INTRODUCTION
Interstitial cystitis/bladder pain syndrome (IC/BPS) is a chronic inflammatory bladder disorder with an undetermined pathophysiology [1]. Recent consensus and guidelines have divided the disorder into ulcer-type and non–ulcer-type IC, as each type exhibits characteristic cystoscopic features [1, 2]. The terminology of Hunner IC (HIC) and non-Hunner’s IC has been widely applied for distinct clinical characteristics and treatment strategies [3, 4]. A new terminology refers to IC for patients with Hunner lesions and to BPS for patients without Hunner lesions [5]. However, to date, no effective or durable treatment for IC/BPS has been established.
Moreover, no optimal treatment for HIC has been established. Previous therapeutic trials adopted several conservative treatments and surgical procedures for HIC patients [6]. Treatment options include oral pentosan polysulfate [7], cyclosporin [8], low-dose prednisolone [9], intravesical triamcinolone injection [10], intravesical botulinum toxin A (BoNT-A) injection [11], transurethral resection, fulguration, and laser ablation of Hunner lesions [12, 13]. Although early treatment results are satisfactory, high recurrence rates of Hunner lesions have been reported, and repeat fulguration of Hunner’s lesions is inevitable [13-15]. Therefore, partial cystectomy with ileal augmentation, ileal conduit without cystectomy, and urinary diversion with total cystectomy have been used to treat intractable HIC [16-18].
Currently, the predictive factors for the recurrence of Hunner lesions after surgical or nonsurgical bladder therapy in HIC patients are not known [19]. Hunner lesions can be hidden in the bladder wall, and thus the recurrence of HIC is common [20, 21]. Patients with severe bladder pain and small bladder capacity can also choose conservative treatment; however, bladder pain is usually not satisfactorily improved with such treatment. Bladder augmentation can result in rapid relief of bladder pain and increased bladder capacity. However, many factors can decrease the satisfaction with the surgical procedure and prevent patients from choosing this option, including the risk of reoperation, need for further bladder therapy, bowel obstruction, urinary tract infection (UTI), persistent bladder pain, and difficult urination [22, 23]. To date, the treatment outcomes of reconstructive surgical procedures and bladder-preserving therapies have not been well documented. Selecting the procedure for HIC largely depends on the patient’s and surgeon’s preferences.
This study analyzed the long-term treatment outcomes of HIC patients who received augmentation enterocystoplasty (AE) and bladder-preserving therapies and compared the subjective and objective results between the 2 groups. The results of this study provide insights into appropriate procedures for HIC.
MATERIALS AND METHODS
From 2013 to 2024, patients with cystoscopically confirmed HIC who received AE or non-AE bladder-preserving therapy were retrospectively analyzed regarding treatment outcomes. The following was employed: the subjective global response assessment (GRA), IC symptom index (ICSI), IC problem index (ICPI), visual analogue scale (VAS, from 0 to 10), and uroflowmetry parameters. These factors were assessed at baseline and postoperative follow-up visits at least once per year. A GRA score of 3, 2, or ≤1 indicated a successful, improved, or failed outcome, respectively, at the recent follow-up visit after AE or non-AE bladder therapy. Patients with a successful or improved treatment outcomes were considered having a satisfactory result.
All patients received validated IC questionnaires, cystoscopic examination, videourodynamic study, and their first transurethral electrofulguration or laser ablation of the Hunner lesion. Before fulguration or ablation of Hunner lesion, cystoscopic hydrodistention was also performed under anesthesia and an intravesical pressure of 80 cm H2O. The maximal bladder capacity was measured and grade of glomerulations outside the Hunner lesions were recorded. Part of the patients underwent bladder computed tomography examination of bladder wall thickness before planning to undergo AE or fulguration of Hunner lesions [24]. When the functional bladder capacity was smaller than 150 mL and the bladder pain severity could not be relieved after BoNT-A injection and repeated fulguration of the Hunner lesion, partial cystectomy and AE using a 40-cm segment of the terminal ileum was recommended [25]. Patients who did not agree to AE were regularly followed up and received different bladder therapies, including oral pentosan polysulfate, intravesical hyaluronic acid instillation, transurethral fulguration, laser ablation, low-energy shock wave (LESW), antiviral medication, and intravesical injections of BoNT-A, platelet-rich plasma (PRP), and triamcinolone.
All patients were followed up for bladder pain and IC symptom improvement at the department of urology of the hospital. After AE, patients were regularly followed up, their urination status was monitored, and UTIs were treated with appropriate antibiotics. If gross hematuria occurred, cystoscopy was annually performed to check for stitch stones. Otherwise, cystoscopy was only performed for symptoms of bladder pain or difficult urination or persistent pyuria. The patients’ voiding efficiency, postvoid residual volume, and upper urinary tract were also followed up. If patients still complained of bladder pain, and cystoscopic examination revealed the presence of erythematous Hunner lesions, repeat electrofulguration or intravesical injection of triamcinolone or PRP was performed to eradicate Hunner lesions and chronic inflammation. Patients who were found to have multiple recurrent Hunner’s lesions at the native bladder and were refractory to conservative treatment underwent repeat fulguration or repeat partial cystectomy to remove the diseased bladder wall. For patients who had difficulty urinating, clean intermittent self-catheterization was recommended. If large postvoid residual volumes and recurrent UTIs persisted, transurethral incision of the bladder neck, which facilitates spontaneous voiding by abdominal straining, was performed [26]. After long-term follow-up, adverse events were recorded, and the complications were appropriately treated.
Not all patients underwent AE, mostly because of fear regarding partial cystectomy and reconstructive intestinal surgery. Although they had small functional bladder capacity, they usually chose to tolerate the bladder pain and severe urinary frequency and urgency. During the follow-up period, the patients received several different bladder therapies that relieve bladder pain and urinary frequency and urgency, including repeated hydrodistention, oral pentosan polysulfate medication, intravesical hyaluronic acid instillation, intravesical injections of BoNT-A or PRP, transurethral fulguration of Hunner lesions, LESW therapy, and antiviral medication. The bladder symptoms diminished after bladder therapy but would recur with time. The individual GRA scores and final treatment outcomes were recorded.
In the AE and non-AE groups, the patients’ symptoms and urodynamic parameters were compared between the baseline and follow-up endpoint and between those who had improved or nonimproved treatment outcomes. Continuous variables were expressed as means with standard deviations, and categorical data were presented as numbers and percentages (%). The chi-square test for categorical variables and the Wilcoxon rank-sum test for continuous variables were used to determine P-values between groups for statistical comparisons.
RESULTS
This study included 54 patients (48 women and 6 men). The mean age at the diagnosis of HIC was 58.6±11.4 (range, 30–81) years, and the duration from the initial treatment to the followup endpoint was 9.4±5.8 (range, 1–22) years. AE was performed in 17 patients (31.5%), of which 13 (76.5%) exhibited a satisfactory final outcome. The final satisfactory outcomes were reported in 26 of the 37 patients (70.3%) that received non-AE bladder therapy. Table 1 shows the baseline demographics of patients treated with AE or non-AE. There were no significant differences in the symptom scores, maximal bladder capacity under anesthesia, videourodynamic parameters, or the focal or diffuse bladder wall thickness between the 2 groups.
AE relieved symptoms of bladder pain and improved bladder capacity soon after operation. However, some patients complained of difficult urination and required clean intermittent self-catheterization (n=5) or received transurethral incision of the bladder neck (n=2). Recurrence of Hunner lesions was noted in 4 patients after AE, of which 3 required fulguration of Hunner lesions and one required repeat partial cystectomy to remove the residual native bladder wall. Recurrent UTIs were noted in 5 patients, and bladder stitch stones were found in 3 patients (Table 2). Among the patients that underwent AE, only 4 (23.5%) needed further bladder therapy during the follow-up period. All the patients that did not undergo AE had recurrence of Hunner lesions which required further bladder therapy. After intravesical BoNT-A injection, 5 patients had recurrent UTIs, and 3 had difficulties urinating.
The bladder therapies of the patients who declined AE are listed in Table 3. None of the patients reported satisfactory outcomes after cystoscopic hydrodistention, pentosan polysulfate, or LESW therapy. Satisfactory results were reported in 9.7% (3 of 31) of patients after hyaluronic acid instillation, 42.9% (6 of 14) of patients after repeated BoNT-A injection, 74.1% (20 of 27) of patients after electrofulguration of Hunner’s lesions, 72.2% (13 of 18) of patients after repeated PRP injection, 66.7% (8 of 12) of patients after antiviral therapy, and 100% (3 of 3) of patients after intravesical triamcinolone injections. The rates of success, improvement, and failure were 24.3% (9 of 37), 45.9% (17 of 37), and 29.7% (11 of 37), respectively, at the final followup visit. Among the patients with non-AE bladder therapy, 12 (70.6%) were satisfied during the follow-up period.
Table 4 shows the changes in symptom scores and urodynamic parameters from baseline to the follow-up endpoint in patients with and without AE who had improved or nonimproved treatment outcomes. The largest change was observed for the VAS pain score. Compared with patients without improvement, patients with improved outcomes after AE exhibited significantly decreased ICSI (P=0.007) and VAS (P=0.013) scores and significantly increased bladder fullness sensation (P=0.002) and cystometric bladder capacity (P=0.019). Patients without improved outcomes after AE did not experience pain relief or significant increases in bladder fullness sensation or bladder capacity. However, VAS scores were significantly decreased after multiple bladder therapies in patients without AE who reported either improved or nonimproved outcomes. Patients without AE and with improved outcomes had decreased IC symptoms and increased functional bladder capacity; however, the urodynamic parameters did not change after treatment.
The satisfaction rates were similar between patients treated with AE and non-AE bladder therapy. Only 23.4% of patients treated with AE underwent repeat surgery or intravesical therapy in the first 1–3 years, after which the bladder condition stabilized and no further bladder therapy was necessary. By contrast, patients treated with non-AE bladder therapy required repeated intravesical therapy for the recurrence of Hunner’s lesions or bladder symptoms. Nevertheless, more than 70% of patients with non-AE bladder therapy were satisfied with their current bladder condition and continued treatment when they had bladder symptom recurrence.
DISCUSSION
The results of this study reveal that either AE or non-AE bladder therapy can improve bladder symptoms and increase bladder capacity long-term. The satisfaction rates were similar between the AE and non-AE groups. Although AE can rapidly relieve bladder pain and increase bladder capacity, long-term complications, such as UTIs and the need for repeat procedures to improve voiding efficiency and treat recurrent Hunner lesions, remain potential issues. Conversely, using bladder-preserving therapy to repeatedly fulgurate Hunner’s lesions and intravesical BoNT-A or PRP injection to treat intractable inflammation and bladder pain can still effectively achieve a satisfactory outcome.
Hunner Iesions are usually not solitary. Computed tomography of the bladder revealed that a high percentage of HIC patients have focal or diffuse bladder wall thickness [24]. Focal and diffuse bladder wall thickness are prominent in the image study. The thickness portion is also compatible with the locations of Hunner lesion. Using bladder computed tomography, we can adequately resect the part of bladder wall with Hunner lesions and severe inflammation [27]. In this study, 4 patients were noted to have recurrence of Hunner lesion. The recurrence of Hunner lesions in native bladder was difficult to identify whether the lesions are new or residual. HIC is potentially a pan-cystitis bladder disease [4], although partial cystectomy and AE was performed, patients might still have residual inflammation in the native bladder, and the mucosal eruption might occur with time. Therefore, cystoscopy is indicated to search for recurrence of Hunner lesion after AE and fulguration for the lesions if presence. Under this consideration, a bladder computed tomography for assessing HIC is important to identify possible Hunner’s lesions involved in the bladder wall.
Partial cystectomy with or without augmentation cystoplasty can effectively remove most of the bladder’s thickened wall, which may prevent recurrent Hunner lesions from erupting from the underlying inflamed tissue [28]. However, most HIC cases have a thick and contracted bladder; therefore, cystoplasty after partial cystectomy usually requires augmentation with a segment of the terminal ileum or sigmoid colon [29]. Usually, enterocystoplasty for HIC bothers patients with mucus secretion, recurrent UTIs, incomplete bladder emptying, and the need for clean intermittent self-catheterization [23]. For patients with recurrent UTI after AE or non-AE bladder therapy, intravesical hyaluronic acid was instilled to reduce the risk of UTI recurrence and relieve bladder pain symptoms [30]. The advantages and disadvantages of AE often complicate recommendations to patients. The potential complications of using an intestinal segment to augment a contracted bladder might also prevent a high percentage of HIC patients from accepting this invasive treatment modality, as they prefer bladder-preserving therapies for symptom relief.
The current guidelines for treating IC/BPS prioritize transurethral fulguration of Hunner lesions before partial cystectomy and bladder augmentation because accumulating evidence shows that fulguration of Hunner’s lesions can also effectively eradicate bladder pain [1, 2, 5]. With additional bladder therapy, such as dimethyl sulfoxide instillation or injections with BoNT-A, PRP, and triamcinolone, the inflamed bladder wall can be successfully treated [6]. If all Hunner lesions of the bladder wall can be effectively fulgurated in HIC patients, the therapeutic effects would be similar to those of partial cystectomy [31]. In this study, we found LESW did not provide therapeutic benefit for non-AE HIC patients. LESW has been suggested to temporarily increase urothelium permeability and facilitate intravesical drug delivery or retention [32]. LESW alone might not adequate to eradicate the dense inflammatory tissues in the Hunner’s lesions of bladder wall. Combination of LESW with other anti-inflammatory agents like botulinum toxin or triamcinolone might provide a better drug penetration and anti-inflammatory effect for treatment of HIC. Although multiple different bladder therapies might still be necessary, the advantages of bladder preservation via non-AE treatment outweigh AE-associated long-term complications.
Recent studies have revealed that a high proportion of HIC patients also experience Epstein-Barr viral infections [33]. Interferon intravesical instillation can also decrease the ICSI and ICPI scores and pain reduction in IC/BPS patients [34]. The antiviral medication valacyclovir effectively decreases bladder pain, IC symptoms, and the concentration of urinary inflammatory proteins and increases bladder capacity [35]. This study demonstrated acceptable satisfaction rates after different bladder therapies, including electrofulguration, antiviral medication, and intravesical injections with PRP and triamcinolone. Employing multiple different bladder therapies can result in long-term therapeutic efficacy.
Much time is needed for a contracted bladder to develop in HIC patients. Patients with effective bladder-preserving therapy usually have a larger bladder capacity and smooth or focal bladder wall thickness in bladder computed tomography [24]. Thus, the early discovery of HIC in IC/BPS patients is important to achieve a satisfactory outcome. Using a cluster of urine biomarkers, HIC can be distinguished from IC/BPS [36]. With office cystoscopy, we can detect early HIC lesions in patients with severe bladder pain [37]. If HIC can be detected in the early stage, transurethral fulguration plus intravesical therapies can effectively eradicate bladder inflammation and achieve long-term remission and improved quality of life [38].
This study indicates that AE is inevitable in HIC patients who did not obtain successful outcomes after conservative and bladder-preserving therapies. Although AE is invasive and linked to potential complications, the short- and long-term satisfaction rates are high [16-18]. Patients who reported a nonimproved outcome were usually unsatisfied because of voiding difficulties, UTIs, or recurrent bladder pain. For these patients with a destroyed bladder, AE is still the treatment of choice. The symptomatic relief was soon achieved in patients after AE, but lasted for long period in non-AE patients who were treated with a long series of bladder therapy. Moreover, only 23.5% of patients with AE required further bladder therapy, which was significantly lower than that in patients with non-AE bladder therapy (70.6%). To date, no study has reported successful treatment, i.e., the reversal of a contracted IC bladder to a normal smooth bladder with bladder-preserving therapies. Therefore, the treatment of choice for HIC and contracted bladders still depends on the symptom severity and patients’ will.
The limitation of this study is the small case number and non-randomization of the treatment subgroups. However, because this is a single-center study, the number of HIC patients is adequate for analysis. The strength of the study is that all patients were followed up for a long time, and that their bladder therapies involved many novel treatment modalities. In the future, with early diagnosis of IC/BPS subtypes and identification of HIC, early intervention with multiple novel treatments, such as fulguration of Hunner lesions, antiviral medication, and injection with PRP and triamcinolone, might completely cure HIC.
In conclusion, this study demonstrates that either AE or non-AE bladder therapy can provide a satisfactory outcome for more than 70% of HIC patients. AE provides early relief of bladder pain and results in less repeat bladder therapy. Conversely, non-AE therapy does not result in postoperative complications but does require repeat bladder therapy. The early identification of HIC in addition to novel and effective therapies for HIC might abolish the need for invasive surgery such as AE.
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