Andrew Riddehough

Trial of Minocycline in a Clinically Isolated Syndrome of Multiple Sclerosis

BACKGROUND On the basis of encouraging preliminary results, we conducted a randomized, controlled trial to determine whether minocycline reduces the risk of conversion from a first demyelinating event (also known as a clinically isolated syndrome) to multiple sclerosis. METHODS During the period from January 2009 through July 2013, we randomly assigned participants who had had their first demyelinating symptoms within the previous 180 days to receive either 100 mg of minocycline, administered orally twice daily, or placebo. Administration of minocycline or placebo was continued until a diagnosis of multiple sclerosis was established or until 24 months after randomization, whichever came first. The primary outcome was conversion to multiple sclerosis (diagnosed on the basis of the 2005 McDonald criteria) within 6 months after randomization. Secondary outcomes included conversion to multiple sclerosis within 24 months after randomization and changes on magnetic resonance imaging (MRI) at 6 months and 24 months (change in lesion volume on T2‐weighted MRI, cumulative number of new lesions enhanced on T1‐weighted MRI [“enhancing lesions”], and cumulative combined number of unique lesions [new enhancing lesions on T1‐weighted MRI plus new and newly enlarged lesions on T2‐weighted MRI]). RESULTS A total of 142 eligible participants underwent randomization at 12 Canadian multiple sclerosis clinics; 72 participants were assigned to the minocycline group and 70 to the placebo group. The mean age of the participants was 35.8 years, and 68.3% were women. The unadjusted risk of conversion to multiple sclerosis within 6 months after randomization was 61.0% in the placebo group and 33.4% in the minocycline group, a difference of 27.6 percentage points (95% confidence interval [CI], 11.4 to 43.9; P=0.001). After adjustment for the number of enhancing lesions at baseline, the difference in the risk of conversion to multiple sclerosis within 6 months after randomization was 18.5 percentage points (95% CI, 3.7 to 33.3; P=0.01); the unadjusted risk difference was not significant at the 24‐month secondary outcome time point (P=0.06). All secondary MRI outcomes favored minocycline over placebo at 6 months but not at 24 months. Trial withdrawals and adverse events of rash, dizziness, and dental discoloration were more frequent among participants who received minocycline than among those who received placebo. CONCLUSIONS The risk of conversion from a clinically isolated syndrome to multiple sclerosis was significantly lower with minocycline than with placebo over 6 months but not over 24 months. (Funded by the Multiple Sclerosis Society of Canada; ClinicalTrials.gov number, NCT00666887.)

Clinical and Magnetic Resonance Imaging Changes Correlate in a Clinical Trial Monitoring Cyclosporine Therapy for Multiple Sclerosis

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.

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.

Low-fat, plant-based diet in multiple sclerosis: A randomized controlled trial

BACKGROUND The role that dietary interventions can play in multiple sclerosis (MS) management is of huge interest amongst patients and researchers but data evaluating this is limited. Possible effects of a very-low-fat, plant-based dietary intervention on MS related progression and disease activity as measured by brain imaging and MS related symptoms have not been evaluated in a randomized-controlled trial. Despite use of disease modifying therapies (DMT), poor quality of life (QOL) in MS patients can be a significant problem with fatigue being one of the common disabling symptoms. Effective treatment options for fatigue remain limited. Emerging evidence suggests diet and vascular risk factors including obesity and hyperlipidemia may influence MS disease progression and improve QOL. OBJECTIVES To evaluate adherence, safety and effects of a very-low-fat, plant-based diet (Diet) on brain MRI, clinical [MS relapses and disability, body mass index (BMI)] and metabolic (blood lipids and insulin) outcomes, QOL [Short Form-36 (SF-36)], and fatigue [Fatigue Severity Scale (FSS) and Modified Fatigue Impact Scale (MFIS)], in relapsing-remitting MS (RRMS). METHODS This was a randomized-controlled, assessor-blinded, one-year long study with 61 participants assigned to either Diet (N=32) or wait-listed (Control, N=29) group. RESULTS The mean age (years) [Control-40.9±8.48; Diet-40.8±8.86] and the mean disease duration (years) [Control -5.3±3.86; Diet-5.33±3.63] were comparable between the two groups. There was a slight difference between the two study groups in the baseline mean expanded disability status scale (EDSS) score [Control-2.22±0.90; Diet-2.72±1.05]. Eight subjects withdrew (Diet, N=6; Control, N=2). Adherence to the study diet based on monthly Food Frequency Questionnaire (FFQ) was excellent with the diet group showing significant difference in the total fat caloric intake compared to the control group [total fat intake/total calories averaged ~15% (Diet) versus ~40% (Control)]. The two groups showed no differences in brain MRI outcomes, number of MS relapses or disability at 12 months. The diet group showed improvements at six months in low-density lipoprotein cholesterol (Δ=-11.99mg/dL; p=0.031), total cholesterol (Δ=-13.18mg/dL; p=0.027) and insulin (Δ=-2.82mg/dL; p=0.0067), mean monthly reductions in BMI (Rate=-1.125kg/m2 per month; p<0.001) and fatigue [FSS (Rate=-0.0639 points/month; p=0.0010); MFIS (Rate=-0.233 points/month; p=0.0011)] during the 12-month period. CONCLUSIONS While a very-low fat, plant-based diet was well adhered to and tolerated, it resulted in no significant improvement on brain MRI, relapse rate or disability as assessed by EDSS scores in subjects with RRMS over one year. The diet group however showed significant improvements in measures of fatigue, BMI and metabolic biomarkers. The study was powered to detect only very large effects on MRI activity so smaller but clinically meaningful effects cannot be excluded. The diet intervention resulted in a beneficial effect on the self-reported outcome of fatigue but these results should be interpreted cautiously as a wait-list control group may not completely control for a placebo effect and there was a baseline imbalance on fatigue scores between the groups. If maintained, the improved lipid profile and BMI could yield long-term vascular health benefits. Longer studies with larger sample sizes are needed to better understand the long-term health benefits of this diet.

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.

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.

Optimizing the Use of Radiologist Seed Points for Improved Multiple Sclerosis Lesion Segmentation

Many current methods for multiple sclerosis (MS) lesion segmentation require radiologist seed points as input, but do not necessarily allow the expert to work in an intuitive or efficient way. Ironically, most methods also assume that the points are placed optimally. This paper examines how seed points can be processed with intuitive heuristics, which provide improved segmentation accuracy while facilitating quick and natural point placement. Using a large set of MRIs from an MS clinical trial, two radiologists are asked to seed the lesions while unaware that the points would be fed into a classifier, based on Parzen windows, that automatically delineates each marked lesion. To evaluate the impact of the new heuristics, an interactive region-growing method is used to provide ground truth and the Dice coefficient (DC) and Spearmans rank correlation are used as the primary measures of agreement. A stratified analysis is performed to determine the effect on scans with low-, medium-, and high lesion loads. Compared to the unenhanced classifier, the heuristics dramatically improve the DC (+32.91 pt.) and correlation (+0.50) for the scans with low lesion loads, and also improve the DC (+14.55 pt.) and correlation (+0.15) for the scans with medium lesion loads, while having a minimal effect for the scans with high lesion loads, which are already segmented accurately by Parzen windows. With the heuristics, the DC is close to 80% and the correlation is above 0.9 for all three load categories.

Detection of unusual increases in MRI lesion counts in individual multiple sclerosis patients

Data Safety and Monitoring Boards (DSMBs) for multiple sclerosis clinical trials consider an increase of contrast-enhancing lesions on repeated magnetic resonance imaging an indicator for potential adverse events. However, there are no published studies that clearly identify what should be considered an “unexpected increase” of lesion activity for a patient. To address this problem, we consider as an index the likelihood of observing lesion counts as large as those observed on the recent scans of a patient conditional on the patient’s lesion counts on previous scans. To estimate this index, we rely on random effects models. Given the patient-specific random effect, we assume that the repeated lesion counts from the same patient follow a negative binomial distribution and may be correlated over time. We fit the model using data collected from the trial under DSMB review and update the estimation when new data are to be reviewed. We consider two estimation procedures: maximum likelihood for a fully parameterized model and a simple semiparametric method for a model with an unspecified distribution for the random effects. We examine the performance of our methods using simulations and illustrate the approach using data from a clinical trial. Supplementary materials for this article are available online.

Detection and measurement of coverage loss in interleaved multi-acquisition brain MRIs due to motion-induced inter-slice misalignment.

In MRI scans that are acquired in a slice-by-slice manner, patient motion during scanning can cause adjacent slices to overlap, resulting in duplicate coverage in some areas and missing coverage in others. Scans in which multiple slices are acquired simultaneously and interleaved with other sets of slices are particularly vulnerable because a single movement can result in the misalignment and overlap of many slices. Despite the fact that considerable data losses can occur even with few visible artifacts, this problem has received very little attention from MRI researchers. The primary goals of this paper are: (1) to raise awareness of the problem in the MRI community and (2) to present an efficient multiscale algorithm that accurately quantifies the amount of data loss. Validation of the algorithms accuracy is performed on 200 scans with simulated patient motion so that the true amount of data loss is known for each scan. The motion parameters are chosen to simulate scans that have significant data loss (mean missing coverage=14.39% of head volume, SD=6.61%, range=2.76-32.98%) but with few visual indications of the problem. The algorithm is shown to be very accurate, yielding estimates that differ from the true values by a mean of only 1.1% point (SD=0.98pt, range=0.00-6.54pt). The algorithm is also shown to be consistent and robust when tested on a large set of scans from a recent multiple sclerosis clinical trial.

Improving the clinical correlation of multiple sclerosis black hole volume change by paired-scan analysis☆

The change in T1-hypointense lesion (“black hole”) volume is an important marker of pathological progression in multiple sclerosis (MS). Black hole boundaries often have low contrast and are difficult to determine accurately and most (semi‐)automated segmentation methods first compute the T2-hyperintense lesions, which are a superset of the black holes and are typically more distinct, to form a search space for the T1w lesions. Two main potential sources of measurement noise in longitudinal black hole volume computation are partial volume and variability in the T2w lesion segmentation. A paired analysis approach is proposed herein that uses registration to equalize partial volume and lesion mask processing to combine T2w lesion segmentations across time. The scans of 247 MS patients are used to compare a selected black hole computation method with an enhanced version incorporating paired analysis, using rank correlation to a clinical variable (MS functional composite) as the primary outcome measure. The comparison is done at nine different levels of intensity as a previous study suggests that darker black holes may yield stronger correlations. The results demonstrate that paired analysis can strongly improve longitudinal correlation (from -0.148 to -0.303 in this sample) and may produce segmentations that are more sensitive to clinically relevant changes.