The following article is based on a study which addresses the evidences available in the medical literature on the efficacy of Botulinum Toxin A (BoNT-A) and sacral neuromodulation (SNM) in patients suffering from interstitial cystitis (IC)/bladder pain syndrome (BPS). We will discuss this study to identify the mechanism of action and draw a clear conclusion based on the clinical efficacy of both therapies.
Introduction
The terms interstitial cystitis and bladder pain syndrome are used side by side. IC/BPS is often used like this in the medical world, boasting symptoms such as urinary frequency, urgency and bladder pain, pressure and/or discomfort in the absence of other pathological findings. Current management aims to decrease symptoms such as bladder pain and lower urinary tract (LUT) symptoms.
Method & Aim
A panel board consisting of functional urologists, urogynecologists discussed the diagnoses and classification of IC/BPS according to current guidelines and discussed the efficacy of various treatments including the use of BoNT-A injections and SNM.
Diagnosis of IC/BPS
There is a lack of universally accepted clinical diagnostic criteria for IC/BPS hence there is a recommendation to establish a clinical diagnosis based of symptoms to stratify patients for cystoscopy. A thorough history must be taken and an examination has to be done. Urine dipstick positive patients must be tested for culture of their urine, with urine cytology in high risk groups. The O’Leary-Sant symptom score can be used for the quantification of pain. Cystoscopy remains a keystone in the diagnostic workup of IC/BPS. The European Society for the Study of Interstitial Cystitis (ESSIC) has suggested a standardized procedure for cystoscopy and hydrodistension, under anesthesia, including bladder mapping by drawing. Classical findings include Hunner’s lesions and glomerulations. Bladder biopsy is still controversial.
Classification of IC/BPS
According to ESSIC:
- Cystoscopic a classification system of IC/BPS
- Grade 0 Normal mucosa
- Grade I Petechiae in at least two quadrants
- Grade II Large submucosal bleeding (ecchymosis)
- Grade III Diffuse global mucosal bleeding
- Grade IV Mucosal disruption, with or without bleeding/edema
Mechanism of Action of BONT-A in IC/BPS
- BoNT-A have been investigated on the afferent pathways of LUT. BoNT-A has been shown to decrease SP and CGRP expression in rat DRG neurons as well as the SP and GGRP release in the inflammatory bladder.
- There is also the ability of BoNT-A in the attenuation of bladder afferent activity which could be due to an increased Urothelial ATP release during bladder distension.
- There is a decrease of NGF after bladder BoNT-A injections which improved bladder pain in IC/BPS patients.
- Many chronic inflammatory mediators and apoptotic signalling molecules also decreased after BoNT-A injections.
- COX-2 and PGE2 are known to increase bladder inflammation. This is attenuated with injections of BoNT-A.
These results, in conjunction with the findings suggesting an effect on afferent LUT pathways, indicate that the mechanism of action may involve neurochemical modulation with possible additional amelioration of histological pathology.
Clinical Results of Botulinum Toxin A in the IC/BPS treatment
Several studies have confirmed the efficacy of BoNT-A in patients suffering from IC/BPS36–45. Long term results of repeated injection have confirmed the clinical efficacy of BoNT-A in IC/BPS associated with a decrease of chronic inflammation and apoptosis. However, based on the inconstant results available in the literature and the lack of efficacy in randomized clinical trials (RCTs), it appears that no clear statement on the efficacy on BoNT-A in the treatment of IC/BPS can be drawn.
Mode of action of SNM in the IC/BPS treatment
- One mechanism for neuromodulation in the treatment of pain is based on gate-control theory. This theory states that non-painful input closes the “gates” to painful input, which prevents pain sensation from traveling to the central nervous system. Therefore, stimulation by non-noxious input is able to suppress pain. Neuromodulation is believed to restore control at the spinal segmental gate as well as at supraspinal sites such as the brainstem and the limbic system nuclei.
- SNM reduces pelvic floor hypertonicity which might be the case for patients with chronic pelvic pain by inhibiting motor fibers innervating the pelvic floor muscles.
- SNM also inhibits the amplified afferent output of the urethral sphincter thereby restoring bladder function.
- Decreased levels of Chemokines were appreciated after SNM treatments
- Rise in c-fos immunoreactive cells in the dorsal horn of the spinal cord is inhibited by SNM.
Clinical results of SNM in ICS/BPS treatment
Following the treatment with SNM, the average decrease in pain was from 9.7 at baseline to 4.4 on a scale of 10 (always) to 0 (never) having pain. More than two-thirds of patients with interstitial cystitis who underwent SNM implantation reported a moderate or marked improvement in urinary frequency, urgency, pelvic pain, pelvic pressure, incontinence, and overall quality of life.
Discussion
Clinical symptoms of IC/BPS are shared with other comorbid diseases like IBS, fibromyalgia, chronic fatigue, anxiety and depression. Despite level of evidence one data available on the effect of intravesical BoNT-A treatment on symptoms of IC/BPS (randomized trials), a consistent overall conclusion cannot be drawn at the moment as these studies do not appear to consistently support a positive effect. There is a clear need for large, prospective randomized trials with long term follow-up. Both symptoms and the treatment evaluation should be conducted in a standardized, uniform way in order to adequately compare results.
Conclusion
Both intravesical BoNT-A treatment and SNM have been shown to have positive effects in patients with IC/BPS. However, firm conclusions cannot yet be drawn. Patient-reported outcomes and the quality of life should be assessed in addition to urinary and pain symptoms. Since current treatments mainly focus on symptomatic relief, future research should also focus on clarifying the pathogenic mechanisms involved in IC/BPS.
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