Whole-brain diffusion MR histograms differ between MS subtypes A.O. Nusbaum, MD; C.Y. Tang, PhD; T.-C. Wei, BS; Monte S. Buchsbaum, MD; and Scott W. Atlas, MD Article abstract—Objective: To determine whether quantitative whole-brain MR diffusion histograms in patients with MS differ from those of normal control subjects. Background: MRI detects macroscopic cerebral lesions in MS, but the white matter lesion burden on MRI correlates imperfectly to clinical disability. Previous reports have further suggested abnormalities in white matter of MS patients with no visible lesions on conventional MRI. Methods: A total of 25 subjects (13 with MS 9 relapsing–remitting, 4 secondary progressive and 12 healthy control subjects) underwent diffusion- weighted echoplanar MRI encompassing the entire brain. The average apparent diffusion coefficient (ADC ave , or diffusion trace) was calculated on a pixel-by-pixel basis after segmentation of intracranial space from calvarium and extracranial soft tissues. Whole-brain ADC ave histograms were calculated and plotted for statistical comparison. Results: Mean whole-brain MR ADC ave in MS patients was elevated and histograms were shifted to higher values compared with normal control subjects. Mean whole-brain ADC ave of secondary progressive patients was shifted to higher values compared with relapsing–remitting patients. Whole-brain ADC ave histograms of relapsing–remitting patients showed no significant difference from normal control subjects. Conclusion: Whole-brain MR diffusion histograms may quantitate overall cerebral lesion load in patients with MS and may be able to discern differences between clinical subgroups. Key words: MS— Brain MR—Diffusion MR. NEUROLOGY 2000;54:1421–1426 Although MRI is thought to be highly sensitive to macroscopic cerebral lesions in MS, it has been shown that the visible lesion load on conventional T2-weighted MRI correlates imperfectly to clinical disability. 1-3 It has been further suggested that it may be the disease burden that is not visible by conventional MRI techniques that is more clinically significant. Several studies, in fact, suggest that this occult disease burden, or “invisible lesion load,” can be detected by abnormalities on other quantitative MRI techniques. 4-9 These imaging data are supported by several pathology studies that have shown that MS is actually a diffuse disease, rather than simply limited to the grossly visible (i.e., macroscopic) focal white matter lesions. 10-13 Moreover, although it is well known that the disease in MS predominantly affects the white matter, as many as 5 to 10% of lesions involve the gray matter, 14 which supports the idea that the entire brain parenchyma should be considered. MS patients are categorized into one of several clinically defined forms of the disease. Relapsing– remitting MS (RRMS) is the most common subtype, characterized by stable periods interspersed with re- lapses, which are followed within weeks to months by a partial or full recovery. Frequently, after inter- mittent periods of stability and relapse, secondary progressive MS (SPMS) patients (also known as re- lapsing–progressive) begin a course of steady pro- gression. SPMS patients differ clinically from RRMS patients by degree of disability and lack of substan- tial recovery after subsequent relapses. A large pro- portion of patients with RRMS disease eventually develop the SPMS course, but the precise mecha- nisms and predictors of such progression are un- known, although Trapp et al. 15 have hypothesized that there is a threshold of axonal loss that is reached eventually in the disease, beyond which there is progressive neurologic deterioration. Differ- ences by quantitative MRI between clinical subtypes of MS patients by either lesion analysis or in normal- appearing white matter have been described with variable results, 16-19 including by MRS 9,20 and magne- tization transfer (MT) analysis. 21,22 Diffusion MRI is a quantifiable imaging method that is uniquely sensitive to molecular water mobil- ity. Because water diffusion is restricted in highly organized tissues like white matter, 23,24 diffusion MRI has the potential to be very useful in assessing cerebral white matter and disorders thereof. Prelim- inary investigations have reported abnormal diffu- sion measurements in focal MS lesions and in focal areas of normal-appearing white matter in MS patients. 25-28 The purpose of our study was to analyze whole-brain MR diffusion trace histograms in pa- tients with MS and to compare these whole-brain data with normal control subjects. We also sought to determine whether there was a difference in the histograms between MS patients with RRMS and SPMS. From the Departments of Radiology (Drs. Nusbaum and Atlas, and C. Tang) and Psychiatry (C. Tang, T.-C. Wei, and M. Buchsbaum), Mount Sinai School of Medicine, New York, NY; and the Department of Radiology (Dr. Atlas), Stanford University Medical Center, CA. Received February 19, 1999. Accepted in final form December 16, 1999. Address correspondence and reprint requests to Dr. Scott W. Atlas, Department of Radiology, Stanford University Medical Center, S-047, 300 Pasteur Drive, Stanford, CA 94305-5105; e-mail: swatlas@stanford.edu Copyright © 2000 by the American Academy of Neurology 1421