) as compared to the baseline MRI evaluation. The mean number of enhanced lesions after two years of Avonex therapy was reduced by 46.1% (p = 0.0035). The total number of enhanced lesions decreased by 49.8% (p = 0.0078). Both the number of new T2-weighted lesions, 3.7 per patient, and that of new T1-weighted gadolinium-enhanced lesions, 0.7 per patient, were comparable with the results obtained in other Avonex trials. CONCLUSION: The results confirmed that interferon beta-1a (Avonex) has a significant effect in MS patients, slowing down the progress of their disease. This effect is particularly visible in T1-weighted contrast-enhanced images, indicating an impact of the treatment particularly on the inflammatory stage of the demyelination process.     

Bimonthly cranial MRI activity following an isolated monosymptomatic demyelinating syndrome: potential outcome measures for future multiple sclerosis 'prevention' trials.

Patients with characteristic white matter lesions on MR imaging are at increased risk for the subsequent development of clinically definite MS (CDMS) following an isolated, monosymptomatic demyelinating syndrome (IMDS). These MR positive first-onset patients are thus candidates for MS prevention trials. Seven consecutive patients with IMDS and two or more periventricular and/or oval lesions on MR imaging were enrolled into a prospective trial based on serial T2-weighted and enhanced MR imaging at two month intervals for 12 - 15 months. Forty-seven new enhancing lesions were detected with triple dose MR contrast compared to 31 lesions using the standard dose. Four of the seven patients accounted for 98% of all enhancing lesions in this study, while the remaining three patients showed little MRI or clinical disease activity. New T2 lesion counts correlated strongly with enhanced lesion counts (r=0.82 - 0.98). We detected 49 new T2-hyperintense (T2) lesions based on short-interval (2 monthly) follow-up, and 31 new T2-lesions comparing exit and entry examinations. These results suggest several potential MR-based strategies for evaluating first onset patients in a phase III MS prevention trial. Since these patients have a small average T2-lesion load, it is quite easy to visually detect new T2 lesions. As a result, at a bimonthly study interval, T2-weighted lesion analysis is an effective measure of cumulative disease activity, provided high-resolution T2-weighted imaging studies are acquired to quantitate new T2-lesions. Enhanced lesion activity remains an important measure of blood - brain - barrier breakdown and may predict short term MRI and clinical disease activity in IMDS patients.     

Progressive gray matter damage in patients with relapsing-remitting multiple sclerosis: a longitudinal diffusion tensor magnetic resonance imaging study

BACKGROUND: Diffusion tensor magnetic resonance imaging (DT MRI) has the potential to provide in vivo information about tissue microstructure. In multiple sclerosis (MS), DT MRI has disclosed the presence of occult structural damage in the normal-appearing brain tissues. OBJECTIVE: To investigate whether DT MRI is sensitive to longitudinal changes of brain damage that may occur beyond the resolution of T2-weighted images in patients with relapsing-remitting MS. DESIGN: Twenty-six untreated patients with relapsing-remitting MS were followed up for 18 months. Dual-echo, DT and postcontrast T1-weighted MRIs of the brain were obtained at baseline and then every 3 months. Mean diffusivity (D) histograms of normal-appearing gray (GM) and white matter were produced. Total T2-hyperintense and T1-hypointense lesion volumes; normalized whole brain tissue, GM, and white matter volumes; percentage brain volume change between the study entry and exit images; average lesion D; and fractional anisotropy were also calculated. RESULTS: During the study period, a significant decrease of normalized whole brain tissue, average lesion fractional anisotropy and normal-appearing GM D histogram peak height, and a significant increase of average normal-appearing GM D and T2-hyperintense lesion volumes were observed. Changes of normal-appearing GM diffusivity were independent of the concomitant changes of normalized whole brain tissue and GM volumes. CONCLUSIONS: The DT MRI findings show progressive microstructural changes in the normal-appearing GM of patients with untreated relapsing-remitting MS. Such changes do not reflect a concomitant development of brain atrophy and confirm the importance of GM pathology in MS.     

Heterogeneity of blood-brain barrier changes in multiple sclerosis: an MRI study with gadolinium-DTPA enhancement

We performed 15 dynamic gadolinium-DTPA (Gd-DTPA)-enhanced MRI studies in 8 patients with relapsing and remitting multiple sclerosis; 7 were follow-up studies. We measured the time course of enhancement in 102 enhancing lesions for up to 384 minutes, with rest breaks. Immediate postcontrast MRIs demonstrated many different patterns of enhancement. We observed both uniformly enhancing and ring enhancing lesions. The enhancing regions were often less extensive than the corresponding high signal on T2-weighted images. Three lesions were seen with Gd-DTPA but not on unenhanced scans; 1 was seen on unenhanced scans 10 days later, suggesting that blood-brain barrier disturbance may precede other MRI signs of MS lesions. Three months later, some high-signal areas on T2-weighted scans had decreased in size to resemble the areas previously outlined by Gd-DTPA. This technique provides useful information about the pathogenesis and behavior of MS lesions.