Regional Cervical Cord Atrophy and Disability in Multiple Sclerosis: A Voxel-based Analysis 1

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1 Note: This copy is for your personal non-commercial use only. To order presentation-ready copies for distribution to your colleagues or clients, contact us at Paola Valsasina, MSc Maria A. Rocca, MD Mark A. Horsfield, PhD Martina Absinta, MD Roberta Messina, MD Domenico Caputo, MD Giancarlo Comi, MD Massimo Filippi, MD Regional Cervical Cord Atrophy and Disability in Multiple Sclerosis: A Voxel-based Analysis 1 Purpose: Materials and Methods: To (a) apply an active surface method to map the regional distribution of cord atrophy across levels and sectors in a relatively large group of patients with multiple sclerosis (MS), (b) compare the anatomic location of cord atrophy between patients with relapsing-remitting (RR) MS and those with secondary progressive (SP) MS, and (c) assess correlations between atrophy and disability. This study was approved by the local ethical committee, and written informed consent was obtained from each participant. High-spatial-resolution magnetic resonance (MR) images of the cervical cord were acquired from 45 patients with RR MS, 26 patients with SP MS, and 67 age-matched healthy control subjects. The active surface method segmented the cord surface from C1 to C7 and created output images reformatted in planes perpendicular to the estimated cord center line. These unfolded cervical cord images were coregistered into a common standard space, and smoothed cord binary masks were used as input images for spatial statistics. Voxel-wise betweengroup comparisons and the correlation between regional cord atrophy versus clinical and conventional MR imaging variables were assessed with software. Original Research n Neuroradiology 1 From the Neuroimaging Research Unit, Institute of Experimental Neurology (P.V., M.A.R., M.A., R.M., M.F.), and Department of Neurology (M.A.R., M.A., R.M., G.C., M.F.), San Raffaele Scientific Institute, Vita-Salute San Raffaele University, Via Olgettina 60, Milan 20132, Italy; Department of Cardiovascular Sciences, University of Leicester, Leicester, England (M.A.H.); and Department of Neurology, Scientific Institute Fondazione Don Gnocchi, Milan, Italy (D.C.). Received April 10, 2012; revision requested June 4; revision received June 13; accepted July 2; final version accepted July 24. Address correspondence to M.F. ( m.filippi@hsr.it). q RSNA, 2012 Results: Conclusion: Compared with control subjects, patients with RR MS showed localized clusters of atrophy in the posterior cord. Conversely, patients with SP MS showed a widespread pattern of cord atrophy, predominantly in the posterior and lateral cord columns. In patients with MS, cervical cord atrophy was correlated with clinical disability, disease duration, and, to a lesser extent, conventional MR imaging measures of brain injury. No correlation was found between cord atrophy and the presence of focal cord lesions. Voxel-wise assessment of the regional distribution of damage in the cervical cord is feasible and might improve our understanding of the mechanisms related to the development of irreversible clinical disability in MS. q RSNA, 2012 Supplemental material: /suppl/doi: /radiol /-/dc1 Radiology: Volume 266: Number 3 March 2013 n radiology.rsna.org 853

2 The spinal cord is frequently involved in multiple sclerosis (MS), with conventional magnetic resonance (MR) images showing hyperintense cord lesions, mainly located at the cervical level, in up to 90% of patients with definite MS (1). In addition to having focal and/or diffuse lesions, these patients usually have cord atrophy (2 6), which is the consequence of demyelination and axonal loss, as suggested in pathologic investigations (7,8). Studies assessing cord atrophy in patients with MS have consistently demonstrated that the cervical portion of the cord is more affected than the lower segments (1,9,10), that cord tissue loss is more pronounced in patients with progressive MS than in those with relapsing-remitting (RR) MS (3,5,6), and that there is a significant association between cord atrophy and clinical disability as quantified with the Expanded Disability Status Scale (EDSS) (2,3,5). Most previous studies investigated cervical cord atrophy at a single anatomic level, typically at C2 or C5 (2,3,11). Recently, a semiautomated method based on an active surface model has been developed that enables the segmentation of large portions of the spinal cord (6). This approach has been successfully applied to the measurement Advances in Knowledge nn Voxel-based analysis of high-spatial-resolution images of the cervical cord enabled mapping of the regional distribution of cervical cord atrophy in 71 patients with relapse-onset multiple sclerosis (MS). nn Cervical cord atrophy involved mainly the lateral and posterior cord columns and was more severe in patients with locomotor disability than in those without locomotor disability (P,.05, corrected for family-wise error). nn Cervical cord atrophy was correlated with clinical variables and, to a lesser extent, conventional MR imaging measures of brain injury (r = to 20.57, P,.001). of cervical cord atrophy in a large, multicenter cohort of patients with MS of different clinical phenotypes (5). The active surface method includes the cord center line as an explicit part of the model; this allows the reformatting of cord images in planes perpendicular to the cord center line, in which the cord is artificially straightened and can be visualized as a cylinderlike structure (6). These reformatted images can be coregistered into the same space, and the reformatted cord masks, created by using cord contours calculated with the active surface method, can be analyzed by using voxel-wise comparisons (12). The aims of this study were to (a) apply an active surface method to map the regional distribution of cord atrophy across levels and sectors in a relatively large group of patients with MS, (b) compare the anatomic location of cord atrophy between patients with RR MS and those with secondary progressive (SP) MS, and (c) assess correlations between atrophy and disability. Materials and Methods Subjects This study was approved by the local ethical standards committee, and written informed consent was obtained from all participating subjects. Seventy-one patients with MS (13) (25 men, 46 women; mean age: 42.1 years, range: years; median EDSS score [14]: 4.0, range: ; median disease duration: 14 years, range: 1 39 years) and 67 age- and sexmatched healthy subjects with no history of neurologic dysfunction and a normal neurologic examination were enrolled in this prospective study. Enrollment Implication for Patient Care nn An accurate localization technique for identifying cervical cord atrophy in MS holds promise for improving our understanding of the mechanisms responsible for the accumulation of irreversible disability in this condition. began January 2010 and ended January For all subjects, exclusion criteria included history of cervical trauma and evidence of cord compression and/or deformity on previous MR images (six subjects excluded), presence of major medical conditions other than MS (three subjects excluded), and history of alcohol or drug abuse (two subjects excluded). For patients, corticosteroid treatment for clinical relapses had to be terminated at least 4 weeks before MR imaging for inclusion in the study (seven patients excluded). Forty-five patients had RR MS and 26 had SP MS (15). Thirty-nine of 71 patients (55%, 13 with RR MS and all 26 with SP MS) had locomotor impairment (defined as an EDSS score 4.0). The demographic, clinical, and MR imaging characteristics of the three study groups are shown in Table 1. MR Imaging In all subjects, imaging of the cervical cord and brain was performed with use of a 1.5-T MR unit (Avanto; Siemens, Erlangen, Germany) equipped with standard matrix neck coils. Cervical cord. Two sequences were used to image the cervical cord: (a) a sagittal three-dimensional T1- weighted magnetization-prepared rapid acquisi tion gradient-echo sequence (1160/4.24/600 [repetition time msec/ Published online before print /radiol Content code: Radiology 2013; 266: Abbreviations: ANOVA = analysis of variance EDSS = Expanded Disability Status Scale MS = multiple sclerosis RR = relapsing remitting SP = secondary progressive Author contributions: Guarantors of integrity of entire study, D.C., M.F.; study concepts/study design or data acquisition or data analysis/ interpretation, all authors; manuscript drafting or manuscript revision for important intellectual content, all authors; manuscript final version approval, all authors; literature research, P.V., M.A.H., R.M., D.C., M.F.; clinical studies, M.A., D.C.; statistical analysis, P.V.; and manuscript editing, P.V., M.A.R., M.A.H., D.C., G.C., M.F. Conflicts of interest are listed at the end of this article. 854 radiology.rsna.org n Radiology: Volume 266: Number 3 March 2013

3 echo time msec/inversion time msec], 80-mm-thick slabs, two signals acquired, matrix zerofilled to , mm 3 field of view) and (b) a sagittal dual-echo turbo spin-echo sequence (2000/ [repetition time msec/ echo time msec], echo train length of 23, seven sections, 4-mm-thick sections, five signals acquired, matrix, mm 2 field of view). Brain. Two sequences were used to image brain: (a) an axial dual-echo turbo spin-echo sequence (3460/27 109, echo train length of five, 44 sections, 3-mmthick sections, matrix, mm 2 field of view) and (b) a sagittal three-dimensional magnetization-prepared rapid acquisition gradient-echo sequence (2000/3.93/900, mmthick slabs, one signal acquired, matrix, mm 3 field of view). Table 1 Main Characteristics of the Study Groups Parameter Control Subjects Patients with RR MS Patients with SP MS P Value Sex.88* Men Women Mean age (y) 42.5 (26 67) 39.2 (28 60) 47.1 (34 66).009* Median EDSS score NA 3.5 ( ) 6.0 ( ),.001 Median disease duration (y) NA 11 (1 23) 19 (9 39),.001 Brain mean T2 LV (ml) NA 11.0 (11.3) 24.2 (19.4).001 Mean NBV (ml) (94.9) (89.8) (92.7),.001* Mean no. of cervical cord lesions NA 0.58 (0 4) 0.58 (0 3).83 Mean normalized cord volume (ml) 8.9 (1.2) 8.2 (1.3) 7.3 (1.0),.001* Note. Except where indicated, numbers in parentheses are ranges. LV = lesion volume, NA = not applicable, NBV = normalized brain volume. * Determined with ANOVA. Determined with the Mann-Whitney U test. Numbers in parentheses are standard deviations. Voxel-based Analysis of Cervical Cord Atrophy Postprocessing of cervical cord images was performed (P.V., with 9 years of experience in MR image analysis). Sagittal T1-weighted cord images from all study subjects were reformatted in the axial plane and resampled to a 1-mm section thickness. Then, we applied the active surface method, which is described in detail elsewhere (6), to each image to find the cord surface and cord center line. Briefly, this procedure required the placement of landmarks at the extremes of the cord region to be studied (in this case, at the center of the cord on the most superior axial section in which the odontoid process of the epistropheus [C1] was still visible and on the section passing through the inferior border of C7) and on several sections between these landmarks, approximately every 10 mm. Starting from this initial marking, the cord center line and cord outline at each section were estimated by using a segmentation algorithm based on a multiresolution approach (6). The total cervical cord volume was calculated from the cord contours obtained, as previously described (6), and the cord length was calculated as the distance along the center line between the two landmarks at C1 and C7. The mean cervical cord cross-sectional area was then derived as the total cord volume divided by the cord length. Normalized cord volume was calculated by adjusting total cord volume to the intracranial volume, as previously suggested (6,16). Unfolded cervical cord images of each subject were created by reformatting the input images in planes perpendicular to the estimated cord center line (6). Cervical cord contours generated with the active surface method were used to produce binarized cervical cord masks, which were also straightened by applying the same procedure used to reformat the T1-weighted axial images. To adjust for intersubject variability of cervical cord length, unfolded cord images were first matched by rescaling them in the through-section direction to the median cord length of the control subjects (ie, 115 mm). Then, they were coregistered to the average cord image from control subjects, which served as a cervical cord template, by using the VTK- CISG toolkit (available at vtk.org/vtk/resources/software.html) (17). The transformation between an individual subject s image and the template image, which consisted of a scaling factor along the craniocaudal direction, was then applied to the straightened cord mask from the same subject. The accuracy of this procedure has been tested and validated previously (12). Before entering the statistical analysis, the normalized cervical cord masks were smoothed with an anisotropic Gaussian kernel with full width at half maximum of mm 3, which allowed the assumptions of Gaussian random field theory to be satisfied while maintaining precise spatial localization of atrophy (12). Conventional MR Image Analysis The number of cervical cord lesions that were hyperintense to normal-appearing cord tissue on the sagittal dual-echo images was counted. Brain T2 lesion volumes were measured by using a local thresholding segmentation technique (Jim 5.0; Xinapse Systems, Northants, England). On magnetization-prepared rapid acquisition gradient-echo brain images, the normalized brain volume and the intracranial volume were calculated by using software (Structural Imaging Evaluation of Normalized Atrophy, SIENAx, fsl/fslwiki/siena) (18). Statistical Analysis With use of SPSS software (version 13.0; SPSS, Chicago, Ill), analysis of variance Radiology: Volume 266: Number 3 March 2013 n radiology.rsna.org 855

4 Figure 1 Figure 1: Regional distribution of cervical cord atrophy in different study groups. Sagittal and axial MR images at various cervical cord levels show clusters of significant cord atrophy (color coded for t values; P,.001, uncorrected only for display purposes) in, A, patients with MS versus healthy control subjects (HC), B, patients with RR MS versus control subjects, and, C, patients with SP MS versus those with RR MS. A = anterior, L = left, P = posterior, R = right. (ANOVA) was used to compare clinical and conventional MR imaging quantities among the study groups. The following between-group comparisons were defined a priori on the basis of the clinical evolution of the disease: control subjects versus patients with RR MS, and patients with RR MS versus patients with SP MS. Statistical tests on smoothed cervical cord masks were performed with SPM8 software ( spm/). An ANOVA model, adjusted for age, sex, and total cord volume, was used to assess differences in cervical cord atrophy among the study groups. Posthoc comparisons were performed by using the previously defined a priori contrasts. In patients with MS, multiple regression models, adjusted for age, sex, and total cord volume, were used to assess correlations between regional cord atrophy and clinical (EDSS score, disease duration) and structural MR imaging (number of cord lesions, brain T2 lesion volume, and normalized brain volume) variables. In addition, two-sample t tests were performed to assess regional cord atrophy differences between (a) patients with and patients without focal T2 cord lesions and (b) patients with an EDSS score of less than 4.0 and those with an EDSS score of 4.0 or greater. All results obtained with SPM8 software were thresholded at P,.05 (corrected for family-wise error for multiple comparisons). Results were also tested at P,.001 (uncorrected for multiple comparisons; cluster extent, 20 voxels). Clusters of cord atrophy surviving at these two statistical thresholds were then superimposed on a custom-made region-label cord mask in the normalized space (12). In this way, we were able to quantify the extent of cord atrophy at each cord quadrant separately. This voxel count was also used to compare the total extent of cord atrophy in the left, right, anterior, and posterior cord among subject groups and cervical cord levels by using SPSS software and two-sample t tests and ANOVA models. Results Compared with patients with RR MS, patients with SP MS were older (P,.001) and had higher EDSS scores, longer disease duration, and higher brain T2 lesion volume (P =.001). Normalized brain volume was lower in patients with RR MS than in control subjects (P =.001) and in patients with SP MS compared with those with RR MS (P,.001). No cervical cord lesions were detected on conventional MR images obtained in the control subjects and in 47 of the 71 patients with MS (66%, 29 with RR MS and 18 with SP MS). One cervical cord T2 lesion was detected in 13 of the 71 patients with MS (18%, nine with RR MS and four with SP MS), two cord lesions were detected in six patients (9%, three with RR MS and three with SP MS), three cord lesions were detected in 856 radiology.rsna.org n Radiology: Volume 266: Number 3 March 2013

5 Table 2 Regional Distribution of Cervical Cord Atrophy in Different MS Phenotypes Group Comparison and Cord Level four patients (6%, two with RR MS and two with SP MS), and four cord lesions were detected in one patient with RR MS FWE Corrected Cluster Extent* Uncorrected t Value P Value Patients with RR MS vs control subjects C3 AR 0 0 NS NS AL 0 0 NS NS PR 0 0 NS NS PL ,.001 C7 AR 0 0 NS NS AL 0 0 NS NS PR ,.001 PL ,.001 Patients with SP MS vs patients with RR MS C1/C2 AR 0 0 NS NS AL , ,.03 PR , ,,.001 PL C3 AR ,.001 AL , ,.001 PR , ,.001 PL , ,,.001 C4 AR 0 0 NS NS AL , ,.05 PR , ,.002 PL C5 AR ,.001 AL , ,.002 PR , ,.001 PL C6 AR , ,.025 AL , ,.006 PR PL , ,.001 C7 AR ,.001 AL PR PL , ,,.001 Note. Data show significant clusters of cervical cord atrophy in patients with RR MS versus healthy control subjects and in patients with SP MS versus those with RR MS (ANOVA model adjusted for age, sex, and total cord volume; P,.001, uncorrected; cluster extent k = 20). AL = anterior left, AR = anterior right, NS = not significant, PL = posterior left, PR = posterior right. * Data are numbers of voxels. FWE = family-wise error. P,.05, family-wise error corrected for multiple comparisons. (1%). Normalized cord volume was lower in patients with RR MS than in control subjects (P =.009) and in patients with SP MS compared with those with RR MS (P =.008). Figure 1 shows the regional distribution of cervical cord atrophy in patients with MS compared with control subjects as well as between-group differences of cord atrophy. Table E1 (online) summarizes clusters of regional cord atrophy in the whole MS cohort versus the control subjects. The average extent of cord atrophy (voxel count) was higher in the posterior than the anterior cord sections (P =.001), whereas it did not differ between the left and right cord sections (P =.42) or among cervical cord levels (P =.31). Compared with control subjects, patients with RR MS had a few clusters of cervical cord atrophy located in the posterior cord at the level of C3 and C7 (Table 2, Fig 2), whereas, compared with patients with RR MS, those with SP MS showed a widespread pattern of regional cord atrophy, predominantly in the posterior and left cord columns (Table 2, Fig 2). The average extent of cord atrophy (voxel count) was higher in the posterior than the anterior cord sections (P =.01), whereas it did not differ between the left and right cord sections (P =.48) or across cervical cord levels (P =.51). Regions that showed more significant cord atrophy in patients with locomotor impairment than in those without locomotor impairment are summarized in Table E2 (online) and shown in Figure 3. Similar results were also obtained when considering only patients with RR MS. In the whole group of MS patients, correlations (P,.001) were found between (a) EDSS score and atrophy of the posterior cord, especially at C4 and C5 levels (r = to 20.57) (Table E3 [online], Fig 4); (b) disease duration and atrophy of the left cord at the C4 level (r = 20.55) (Table E3 [online], Fig 4); (c) brain T2 lesion volume and atrophy of the posterior cord at the C6 level (r = to 20.49) (Table E3 [online], Fig 4); and (d) normalized brain volume and atrophy of the posterior cord between C4 and C6 levels (r = ) (Table E3 [online], Fig 4). Regional cord atrophy did not differ between patients with and patients Radiology: Volume 266: Number 3 March 2013 n radiology.rsna.org 857

6 without cord T2 lesions. In addition, no correlation was found between regional cord atrophy and the number of cervical cord lesions. Figure 2 Discussion In this study, we applied a method for segmenting and normalizing cervical cord images to a standard space. This allowed us to analyze the regional distribution of cord atrophy in a large sample of patients with relapse-onset MS by using voxel-wise statistical tests similar to those widely applied for analysis of the brain (19). This was possible because the active surface method we used to segment cord area (6) includes the cord center line as an explicit part of the cord model, enabling reformatting of the original cervical cord images with the distance along the curved center line as the new craniocaudal coordinate in the resampled image (6). The resulting unfolded images, in which the cord is a cylinderlike straight structure, could be coregistered by means of a simple scaling transformation, and corresponding binary cord masks could be used as input images for spatial statistics. The feasibility of this approach and the reliability of its results were previously validated in a study of a large group of healthy individuals (12). One of the main strengths of this procedure is that it enables the creation of a template of the cervical cord, which permits the quantitative and automatic anatomic localization of clusters of atrophy across different levels and quadrants. Our analysis showed a relative sparing of cervical cord tissue in patients with RR MS, whereas those with SP MS had a diffuse loss of cord tissue. The notion that cord atrophy is more pronounced in patients with progressive MS is in line with the results of previous studies (3,5,6); investigations of patients with RR MS gave inconclusive findings, as some studies detected cord atrophy in this clinical phenotype (20) and others did not (2,5,10,16). The use of a voxel-based approach allowed us to define the regional distribution of cord atrophy throughout Figure 2: Regional distribution of cervical cord atrophy in different study groups. Bar charts represent regional distribution of cervical cord atrophy (expressed as voxel count) across cervical cord levels and sectors in, A, patients with RR MS versus control subjects (P,.001, uncorrected) and, B, patients with SP MS versus those with RR MS (P,.05, family-wise error corrected). AL = anterior left, AR = anterior right, PL = posterior left, PR = posterior right. Figure 3 Figure 3: Regional distribution of cervical cord atrophy in patients with locomotor impairment (EDSS score 4.0) versus those without locomotor impairment. Sagittal, coronal, and axial MR images at various cervical cord levels show clusters of significant cord atrophy (color coded for t values; P,.001, uncorrected only for display purposes) in patients with locomotor impairment. A = anterior, L = left, P = posterior, R = right. 858 radiology.rsna.org n Radiology: Volume 266: Number 3 March 2013

7 Figure 4 Figure 4: Correlation of regional cord atrophy with clinical and conventional MR imaging measures. Illustrative sagittal and axial MR images at various cervical cord levels show clusters of significant cord atrophy (color coded for t values; P,.001, uncorrected only for display purposes) in patients with MS, which correlated with, A, EDSS score, B, disease duration, C, brain T2 lesion volume (T2 LV), and, D, normalized brain volume (NBV) (P,.001 for all). A = anterior, L = left, P = posterior, R = right. different cervical cord levels and across its cross-sectional section. With regard to the longitudinal distribution of atrophy, we found uniform tissue loss along the cervical cord from C1 and/or C2 to C7. This is consistent with the results of two recent studies (5,10) that simply quantified cord area at different cord levels. Specifically, one of the previous studies assessed an extended portion of the cervical cord in a large cohort of patients with MS spanning the main disease clinical phenotypes (5), whereas the other study measured both cervical and thoracic cord areas in a relatively small group of patients with MS (10). A different distribution of cord atrophy was only found in the comparison between the cervical and thoracic cord segments (10), with the cervical segment showing a reduced cross-sectional area in progressive MS and the thoracic segment showing an increased cross-sectional area in patients with relapsing and/or early MS versus control subjects, possibly owing to an effect of inflammation or edema at the latter level (10). Quantification of the distribution of cord atrophy demonstrated a prevalent involvement of the posterior and lateral cord regions, which was more pronounced in patients with SP MS than in those with RR MS. Structural abnormalities in the posterior and lateral cord columns of patients with progressive MS have been previously demonstrated by using quantitative magnetization transfer MR imaging (21). It is noteworthy that, in that study, magnetization transfer abnormalities were strongly correlated not only with the EDSS score but also with measures of sensorimotor impairment (21), suggesting a strict relationship between damage of specific cord portions and real-world impairments in these patients. The clinical relevance of cord atrophy in specific regions in MS is further supported by the association we found between the severity of clinical disability, as quantified with the EDSS score, and clusters of cord atrophy as well as by the difference we found in the regional distribution of atrophy between patients with versus those without locomotor impairment. The correlation between disability and cervical cord atrophy is a common finding in MS research (2,3,5,22,23) and can be explained by the composition of this structure: The cervical cord contains all descending corticospinal fibers destined for motor units in the trunk, arms, and legs. Therefore, damage in this region is likely to have a disproportionately severe effect on locomotor functions compared with damage to the brain or to other cord segments. Regional cord atrophy was also partially correlated with disease duration, suggesting a cumulative effect with time of all pathologic processes leading to irreversible tissue loss in the cord. This notion is also supported by the results of previous longitudinal MR imaging studies, Radiology: Volume 266: Number 3 March 2013 n radiology.rsna.org 859

8 which detected a significant decrease of cord cross-sectional area over time in both relapsing and progressive MS phenotypes (24 27). The final aspect we wished to investigate was the possible pathologic substrates of regional atrophy in our patients, which we did by assessing its correlation with conventional MR imaging measures of brain and spinal cord damage. This analysis showed no correlation between the presence of cervical cord lesions and regional atrophy of the cervical cord. Unfortunately, because we did not map the distribution of focal cord lesions, we cannot determine whether localized atrophy developed in the region of focal T2 lesions. However, the notion that individual lesions play a minor role in local atrophy of the cord is supported by previous pathologic (9,28) and in vivo (5) studies of atrophy, which have suggested that Wallerian degeneration of long fiber tracts, rather than local damage to these tracts, is one of the main factors leading to tissue loss in the cord. This hypothesis is strengthened by the correlation we found in this study between regional cord atrophy and brain damage, measured as the volume of focal T2 lesions, and irreversible tissue loss. In agreement with the results of previous studies, the strength of the relationship between cord atrophy and brain damage was weak to moderate (22,29 31), suggesting that degenerative and inflammatory processes typical of MS affect cord and brain with at least partially independent dynamics. Clearly, this study is not without limitations. First, the proposed method might not be straightforwardly applicable to subjects with vertebral column disease causing cervical cord compression. Indeed, to exclude the possibility of clusters of cord atrophy simply due to cord compression rather than to cord disease, we excluded six subjects from our analysis. Another limitation of this study is that image quality did not allow reliable segmentation of gray and white matter within the cervical cord; therefore, at present, we cannot determine whether cord atrophy is caused by loss of white matter rather than gray matter, as suggested by results of a pathology study (32). The in vivo assessment of the relative contributions of these two tissue compartments to overall atrophy remains an open question for future MR imaging studies employing advanced high-spatial-resolution MR imaging sequences (33). To conclude, we were able to map the distribution of cervical cord atrophy in a relatively large cohort of patients with relapse-onset MS. An accurate assessment of spinal cord atrophy helps improve our understanding of the major clinical manifestations of MS (eg, locomotor impairment) and might be useful for future longitudinal studies monitoring disease evolution and defining the mechanisms responsible for the accumulation of irreversible disability. Disclosures of Conflicts of Interest: P.V. No relevant conflicts of interest to disclose. M.A.R. Financial activities related to the present article: none to disclose. Financial activities not related to the present article: is a paid consultant for Bayer Schering Pharma; receives payment for lectures including service on speakers bureaus from Biogen Idec. Other relationships: none to disclose. M.A.H. Financial activities related to the present article: none to disclose. Financial activities not related to the present article: is a paid consultant for Biogen Idec and GE Healthcare; owns stock in Xinapse Systems. Other relationships: none to disclose. M.A. No relevant conflicts of interest to disclose. R.M. No relevant conflicts of interest to disclose. D.C. No relevant conflicts of interest to disclose. G.C. Financial activities related to the present article: none to disclose. Financial activities not related to the present article: is a paid consultant for Bayer Schering, Merck Serono, Sanofi-Aventis, Teva Pharmaceuticals, Acetelion, and Biogen Idec; receives travel/accommodations/meeting expenses from Bayer Schering, Merck Serono, Sanofi-Aventis, Teva Pharmaceuticals, Acetelion, and Biogen Idec. Other relationships: none to disclose. M.F. Financial activities related to the present article: none to disclose. Financial activities not related to the present article: receives payment for board membership from Teva Pharmaceuticals and Genmab A/S; is a paid consultant for Bayer-Schering Pharma, Biogen Idec, Genmab A/S, Merck Serono, and Teva Pharmaceutials; has a grant/grant pending from Bayer-Schering, Biogen Idec, Genmab A/S, Merck Serono, and Teva Pharmaceuticals; receives payment for lectures including service on speakers bureaus from Bayer-Schering Pharma, Biogen Idec, Genmab A/S, Merck Serono, and Teva Pharmaceutials. Other relationships: none to disclose. References 1. Nijeholt GJ, van Walderveen MA, Castelijns JA, et al. Brain and spinal cord abnormalities in multiple sclerosis: correlation between MRI parameters, clinical subtypes and symptoms. Brain 1998;121(Pt 4): Losseff NA, Webb SL, O Riordan JI, et al. Spinal cord atrophy and disability in multiple sclerosis: a new reproducible and sensitive MRI method with potential to monitor disease progression. 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