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(Radiology. 1999;210:769-774.)
© RSNA, 1999

Neuroradiology

Differences between Relapsing-Remitting and Chronic Progressive Multiple Sclerosis as Determined with Quantitative MR Imaging

Yukio Miki, MD, PhD1,3, Robert I. Grossman, MD1, Jayaram K. Udupa, PhD1, Mark A. van Buchem, MD, PhD1,4, Luogang Wei, MS1, Michael D. Phillips, MD1,5, Upen Patel, MD1, Joseph C. McGowan, PhD1 and Dennis L. Kolson, MD, PhD2

1 Departments of Radiology (Y.M., R.I.G., J.K.U., M.A.v.B., L.W., M.D.P., U.P., J.C.M.)
2 Neurology (D.L.K.), University of Pennsylvania School of Medicine, 3400 Spruce St, Philadelphia, PA 19104-4283
3 Department of Nuclear Medicine and Diagnostic Imaging, Kyoto University Hospital, Japan (Y.M.)
4 Department of Diagnostic Radiology and Nuclear Medicine, Leiden University Hospital, the Netherlands (M.A.v.B.)
5 Department of Radiology, Indiana University Medical Center, Indianapolis (M.D.P.).


   Abstract
TOP
 Abstract
Introduction
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 References
 
PURPOSE: To investigate the cross-sectional relationships among multiple quantitative brain magnetic resonance (MR) imaging measurements in patients with relapsing-remitting versus chronic progressive multiple sclerosis (MS).

MATERIALS AND METHODS: Thirty-eight patients with MS (relapsing-remitting, 26; chronic progressive, 12) were examined. Lesion volume on T2-weighted MR images, contrast material–enhancing lesion volume, percentage of brain parenchymal volume (brain volume/[brain volume + cerebrospinal fluid volume]), and magnetization transfer ratio histogram peak height for the whole brain were calculated.

RESULTS: Significant negative correlation was noted between volume on T2-weighted images and magnetization transfer ratio histogram peak height for both the relapsing-remitting and chronic progressive groups (P < .001 for both). A positive correlation was demonstrated for lesion volume on T2-weighted images and enhancing lesion volume in the relapsing-remitting group (P < .01) but not in the chronic progressive group. Negative correlations were demonstrated for enhancing lesion volume and magnetization transfer ratio histogram peak height (P = .02), for Expanded Disability Status Scale score and magnetization transfer histogram peak height (P = .02), and for Expanded Disability Status Scale score and percentage of brain parenchymal volume in the relapsing-remitting group (P = .004) but not in the chronic progressive group.

CONCLUSION: The cross-sectional relationships among multiple quantitative brain MR imaging measurements are different between relapsing-remitting and chronic progressive MS.

Index terms: Brain, MR, 10.12143 • Brain, white matter, 10.871 • Magnetic resonance (MR), magnetization transfer contrast, 10.121417 • Sclerosis, multiple, 10.871


   Introduction
TOP
 Abstract
 Introduction
MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 References
 
Magnetic resonance (MR) imaging has established itself as the most sensitive imaging modality of choice for the detection of lesions of the central nervous system in patients with multiple sclerosis (MS) (1–4). In addition, MR imaging is thought to be the modality of choice for understanding the natural course of the disease and for evaluating findings of clinical trials (5–12). Several quantitative measurements obtained from MR images of the brain have been advocated to objectively monitor "total disease burden" (lesion volume) or "total activity" (gadolinium enhancement). The volume of the lesions demonstrated on T2-weighted images has been used to determine the total lesion load of the brain (10,13–22), while the volume of the lesions demonstrated on gadolinium-enhanced images (the enhancing lesion volume) has been used as an indicator of total lesion activity in the brain (23–26). The peak height of the magnetization transfer ratio histogram was recently advocated as an indicator to represent the residual amount of normal white matter in the brain (27,28). The degree of brain atrophy is also an important indicator of disease severity (25,29–32).

To our knowledge, however, cross-sectional relationships among these quantitative measurements of the brain or the relationships between these quantitative measurements and a patient's physical disability have not been established. We performed this study to statistically analyze the relationships between different quantitative measurements on MR images for relapsing-remitting and for chronic progressive MS.


   MATERIALS AND METHODS
TOP
 Abstract
 Introduction
 MATERIALS AND METHODS
RESULTS
 DISCUSSION
 References
 
Patients
Thirty-eight patients (25 women, 13 men; age range, 25–62 years; mean age ± SD, 43.3 years ± 8.2) with clinically definite MS as defined by the Poser criteria (33) were entered into a prospective study. Patients treated with immunosuppressants or cytotoxic or immunomodulatory drugs, other than brief courses of pulsed corticosteroids to treat exacerbations, were excluded. Acute exacerbations were treated with brief (<15-d) courses of corticosteroids. Patient disability was classified according to the Expanded Disability Status Scale (34). The patients had been classified clinically into either a relapsing-remitting MS (n = 26) or a chronic progressive MS (n = 12) group according to the following criteria: Patients with relapsing-remitting MS had had at least two relapses over the preceding 2 years, with a relapse defined as a new neurologic deficit or exacerbation of a previous deficit, confirmed by means of examination, that developed over 1–5 days when conditions had previously been stable and that lasted at least 48 hours. Patients with chronic progressive MS had an increase in the Expanded Disability Status Scale score of at least 1.0 over the preceding year without an acute exacerbation. Clinical examinations were performed in a nonblinded manner by a neurologist (D.L.K) who specialized in the care of patients with MS. Written informed consent was obtained from each patient, and our study was approved by our committee on studies involving human beings.

MR Imaging Parameters
All MR studies were performed with a 1.5-T magnet (Signa; GE Medical Systems, Milwaukee, Wis) with the use of a quadrature transmitter-receiver head coil. After sagittal localizer spin-echo T1-weighted images (600/11 [repetition time msec/echo time msec], one signal acquired) had been obtained, 3-mm-thick, interleaved contiguous axial fast spin-echo proton-density–weighted or T2-weighted (2,500/18, 90, one signal acquired) images were obtained with a 256 x 192 matrix and a 22-cm field of view. The echo train length was eight, and the dual echo was a split echo train. Three or four acquisitions were performed to cover the entire brain.

After the intravenous administration of gadopentetate dimeglumine (Magnevist; Berlex, Wayne, NJ; 0.1 mmol/kg), 3-mm-thick, interleaved, contiguous, axial, spin-echo T1-weighted images (600/27, one signal acquired) were obtained with a 256 x 192 matrix, a 22-cm field of view, and a flow-compensation technique. The echo time of 27 msec was to our knowledge the shortest available with use of a flow-compensation technique when the study was initiated; we used the same echo time throughout the study for consistency. The sequences for T1-weighted and proton-density– and T2-weighted imaging were identical to those reported earlier (26,35).

Magnetization transfer imaging was achieved with a standard three-dimensional gradient-echo sequence (106/5, one signal acquired, 12° flip angle), a 256 x 128 matrix, and a 22-cm field of view before the administration of the contrast material (36). Images were obtained at identical 5-mm intervals with or without the application of a saturation pulse. This saturation pulse consisted of a 19-msec single-cycle sinc pulse with an average radio-frequency field intensity of 3.67 x 10-6 T and was applied at a frequency 2 kHz below water resonance (36). The interval between the end of the saturation pulse and the beginning of each excitation was approximately 1 msec. This pulse sequence was chosen to minimize T1 and T2 effects, thereby resulting in a proton-density–weighted contrast in the absence of magnetization transfer saturation pulses (36). These magnetization transfer parameters are identical to those in previous studies (27,28,37–41).

Postprocessing
All imaging data were transferred from the imager directly to a Sparc 20 workstation (Sun Microsystems, Mountain View, Calif; four processors, 256 MB RAM) by using the picture archiving and communications system of our department. An internal version of the 3DVIEWNIX software (Sun Microsystems) was used to measure the lesion volume on T2-weighted images and the enhancing lesion volume on T1-weighted images (22,26,42). The software automatically selected and delineated potential lesion sites by using a method based on a theory of "fuzzy connectedness" (43). The algorithms used for the software have been described in separate articles in detail (22,42). The operator indicated which were the true lesions among these computer-detected potential lesions by clicking a mouse button. Lesion volume on T2-weighted images and enhancing lesion volume were subsequently computed. These methods are based on the notion that computer algorithms surpass humans in the delineation of objects and that humans surpass computer algorithms in most recognition tasks (22,26,42,44). The software used to quantitate lesion volume on T2-weighted images has been shown to have intra- and interobserver variability, with a coefficient of variation of 0.9% and a false-negative volume fraction of 1.3% (22,44). The software used to quantitate the enhancing lesion volume has been shown to have 0% intra- and interobserver variability and a false-negative volume fraction of 1.3% (42).

The volumes of brain parenchyma and cerebrospinal fluid were also calculated by using the software. The process begins with segmentation of the extracranial contents, which is achieved after an operator specifies points for identifying white matter, gray matter, and cerebrospinal fluid by using a previously described method (22,44). Gray matter, white matter, and cerebrospinal fluid regions are subsequently segmented by treating each as a fuzzy connected three-dimensional object containing the specified points (43). All the segmented sections are then reviewed. Any residual extracranial components are excluded, if needed, by an operator. The value for total brain parenchymal volume is then calculated by subtracting the cerebrospinal fluid volume from the volume of the intracranial contents (brain parenchymal volume plus cerebrospinal fluid volume). To normalize for baseline differences in brain parenchymal volume among patients, an additional parameter, the percentage of brain parenchymal volume is also calculated as the percentage of the brain volume that is the volume of the intracranial contents (brain volume/[brain volume + cerebrospinal fluid volume]).

The amount of magnetization transfer was quantitated with calculation of the magnetization transfer ratio, defined by the following equation (37): MTR = [(M0 - Ms)/M0] x 100%, where M0 and Ms represent the signal intensities of a voxel in the image with the saturation off and on, respectively. This magnetization transfer ratio indicates the percentage loss of signal intensity due to magnetization transfer. The software was used to segment the parenchyma of the whole brain on the magnetization transfer images and to generate a histogram of magnetization transfer ratios of the whole brain. To compare magnetization transfer ratio histograms of brains among individuals with different volumes, the histograms were normalized by dividing the histogram frequency values by the total number of voxels in the brain parenchyma (28). The magnetization transfer ratio histogram peak height, an indicator of the residual amount of normal white matter of the brain, was subsequently calculated (28). The algorithms used for generating the whole-brain magnetization transfer ratio histograms have been described in a separate article in detail (28).

Statistical Analysis
For each patient, one complete MR imaging examination, including fast spin-echo proton-density– and T2-weighted imaging, gadolinium-enhanced spin-echo T1-weighted imaging, and a magnetization transfer ratio study, was randomly selected for analysis. The Spearman test was used to correlate every possible pair from the lesion volume on T2-weighted images, the enhancing lesion volume, the magnetization transfer ratio histogram peak height, the percentage of brain parenchymal volume, and the Expanded Disability Status Scale score for each clinical subgroup.


   RESULTS
TOP
 Abstract
 Introduction
 MATERIALS AND METHODS
 RESULTS
DISCUSSION
 References
 
A significant positive correlation between lesion volume on T2-weighted images and enhancing lesion volume was revealed with analysis of the MR imaging parameters in the group of patients with relapsing-remitting MS but not in the patients with chronic progressive MS (r = 0.66, P < .001 for relapsing-remitting MS and r = -0.017, P = .96 for chronic progressive MS), as summarized in the Table. Despite the strong correlation between the lesion volume on T2-weighted images and the enhancing lesion volume in the patients with relapsing-remitting MS, we failed to detect a significant correlation between either the volume on T2-weighted images or the enhancing lesion volume and the clinical status reflected by the Expanded Disability Status Scale scoring (Table, Fig 1). In addition, the patients with chronic progressive MS in our series tended to have higher Expanded Disability Status Scale scores than did the patients with relapsing-remitting MS (Figs 1, 2), reflecting the substantial ambulatory difficulty in the patients with chronic progressive MS. However, as in the relapsing-remitting group, the Expanded Disability Status Scale scores showed no correlation to the volume on T2-weighted images in the chronic progressive group (Fig 1).


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  		Cross-sectional Relationships among MR Imaging Measurements in Patients with MS
 


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  		Figure 1. Graph of Expanded Disability Status Scale (EDSS) scores versus volume on T2-weighted images for each patient. No significant correlation was noted between the Expanded Disability Status Scale score and the volume on T2-weighted images for each MS classification. Note the difference of distribution between the chronic progressive group ({square}) and the relapsing-remitting group (+). Patients with chronic progressive MS tend to show worse Expanded Disability Status Scale scores than do patients with relapsing-remitting MS and with a matched range of volumes on T2-weighted images.

 


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  		Figure 2. Graph of Expanded Disability Status Scale (EDSS) scores versus magnetization transfer ratio histogram peak heights (MTRHPH) for each patient. There was a significant correlation between Expanded Disability Status Scale scores and magnetization transfer ratio histogram peak heights in the relapsing-remitting group (+) but not in the chronic progressive group ({square}). Note the difference of distribution between the chronic progressive group and the relapsing-remitting group. The patients with chronic progressive MS tend to show worse Expanded Disability Status Scale scores than do patients with relapsing-remitting MS and with a matched range of magnetization transfer ratio histogram peak heights.

 
In contrast, among the patients with relapsing-remitting MS and the patients with chronic progressive MS, a negative correlation was demonstrated between lesion volume on T2-weighted images, magnetization transfer ratio histogram peak height, and the proportion of residual total brain volume (percentage of brain parenchymal volume) (Table). The peak height of the magnetization transfer ratio histogram reflects the amount of normal white matter (27,28), and the percentage of brain parenchymal volume represents the sum of the total white matter and gray matter volumes; thus, loss of normal brain parenchyma with increasing MS lesion volume is suggested, as discussed later. Furthermore, the enhancing lesion volume, which also reflects the abnormal brain signal (45), was also, as expected, negatively correlated to the magnetization transfer ratio histogram peak height and the percentage of brain parenchymal volume in patients with relapsing-remitting MS—albeit weakly (r = -0.46, P = .02, and r = -0.51, P = .009, respectively). However, no such correlation was seen in the patients with chronic progressive MS, who generally tend to have lower enhancing lesion volumes (46).

Finally, we found a marked distinction between the patients with relapsing-remitting MS and the patients with chronic progressive MS with respect to the Expanded Disability Status Scale score and the percentage of brain parenchymal volume and the Expanded Disability Status Scale score and the magnetization transfer ratio histogram peak height (Table). While the patients with relapsing-remitting MS demonstrated a significant negative correlation between the Expanded Disability Status Scale score and the percentage of brain parenchymal volume, the patients with chronic progressive MS did not. In addition, the patients with relapsing-remitting MS showed a negative correlation between the Expanded Disability Status Scale score and the magnetization transfer ratio histogram peak height, while the patients with chronic progressive MS did not.


   DISCUSSION
TOP
 Abstract
 Introduction
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
References
 
We have used unique quantitative MR volumetric measures of intracranial white matter and gray matter to attempt to develop objective correlates to clinical status in both patients with relapsing-remitting MS and patients with chronic progressive MS. These include highly reproducible measures of lesion volume on T2-weighted images (22), total enhancing lesion volume (26), magnetization transfer ratio histogram peak height (27,28), and the percentage of total brain parenchyma. To our knowledge, this is the first correlative study to use these unique multiple quantitative white and gray matter volumetric parameters and the clinical status in both patients with chronic progressive MS and patients with relapsing-remitting MS.

There was a significant positive correlation between the enhancing lesion volume and the volume on T2-weighted images in the relapsing-remitting group but not in the chronic progressive group. Similarly, there was a negative correlation between the enhancing lesion volume and the magnetization transfer ratio histogram peak height and the enhancing lesion volume and the percentage of brain parenchymal volume in the relapsing-remitting group but not in the chronic progressive group. These findings are striking. This is consistent with the notion that gadolinium enhancement reflects white matter lesions with acute inflammation and that these may represent a higher proportion of the total lesion volume (reflected by the volume on T2-weighted images) in patients with a relapsing-remitting MS clinical course (45,46). It is likewise consistent with the hypothesis that a greater percentage of lesions in patients with chronic progressive MS are chronic (due to demyelination or gliosis), with no clinically important inflammatory activity (4).

There was a strong negative correlation between the volume on T2-weighted images and the magnetization transfer ratio histogram peak height in both patients with relapsing-remitting MS and patients with chronic progressive MS. The magnetization transfer ratio histogram peak height is believed to represent the amount of the residual normal white matter (27,28), while the volume on T2-weighted images is believed to represent the total lesion load, including edema, inflammation, demyelination, and gliosis (12). As the total lesion load (volume on T2-weighted images) increases, the amount of remaining normal white matter (magnetization transfer ratio histogram peak height) within a given patient is considered to decrease. Thus, one would expect that the amount of the residual normal white matter tissue (magnetization transfer ratio histogram peak height) has a strong negative correlation with the total lesion load (volume on T2-weighted images).

The Expanded Disability Status Scale score correlated with the magnetization transfer ratio histogram peak height and the percentage of brain parenchymal volume in the relapsing-remitting group, but the Expanded Disability Status Scale score did not correlate with the magnetization transfer ratio histogram peak height, the percentage of brain parenchymal volume, or the volume on T2-weighted images in the chronic progressive group. It has been recognized that there is a poor correlation between the lesion load on T2-weighted images and physical disability (47–49), but why the Expanded Disability Status Scale score does not correlate with any of the quantitative measurements derived from brain MR imaging in the chronic progressive group is unclear. One possibility is that most brain lesions in patients with chronic progressive MS do not directly contribute to physical disability. Another possibility is that spinal cord lesions may affect disability more than brain lesions do in patients with chronic progressive MS. In our study, patients with chronic progressive MS had the tendency to have worse Expanded Disability Status Scale scores than did patients with relapsing-remitting MS, with a matched range of volumes on T2-weighted images and magnetization transfer ratio histogram peak heights (Figs 1, 2); the Expanded Disability Status Scale scores may indicate the presence of factors other than the brain lesion load that cause physical disability. This is consistent with the suppositions by Comi et al (50) and by Filippi et al (51) that disability in patients with primary progressive MS (a subtype of chronic progressive MS) may be predominantly due to spinal cord damage. Our latter hypothesis is also supported by the findings of Kidd et al (52) and Losseff et al (53) that physical disability correlated with cross-sectional areas of the spinal cord on selected axial MR images in patients with MS. It would be valuable to develop methods to quantitate both cord volume and cord lesion load (including volume on T2-weighted images and magnetization transfer ratio analysis) in the future.

In conclusion, the relationship between the quantitative measurements reflecting total disease burden (volume on T2-weighted images) and that reflecting total disease activity (enhancing lesion volume) is significantly different between the two clinical classifications of MS. Three different quantitative measurements (volume on T2-weighted images, magnetization transfer ratio histogram peak height, and percentage of brain parenchymal volume) significantly correlated with each other in both subtypes. None of the quantitative measurements reflecting total brain disease burden, total brain disease activity, and the degree of brain atrophy correlated with physical disability in patients with chronic progressive MS. The cross-sectional relationships among multiple quantitative brain MR imaging measurements are important for understanding the natural course of MS and for determining the efficacy of therapeutic trials.


   Footnotes
 
Supported in part by U.S. National Institutes of Health grants R01 NS2 9029-01A1 and M01-RR00040.

Address reprint requests to R.I.G.

From the 1997 RSNA scientific assembly.

Abbreviation: MS = multiple sclerosis

Author contributions: Guarantors of integrity of entire study, Y.M., R.I.G.; study concepts and design, Y.M., R.I.G.; definition of intellectual content, Y.M., R.I.G.; literature research, Y.M.; clinical studies, D.L.K.; data acquisition, Y.M., J.C.M.; data analysis, Y.M., J.K.U., M.A.v.B., L.W., M.D.P., U.P.; statistical analysis, Y.M.; manuscript preparation and editing, Y.M.; manuscript review, Y.M., R.I.G., J.K.U., M.A.v.B., J.C.M., D.L.K.

Received January 27, 1998; revision requested April 6, 1998; revision received July 2, 1998; accepted October 13, 1998.
   References
TOP
 Abstract
 Introduction
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 References
 

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