Introduction

Lower urinary tract symptoms (LUTS) are described in more than 80% of multiple sclerosis (MS), with overactive bladder (OAB) being the commonest. In recent years, magnetic resonance imaging (MRI), in particular functional MRI (fMRI) has provided considerable insight into the central neural control of lower urinary tract (LUT) functions.¹ In patients with MS, activation and deactivation have been seen in cortical and subcortical grey matter (GM) regions following a bladder infusion task.² These studies focus on the GM changes, however MS is overwhelmingly a white matter (WM) disease and the nature of the association between WM changes and LUTS is unknown. Structural MRI studies in patients with small vessel disease affecting WM suggest that the anterior thalamic radiation (ATR) and the superior longitudinal fasciculus (SLF) are specifically important for LUT functions and are involved in continence control.³ WM hyperintensity (WMH) in the anterior corona radiata (ACR) and the cingulate gyrus are reported to predict urinary incontinence and degree of bother.⁴ However, the relative contribution of brain WM changes to the clinical symptoms of OAB in MS is poorly understood. The aims of this study are to determine by means of MRI, in particular diffusion-weighted imaging (DWI): i) microstructural WM difference between health and MS, and MS with OAB symptoms and MS without LUTS; ii) whether there are associations between microstructural indices and clinical scores of OAB symptoms in MS.

Methods

Methods: Twenty-nine right-handed female MS patients [Mean age (±SD) = 43.3(9.4), mean EDSS (±SD) = 2.3(1.8)] were scanned at 3.0 Tesla scanner (Philips Achieva, Best, The Netherlands) with a DWI protocol and clinical MRI. Image processing and Tract-Based Spatial Statistics (TBSS) were performed using the FMRIB Software Library (FSL, Oxford, UK, https://fsl.fmrib.ox.ac.uk/fsl). The diffusion-weighted images were corrected for eddy current-induced distortions and movements using FSL. DTI fitting and calculation of FA maps were performed using the NiftyFit toolbox.³ TBSS was performed to determine possible fractional anisotropy (FA) differences between the two groups. The standard TBSS pipeline was applied to the data: all FA images were non-linearly registered to the 1x1x1 mm3 FMRIB58_FA template in 1x1x1 mm3 MNI152 space (MNI, McConnell Brain Imaging Centre), then skeletonised and concatenated into a 4D file (skeletonized). The WM skeleton was created with a FA threshold of 0.2. Clinical scans were used for WM lesion segmentation. The Urinary Symptom Profile (USP) questionnaire assessed OAB severity. Descriptive statistics of age, EDSS, lesion volume, disease duration, and the OAB sub-score from the USP questionnaire (USP-OAB) were expressed as mean and standard deviation and all variables were checked for skewness and presence of outliers. SPSS version 24 was used for the statistical analysis and a p value < 0.05 was considered statistically significant, and p value < 0.1 was considered a favourable statistical trend. Differences of distribution and frequency of WM changes were plotted in a bullseye plot of WM regions.⁴ The lesion volume frequency plots represented the ratio between the median and the interquartile range (IQR, measuring statistical dispersion) of lesion volume in the given region and volume of that region.

Results

An inverse correlation was found between FA in areas of frontal and parietal lobes and OAB sub-scores from USP questionnaire (p=0.021) in MS. Areas of lower FA were found in both frontal lobes and the rest of the non-dominant hemisphere, including corpus callosum, anterior corona radiata bilaterally, right anterior thalamic radiation, superior longitudinal fasciculus bilaterally, right inferior longitudinal fasciculus, in MS with OAB compared with MS without LUTS (p=0.072).

Discussion

We explored differences in WM changes in MS-OAB and MS-no-LUTS by evaluating changes in FA using diffusion MRI, and, to the best of our knowledge, this is the first study establishing the WM changes subtending OAB in MS. Current understanding of the central neural network controlling LUT functions is informed by positron-emission tomography (PET) and fMRI studies of the GM which suggests a network involving different regions including thalamus, insula, ACC, mPFC and lPFC. The involvement of WM tracts in determining the function/dysfunction of this network is currently only speculative,¹ therefore this study aimed to evaluate the extent of WM tracts damage, specifically in MS. The scenario is very much complicated in MS given the mixture of disability in motor, sensory, autonomic and visual functions. The current study compensates our understanding of WM changes related to OAB in MS by identifying: i) FA reductions in the MS-OAB group, compared with MS-no-LUTS; ii) a negative correlation between FA and the USP-OAB sub-score, suggesting that a lower FA was associated with more severe OAB symptoms.

Conclusion

By using DWI, the association between OAB symptoms and WM changes are identified and adds knowledge to the current LUT working model. As MS is predominantly a WM disease, these findings suggest that WM involvement, including cingulum, anterior corona radiata, anterior thalamic radiation, superior longitudinal fasciculus, and superior frontal-occipital fasciculus and a non-dominant prevalence in WM, can result in significant problems with OAB symptoms, possibly even with minimal direct GM involvement.

Acknowledgements

No acknowledgement found.