Hypothesis / aims of study
Interstitial Cystitis/Bladder Pain Syndrome (IC/BPS) is defined by persistent or chronic pelvic pain, pressure or discomfort perceived to be related to the urinary bladder accompanied by an urgent need to void or by increased urinary frequency. To guide clinical decision making and treatment, the chronic pelvic pain working group of the ICS recently classified IC/BPS into either hypersensitive bladder with no identifiable pathology explaining the symptoms, IC/BPS with Hunner lesion (HIC) or IC/BPS with no lesions on cystoscopy (NHIC). However, there remains significant variability (5-57%) in the detection of Hunner lesions, and it remains poorly understood why some patients with NHIC benefit from anti-inflammatory drugs. As such, there is an unmet need for an objective imaging technique to better phenotype IC/BPS patients. Here, we examined the role of intravesical contract enhanced (ICE)-MRI (ref.1) in phenotyping IC/BPS patients (Fig.1).
Study design, materials and methods
After obtaining informed consent, we screened female subjects (ages 18-80) with chronic pelvic pain due to IC/BPS. Inclusion criteria included having an ICSI index >9 and an ICPI > 8. Inclusion criteria also included performing cystoscopy within 6 months of the imaging. Exclusion criteria included previous history of neurogenic bladder, prior urologic malignancy, pelvic radiation, current or planned pregnancy, and contraindication to MRI. ICE-MRI involves the acquisition of 3-Dimensional T1 weighted fast‐low‐angle‐shot (FLASH) images in volume‐interpolated‐breath-hold exam (VIBE) and free breathing T2 weighted bladder images in axial and sagittal plane at 3T scanner using 4-channel flexible receiver coil before and after transurethral 50mL instillation of Gadobutrol [20mM] and Ferumoxytol [0.1mM] in sterile water with a dwell time of 30 min. Since the paramagnetic properties of Gadobutrol decrease the T1 relaxation time of normal and lesioned areas of the bladder wall, the permeability of instilled Gadobutrol into the bladder wall with ICE-MRI can be derived from the rate constant for the exponential rise in color-coded T1 weighted signal intensity in 72 contiguous axial slices of 1 mm thickness acquired within 23.30s at each flip angle (3° to 20°) by FLASH-VIBE. A representative calculation of this T1 relaxation time calculation is shown in Fig.2.
Results
Of the 5 patients that completed the study, only 1 had Hunner lesion IC, and this lesion seen at the dome on cystoscopy was clearly visible on ICE-MRI. Furthermore, there was diffuse bladder wall thickening (BWT) that was 2 cm long and 4.6 mm deep was seen near the Hunner lesion. The other 4 patients had NHIC, and ICE-MRI classified these subjects with normal cystoscopy into either lower or higher permeability to instilled Gadobutrol as measured by T1-relaxation time. Since differential diffusion of Gadobutrol created brighter and faint areas in the bladder wall of each subject, we calculated the Gadobutrol concentration difference between the brightest and faintest regions of the bladder lining in each subject, and the difference between these regions were more conspicuous in the post-instillation T1 weighted fast‐low‐angle‐shot (FLASH) images acquired at lower flip angle 3° than 20°. The dark lumen (from the ferumoxytol) enhanced the image contrast in T1 and T2 weighted images of 3 pre-menopausal IC/BPS patients (lower Gadobutrol permeability) with normal cystoscopy and dysmenorrhea. In one patient (higher Gadobutrol permeability), free breathing T2 weighted ICE-MRI sagittal slices (3 mm thickness) supported the suspicion of endometriosis (E) from thickened uterosacral ligament in the torus uterinus (red circle) (ref.2). Whilst the representative classification of HIC and NHIC by ICE-MRI is shown with pictures, gadobutrol permeability data of each enrolled human subject is displayed by different colored line in the attached graph.
Interpretation of results
Bladder inflammation is hallmarked by a rise in vascular and urothelial permeability. Virtual measurement of urothelial permeability can be a reliable virtual surrogate for bladder inflammation that may obviate the need for biopsy in phenotyping of NHIC patients (ref.3). Instead of measuring differential absorption of instilled drugs/dyes and radiolabeled antibodies into normal and lesioned areas, ICE-MRI can virtually track the absorption of paramagnetic dye (Gadobutrol) in normal and lesioned areas of the bladder for data mining (radiomics) and to associate inflammatory loci with urinary chemokines. Our interdisciplinary research (involving urology and radiology) leverages well established principle of shortening of T1 relaxation time being directly proportional to the tissue concentration of Gadobutrol for stratifying NHIC patients into two groups of either low or high urothelial permeability. The symptoms of NHIC patients with high urothelial permeability may be more likely to respond to anti-inflammatory drugs like cyclosporine versus those with NHIC that have urothelial permeability comparable to controls can avoid unnecessary cyclosporine exposure.