https://orcid.org/0000-0001-5894-5283
Abstract
Purpose: There are no established treatments for treating interstitial cystitis/bladder pain syndrome (IC/BPS). We conducted a study to verify the effectiveness of non-ablative vaginal erbium:YAG laser (VEL) treatment for patients with IC/BPS who were resistant to conventional treatments.
Methods: A total of 12 patients without improvement after several treatments before 2016 underwent VEL treatment once a month for 12 months as per their convenience. The numeric rating scale-11 (NRS-11), O'Leary–Sant interstitial cystitis symptom and problem indexes (ICSI and ICPI), functional bladder capacity, and daily urinary frequency were obtained.
Results: In total, nine patients responded to the treatment and three did not. The NRS-11 scores and ICSI and ICPI improved in all responders. The bladder capacity and urinary frequency also normalized. The residual effect lasted for 18 months from the first treatment without long-term side-effects.
Conclusions: VEL treatment is a safe and effective treatment in patients with IC/BPS.
摘要
目的：没有确切的治疗间质性膀胱炎/膀胱疼痛综合征(IC/BPS)的方法。我们进行了一项研究以验证非消融阴道饵YAG激光（VEL）治疗对抗拒常规治疗方法的IC / BPS患者的有效性。
方法：对2016年之前接受多种治疗后均无改善的共12例患者进行VEL治疗, 每月一次, 共12个月, 在其方便时进行。收集数字评价量表-11（NRS-11）, O'Leary–Sant间质性膀胱炎的症状指数评分和问题指数评分(ICSI评分和ICPI评分)、功能性膀胱容量和每日排尿次数
结果：总共9例患者对治疗有反应, 3例无反应。所有有反应者其NRS-11评分以及ICSI和ICPI评分均得到改善。膀胱容量和排尿次数也趋于正常。
结论：VEL对于IC / BPS患者是一种安全且有效的治疗方法。
Introduction
Interstitial cystitis/bladder pain syndrome (IC/BPS) is limited to the pelvic organs, pelvic floor myofascial support, or external genitalia and is characterized by the hallmark symptoms of chronic pain accompanied by urinary symptoms, such as urgency or frequencyCitation1. The RAND Interstitial Cystitis Epidemiology study reported that, based on the high-sensitivity definition, 6.53% (95% confidence interval 6.28–6.79) and, based on the high-specificity definition, 2.70% (95% confidence interval 2.53–2.86) of the women met the symptomatic criteriaCitation2.
IC/BPS has been defined based on patient reports. A broad variety of clinical symptoms have been observed that have been attributed to the various causes of IC/BPSCitation1. Furthermore, subgroups possibly exist with fundamentally differing etiologiesCitation2. Based on bladder endoscopic findings, IC/BPS can be classified into either an ulcer type exhibiting a lesion called Hunner’s lesion and a non-ulcer type. IC/BPS is reportedly associated with various conditions characterized by chronic pain, such as vulvodynia, fibromyalgia, and irritable bowel syndrome, as well as other pain conditions suggestive of systemic involvement beyond the bladderCitation1–3.
Surgical treatments for IC/BPS can be broadly divided into a direct approach involving only the bladder and an indirect approach involving the bladder and surrounding tissues. The former includes performing bladder hydrodistention for diagnosisCitation3, intravesical infusion therapy (using dimethyl sulfoxide or heparin), neodymium-doped yttrium aluminum garnet (YAG) laser treatment for Hunner’s lesion, and submucosal intravesical injection with botulinum toxin type ACitation3. However, these treatments are believed to alleviate symptoms for only a limited time period. The latter treatment approach includes performing hyperbaric oxygen therapy (HBO), which is reportedly effective for IC/BPSCitation4. HBO greatly differs from other treatments; it improves the blood flow not only in the bladder but also throughout the entire body and simultaneously helps to relieve ischemia and low functional bladder capacity caused by bladder wall fibrosisCitation1–4.
Non-ablative vaginal erbium:YAG laser (VEL) treatment is an effective, safe, and easy method for treating urinary incontinency and frequent urinationCitation5. It is a new treatment whereby irradiation via the vagina acts on the connective tissues of the vaginal tissues and at an angiogenesis level. Previous studies have reported the enhancement of the collagen component and vascularization by thermal energy from a laser sourceCitation5. VEL treatment reportedly improves stress urinary incontinence and urgency urinary incontinence by regenerating not only the vagina but also the tissues up to the urethra and bladderCitation5, suggesting the efficacy of VEL treatment for various symptoms of IC/BPS. Moreover, to the best of our knowledge, there are no reports regarding the use of VEL treatment for use in IC/BPS. Therefore, we prospectively examined the effects of VEL treatment in a single group of patients with IC/BPS who were refractory to other treatments.
Subjects and methods
Subject selection
A total of 12 female patients with IC/BPS who were examined at our hospital from 2015 to 2016 were included. All patients were previously diagnosed with IC/BPS at other hospitals and had received several treatments in accordance with the Japanese guidelinesCitation3. The therapeutic effects of these treatments lasted for only a few months. In our hospital, IC/BPS was definitively diagnosed based on bladder hydrodistention in accordance with the Japanese guidelines of the Society of Interstitial Cystitis of Japan (Office; Department Urology, University of Tokyo, Tokyo, Japan)Citation3.
The inclusion criteria included scores of ≥4 on the numeric rating scale (NRS-11)Citation3 as baseline screening for bladder, urethra, and perineum-derived pain associated with bladder fullness. Pain intensity was measured at the moment the patient had to urinate due to unbearable pain and not only when the bladder was full. Frequent urination, nocturia, and impending incontinence were not analyzed.
Women were excluded if they were pregnant or breastfeeding or suspected of being pregnant; if they had a urinary tract infection (as confirmed using urinary culture during the past 6 months), or receiving preventive microbials, intravesical chemotherapy/immunotherapy, and pelvic radiotherapy; and if they had urinary tract tuberculosis. Patients with hematuria who were not closely examined until that date were also excluded. Women with creatinine clearance levels of <30 ml/min measured using the Cockcroft–Gault formula and those with severe myasthenia gravis, Lambert–Eaton myasthenia syndrome, and amyotrophic lateral sclerosis were also excluded.
Non-ablative VEL treatment
For VEL treatment, the vagina was sprayed with 9% xylocaine using FotonaSmooth™ XS (Fotona d.o.o., Ljubljana, Slovenia); subsequently, the terminal was inserted into the vagina and, with a 2940-nm non-ablative Er:YAG laser with proprietary ‘long-pulse’ setting, laser energy was applied to the entire anterior vaginal wall for 10 min and then to the entire vagina for 10 minCitation5. Treatment was postponed and given on a different day in the event of bacterial cystitis and bacterial vaginosis or during menstruation, making the state of the vagina inappropriate on the treatment day. VEL treatment was scheduled once per month. Treatment was prolonged in accordance with the subject’s pain. Follow-up observation was performed for 1 year, with the day of the initial session counted as day 1. VEL treatment was completed when the subject was satisfied with the results during the first year.
Evaluation of effectiveness and side-effects of VEL treatment
To determine the therapeutic effects of VEL treatment for IC/BPS, we recorded the NRS-11Citation3 and O'Leary–Sant interstitial cystitis symptom and problem indexes (ICSI and ICPI)Citation3 weekly, and analyzed the mean value for the month. The NRS-11 is a pain-specific questionnaire, and both ICSI and ICPI can evaluate urgency, incontinence, frequent urination, and pain.
Functional bladder capacity and daily urinary frequency were measured using the frequency volume chart for a 3-day period each month. Patients with IC/BPS tend to urinate frequently because of pain caused by urine accumulation in the bladder. However, when the pain subsides, the bladder volume increases and the urinary frequency normalizes, making it possible to evaluate IC/BPS.
In this study, a ‘responder’ was defined as a patient with improvement of ≥1 in the NRS-11 score. Adverse events were recorded by free description and recorded every month. All treatments were administered by the same physician. Statistically significant differences were evaluated using Student’s t-test. A value of p < 0.01 was considered to be statistically significant. All analyses were performed using the Office 365 Pro Plus software (Microsoft Corporation, WA, USA).
Results
Nine out of 12 patients responded to VEL treatment
A total of 12 patients (mean age 51.6 ± 8.96 years) with IC/BPS met the inclusion criteria for the study. All patients had undergone VEL treatment and received prior treatment, including oral agents, intravesical infusion of dimethyl sulfoxide, and bladder hydrodistention, in accordance with the Japanese guidelines; however, none of them showed improvement. Furthermore, no patient received HBO. Cystoscopic findings were ulcerative in two patients and non-ulcerative in ten. All patients were examined for a mean duration of 19.75 ± 1.00 months from the initial VEL treatment session. Nine patients were classified as responders and three as non-responders. One of the non-responders requested treatment discontinuation owing to the absence of therapeutic effects after the initial VEL treatment session and was thus considered as a non-responder. This patient was referred to the psychiatric department because of symptoms of psychiatry. Two non-responder patients underwent ten rounds of VEL treatment; however, pain did not improve at all.
Improvement results
The nine responders demonstrated significant improvement in symptoms after VEL treatment as compared with those at the baseline before the treatment (). Thereafter, the NRS-11 scores improved from 10.11 ± 0.92 to 2.09 ± 2.03 and 1.44 ± 1.33 at 12 and 18 months, respectively (p < 0.01). Furthermore, the ICSI scores improved from 15.6 ± 1.33 to 5.67 ± 2.17 and 4.56 ± 1.67 and the ICPI scores improved from 13.0 ± 1.50 to 4.78 ± 0.67 and 4.11 ± 0.33 at 12 and 18 months, respectively (p < 0.01). The three non-ulcerative patients showed no improvements in any of the questionnaires. ICSI and ICPI scores indicated an improvement in urgency and pain, whereas NRS-11 indicated an improvement in pain. Initially, all patients underwent therapy with non-steroidal anti-inflammatory drugs (NSAIDs). In the responders, one, two, two, and three patients did not require NSAIDs at 2, 7, 8, 14 months after VEL treatment, respectively.
Figure 1. Effects of VEL treatment according to (a) the numeric rating scale-11 (NRS-11), (b) the O'Leary–Sant interstitial cystitis symptom index (ICSI), (c) the O'Leary–Sant interstitial cystitis problem index (ICPI), (d) functional bladder capacity (IVIL) in ml and (e) daily urinary frequency. The x-axis of all graphs indicates time, showing progress from before VEL treatment to 1, 3, 6, 9, 12, 15 and 18 months.
In the responders, the functional bladder capacity improved from 68.78 ± 15.0 to 186.7 ± 25.0 and 195.6 ± 12.4 ml at 12 and 18 months, respectively (p < 0.01). The daily urinary frequency decreased from 18.5 ± 6.51 to 7.56 ± 1.58 and 7.11 ± 0.6 times at 12 and 18 months, respectively (p < 0.01). Conversely, the non-responders showed no improvement at all. Furthermore, cystoscopy performed after 1 year of VEL treatment revealed the granulation of an ulcer in the bladder mucosa, indicating tissue repair in patients with ulcerative lesions.
The adverse events observed included increased pain immediately after VEL treatment in five patients, which lasted for approximately 3–7 days. No side-effects were observed after the third and subsequent treatment sessions.
Discussion
VEL treatment demonstrated efficacy for both ulcerative and non-ulcerative patients with IC/BPS. The response rate was 75% (nine out of 12), which is similar to that previously reported in studies on HBO treatments; moreover, the response rate of 63% (five out of eight)Citation6, and 64% (seven out of 11)Citation4 illustrated the efficacy of laser treatments. The following section discusses the underlying mechanism of this effect.
Hypothesis of blood flow impairment caused by IC/BPS
Although the mechanism of IC/BPS is currently unknown, several explanations have been proposedCitation7. Several studies have been conducted to investigate the diseases of the vascular system, immune system, and proinflammatory signaling moleculesCitation8. Laser Doppler flowmetry was used to study impaired bladder perfusion in 16 patients with interstitial cystitisCitation8. A dual-channel endoscopic laser Doppler flow probe was used to study bladder perfusionCitation8. These studies suggested the hypothesis of blood flow impairment in the bladder as a cause of IC/BPS. Ischemia induces hypoxia and damages the bladder tissues. Therefore, it was hypothesized that HBO is the first method successfully to demonstrate that IC/BPS can essentially be cured by improving the impaired blood flowCitation6. Since the first study reported in 2004Citation6, several researchers have demonstrated the effects of HBOCitation4. It is effective for treating hypoxic injuries due to impaired blood flow in IC/BPS.
VEL treatment improves IC/BPS
VEL treatment acts by the mechanism of absorption into the tissue surface, thereby temporarily increasing the temperature of the mucous membrane and inducing reconstruction of the lamina propriaCitation9. A histological study reported that VEL treatment improved basal cell hyperplasia, parakeratosis, and papillomatosis as well as exerting a vasodilator effect in the lamina propria and increasing the extracellular matrix. In other words, improving the impaired blood flow increases the oxygen and nutrient supply to the treatment area. Accordingly, it is conceivable that the mechanism by which VEL treatment improves IC/BPS probably lies in the blood improvement theory, which is also the mechanistic theory of HBO.
The improvement in pain exceeded the initial expectation, probably due to the blood improvement theory and because an improvement of urgency has already been confirmed for VEL treatment.
Advantages and precautions to be undertaken for VEL treatment
Increasing the efficacy of the surgery for the treatment of IC/BPS is advantageous. Compared with HBO, VEL treatment is less expensive and can be conducted using small-sized equipment; thus, VEL treatment has readily gained popularity for treating IC/BPS and is easily available in various regions in Japan. In contrast, HBO requires large-sized equipment and is therefore available only at limited institutions. Thus, we believe that VEL treatment has more advantages.
Conclusions
VEL treatment improved IC/BPS. The treatment was safe and resulted in favorable improvement for at least 18 months. Thus, VEL treatment can be proposed as a new treatment.
Ethical approval
All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Declaration of Helsinki and its later amendments or comparable ethical standards. The study protocol was approved by the Ethical Review Board of Kanagawa Association of Medical and Dental Practitioners of Japan (1903) and registered at University Hospital Medical Information Network- Clinical Trial Registration Japan: UMIN-CTR (R000043397). The study was conducted in accordance with the protocol (UNICORN-2 study). The study website is http://unicorn-study.net/.
Informed consent
Informed consent was obtained from all participants included in the study.
Potential conflict of interest
The authors declare that they have no conflicts of interest.
Source of funding
Nil.
Acknowledgements
The authors thank F. Hirata MD (Yokosuka Tower Clinic, Yokosuka) for management of internal medical condition, Y. Kono RN, Y. Nakano RN (Dr Okui’s Urogynecology and Urology Clinic) for professional nursing, H. Aoki, I. Aoki and M. Ishikawa (external audit legal and economy committee) for ethical standards.
Correction Statement
This article has been republished with minor changes. These changes do not impact the academic content of the article.
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