Take the baseline in the warmer months and your primary endpoint measurement in the colder months and you can get get a placebo approved :)
Seasonal MRI Changes Seen in MS
By Nancy Walsh, Staff Writer, MedPage Today
Published: August 30, 2010
Reviewed by Michael J. Olek, DO; Director, Newport Doctors Multiple Sclerosis Clinic. Earn CME/CE credit
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Significantly increased levels of multiple sclerosis (MS) disease activity can be seen in MRI scans during the spring and summer months, researchers found.
Mean new lesion count for patients with MS on T2-weighted MRI scans was 2.2 in spring and 3.1 in summer compared with 1 and 1.5 in the fall and winter, respectively (four-season P=0.025), according to Dominik S. Meier, PhD, of Brigham and Women's Hospital in Boston, and colleagues.
This represented a group average of 1.8 times as many new lesions during the warmer months, Meier and colleagues reported in the Aug. 31 issue of Neurology.
Seasonal variations have been reported before in clinical markers of MS disease activity and in levels of proinflammatory cytokines, but MRI investigations into seasonality have been few and limited, the researchers wrote.
To address this gap, Meier and colleagues retrospectively analyzed MRI data from a group of 44 Boston-area patients who underwent frequent scans and clinical exams from 1991 to 1993.
Patients ranged in age from 25 to 52 years, with a mean disease duration of eight years.
A total of 13 were diagnosed with progressive MS at baseline, while the remainder had the relapsing-remitting subtype.
Patients underwent high-frequency serial MRI scanning on a weekly to monthly basis, for a median of 22 scans per patient. Both T2- weighted and conventional T1-weighted contrast enhancing lesions were assessed.
A total of 310 new T2 lesions were detected in 31 patients, and a mean of 22 new contrast-enhancing lesions were found in 42 patients.
Clinical examinations identified 51 episodes of disease worsening among 24 patients, with a mean of 2.1 attacks per patient.
Plotting the distribution of new T2 lesions across the calendar year revealed distinctly higher levels of activity, along with greater intensity of activity, from March to August, according to the investigators.
When they analyzed likelihood estimates of seasonal effects, they found these point estimates for the rate of new lesions per day:
•Spring, 0.024 (95% CI 0.012 to 0.035, P<0.001)
•Summer, 0.030 (95% CI 0.015 to 0.045, P<0.001)
•Fall, 0.010 (95% CI 0.0046 to 0.016, P<0.001)
•Winter, 0.016 (95% CI 0.0073 to 0.024, P<0.001)
This confirmed that disease activity was twice as likely during the warmer months, Meier and colleagues wrote.
The investigators then tested for associations of seasonality with meteorologic data, and found strong correlations of disease activity with warmer temperatures (r=0.55, P<0.0001), and levels of solar radiation (r=0.55, P<0.0001), but not for precipitation.
No seasonal prevalence was seen on contrast-enhancing lesions or in episodes of disease exacerbation.
The investigators explained that they used T2 lesions as their primary measure in the study because these typically result in a longer lasting area of signal hyperintensity and represent "a more robust outcome measure" than contrast-enhancing lesions.
The study findings raise important concerns for the design of future clinical trials in MS that use MRI for outcome, Meier and colleagues argued.
If the differences in seasonality are not adjusted for, longitudinal assessments could be biased, the investigators explained.
Bias could also be introduced into crossover trials, depending on the time of year when the crossover occurs.
Geographic differences may further contribute to seasonality patterns, which could be additionally problematic in studies where data are pooled from geographically disparate centers.
This concern about seasonality influencing clinical trials, particularly early-phase trials that typically rely on MRI, was echoed in an editorial by two researchers from Washington University in St. Louis.
"Such phase 1 and 2 studies are often of six- to nine-month design, and sometimes use crossover or escalating dose protocols," wrote Anne H. Cross, MD, and Becky Jo Parks, MD.
"The seasonal variability in MS activity detected by MRI could greatly bias results, either positively or negatively," they cautioned.
An important contribution of this study is its further support for the concept that the environment influences MS, according to Cross and Parks.
"If the critical environmental factors could be identified, this information would undoubtedly provide important clues regarding the mechanisms of disease progression in MS," they wrote.
Meier and colleagues cited some limitations to their study: the small sample, lack of data on ethnicity and other sociodemographic variables, and a potentially irregular distribution of participants entering the study (follow-up frequency was highest immediately after study entry).
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