Using gadolinium‐enhanced magnetic resonance imaging lesions to monitor disease activity in multiple sclerosis

Abstract

The highly variable clinical course and the lack of a direct measurement of disease activity have made evaluation of experimental therapies in multiple sclerosis (MS) difficult. Recent studies indicate that clinically silent lesions can be demonstrated by magnetic resonance imaging (MRI) in patients with mild relapsing-remitting MS. Thus, MRI may provide a means for monitoring therapeutic trials in the early phase of MS. We studied 12 patients longitudinally for 12 to 21 months with monthly gadolinium (Gd)-enhanced MRIs. The data have been used to identify the most effective design of a clinical trial using Gd-enhanced lesions as the outcome measure. Frequent (>l/mo) Gd-enhancing lesions were observed in 9 of the 12 patients, indicating that the disease is active even during the early phase of the illness.The frequency of the lesions was not constant; there was marked fluctuation in lesion number from month to month. However, the magnitude of the peak number of lesions and the frequency of the peaks varied among patients. Because of this variability, the most effective use of Gd-enhancing lesions as an outcome measure in a clinical trial was a crossover design with study arms of sufficient duration to allow accurate estimation of lesion frequency. Monitoring Gd-enhancing lesions may be an effective tool to assist in the assessment of experimental therapies in early MS.

Use of Magnetic Resonance Imaging as Well as Clinical Disease Activity in the Clinical Classification of Multiple Sclerosis and Assessment of Its Course

“…[20][21][22][23][24] When sensitive and frequent MRI studies are performed, Gd+ and unequivocally new or enlarging T2 brain lesions (subclinical relapses) can occur much more commonly than clinical symptoms (relapses or progression). [25][26][27][28] This may be explained at least in part by several factors: lesions in "eloquent" brain areas such as the optic nerves are more likely to be clinically expressed than lesions in less eloquent pathways; the degree of matrix and axonal destruction may vary; and the potential exists for rapid symptom recovery. [29][30][31][32][33][34][35][36][37][38] Even patients with progressive forms of MS, particularly those with Gd+ lesions indicating a subclinical relapse, may respond clinically to disease-modifying therapies (DMTs).…”

“…Subclinical MRI exacerbations are quite common, being detected up to 10 times more frequently than clinical symptoms or findings in RRMS patients. [25][26][27][28]49 Further, as previously indicated, progression can be difficult to assess. [16][17][18] The rate of deterioration in patients with established disability may be slow, in…”

Biomarkers and surrogate outcomes in neurodegenerative disease: Lessons from multiple sclerosis

“…In practice, such approaches are rarely used in clinical trials and have little impact on sample size requirements for trials because variability between patients also increases. 31 In relapsing remitting MS, a parallel groups design with a placebo arm requires ϳ2 ϫ 40 patients to show a 60% reduction in new enhancing lesions over 6 months, 32 with a 1-month run in scan reducing sample sizes by ϳ30%. 33 Such a trial design has become the standard way to evaluate efficacy of new anti-inflammatory therapies in phase 2 trials.…”

Immunological questions on hematopoietic stem cell transplantation for multiple sclerosis

“…10 Blood Brain Barrier (BBB) dysfunction alone, however, is not sufficient to start an inflammatory response toward myelin constituents. In fact, resident CNS cells in normal conditions lack major histocompatibility (MHC) molecules, thus preventing the initiation of antigen-specific immune responses.…”