Symptomatic Autonomic Dysfunction in Interstitial Cystitis/Bladder Pain Syndrome.

This study employed a retrospective analysis of data from our prospectively collected database of patients diagnosed with IC/BPS via AUA criteria, 2 between the ages of 18 and 80, undergoing therapeutic hydrodistension (HOD) in our hospital system (IRB00018552). Cystoscopy with HOD was performed under general anesthesia by slowly filling the bladder with sterile normal saline under pressure to a height of 100 cm and holding for 5 minutes. Data collected during hydrodistension included anesthetic bladder capacity (BC) and the presence or absence of Hunner lesions (HL). At the time of enrollment, prior to HOD, demographic information was verified by patients and validated questionnaires including the pain and urgency/frequency symptom scale (PUF) and O’Leary Sant Interstitial Cystitis Symptom and Problem Indices (ICSI/ICPI) were completed. 26 , 27 Patients also completed the COMPASS-31 questionnaire immediately prior to the procedure (note: due to the timing of the addition of this questionnaire to our workflow, approximately half (60/122) patients filled out the questionnaire some time after their HOD). Higher scores on each questionnaire equate to greater symptom burdens. Participants also answered questionnaires with a ‘yes/no’ answer for a known diagnosis of 12 comorbid non-urologic associated syndromes (NUAS) known to co-occur with IC/BPS including irritable bowel syndrome (IBS), chronic pelvic pain (CPP), chronic fatigue syndrome (CFS), fibromyalgia, migraines, depression, allergies, vulvodynia, pelvic floor dysfunction, endometriosis, panic disorder, and asthma. Each individual comorbidity endorsed was counted and summed to obtain a total number of comorbidities (total NUAS) between 0 and 12. Patients were excluded from the study if they had a history of urethral diverticulum, bladder tuberculosis, genital herpes, genitourinary cancer, neurologic conditions that could affect voiding dynamics (i.e., spinal cord injury, stroke, Parkinson’s disease, multiple sclerosis, spina bifida), a history of cyclophosphamide treatment, radiation cystitis, or were pregnant at the time of recruitment. Patients were separated into two groups based on their cumulative COMPASS-31 scores. Those with a “low” symptom load (Group 1; 1 st quartile; N=30) were compared to all remaining patients (Group 2; N=90) by demographic and clinical characteristics. Statistical analyses were performed using Statistical Product and Service Solutions (SPSS) Statistics for Windows (Version 27.0. Armonk, NY: IBM Corp.) and SAS version 9.4 (Cary, NC; SAS Inc.). Clinical characteristics and demographic variables were examined for outliers, and range checks were performed. Continuous variables included age, BMI, anesthetic bladder capacity, and scores from the PUF, ICSI, ICPI, and NUAS questionnaires. All other variables were treated as categorical data including gender (female vs male), race (Caucasian, African American, Hispanic, and other), Hunner lesion status, and the presence or absence of individual NUAS. Total NUAS was an ordinal variable. To study the associations between continuous variables and autonomic symptom severity (i.e., low, and high symptom loads), Wilcoxon rank-sum tests were used. For the associations with categorical variables, Fisher’s exact tests or Chi-squared tests were calculated. Associations with a p-value of <0.05 were considered statistically significant. A logistic regression model was utilized to evaluate the multivariable association analysis with autonomic symptom severity. The variables with a p-value less than 0.15 in the univariate associations were included in the multivariable logistic regression model. The number of comorbidities (total NUAS), rather than the inclusion of each of the 12 individual comorbidities, was adjusted. Backward elimination was performed to keep the significant variables (p-value <0.05) in the model. Age and gender remained in the model regardless of statistical significance.

The COMPASS-31 questionnaire was administered to 122 patients and resulted in a mean score of 35.21 ± 17.90. The 1 st quartile of 20.36 was chosen as the cutoff point to stratify patients by “low” versus “high” symptom load. Average scores were calculated for each of the six domains that comprise the COMPASS-31 questionnaire, including orthostatic intolerance (11.80 ± 11.93), vasomotor (0.93 ± 1.51), secretomotor (5.95 ± 3.83), gastrointestinal (10.32 ± 4.15), bladder (4.03 ± 2.19), and pupillomotor (2.17 ± 1.40) ( Table 1 ). Regarding basic demographic information, patients in the group with low autonomic symptom load ( Group 1 ) had no significant differences in percentage of females (76.7% vs 91.3%; p=0.052), average age (55.50 ± 14.35 vs 49.18 ± 13.24; p=0.056), average BMI (27.84 ± 4.80 vs 30.14 ± 7.37; p=0.165), or race (White: 96.7% vs 84.8%, African American: 3.3% vs 12.0%, Hispanic: 0% vs 1.1%, Other: 0% vs 2.1%; p=0.497), compared to patients in the high autonomic symptom load group ( Group 2 ) ( Table 2 ). Patients in Group 1 had a significantly lower anesthetic bladder capacity (635.00 ± 335.06 vs 823.10 ± 396.07; p=0.027) and were more frequently found to have Hunner lesions (26.7% vs 10.9%; p=0.043) than patients in Group 2. Patients in Group 2 had higher average scores on the PUF questionnaire (23.80 ± 4.98 vs; 19.61 ± 5.22 p<0.001), had a higher number of NUAS (5.65 ± 2.90 vs 2.60 ± 1.89; p<0.001), and were more commonly found to have the diagnosis of multiple comorbid conditions including chronic fatigue syndrome (20.7% vs 0%; p=0.004), fibromyalgia (38.0% vs 10.0%; p=0.003), migraines (46.7% vs 13.3%; p=0.001), allergies (69.6% vs 43.3%; p=0.016), vulvodynia (26.1% vs 3.3%; p=0.008), pelvic floor dysfunction (54.3% vs 23.3%; p=0.003), endometriosis (37.0% vs 6.7%; p=0.001), and asthma (29.3% vs 6.7%; p=0.012). There were no significant differences between Group 1 and Group 2 when comparing ICSI (11.71 ± 5.11 vs 13.15 ± 3.87; p=0.324), and ICPI scores (11.29 ± 4.11 vs 12.73 ± 2.77; p=0.142). Average scores in each of the six COMPASS-31 domains were significantly greater in Group 2 including orthostatic intolerance (15.65 ± 11.32 vs 0 ± 0; p<0.001), vasomotor (1.11 ± 1.63 vs 0.36 ± 0.84; p=0.028), secretomotor (6.89 ± 3.55 vs 3.07 ± 3.22; p<0.001), gastrointestinal (11.54 ± 3.68 vs 6.58 ± 3.15; p<0.001), bladder (4.43 ± 2.15 vs 2.81 ± 1.88; p<0.001), and pupillomotor (2.49 ± 1.35 vs 1.18 ± 1.06; p<0.001) ( Table 2 ). The average percentage of each of the six domains making up the total COMPASS-31 score was also evaluated. Among patients in Group 2, there was a greater percentage of orthostatic intolerance (33.0% ± 21.5% vs 0% ± 0%; p<0.001) and a lower percentage of the gastrointestinal domain (29.6% ± 12.2% vs 48.9% ± 21.1%; p<0.001) and bladder domain (11.5% ± 6.3% vs 23.2% ± 20.5%; p=0.002) contributing to the total COMPASS-31 scores compared to Group 1 ( Table 2 ). Table 3 shows the associations between autonomic symptom load groups with demographic variables and clinical features using a multivariable model. BC was positively associated with high autonomic symptom load after adjusting for age, gender, PUF score, and total NUAS (odds ratio (OR) = 1.002, 95% confidence interval (CI) = (1.001, 1.004)). PUF score and total NUAS also showed positive associations in the multivariable model (OR and 95% CI for PUF = 1.21 (1.07, 1.36); OR and 95% CI for total NUAS = 1.77 (1.25, 2.51)).

This study assessed the relationship between autonomic symptom severity and clinical characteristics in a cohort of IC/BPS patients by utilizing the Composite Autonomic Symptom Score (COMPASS-31) questionnaire. We found that patients with higher COMPASS-31 scores (≥20.36) had a significantly higher anesthetic bladder capacity, higher scores on the PUF questionnaire, a greater number of comorbid non-urologic associated syndromes, and were less likely to have Hunner lesions. These findings suggest a strong correlation between a higher autonomic symptom load and a non-bladder-centric phenotype in IC/BPS patients, indicating the presence of widespread autonomic nervous system dysfunction. Therefore, the COMPASS-31 questionnaire may provide a valuable tool for stratifying IC/BPS phenotypes and guiding providers with targeted treatment approaches.

To the best of our knowledge, this study is the first to administer the COMPASS-31 questionnaire to a large cohort of patients with IC/BPS. While published literature suggests that COMPASS-31 scores in “healthy” individuals are in the range of 8.6–11.1, 17 , 28 – 30 our cohort scored three to four times higher (mean COMPASS-31 score of 35.21) than what is expected in the general population. Since the COMPASS-31 score considers symptoms from multiple body systems, our data provide evidence that patients with IC/BPS commonly experience widespread, multi-system symptoms far beyond the pelvis and genitourinary (GU) tract. Our findings further support the idea of two clinical subgroups of IC/BPS patients (bladder-centric vs non-bladder-centric) and provide evidence that non-bladder-centric patients have a higher autonomic symptom load. Specifically, our data show that patients with a high autonomic symptom load (Group 2) had a higher BC, a lower prevalence of HL, and a higher number of comorbid conditions compared to patients with a low autonomic symptom load (Group 1). This aligns with prior studies that describe characteristics of non-bladder-centric vs bladder-centric phenotypes. 13 , 14 Moreover, the multivariable logistic regression analysis further supports these findings by demonstrating that BC and total NUAS are positively associated with a higher COMPASS-31 score. As the characteristics that distinguish these clinical subgroups come into sharper focus, clinicians will be better equipped to approach IC/BPS patients in a more targeted manner. It is important to note that the higher autonomic symptom load in Group 2 is a result of the combined effect of multiple domains. In fact, patients in Group 2 scored significantly higher in each of the six COMPASS-31 domains compared to those in Group 1. Additionally, although patients with IC/BPS suffer from GU symptoms, the bladder domain of the COMPASS-31 questionnaire comprises only a small portion of the total possible score, accounting for a maximum of 10 points out of 100. Furthermore, the bladder domain only constituted 23.2% of the total score on average in Group 1, and only 11.5% in Group 2. These findings suggest that GU systems may not be the primary driver for the elevated COMPASS-31 scores, but rather these elevations are dependent on multiple other domains. Interestingly, high autonomic symptom load is also correlated with a higher PUF score, demonstrating that GU symptoms may worsen in concert with symptoms in the rest of the body, despite the GU score not overtly elevating the COMPASS-31 scores. Data from one domain of the COMPASS-31 scale, orthostatic intolerance, was especially noteworthy. In our cohort, Group 1 was not affected by orthostatic intolerance, with none of the 30 patients in this group reporting orthostatic symptoms. On the contrary, Group 2 was affected by orthostatic intolerance more than any other domain, with 34.0% of their total COMPASS-31 score attributed to orthostatic symptoms. These data support published literature stating that patients with IC/BPS have a high prevalence of orthostatic intolerance and syncope. 4 While it appears evident that orthostatic symptoms exist within the IC/BPS population, one previous report found that these patients tested negative for positional orthostatic tachycardia syndrome (POTS), orthostatic hypotension, and tilt-table mediated syncope. 4 These findings indicate that orthostasis was not due to proximal cardiovascular autonomic damage, and instead points to alternative mechanisms of action. One proposed hypothesis is central nervous system sensitization. The Multidisciplinary Approach to the Study of Chronic Pelvic Pain (MAPP) Research Network has provided a significant amount of information on central nervous system (CNS) sensitization in IC/BPS. The network has enrolled a large cohort of patients diagnosed with urologic chronic pelvic pain syndrome (UCPPS), which includes IC/BPS and chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS). Similar to our results, the MAPP network demonstrated that patients with UCPPS commonly experience systemic symptoms, with one study of 424 subjects reporting that 75% of UCPPS patients had pain beyond the pelvis and 38% had widespread pain in at least three different areas of the body. 31 The MAPP group used functional and structural magnetic resonance imaging (MRI) to evaluate the CNS, and identified clear reproducible aberrations in regions involved in sensory processing and pain modulation in both the gray and white matter of UCPPS patients when compared to healthy controls. 32 , 33 Further, differences were found in functional connectivity when comparing UCPPS patients with localized pelvic pain compared to those with widespread pain beyond their pelvis (i.e. concordant with a non-bladder centric phenotype). 32 Moreover, after 36 months of follow-up, improvements in these pain centers on MRI were correlated with reduced pain symptoms in patients. 33 While these studies primarily focus on a central sensitization mechanism for pain, it is possible that functional or structural changes in the CNS may exist for autonomic nervous function and/or sensitivity to several bodily symptoms. This would provide a foundation to explain why our cohort is experiencing dysfunction across every ANS domain instead of just one or two, and why these patients appear to have a heightened awareness of subtle changes in multiple organ systems. There are important limitations to note. While there is no documented, validated cutoff number for “normal vs elevated” COMPASS-31 scores, a literature search assessing average COMPASS-31 scores in healthy control populations yielded four studies with mean scores ranging from 8.6 to 11.1. 17 , 28 – 30 Based on these values, we elected to split our cohort at the 1 st quartile (i.e., a maximum score of 20.36), to allow for adequate separation and comparison of patients who approximated a normal symptom load to those with an elevated load. Due to timing of the addition of the COMPASS-31 questionnaire to our standard data collection workflow, roughly half of the COMPASS-31 data were obtained in a retrospective manner, after patients had already undergone HOD, while the other half was obtained in a prospective manner. However, we do not have reason to believe this would significantly impact the COMPASS-31 scores because HOD primarily targets bladder pain while the bladder domain of the COMPASS-31 questionnaire assesses urinary continence and retention. Also, data obtained through the COMPASS-31 questionnaire and the IC/BPS-specific questionnaires are subjective in nature, relying on patients to report and rate their degree of symptoms. Finally, information regarding comorbid conditions such as depression, fibromyalgia, and endometriosis was gathered by asking patients in a “yes or no” manner whether they had these conditions, rather than charting an official diagnosis, which may have led to inaccuracies.

Interstitial Cystitis/Bladder Pain Syndrome (IC/BPS) is a debilitating chronic urologic condition characterized by bladder discomfort and lower urinary tract symptoms, defined by the presence of symptoms for more than 6 weeks without another identifiable cause. 1 , 2 The prevalence of IC/BPS is significant, with estimates of the syndrome affecting between 3.3 to 7.9 million adult women in the United States. 3 While the pathophysiology of the disease remains to be fully elucidated, it is known that patients experience numerous symptoms and syndromes beyond the urinary system. Clinical studies have found strong associations between IC/BPS and other comorbid conditions, including fibromyalgia, irritable bowel syndrome, and migraines. 4 – 6 Additionally, many of these comorbid conditions exhibit similar patterns in gender and race distribution to IC/BPS, with a significantly higher prevalence among females and white individuals. 7 – 12 Patients who experience the greatest number of these comorbid conditions generally fall into a clinical subgroup of IC/BPS characterized as the non-bladder-centric phenotype. Non-bladder-centric patients have higher a bladder capacity (BC), fewer Hunner lesions (HL), lower average scores on IC/BPS symptom questionnaires, and experience a significantly greater number of neurologic and systemic pain diagnoses compared to patients with a bladder-centric phenotype. 13 , 14 Investigators have hypothesized that these comorbid conditions are due to shared pathophysiologic elements, including autonomic nervous system dysfunction. The Composite Autonomic Symptom Score-31 (COMPASS-31) questionnaire is a validated 31-question survey used to assess autonomic symptoms across six domains including orthostatic intolerance, vasomotor, secretomotor, gastrointestinal, bladder, and pupillomotor functions. 15 In patients with fibromyalgia, the COMPASS-31 questionnaire has been used to evaluate the degree of dysautonomia present in the disease. 16 – 18 Some degree of dysautonomia has also been found to be present among patients with IC/BPS, however the degree of dysfunction and the effects as it pertains to IC/BPS symptoms or clinical subgrouping has not yet been assessed. 19 – 25 Based on the usefulness of this questionnaire in determining autonomic symptom severity in fibromyalgia, it may also provide a valuable tool for investigating the IC/BPS population. This study aims to quantitatively assess the degree of dysautonomia in a group of IC/BPS patients by utilizing the COMPASS-31 questionnaire. With these data, we can evaluate the severity of dysautonomia and examine correlations with phenotypic characteristics in the IC/BPS patient population.