Gadolinium Deposition in Deep Brain Structures: Relationship with Dose and Ionization of Linear Gadolinium-Based Contrast Agents.

BACKGROUND AND PURPOSE: Dose-dependent association between hyperintensity in deep brain structures on unenhanced T1WIs and gadolinium-based contrast agent administrations has been demonstrated with subsequent histopathological confirmation of gadolinium deposition. Our aim was to determine whether greater exposure to linear gadolinium-based contrast agent administration is associated with higher signal intensity in deep brain structures on unenhanced T1-weighted MR imaging. Secondary objective was to compare signal intensity differences between ionic and nonionic linear gadolinium-based contrast agents. MATERIALS AND METHODS: Subjects with secondary-progressive MS originally enrolled in a multicenter clinical trial were studied retrospectively. Eighty subjects (high-exposure cohort) received 9 linear gadolinium-based contrast agent administrations (30 nonionic/50 ionic) between week -4 and year 1 and a tenth administration by year 2. One hundred fifteen subjects (low-exposure cohort) received 2 administrations (40 nonionic/75 ionic) between week -4 and year 1 and a third administration by year 2. Signal intensities were measured on unenhanced T1WIs by placing sample-points on the dentate nucleus, globus pallidus, caudate, thalamus, pons, and white matter, and they were normalized using the following ratios: dentate/pons, globus pallidus/white matter, caudate/white matter, and thalamus/white matter. RESULTS: Between week -4 and year 1, subjects in the high-exposure cohort showed increased signal intensity ratios in all regions (P < .01), while the low-exposure cohort showed only an increase in the dentate nucleus (P = .003). Between years 1 and 2, when both cohorts received only 1 additional gadolinium-based contrast agent, no significant changes were observed. In the high-exposure cohort, significantly higher changes in signal intensity ratios were observed in subjects receiving linear nonionic than in those receiving linear ionic gadolinium-based contrast agents. CONCLUSIONS: Hyperintensity in deep brain structures from gadolinium deposition is related to the number of doses and the type of linear gadolinium-based contrast agent (nonionic greater than ionic) administration.

Subcutaneous interferon ß-1a three times weekly and the natural evolution of gadolinium-enhancing lesions into chronic black holes in relapsing and progressive multiple sclerosis: Analysis of PRISMS and SPECTRIMS trials.

BACKGROUND: Evolution of gadolinium-enhancing lesions into chronic black holes (CBH) may be reduced by interferon (IFN) therapy. OBJECTIVE: The objective of this paper is to assess the effect of IFN ß-1a and placebo on CBH evolution and disability in patients with relapsing-remitting multiple sclerosis (RRMS), as well as CBH evolution in patients with secondary progressive multiple sclerosis (SPMS). METHODS: A post hoc, exploratory analysis of patients with RRMS and SPMS with monthly MRI scans (months -1 to 9) from two separate placebo-controlled clinical trials of IFN ß-1a was conducted. RESULTS: In RRMS patients, the risk of ≥1 evolved CBH was lower for IFN ß-1a versus placebo (odds ratio 0.42; p = 0.024); volume of newly evolved CBH was numerically reduced. A numerically higher proportion of patients with ≥1 evolving CBH vs no evolving CBH had confirmed three-month disability progression (four-year rate 55.8% vs 43.1%, respectively). Proportion of lesions evolving into CBH (patient level: 34.7% vs 12.6%, p < 0.0001; lesion level: 28.8% vs 11.0%, p < 0.0001) and evolved CBH volume (median 33.5 mm3 (Quartile 1, 0.0; Quartile 3, 173.4) vs 0.0 mm3 (0.0; 52.4); p = 0.0008) was higher for SPMS than RRMS patients treated with IFN ß-1a. CONCLUSION: In RRMS, IFN ß-1a significantly decreased the proportion of new T1 Gd+ lesions evolving into CBH and the risk of developing a CBH. In patients with SPMS, more lesions develop to CBH, indicating reduced repair capacity, and the natural history of lesion development appears to be unaffected by IFN ß-1a treatment.

Evaluation of safety monitoring guidelines based on MRI lesion activity in multiple sclerosis.

OBJECTIVE: We evaluate variants of a commonly used data safety monitoring guideline in clinical trials in multiple sclerosis (MS) that flags patients who, at a follow-up visit, have 5 or more contrast-enhancing lesions (CELs) above their baseline count. METHODS: We apply the guideline to a relapsing cohort and a secondary progressive cohort. We assess the number of patients that meet the guideline and describe the characteristics of these patients; we also examine the value of the guideline in predicting relapse occurrence in the 28 days following that MRI. These analyses were repeated for thresholds varying from 1 to 10 CELs above baseline. RESULTS: Between 4% and 6% of patients met the threshold of 5 in both cohorts; patients with higher baseline counts and higher T2 lesion burden were more apt to meet the threshold. After adjustment for other covariates, the odds ratio (OR) of relapse associated with meeting the threshold is significant (p < 0.05) or near significant (0.05 ≤ p < 0.10) for thresholds between 5 and 8 for the relapsing cohort, but not for the secondary progressive cohort. Across thresholds, the adjusted OR is consistently greater than 1, and there is an increasing trend as the threshold increases from 1 to 7. CONCLUSIONS: A guideline based on crossing a threshold CEL count above baseline may be valuable in monitoring patient safety. Further study should be conducted using different datasets to assess the generalizability of these results.

The impact of intensity variations in T1-hypointense lesions on clinical correlations in multiple sclerosis.

BACKGROUND: The correlations between T1-hypointense lesion ('black hole') volume and clinical measures have varied widely across previous studies. The degree of hypointensity in black holes is associated with the severity of tissue damage, but the impact on the correlation with disability is unknown. OBJECTIVES: To determine how variations in the intensity level used for lesion classification can impact clinical correlation, specifically with the Expanded Disability Status Scale (EDSS), and whether using a restricted range can improve correlation. METHODS: A highly automated image analysis procedure was applied to the scans of 24 multiple sclerosis (MS) patients with well-distributed EDSS scores to compute their black hole volumes at nine different levels of intensity relative to the reference intensities sampled in normal-appearing white matter (NAWM) and cerebrospinal fluid (CSF). Two methods of volume computation were used. RESULTS: The black hole volume-EDSS Spearman correlations ranged between 0.49-0.73 (first method) and 0.54-0.74 (second method). The strongest correlations were observed by only including the voxels with maximum intensities at 30-40% of the CSF to NAWM range. CONCLUSIONS: Intensity variations can have a large impact on black hole-EDSS correlation. Restricting the measurement to a subset of the darkest voxels may yield stronger correlations.

Does MRI lesion activity regress in secondary progressive multiple sclerosis?

BACKGROUND: The rate of new contrast-enhancing lesions (CELs) on monthly magnetic resonance imaging (MRI) scans has been shown to decrease over a 9-month period in placebo-treated patients with relapsing-remitting (RR) multiple sclerosis (RRMS). OBJECTIVE: We examined this phenomenon in placebo-treated secondary progressive MS (SPMS) patients. METHODS: Patients were chosen from two clinical trials. Monthly scans were taken at screening, baseline and months 1-9 for Cohort-1 and months 1-6 for Cohort-2. We examined the monthly new CEL rates according to initial CEL level: 0, 1-3, >3 CELs at screening, and presence and absence of pre-study relapses. RESULTS: Respectively, 59, 21 and 14 of the 94 Cohort-1 patients, and 36, 17 and 9 of the 62 Cohort-2 patients had 0, 1-3 and >3 initial CELs. For Cohort-1, the monthly new CEL rates did not change during follow-up, regardless of initial CEL level. For Cohort-2, the monthly rate was unchanged in the 0 initial CEL subgroup, but decreased 33% (95% confidence interval: 8%, 52%) from months 1-3 to months 4-6 in the other two subgroups. For the combined cohorts, a decreasing rate was observed in the 12 patients with >3 initial CELs and pre-study relapses. CONCLUSIONS: The short-term trend of new CEL activity in placebo-treated SPMS patients may vary across cohorts.

Clinical and magnetic resonance imaging changes correlate in a clinical trial monitoring cyclosporine therapy for multiple sclerosis. The MS Study Group.

Magnetic resonance imaging (MRI) was used to monitor cyclosporine therapy for chronic progressive multiple sclerosis in a multicenter clinical trial and an analysis was performed to determine whether there was a correlation between clinical changes and MRI changes. MRI was performed on 163 patients at the onset and completion of the 2-year study. Burden of disease (BOD, lesion load) was quantitated by a single observer using a computer program. Active lesions were also identified. The Expanded Disability Status Scale (EDSS) score was determined every 3 months MRI data did not show any effect of cyclosporine treatment on BOD progression (mean 24.5% increase/yr) or lesion activity. However, there was a statistically significant positive correlation between the baseline total BOD value and the baseline EDSS score (r = 0.221, p = 0.005) and a positive correlation between the percent changes in BOD from baseline to exit and EDSS score (r = 0.186, p = 0.018). The study supports the concepts that MRI is a useful technique in monitoring therapeutic trials and that MRI is a direct measure of pathology.