Background
Multiple sclerosis (MS) is a disease of the CNS characterized by lesions and atrophy in both the brain and spinal cord [
1]. Measurement of spinal cord atrophy is of growing interest due to improving MRI technology, regarding both scan acquisition and segmentation techniques, facilitating its quantification [
2‐
7]. In addition, a myriad of studies have shown that such atrophy occurs early in the disease course and is a proposed contributor to neurologic disability [
1,
5,
8]. Despite the availability of more than 10 disease-modifying immunotherapies for the treatment of MS, few studies have assessed therapeutic effects on spinal cord atrophy [
8‐
14]. Such a pursuit might have relevance in complementing the information on disease severity and treatment effects obtained from brain imaging. In support of this concept, spinal cord metrics provide a unique contribution to brain metrics in modeling the relationship between MRI and clinical status in MS [
15]. In addition, a growing body of evidence indicates that spinal cord involvement may occur and progress independently from brain involvement [
8,
16‐
19].
Interferon β-1a (IFNβ-1a), given intramuscularly each week, is an approved MS immunotherapy that has been shown to limit relapse rate, delay the time to a sustained increase in physical disability, and limit cerebral MRI-defined lesion activity and burden of disease in patients with relapsing forms of the disease [
20‐
22]. In addition, studies have indicated the ability of weekly intramuscular IFNβ-1a to limit the rate of brain atrophy [
23,
24]. However, no studies to date have examined spinal cord atrophy treatment effects in patients with relapsing forms of MS receiving weekly intramuscular IFNβ-1a. We performed a pilot study to assess the 2 year change in spinal cord volume associated with established IFNβ-1a treatment in comparison to healthy subjects.
Discussion
In this pilot study, we explored the effect of IFNβ-1a therapy on spinal cord atrophy over 2 years in patients with RRMS. Patients did not develop any atrophy over 2 years and had no difference in their spinal cord volume change as compared to healthy volunteers. This was a “real world” retrospective study without any comparison patient group, such as untreated patients. The sample size was small. Thus, the results should be interpreted with caution and the study design does not permit any strong conclusion regarding a treatment effect of IFNβ-1a. Nonetheless, the data provided here are valuable in that very few studies have examined spinal cord metrics under treatment with disease-modifying MS medications; most of the previous studies have focused on progressive rather than relapsing forms of the disease [
8‐
14]. Thus, we provide a unique set of preliminary results that could serve as a basis for further studies on the role of spinal cord imaging in treatment monitoring in RRMS.
Spinal cord atrophy has been reported to occur in the early stages of MS, such as in patients with clinically isolated demyelinating syndromes or RRMS [
1,
31‐
33]. However, the stage of the appearance of spinal cord atrophy is controversial; other studies have not confirmed these results and have contended that spinal cord atrophy most commonly develops in the later stages of RRMS or in progressive forms of the disease [
2,
6,
9,
10,
30,
34]. In addition, transient changes such as inflammation and edema may increase spinal cord volume, particularly early in the MS disease course, and serve to offset or mask ongoing volume loss due to atrophy [
35]. Thus, our study may have suffered from a diagnostic sensitivity bias in that the lack of spinal cord atrophy may have reflected the early disease stage of our patients rather than the effect of therapy. However, this was tempered by the observation that spinal cord lesions were quite common in our patients.
In the present study, we employed a highly reproducible semiautomated segmentation tool to measure spinal cord volume [
2], which was normalized by our established method [
30]. We applied this segmentation pipeline to 2D images, given their availability in this retrospective study and our previous demonstration that these images showed 1) sensitivity to disease-specific effects and 2) high reproducibility [
29]. We did not have high-resolution 3D images available in this data set, which have been commonly used by several groups to effectively measure spinal cord volume [
16,
36‐
38]. In addition, newer fully automated methods of contouring spinal cord volume have become available and may have relevance to MS [
3,
6,
7], which we did not employ in this study. Thus, we cannot exclude the possibility that our technique, both on the basis of scan acquisition and post-processing methodology, may have lacked sensitivity to ongoing spinal cord atrophy in these patients, irrespective of a drug treatment effect.
Although we had a small sample size, we chose to test the relationship between SCA and clinical status in the MS group at baseline, to explore the validity of our results. We failed to find any significant correlations between SCA and measures of overall physical disability (EDSS score) or ambulatory function (T25FW). However, we showed that SCA significantly correlated inversely with disease duration, indicating that spinal cord atrophy was linked to advancing disease duration. Previous studies have shown inconsistent results regarding the relationship between spinal cord atrophy and clinical status in MS. Some studies have shown a correlation between spinal cord atrophy and advancing EDSS score, [
2,
4,
6,
7,
10,
15,
17,
18,
29,
30,
33,
34,
39], while others have not [
1,
8,
10]. A significant relationship between spinal cord atrophy and ambulatory dysfunction on the T25FW has been shown in some [
4,
6,
30] but not all studies [
18,
29]. Furthermore, a growing body of evidence indicates that spinal cord-disability relationships are more strongly present in patients with advanced disability and progressive stages of the disease [
1,
4,
8,
9,
18,
34,
39], the stage at which spinal cord atrophy is most commonly seen [
2,
6,
10,
30,
34]. Therefore, in addition to the small sample size, our inability to show a relationship between SCA and disability measures may reflect the restricted range of our mildly disabled relapsing-remitting stage patients. Nonetheless, the link we showed between SCA and disease duration is consistent with previous work [
7,
33,
34] and provides some reassurance of the validity of the SCA measure employed in our study.
Conclusion
Established IFNβ-1a therapy was not associated with ongoing spinal cord atrophy or any difference in the rate of spinal cord volume change in RRMS compared to NC over 2 years. These results may reflect a treatment effect. However, due to sample size and study design, these results should be considered preliminary and await confirmation in larger prospective studies.
Acknowledgements
This work was presented in preliminary form at the 2016 meeting of the European Committee on Treatment and Research in Multiple Sclerosis (ECTRIMS), London, UK.
Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (
http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (
http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.