Authors: Jörgen Quaghebeur, Jean-Jacques Wyndaele, Peter Petros
Categories: Review Article, Chronic pelvic pain, Integral theory, Lower urinary tract symptoms, Pelvic organ prolapse, Posterior fornix syndrome, Primary bladder pain syndrome, Visceral plexus
Source: International Neurourology Journal
Authors: Jörgen Quaghebeur, Jean-Jacques Wyndaele, Peter Petros
To critically analyse the relationship of bladder pain syndrome (BPS/IC), as defined, to the posterior fornix syndrome, “PFS” predictably co-occurring bladder urgency, frequency, nocturia, chronic pelvic pain, emptying symptoms/retention, caused by uterosacral ligament (USL) laxity and cured by USL repair. The starting and end points of this paper are the questions, “Are there arguments that BPS/IC can, in some cases, be linked to PFS?” And if so, “To what extent?” We used the criteria required by Ueda for proper “understanding symptoms, detecting abnormal findings and verifying them as a cause of the symptoms.” Literature, diagnostic and surgical, indicate that chronic pelvic pain “of unknown origin” can be caused by unsupported visceral pelvic plexuses because of weak USLs; these cause fire of afferent impulses, which the brain mistakenly interprets as coming from the end-organ itself (i.e., genitourinary pain, lower urinary tract symptoms). The same lax USLs can also weaken the pelvic muscles which contract to stretch the vagina to support the urothelial stretch receptors from these may prematurely fire off afferent impulses to activate micturition at lower bladder volumes, interpreted as urgency. A speculum placed in the vagina can relieve pain and urgency by mechanically supporting the vaginal wall and USLs, thus predicting an eventual cure by USL repair. There is need to evaluate what percentage of women with known BPS/IC also pass the criteria for PFS. Identifying a significant percentage of BPS/IC women with the causative relation between PFS pathogenesis and BPS/ IC may open a new way of diagnosing and treating BPS/IC in some women.
In recent European guidelines on chronic pelvic pain syndrome (CPPS) and the upgraded terminology [1], CPPS became chronic primary pelvic pain syndrome (CPPPS) and BPS/IC became primary bladder pain syndrome (PBPS), according to the International Association for the Study of Pain classification system [2]. CPPPS is a symptomatic diagnosis excluding pathology and confusable diseases [1]. As defined by the ICS, the PBPS includes bladders with and without Hunner lesions (HL) that present with pain during filling and at least one bladder symptom (e.g., urgency, frequency, nocturia, emptying) [1]. HL show profound submucosal inflammation and epithelial denudation in the bladder by cystoscopy and differ pathologically from non-HL PBPS [3, 4]. ESSIC (International Society for the Study of BPS) developed a classification system differentiating different phenotypes based on cystoscopy with hydrodistension and biopsy [5]. The guidelines on PBPS describe the presence or absence of HL as the only universally accepted phenotype today [4]. Glomerulations are no longer a diagnostic sign of PBPS having no diagnostic, prognostic or therapeutic significance but may still be relevant for research purposes [6]. The abandoning of glomerulations for diagnosis implies that patients with PBPS symptoms remain without a good indication for diagnosis, which results in consulting multiple specialists [7]. Various extravesical causes of pelvic pain, such as endometriosis or pelvic organ prolapse (POP), may cause secondary bladder symptoms. Any such associated secondary bladder dysfunction may partly be attributed to possible mechanisms of neuronal crosstalk and central sensitization. Posterior fornix syndrome (PFS) is one of many causes of pelvic pain that may result in secondary bladder dysfunction as a consequence of weak uterosacral ligaments (USLs). We examined the hypothesis that, at least in some women, the originating cause of PBPS is not in the urothelium but is located outside the bladder, in damaged USLs, leading to a loss of visceral plexus (VP) support.
We evaluated the PFS concept in toto: symptom co-occurrence, pathogenesis, testing by a speculum or other, and cure/improvement by USL repair, for consistency with the Ueda criteria for BPS/IC, with regard to diagnosis, pathogenesis and cure. Ueda et al., in 2021, “Despite the tremendous medical advances made by developing many testing modalities and biomarkers, there can be no successful treatment in the absence of an accurate diagnosis. Thus, there can be no bright future for BPS/IC without these 3 (1) understanding the symptoms, (2) detecting abnormal findings in or outside the bladder, and (3) verifying that the abnormality is the cause of the symptoms [8]. BPS/IC is a symptom complex with no apparent cause. Without anatomically-defined causal abnormality, pain is related to the bladder as a primary bladder pain syndrome (PBPS/IC) by definition, not science (there may be causes not yet defined or discovered). In this context, where chronic pelvic pain (“CPPPS”) plus urinary symptoms (“PBPS”) are demonstrated by scientifically-validated data to have an established causal relationship (for example a positive speculum test (Fig. 1), followed by surgical cure of USLs, as described later in this paper), the bladder pain syndrome [1, 2] must be considered as possibly secondary to weak USLs. Far from clarifying BPS/IC, the new definitions [1, 2] only serve to further confuse a confusing subject. We critically examine PFS according to the UEDA criteria, 1–3 below. The starting and end points of this paper are the questions, “Is BPS/IC one and the same as PFS”? If so, “To what extent?”
With reference to the diagnostic algorithm (Fig. 2), the symptoms within the rectangle identify co-occurring PFS symptoms which are caused by lax or weak USLs. Symptoms relevant to BPS/IC are addressed separately below.
The pelvic VPs are supported by the lateral part of the USLs 2 cm prior to their insertion on the cervix (Fig. 1). Inability of a lax USL to support the VPs may allow gravity “G” or muscle movements to directly stimulate the end-organ axons passing through the VPs which act as a type of relay station. The afferent impulses from this direct stimulation proceed to the cortex and are (wrongly) interpreted originating from the LUT. This hypothesis can reasonably explain why chronic pelvic pain (CPP) occurs in multiple end organs, why the positive speculum test (Fig. 1), immediately relieves pain in several locations at the same time [9] and why the pain is relieved in all sites by the Bornstein LA test (The Borstein LA test installs anaesthetic in the USLs at their insertion points to the cervix) [10].
Fig. 1 shows that if the USLs against which the posterior vector forces levator plate/longitudinal muscle anus (LP/LMA) (large arrows) contract are weak or loose, the LP/LMA cannot stretch the vagina sufficiently to support the urothelial stretch receptors “N.” These stretch receptors may fire off afferent impulses prematurely, at a low bladder volume, to activate the micturition reflex, which the cortex perceives as urgency [11]. Reduction of urge symptoms and detrusor overactivity tracings were observed by digital support of bladder base [11].
During normal micturition, the forward vector, “PCM” (Fig. 1) relaxes [11]; PCM relaxation removes the backward forces exerted by PCM against the posterior urethral wall and allows LP/ LMA to pull open the posterior urethral wall prior to micturition freely. Stretching the urethral opening exponentially reduces the internal resistance to urine flow inversely by the fourth power [12]. If USLs are weak, the LP/LMA muscle forces cannot open the urethra sufficiently; the detrusor necessarily contracts against a relatively unopened urethra, and this is perceived as “obstructed micturition.” Normal bladder emptying was restored with posterior slings which repaired the USLs [13, 14].
Though pain and urgency can originate from lax USLs, their nervous pathways may differ. Pain originates from mechanically unsupported VPs (Fig. 1), while urgency originates from mechanically unsupported urothelial stretch receptors “N” (Fig. 1).
The diagnostic algorithm (Fig. 2), graphically confirms whether PFS is the cause of the pain and the urgency. The grouping of symptoms is well illustrated by Fig. 2 [13] which shows the relative incidence of symptoms in women treated for PFS, with CPP (n=198) as the presenting symptom. The variable cure rates for different PFS symptoms, by the same USL repair [14], attest to different anatomical pathways.
In another study [15], shows the co-occurrence of CPP, nocturia, frequency, and urgency incontinence (n=611) relative to uterine/apical prolapse [15]. All surgeons used the validated Integral Theory System Questionnaire (ITSQ) [16] and PFS diagnostic protocol (Figs. 1, 2). The ITSQ is designed to specifically detect PFS, CPP, urgency, and emptying problems caused by USL laxity. The ITSQ quantifies symptom severity and variation and provides a simple patient-administered test to confirm USL causation, placing a large menstrual tampon in the posterior fornix.
“Simulated actions” simulate surgical correction of anatomical abnormalities, for example, mechanical support of pelvic ligaments or vagina (Fig. 1) and observing if there is any change in symptoms of urgency or pain. Anything which can mechanically support these structures will relieve pain or urgency symptoms if lax USLs are the cause, e.g., use of a speculum test (Fig. 1), tampon or roll gauze in the fornix. Digital support of the bladder base was demonstrated to be a reliable method for testing vaginal laxity as the cause of urgency [11]. In 18 of 20 patients, the urgency disappeared for a short period and returned on removing that support in a comparable period. Overstretching the vagina upward consistently worsened the urgency due to pressure on the bladder base stretch receptors “N” (Fig. 1). The cystometric patterns in these 20 patients fluctuated considerably with digital stretching, indicating a susceptible peripheral control mechanism. In 6 of the 20 patients, it was possible to demonstrate the temporary disappearance of the instability pattern. The hypothesized pathogenic rationale for the foregoing urodynamic observation was that digital support counteracted the activated micturition reflex (Fig. 1).
Shkarupa et al. [17] from the University of St Petersburg found that a roll of gauze placed in the posterior vaginal fornix was superior to the speculum test as a confirmative test for the relation to urgency and pain.
Wu et al. [9] assessed a woman using the Pictorial Algorithm; 2nd-degree uterovaginal prolapse was confirmed, with the symptoms suggesting USL laxity. Vaginal examination showed extreme tenderness in the suburethral area of the vagina immediately below the urethra. There was no hypersensitivity in the hymenal area on testing for vulvodynia. The gentle insertion of the posterior blade of a Cusco speculum into the posterior fornix relieved the tenderness. Repeating the test twice showed the same findings.
Local anaesthetic (LA) injection into the “VPs” (Fig. 1) (Bornstein test) [18] is the definitive test for VP causation of CPP. In 3 women who had BPS/IC and CPP in several sites pain relief occurred to various degrees, simultaneously in all locations for 20 minutes, after the LA Bornstein [15].
Surgical cure of CPP and urgency by USL repair has been described by many surgeons confirming cure of both urgency, CPP and other PFS symptoms [14-17, 19-26].
With reference to Fig. 1, when the quiescent afferent axons sited in VP are stimulated by gravity “G” or muscle movement, they send afferent impulses to the brain, which (wrongly) interprets them as pain from a wound and sends efferent impulses to the end-organ to heal it. Inflammatory cytokines are involved in nerve injury or inflammation-induced central sensitization and develop hyperalgesia/allodynia [27]. Specific cytokines in the spinal cord, dorsal root ganglion (DRG), or injured nerves generate abnormal spontaneous activity from injured nerve fibres or compressed/inflamed DRG neurons [27]. Patients with primary vestibular pain syndrome have a neurogenic plasticity with significantly increased nerve fibres and mast cell counts in the vestibular area [28]. The urothelium in PBPS shows sensory hyperinnervation and increased mast cells and other inflammatory cells [29]. Because the urothelium is much thinner than the vulvar wall, the inflammatory reaction may erode the urothelium to cause a Hunner lesion. Hunner’s lesions occur mainly in older patients between 53 to 65 years of age and represent less than 7% of BPS/IC patients [30]. The prevalence of HL is disparate, ranging from 3.5% to 56% [4]. HL, also present at an older age compared to non-Hunner-PBPS, are associated with a smaller bladder capacity and represent 5%–57% [31]. HL patients are clinically and pathologically distinct from non-HL PBPS patients [3, 4]. A HL is determined with cystoscopy as a local inflammatory reaction and disrupted urothelium or urothelial denudation [4, 32]. A reddened mucosal area with small vessels radiating towards a central scar, splitting at distension, is visualized and usually associated with a waterfall bleeding under hydrodistension, as seen in glomerulations [31]. Biopsies from the inflamed area show inflammatory infiltrates, granulation tissue, detrusor mastocytosis, and fibrin deposits [31, 33, 34].
We hypothesize that sustained traction on the VP results in continuous neuroinflammatory reactions, and the lesion converts in time to collagen 3, and then collagen 1 [35], to form endstage fibrosis.
There is substantial doubt that mast cells are relevant for PBPS and HL as there has not been a significant between the number of mast cells and the clinical symptoms and lesions [6, 36].
BPS/IC symptomatology combined with a PFS might occur with or without a HL, although the mechanism of origin of HL remains unclear.
In 2021, Scheffler et al. [37] reported the first histologically-validated cure of nonulcerating HL PBPS in a 73-year-old patient with CPP, urgency and POP. She was treated according to the PFS protocol [38] of the 1993 Integral Theory [35]. Based on the positive result in this one case, Scheffler hypothesized that PBPS could perhaps be part of the PFS [38]. The PFS was first described as part of the 2nd iteration of the Integral Theory [35]. The PFS (rectangle, Fig. 2) summarizes the symptoms of CPP and bladder dysfunction which constitute the PFS [38], which was the indication for surgery by USL repair for both the Scheffler et al. [37] and the study of Goeschen et al. [13].
In 1697, the Dutch explorer Willem de Vlamingh noted black swans living in the estuary of the Swan River, Perth Western Australia. Until that time, all swans were considered white. Like the black swan story, following histologically-validated cure of Hunner BPS/IC by following USL repair, the science of BPS/IC would never be the same again. Such a validated discovery cannot be discounted because it is a single case. It could no longer be said that Hunner’s BPS/IC had unknown pathogenesis and was not curable. Even if it was one case in a million, one HU BPS/IC Scheffler case was cured. The question now is, how many women with HL BPS/IC also have PFS?
Goeschen et al. [13] set out to test the Scheffler hypothesis [37]. Excluding SUI (66 cases), they retrospectively studied clinical data from 198 women who had presented with CPP, and 313 other bladder dysfunction symptoms [13]. The women were treated with a posterior IVS sling (intravaginal slingplasty) [13], which repaired the USLs using a collagen-producing tape. Goeschen et al. [13] applied the same PFS diagnostic and treatment protocol as Scheffler [37] (Fig. 1). Both pain and several bladder symptoms were variously cured by the USL sling in their study (Fig. 2). There were no HL found.
In study of Goeschen et al. [13], all participants had a POP at different stages, which contradicts the guidelines of the ICS defining CPPPS [1]. CPPPS is a symptomatic diagnosis determined by excluding pathology and confusable disease. POP-associated chronic pain, with or without LUTS, results from pathology (e.g., ligament injury or weakness). So, the diagnosis must exclude POP in patients with CPPPS, and determining the gradation of the POP is essential. Laxity of the USLs which causes pain can be detected manually by palpating the cervix (which replicates the pain) or by using a speculum blade to support the posterior fornix, which decreases the pain and urinary urgency during the test. The PFS states that patients with PBPS have pain and LUTS due to a damaged suspension mechanism, but with different anatomical pathways (Fig. 1). Must PBPS and overactive bladder (OAB) be classified as complications from inside or outside the organ? Cystoscopic signs inside the bladder (glomerulations, HL) can provoke LUTS and pain in a specific area. However, are these Hunner signs primary, or secondary to outside structural causes as hypothesized by Scheffler et al. [37]. Another “outside cause,” disturbed neurogenic causes, such as nerve injury and the accompanying inflammatory reactions, might also provoke these signs.
Other origins for CPP or LUTS outside the bladder are endometriosis, nerve entrapments of the lumbosacral plexus, referred pain, and central or cross-sensitization [39-50]. However, these causes are unlikely to have a positive speculum test (Fig. 1). The PFS may be essential in understanding the consequences of traction on the VP, explaining symptoms such as CPPPS, OAB, LUTS, PBPS, defecation problems and genitourinary pain.
The studies of Scheffler and Goeschen suggested new causative factors for the pathogenesis with other potential treatment modalities of PBPS conditions well beyond previous concepts and treatments concentrated on the urothelium [13, 37]. The question raised after Scheffler’s report of Hunner lesion BPS/IC cure remained, “How widespread is PFS in BPS/IC women?”
These studies led to several research questions and discussions between the authors of this paper.
(1) Do HL BPS and non-HL BPS which have classic PFS symptoms [13, 37] have a common origin? If so, what tools could be used to assess this? What would these tools look for – evidence of inflammatory reaction, origins of the urgency, or both–? The origins of urgency are rarely mentioned in previous writings on BPS/IC. Regauer et al. [29] found evidence of sensory hyperinnervation in almost all PBPS patients with HL and without, and in 30% (4 of 13) of patients with OAB and no pain. Is 4 of 13 sufficient to say there is a common histologically relevant origin? If so, what tools could be used to assess this? Ueda et al. [3] recently applied artificial intelligence methods to develop the machine-learning algorithm to detect HL using large-scale unannotated medical images of the bladder mucosa obtained under conventional white light imaging 90% or narrow-band imaging 67%. It seems possible that the same machine learning could be applied to search and quantify specific inflammatory cells, such as leukocytes, macrophages, mast cells, etc.
It has been demonstrated that pain and urgency co-occur and are cured or improved variously, but not always simultaneously, by USL repair [13-17, 19-26, 37] (Fig. 2). Based on this, one could assume that pain and urgency have a common cause, USL laxity, but have very different pathways corresponding with the dorsal column or spinothalamic pathways [51, 52]. Liedl et al. found that urgency (84%), frequency (82%), nocturia (70%), and CPP (78%) had differentincidences (Fig. 2) and different cure rates. Petros et al. [25] and Goeschen et al. [13] also found significantly different incidences of pain and urgency symptoms and different cure rates. With both studies [13, 25], there was equivalent incidence and cure rate for pain and the various bladder dysfunction symptoms, whether the prolapse was minimal (1st or 2nd degree) or major (3rd and 4th degree) [13, 25].
(2) If, as hypothesized in Fig. 1, “bunched” unsupported visceral nerves” are the cause for CPP, it could be predicted that the pain element of PBPS would co-occur in other sites, for example, the vulva (vulvodynia) lower abdomen, paraurethral area. Pain in these multiple sites was reported and cured by Petros with USL plication [53], by Wu et al. [9], relieved by a speculum test and in 3 BPS/IC women after the Bornstein Test which injected LA into the USLs [54].
(3) Inserting a large tampon into the apex overnight to support it shows a statistically validated relief of urge and nocturia [55]. Nocturia and other symptoms, such as urgency, abnormal emptying, and CPP associated with the posterior fornix, can be improved by surgery. Four different surgical operations suspend the vaginal USL plication, infra-coccygeal sacropexy sling, posterior tissue fixation system sling, and abdominal sacrocolpopexy showed can be cured or improved in up to 86% [55]. The improved symptoms after placing a vaginal tampon or pessary ring in the posterior fornix and the impressive pain relief after uterosacral suspension done vaginally or laparoscopically suggest that the PFS and the Allen-Masters Syndrome are synonyms and caused by posterior fornix ligamentous laxity (USL) [56]. A study showed that the pessary improves many of the associated symptoms of POP and is an effective treatment option for managing POP. It is well-accepted and rapidly adequate, and its effects seem to last over time [57]. The posterior intravaginal slingplasty showed satisfactory long-term results for vault and posterior compartment prolapse, with a 75%–90% improvement in vault prolapse [58].
With reference to Fig. 2, which distils the evidence we have presented into a single diagram, our concluding hypothesis is that, at least in some women, a lax USL itself may well be the major pathogenic factor not only for anatomical uterine/apical prolapse, enterocele, but chronic pain [53] several bladder dysfunctions [35], and also, bowel faecal incontinence, obstructed defecation syndrome, anterior rectal wall intussusception [59]. Viewed in this way, non-Hunner BPS/IC and PFS itself, may both be manifestations (“phenotypes”) of USL laxity.
In accordance with the UEDA criteria, and our own view, the prime research objective now is to determine the proportion of interstitial cystitis/bladder pain syndrome women fitting the proposed USL pathogenesis (PFS), as such women are potentially curable. If the number is significant, PFS pathogenesis opens a new research pathway for researching appropriate surgical/nonsurgical methodology which can relieve or cure PBPS.
In parallel with such testing, a rigorous examination of chronic pelvic pain (CPPPS) and interstitial cystitis/bladder pain syndrome (PBPS) definitions is required as a priority. Definitions are a major influence, indeed, a control, of clinical treatment, and especially, research. Existing definitions [1] are strangely in denial of USL-based CPP cure which has been in the English literature since 1996 [53], and in the German literature since 1938 [60]. Changing names of conditions to (CPPPS and PBPS) as has been done recently, does not alter the facts, and only creates further confusion. Once USL-based pathogenesis of CPP and interstitial cystitis/bladder pain syndrome have a more solid grounding, more relevant definitions and clinical guidelines can be made.