Multiple sclerosis is an inflammatory demyelinating and neurodegenerative disease of the central nervous system [15,16,17]. In MS, brain volume correlates with and predicts future disability [18, 19], making brain volume loss a relevant measure of diffuse CNS damage leading to clinical disease progression, as well as serving as a useful outcome in evaluating MS therapies [20, 21].
The use of automated methods for segmentation of deep GM structures, including FSL [11] or FreeSurfer [22], reveals volume loss in deep GM structures in MS patients, particularly the thalamus [23,24,25,26]. Although the thalamus was examined most extensively in patients with MS [23], some studies also demonstrated the involvement of other subcortical structures such as the putamen [27]. Recently, measurement of the total lesion load or volume detectable lesions on MRI has become a widely used outcome measure for assessing the efficacy of new therapies in multiple sclerosis [28, 29] (Figs. 6, 7 and 8).
Version 5.0.10 of FSL and Version 7.4.0 of MIPAV software package was used in our study.
Our study included 31 patients diagnosed with RRMS and 31 control subjects of the same age range.
The studied patients group presented variable degrees of clinical disability; this variability was represented by different EDSS scores which ranged from 1 to 6.5, with a mean score of 3.64 and a standard deviation of 1.39.
Each subject in this study underwent a specialized brain imaging protocol with the two main sequences specific for this study being 3D T1W SPGR and 3D T2 FLAIR; both were later used to quantify the volumes of deep grey matter structures and white matter lesions, respectively. This is consistent with the study by Hu et al. [30], stating that 3D MRI sequences are the most commonly used scans for measuring brain volumes and that 3D versions of MRI scans for MS will continue to replace their 2D counterparts, as the 3D scans have a more superior image quality and provide more information.
After calculating the volumes of deep grey matter structures and white matter lesions, these absolute volumes were later converted to relative volumes by correcting for intracranial volume (ICV) of each subject. According to Sanfilipo et al. [31] and Miller et al. [32], this step is crucial as such normalization is particularly important in cross-sectional studies where inter-subject comparisons are performed to adjust raw inter-subject differences in regional brain measurements and reduce the error variance, in contrast with longitudinal studies based on intrasubject comparisons.
The results of our study indicated that the thalamus and putamen in both hemispheres had significantly smaller volumes in RRMS patients compared with age matched controls. Furthermore, the other deep grey matter structures showed no significant volume differences between RRMS patients and controls. Additionally, they showed that higher EDSS scores were associated with smaller volumes of the thalamus and putamen, and larger volumes of white matter lesions. A significant positive correlation was found between the corrected white matter lesion volumes and EDSS scores, while a significant negative correlation was found between the corrected volumes of the thalamus and putamen, and EDSS scores.
Our work has matched previous studies to a great extent as in Azevedo et al. [33] and Jakimovski et al. [34] which has shown that thalamic volume decreases significantly in MS patients with significant negative correlation with EDSS scores.
Another study by Magon et al.[35] has shown that volumes of the thalamus and the putamen were associated with the EDSS, as they found significant negative correlation between their volumes and the EDSS scores, with the thalamic volume having more significant results.
While the thalamic atrophy was the main focus of many studies done on RRMS patients, some other studies reported volume loss of the putamen in MS patients; as in the study by Debernard et al. [36] where they reported significant volume reduction in the thalamus as well as the putamen, and they found association between putamen volume loss and performance deficits in executive functions and working memory.
On the other hand, Krämer et al. [37] focused primarily on the putamen volume loss in their study, where they reported early and degressively increasing putamen atrophy in patients with RRMS; they also associated these findings with EDSS scores and cognitive performance which is in agreement with the findings of our study.
In the study by Shiee et al. [38], it was reported that there was significant volume loss of all deep grey matter structures in MS patients (including thalamus, putamen and caudate), which is partially consistent with our findings where the caudate didn’t show significant atrophy. This can be due to differences in sample size and age as our study had a smaller sample and our studied subjects were younger.
A study by Anderson et al. [39] reported a significant hippocampal volume loss in RRMS patients when compared with healthy controls. This is inconsistent with our findings, as we found only a few cases with unilateral hippocampal volume loss in RRMS patients, but on the group level analysis there was no significant difference in hippocampal volume between RRMS and healthy controls. This can be due to differences in demographics between the studies, as our studied sample was a younger age group.
Regarding the white matter lesion volume and its correlation with EDSS scores, a recent study by Nakamura et al. [40] reported a significant positive correlation between T2W white matter lesion volumes and EDSS scores in MS patients, which is consistent to a great extent with our findings.
This significant positive correlation between white matter lesion volume and EDSS scores in RRMS patients was also reported in other studies by Caramanos et al. [41] as they studied the relationship between clinical disability and cerebral white matter lesion load in patients with MS and they found high positive correlation between white matter lesion volume and EDSS scores specifically in RRMS patients.