Journal of Psychosomatic Research 77 (2014) 510–515
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Journal of Psychosomatic Research
Bladder pain syndrome/interstitial cystitis as a functional somatic syndrome John W. Warren Department of Medicine, University of Maryland School of Medicine, 10 South Pine Street, #900, Baltimore, MD 21201, United States Department of Epidemiology and Public Health, University of Maryland School of Medicine, United States
a r t i c l e
i n f o
Article history: Received 12 June 2014 Received in revised form 19 August 2014 Accepted 2 October 2014 Keywords: Bladder pain syndrome Interstitial cystitis Functional somatic syndromes Chronic fatigue syndrome Fibromyalgia Irritable bowel syndrome
a b s t r a c t Purpose: To determine whether bladder pain syndrome/interstitial cystitis (BPS/IC) has the characteristics of a functional somatic syndrome (FSS). Materials and methods: There is no accepted definition of an FSS. Consequently, this paper reviewed the literature for common FSS characteristics and for reports that BPS/IC has these characteristics. Results: Eleven articles met inclusion and exclusion criteria and yielded 18 FSS characteristics. BPS/IC patients manifest all but two: the exceptions were normal light microscopic anatomy (after hydrodistention under anesthesia, some BPS/IC bladders have Hunner's lesions and most have petechial hemorrhages) and normal laboratory tests (many BPS/IC patients have hematuria). Petechial hemorrhages and hematuria are probably related and may appear during naturally-occurring bladder distention. Without such distention, then, the 90% of BPS/IC patients without a Hunner's lesion have all the characteristics of an FSS. Comparisons in the opposite direction were consistent: several additional features of BPS/IC were found in FSSs. Conclusions: This systematic but untested method is consistent with but does not test the hypothesis that BPS/IC in some patients might best be understood as an FSS. Like most conditions, BPS/IC is probably heterogeneous; hence only a proportion of BPS/IC cases are likely to be manifestations of an FSS. This hypothesis has several implications. Explorations of processes that connect the FSSs might contribute to understanding the pathogenesis of BPS/IC. Patients with FSSs are at risk for BPS/IC and may benefit from future preventive strategies. Therapies that are useful in FSSs also may be useful in some cases of BPS/IC. © 2014 Elsevier Inc. All rights reserved.
Introduction BPS/IC is a chronic disorder defined by pain perceived to be from the bladder plus the urinary symptoms of urgency, frequency and nocturia [1]. The condition was first described in the nineteenth century and came to be characterized by the presence of red, bleeding areas on the bladder wall, known as Hunner's lesions. Since then, BPS/IC has evolved to a diagnosis of symptoms, primarily pain which in the great majority of patients changes with bladder filling and emptying; most such patients do not have a Hunner's lesion. The prevalence of BPS/IC in the United States is 3–6% of women and 2–4% of men [2,3]. Since the recognition of BPS/IC, investigations of its pathogenesis have focused on the bladder. Candidate etiologies have included infections, autoimmunity, other inflammatory processes, mucosal abnormalities, urinary toxins, and local neuronal dysfunction. None have persuasively explained the syndrome and the lack of understanding of its pathogenesis has led to empiric and often inadequate therapies.
E-mail address: [email protected].
http://dx.doi.org/10.1016/j.jpsychores.2014.10.003 0022-3999/© 2014 Elsevier Inc. All rights reserved.
Recent studies have shown that significantly more BPS/IC patients than controls have other syndromes with symptoms well beyond the bladder, often numerous such conditions [4–9]. These non-bladder disorders include chronic fatigue syndrome (CFS), fibromyalgia (FM), irritable bowel syndrome (IBS), temporomandibular joint disorder (TMD), chronic pelvic pain (CPP), vulvodynia, migraine, low back pain, sicca syndrome, allergies, asthma, depression, and anxiety. Several of these are functional somatic syndromes (FSSs), the most venerable of which are CFS, FM, and IBS. Peter D. White, an expert on FSSs, recently remarked: “Probably the most replicated risk marker for an FSS is that having one is strongly associated with having another …” [10]. The fact that BPS/IC is associated with FSSs, then, generates the hypothesis that it too is an FSS. If so, then findings of mechanism(s), treatments and prevention of FSSs might be applicable to BPS/IC. Testing the hypothesis that BPS/IC is an FSS is difficult, however, because there is as yet no pathophysiologic definition of an FSS nor even consensus as to which disorders are FSSs. Given this uncertainty, this paper outlines two available published features pertinent to the diagnosis of an FSS: 1) characteristics said to be common to FSSs and 2) statements that appear to define an FSS. It then assesses published knowledge of BPS/IC to determine whether this syndrome has these characteristics or meets these definitions.
J.W. Warren / Journal of Psychosomatic Research 77 (2014) 510–515
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Female predominance
Materials and methods PubMed was used for two searches of the MEDLINE database of the National Library of Medicine, for reviews and editorials on 1) functional somatic syndromes, and then 2) chronic fatigue syndrome AND fibromyalgia AND irritable bowel syndrome. The combined results were reviewed for articles that met the following inclusion and exclusion criteria. An article was included if it referenced all of the classic FSSs, i.e., CFS, FM, and IBS, and commented upon two or more characteristics considered by the authors to be common to the FSSs. Excluded articles were those that discussed symptoms but not syndromes (e.g., somatoform disorders), that primarily addressed more controversial or contested syndromes (e.g., chronic candidiasis or multiple chemical sensitivity) [11,12], or that mainly reviewed mechanisms or management. From each accepted article, two types of items were extracted: 1) characteristics stated by the authors as common to FSSs, and 2) if present, any statement that could be construed as a definition of an FSS. The first group, i.e., attributes said to be shared by FSSs, was then used to develop literature searches for studies of BPS/IC patients; those comparing BPS/IC patients to controls were preferentially reviewed. All searches were limited to studies of humans and in the English language.
In urology practices, most BPS/IC patients have been women [23]. Recent populationbased studies suggest that about 60% of BPS/IC cases are female [2,3]. Given that some men diagnosed with BPS/IC also meet criteria for chronic prostatitis/chronic pelvic pain syndrome [3,24], the actual proportion of BPS/IC cases that are female might be higher. Precipitating event In some patients, an acute event appears to precipitate an FSS. Minorities of patients report physical trauma before FM and bacterial gastroenteritis before IBS, and several acute infections precede CFS onsets. Similarly, at the first medical encounter following the appearance of BPS/IC, 18%–36% of women had laboratory or clinical evidence of a urinary tract infection [25]. Pain The pain of BPS/IC has been well described [26] and is a necessary component of its definition [1]. Fatigue Clauw et al. found that 77% of female BPS/IC patients reported “fatigue” vs. 13% of control women of similar ages [4]. Overlap of defining symptoms of FSSs
Results The literature searches yielded 157 reviews or editorials that discussed functional somatic syndromes and 71 that mentioned all of CFS, FM, and IBS. Of these, eleven articles met inclusion but not exclusion criteria and are listed by publication date in Table 1 [10,13–22]. Each of these referenced CFS, FM, and IBS, an inclusion criterion. The first, by Wessely et al. also listed the following conditions as FSSs: tension headache, TMD, atypical facial pain, atypical chest pain, hyperventilation syndrome, non-ulcer dyspepsia, globus syndrome, premenstrual syndrome, CPP, and multiple chemical sensitivity [13]. Subsequent articles [14,15,17,19–21] added others that those authors considered to be FSSs: insomnia, post-concussion syndrome, tinnitus, dizziness, pseudoseizures, neck pain, chronic whiplash, repetitive strain injury, low back pain, palpitations, mitral valve prolapse, vulvodynia, hypoglycemia, sick building syndrome, chronic Lyme disease, silicone breast implant effects, candidiasis hypersensitivity, food allergy, and Gulf War syndrome. Interestingly, several listed BPS/IC as an FSS [14,15,20,21].
Although this was introduced by Wessely et al. in their seminal article, each such symptom mentioned (abdominal pain, bloating, headache, and fatigue) overlapped ≤8 of the 13 listed syndromes [13]. Moreover, there is no overlap of the symptoms that define two classic FSSs, i.e., CFS [27] and IBS [28]. Hence, this FSS characteristic might not stand the test of time. Nevertheless, because Wessely et al. included abdominal pain as an “overlapping” symptom and the great majority of BPS/IC patients have lower abdominal, i.e., suprapubic, pain [26], BPS/IC appears to possess this characteristic. Co-morbidity with FSSs This is the characteristic that prompted this project. BPS/IC is associated with FSSs, as well as other conditions that are epidemiologically linked to FSSs: FM, CFS, IBS, temporomandibular disorder, CPP, migraine, depression, anxiety, low back pain, allergies, asthma, sicca syndrome, and vulvodynia [4–9].
Characteristics of functional somatic syndromes
Number of FSSs is a risk factor
Table 1 lists 18 characteristics of FSSs that were mentioned in at least one article, ranked as they might emerge during a patient work-up. Each characteristic is noted below, followed by findings from the literature search of that characteristic in BPS/IC patients.
Many BPS/IC patients have numerous FSSs [29]. Indeed, the greater the number of syndromes, the greater the odds of BPS/IC [9,29–32]. Two studies showed that the presence of multiple FSSs preceded and thus was a risk factor for BPS/IC [31,32]. The number of FSSs is by far the most powerful risk factor yet identified for BPS/IC [33].
Table 1 Characteristics stated or implied to be common to functional somatic syndromes (FSSs) in articles meeting inclusion and exclusion criteria Author
Wessely
Aaron
Katon
Sharpe
Mayou
Henningsen
Masuko
Henningsen
Goldenberg
White
Harvey
Year
1999
2001
2001
2001
2002
2003
2007
2007
2010
2013
2013
Reference
[13]
[14]
[15]
[16]
[17]
[18]
[19]
[20]
[21]
[10]
[22]
√ √ √ √ √ √
√
√
√
√
√ √
√
√ √
√ √ √ √
√ √
BPS/IC
Characteristic Female Precipitating event Pain Fatigue FSS symptom overlap FSS co-morbidity No. FSSs = risk factor Non-FSS symptoms Depression Anxiety Adverse experience Familial Normal laboratory Normal pathology Chronic Diagnosis of exclusion Worsened by stress Disability
√
√ √
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√ √ √ √ √
√
√ √ √ √
√ √ √
√
√ √
√ √
√ √
√ √
√ √
√ √ √
√ √
√ √
√ √
√ √
√
√ √
√ √
√ √
√ √
√ √
√
√ √ √ √
√ √ √ √
√ √
√ √ √ √
√ √
√
√ √ √ √ √ √ √ √ √ √ √ √ ± ± √ √ √ √
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Presence of other, non-FSS symptoms
Disability
Several studies have reported that more BPS/IC cases than controls report nonbladder symptoms that are not in the definitions of FSSs. Clauw et al. reported numbness, dizziness, dry eyes, dry mouth, fingers sensitive to cold, and problems with balance [4]. Chelimsky et al. found significantly more BPS/IC cases than controls reported syncope and sleep abnormalities [34].
Compared to controls, BPS/IC cases report poorer quality of life, and are less likely to be working full time. BPS/IC patients noted less life satisfaction than patients with end stage renal disease [47]. FSS definitions
History of adverse experiences
Several of these reviews had a statement that could be interpreted as a definition of an FSS: physical symptoms “… that, after appropriate medical assessment, cannot be explained in terms of a conventionally defined medical disease”[13,19]; “… appearing in patients who do not have proportional tissue abnormalities”[15]; “… (without) pathologically defined changes in tissue that designate medical conditions …”[16]; “… for which adequate examination does not reveal sufficiently explanatory structural or other specified pathology” [20]; “… that cannot be explained by organ pathology and currently lack definitive diagnostic tests” [21]; and “… for which medicine cannot find presently a convincing explanation” [10]. It appears that many BPS/IC patients would not meet several of these definitions, or descriptions, of FSSs because of abnormal anatomic pathology (Hunner's lesions and glomerulations) or laboratory tests (hematuria).
Significantly more BPS/IC patients than controls report a history of physical, emotional, and/or sexual abuse [6,35].
Discussion
Depression Compared to controls, significantly more BPS/IC patients have depression [5,7].
Anxiety These studies also assessed anxiety disorders and observed significantly more BPS/IC cases than controls with these diagnoses [5,7].
Familial A demonstration that a disorder is clustered in families is generally the first step in identifying a genetic contribution. Family and twin studies [36–38] of BPS/IC have shown such clustering. The largest and best designed, the Swedish Twin Study, albeit of young participants, suggests that in women about 30% of the susceptibility to BPS/IC is genetic [38].
Normal laboratory tests BPS/IC cases have not been reported to have abnormalities in blood counts, electrolytes, or renal and liver function. However, some BPS/IC patients have microscopic hematuria. A chart review indicated that 60/148 (41%) BPS/IC patients had at least one urinalysis demonstrating hematuria over a mean of 18 months [39]. Hence, a proportion of BPS/IC patients do not have this characteristic of the FSSs.
Normal light microscopic anatomy Visible findings at cystoscopy with hydrodistention under anesthesia suggest that the majority of BPS/IC patients do not manifest this characteristic either. The Interstitial Cystitis Database (ICDB) showed that about 10% of North American patients had Hunner's lesions and about 90% petechial hemorrhages, called glomerulations [23]. However, histopathology tells a different story. In a landmark study of 108 BPS/IC patients, Johansson and Fall showed that abnormal pathology indeed accompanied Hunner's lesions: mucosal hemorrhages, marked mononuclear inflammation, elevated mast cell counts, granulation tissue, and perineural infiltrates. However, they noted that nonHunner's bladders had few pathologic findings except for mucosal hemorrhages, often with mucosal ruptures and thought to be glomerulations from the preceding hydrodistentions [40]. The ICDB used cluster analysis of histopathologic findings in 203 BPS/IC patients and defined three subgroups: 3% had denuded epithelium, lymphoid infiltrate, mastocytosis, granulation tissue, edema, and small nerve proliferation; 8% had isolated denuded epithelium; and fully 88% had none of these pathologic features [41]. These two large studies show that about 90% of BPS/IC patients, generally those without Hunner's lesions, have what Johansson and Fall described as “remarkably meager” histopathological findings. Chronic Longitudinal studies of BPS/IC confirm the clinical impression that BPS/IC in most patients persists for years [42,43].
Diagnosis of exclusion
Of the 18 identified FSS characteristics, BPS/IC patients manifest all but two. The exceptions were that many BPS/IC patients do not have normal light microscopic anatomy and/or normal laboratory tests. Two types of abnormal pathology are found in most BPS/IC patients: 1) a Hunner's lesion with accompanying inflammation, and/or 2) glomerulations, with scant inflammation. The abnormal laboratory test is hematuria. These findings also would preclude most BPS/IC patients from meeting many of the definitions of an FSS. However, close inspection of these exceptions is revealing. Firstly, the 10% of BPS/IC cases that have a Hunner's lesion might have a different disease. Not only do they have more bladder histopathology [40], but also they have a smaller bladder capacity and are significantly older [48] than other BPS/IC patients. And very pertinent to this discussion, patients with Hunner's lesions are less likely than those without to have fibromyalgia, migraine, temporomandibular joint dysfunction, and depression [48]. Of the remaining exceptions, glomerulations and hematuria are probably related. Glomerulations appear during hydrodistention and their numbers are directly associated with the appearance of bloody effluent [49]. Glomerulations and bloody effluent are each inversely correlated with bladder capacity [49], yet scattergrams constructed from patient diaries show maximal voided volumes often exceed the volume at which pain occurs, sometimes by a multiple of 2 or 3 [Fig. 4 in [50]]. In aggregate, these observations suggest that over-distention of a chronically small bladder with consequent glomerulations and hematuria likely occur during the normal day in many BPS/IC patients. Additionally thousands of cystoscopies have not revealed another cause of hematuria in BPS/IC patients without a Hunner's lesion. This reasoning suggests that in the absence of bladder distention, there is no light microscopic pathology or abnormal laboratory tests in non-Hunner's BPS/IC patients. If this reasoning is correct, then 90% of BPS/IC patients have all the characteristics and meet all the proffered definitions of an FSS. Other BPS/IC characteristics found in FSSs
The first generally accepted definition of BPS/IC listed a dozen other diseases that would exclude the diagnosis [44]. The more recent American Urological Association definition merely states “… in the absence of infection or other identifiable causes” [1].
BPS/IC as an FSS predicts positive comparisons in the opposite direction, i.e., additional characteristics of BPS/IC would be found in the FSSs. BPS/IC has a number of other features, described below and followed by findings in the best studied FSSs, i.e., FM, CFS and IBS.
Worsened by stress
BPS/IC has a prodrome
Of BPS/IC patients, 60% report that stress exacerbated their symptoms and those with the most stress had quantitatively worse pain and urgency [45]. An experimental study of BPS/IC patients showed that acute mental stress elicited transient increases in pain and urgency [46].
For a median of 22 years before onset of BPS/IC, more cases than controls had urinary symptoms that appeared not to meet the definition of BPS/IC [51]. Studies of CFS, FM, and IBS also have revealed apparently
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relevant symptoms years before onset of the syndrome. A large medical database revealed that more CFS patients than controls had prior visits for lethargy and other symptoms over the 15 years before diagnosis of CFS [52]. A prospective study over 4 years showed that baseline regional pain was a risk factor for FM [53]. Another prospective study over 12 years demonstrated that abdominal pain was a risk factor for IBS [54]. Bladder filling exacerbates BPS/IC This is one of the features of BPS/IC that causes the patient to describe the bladder as the source of pain [55] and is described by a large majority of BPS/IC patients [26]. IBS is the only classic FSS in which a luminal organ is central. In a landmark study, Ritchie showed that IBS patients felt pain at smaller volumes of balloons inflated in the colon than controls [56]. BPS/IC is associated with surgical operations Patients with BPS/IC had more non-bladder surgeries than controls; the number of FSSs correlated with the number of operations [57]. Similarly, patients with FM [58] and with IBS [59], syndromes that are not indications for surgery, had more operations than controls, and in IBS multiple FSSs were associated with multiple procedures [59]. BPS/IC prognosis is predicted by severity and FSSs at baseline At onset of BPS/IC, its severity and the presence of FSSs predicted its poor prognosis [60]. For CFS, FM and IBS, baseline severity plus symptoms and pain elsewhere have been shown to be prognostic factors [61,62]. BPS/IC is heterogeneous Many investigators have compared those with Hunner's lesions to those without [40,48]. Related work has examined differences in histopathology [41]. Other investigators have used clinical presentations to distinguish BPS/IC subgroups [63]. Regarding FSSs, a variety of methods have used symptoms, signs, laboratory tests, and physiologic findings to show heterogeneity in each of CFS, FM and IBS [[64–66] and reviewed in [67]]. A useful approach? Accumulating experts' opinions of FSS characteristics and showing that BPS/IC has these features is a tedious and untested process for concluding that BPS/IC is an FSS. In a general way, one can estimate the sensitivity and specificity of this method by its ability to capture other FSSs and exclude non-FSSs. A perusal of the list of disorders noted as FSSs by these experts (first paragraph of Results) suggests that most of these conditions have most of these characteristics. But what about diseases that are clearly not FSSs? As measured by the World Health Organization, the top ten disabling disorders In the United States are ischemic heart disease, chronic obstructive pulmonary disease, low back pain, respiratory cancer, depression, other musculoskeletal disorders, stroke, diabetes mellitus, road-traffic injury, and drug-use disorders [68]. Three of these have already been noted as possible FSSs in some patients (low back pain and “other musculoskeletal disorders”) or as epidemiologically associated with the FSSs (depression). The other seven indeed have some characteristics of FSSs: they were chosen as chronic, disabling diseases, many are familial and accompanied by fatigue, some by pain, and a few are precipitated by an acute event. However, most are not epidemiologically linked to FSSs (although FM can follow automobile accidents) nor are numerous FSSs a risk factor (except possibly drug-use disorders). None are predominantly in women. And most importantly (with the inconstant exception of drug use), all are accompanied by abnormal laboratory tests and/or pathology.
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Not every feature of BPS/IC should be expected to be found in FSSs, just as every characteristic of, say, IBS, is manifest by other FSSs. This is of course because each syndrome has been distinguished clinically as a result of certain symptoms that differentiate it from other disorders. And it is likely that not all cases of BPS/IC are an FSS. As noted, BPS/IC is probably heterogeneous, which means among other things that it might have several pathogeneses. BPS/IC with the pathogenesis of an FSS would be more likely in patients with numerous FSSs [32]. And it might be more likely in the 90% without Hunner's lesions or in the 10% who have neither Hunner's lesions nor glomerulations [49]. This paper does not itself test the hypothesis that BPS/IC is an FSS but it is a useful exercise because it reveals research and clinical possibilities that can be explored even while the pathogeneses of FSSs and BPS/IC are being pursued. Regarding research, there are only two ways that one syndrome can be significantly associated with another: either the first syndrome initiates a process that leads to the second, or an underlying process leads to both. Therefore, explorations of the processes that connect FSSs could expose a pathogenesis of BPS/IC. Candidate processes found in patients with FSSs include pain amplification, abnormalities in the hypothalamus–pituitary–adrenal axis, and dysfunctions of the autonomic nervous system [69]. Indeed, some of these pathophysiologies have been identified in BPS/IC patients [34,70,71]. The possibility that in some patients, BPS/IC might best be understood as an FSS has clinical implications as well. Therapies that are successful among FSSs [20,72,73] might be applicable to BPS/IC. Patients with FSSs, particularly those with many syndromes, comprise a high risk group for BPS/IC [31,32]; as the process(es) that lead to BPS/IC are revealed, this group might benefit from as yet unknown preventive techniques. This investigation has several weaknesses. Foremost is that there is no precedent for this methodology. But neither has there been suggested a better approach to classify a disorder as an FSS. To date the identification of a syndrome as an FSS has been the prerogative of the authors of a given article. It is interesting to note that some authors of the identified articles have already listed BPS/IC as an FSS [14,15,20, 21]. The most persuasive classification technique almost certainly will require an understanding of the pathogenesis(es) of the FSSs. Another limitation of this study is the use of only one database, restriction to English, and the absence of informal searches. A third is that the list of FSS characteristics does not attempt to rank them in importance. The presence of normal anatomy and laboratory tests are arguably the most critical characteristics of FSSs; were these findings abnormal, another disease would be diagnosed. Finally, the discussion of glomerulations and hematuria during the routine day of a BPS/IC patient, although consistent with extant data, is primarily an exercise in common sense. There are strengths. The most important was that the study was a systematic, unbiased approach to identifying characteristics of FSSs as expressed by experts in this group of syndromes. The review focused on those most widely accepted as FSSs, i.e., CFS, FM and IBS, rather than on more contested syndromes such as multiple chemical sensitivity. A third was its face value: clinicians skilled in FSSs would recognize this list as reflecting features of these syndromes in their patients. Finally, BPS/IC as an FSS had predictive utility: several additional features of BPS/IC were found to be present in the most widely recognized FSSs, i.e., CFS, FM and IBS. Conflict of interest The author has no competing interests to report. References [1] Hanno PM, Burks DA, Clemens JQ, Dmochowski RR, Erickson D, Fitzgerald MP, et al. AUA guideline for the diagnosis and treatment of interstitial cystitis/bladder pain syndrome. J Urol Jun 2011;185:2162–70. [2] Berry SH, Elliott MN, Suttorp M, Bogart LM, Stoto MA, Eggers P, et al. Prevalence of symptoms of bladder pain syndrome/interstitial cystitis among adult females in the United States. J Urol Aug 2011;186:540–4.
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Role of road traffic accidents and other traumatic events in the onset of chronic widespread pain: results from a population-based prospective study. Arthritis Care Res (Hoboken) May 2011;63:696–701. [54] Halder SL, Locke III GR, Schleck CD, Zinsmeister AR, Melton III LJ, Talley NJ. Natural history of functional gastrointestinal disorders: a 12-year longitudinal populationbased study. Gastroenterology Sep 2007;133:799–807. [55] Warren JW, Diggs C, Horne L, Greenberg P. Interstitial cystitis/painful bladder syndrome: what do patients mean by “perceived” bladder pain? Urology Feb 2011; 77:309–12. [56] Ritchie J. Pain from distension of the pelvic colon by inflating a balloon in the irritable colon syndrome. Gut Feb 1973;14:125–32. [57] Warren JW, Morozov V, Howard FM, Wesselmann U, Gallicchio L, Langenberg P, et al. Before the onset of interstitial cystitis/bladder pain syndrome, the presence of multiple non-bladder syndromes is strongly associated with a history of multiple surgeries. 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Contents lists available at ScienceDirect
Journal of Psychosomatic Research
Bladder pain syndrome/interstitial cystitis as a functional somatic syndrome John W. Warren Department of Medicine, University of Maryland School of Medicine, 10 South Pine Street, #900, Baltimore, MD 21201, United States Department of Epidemiology and Public Health, University of Maryland School of Medicine, United States
a r t i c l e
i n f o
Article history: Received 12 June 2014 Received in revised form 19 August 2014 Accepted 2 October 2014 Keywords: Bladder pain syndrome Interstitial cystitis Functional somatic syndromes Chronic fatigue syndrome Fibromyalgia Irritable bowel syndrome
a b s t r a c t Purpose: To determine whether bladder pain syndrome/interstitial cystitis (BPS/IC) has the characteristics of a functional somatic syndrome (FSS). Materials and methods: There is no accepted definition of an FSS. Consequently, this paper reviewed the literature for common FSS characteristics and for reports that BPS/IC has these characteristics. Results: Eleven articles met inclusion and exclusion criteria and yielded 18 FSS characteristics. BPS/IC patients manifest all but two: the exceptions were normal light microscopic anatomy (after hydrodistention under anesthesia, some BPS/IC bladders have Hunner's lesions and most have petechial hemorrhages) and normal laboratory tests (many BPS/IC patients have hematuria). Petechial hemorrhages and hematuria are probably related and may appear during naturally-occurring bladder distention. Without such distention, then, the 90% of BPS/IC patients without a Hunner's lesion have all the characteristics of an FSS. Comparisons in the opposite direction were consistent: several additional features of BPS/IC were found in FSSs. Conclusions: This systematic but untested method is consistent with but does not test the hypothesis that BPS/IC in some patients might best be understood as an FSS. Like most conditions, BPS/IC is probably heterogeneous; hence only a proportion of BPS/IC cases are likely to be manifestations of an FSS. This hypothesis has several implications. Explorations of processes that connect the FSSs might contribute to understanding the pathogenesis of BPS/IC. Patients with FSSs are at risk for BPS/IC and may benefit from future preventive strategies. Therapies that are useful in FSSs also may be useful in some cases of BPS/IC. © 2014 Elsevier Inc. All rights reserved.
Introduction BPS/IC is a chronic disorder defined by pain perceived to be from the bladder plus the urinary symptoms of urgency, frequency and nocturia [1]. The condition was first described in the nineteenth century and came to be characterized by the presence of red, bleeding areas on the bladder wall, known as Hunner's lesions. Since then, BPS/IC has evolved to a diagnosis of symptoms, primarily pain which in the great majority of patients changes with bladder filling and emptying; most such patients do not have a Hunner's lesion. The prevalence of BPS/IC in the United States is 3–6% of women and 2–4% of men [2,3]. Since the recognition of BPS/IC, investigations of its pathogenesis have focused on the bladder. Candidate etiologies have included infections, autoimmunity, other inflammatory processes, mucosal abnormalities, urinary toxins, and local neuronal dysfunction. None have persuasively explained the syndrome and the lack of understanding of its pathogenesis has led to empiric and often inadequate therapies.
E-mail address: [email protected].
http://dx.doi.org/10.1016/j.jpsychores.2014.10.003 0022-3999/© 2014 Elsevier Inc. All rights reserved.
Recent studies have shown that significantly more BPS/IC patients than controls have other syndromes with symptoms well beyond the bladder, often numerous such conditions [4–9]. These non-bladder disorders include chronic fatigue syndrome (CFS), fibromyalgia (FM), irritable bowel syndrome (IBS), temporomandibular joint disorder (TMD), chronic pelvic pain (CPP), vulvodynia, migraine, low back pain, sicca syndrome, allergies, asthma, depression, and anxiety. Several of these are functional somatic syndromes (FSSs), the most venerable of which are CFS, FM, and IBS. Peter D. White, an expert on FSSs, recently remarked: “Probably the most replicated risk marker for an FSS is that having one is strongly associated with having another …” [10]. The fact that BPS/IC is associated with FSSs, then, generates the hypothesis that it too is an FSS. If so, then findings of mechanism(s), treatments and prevention of FSSs might be applicable to BPS/IC. Testing the hypothesis that BPS/IC is an FSS is difficult, however, because there is as yet no pathophysiologic definition of an FSS nor even consensus as to which disorders are FSSs. Given this uncertainty, this paper outlines two available published features pertinent to the diagnosis of an FSS: 1) characteristics said to be common to FSSs and 2) statements that appear to define an FSS. It then assesses published knowledge of BPS/IC to determine whether this syndrome has these characteristics or meets these definitions.
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Female predominance
Materials and methods PubMed was used for two searches of the MEDLINE database of the National Library of Medicine, for reviews and editorials on 1) functional somatic syndromes, and then 2) chronic fatigue syndrome AND fibromyalgia AND irritable bowel syndrome. The combined results were reviewed for articles that met the following inclusion and exclusion criteria. An article was included if it referenced all of the classic FSSs, i.e., CFS, FM, and IBS, and commented upon two or more characteristics considered by the authors to be common to the FSSs. Excluded articles were those that discussed symptoms but not syndromes (e.g., somatoform disorders), that primarily addressed more controversial or contested syndromes (e.g., chronic candidiasis or multiple chemical sensitivity) [11,12], or that mainly reviewed mechanisms or management. From each accepted article, two types of items were extracted: 1) characteristics stated by the authors as common to FSSs, and 2) if present, any statement that could be construed as a definition of an FSS. The first group, i.e., attributes said to be shared by FSSs, was then used to develop literature searches for studies of BPS/IC patients; those comparing BPS/IC patients to controls were preferentially reviewed. All searches were limited to studies of humans and in the English language.
In urology practices, most BPS/IC patients have been women [23]. Recent populationbased studies suggest that about 60% of BPS/IC cases are female [2,3]. Given that some men diagnosed with BPS/IC also meet criteria for chronic prostatitis/chronic pelvic pain syndrome [3,24], the actual proportion of BPS/IC cases that are female might be higher. Precipitating event In some patients, an acute event appears to precipitate an FSS. Minorities of patients report physical trauma before FM and bacterial gastroenteritis before IBS, and several acute infections precede CFS onsets. Similarly, at the first medical encounter following the appearance of BPS/IC, 18%–36% of women had laboratory or clinical evidence of a urinary tract infection [25]. Pain The pain of BPS/IC has been well described [26] and is a necessary component of its definition [1]. Fatigue Clauw et al. found that 77% of female BPS/IC patients reported “fatigue” vs. 13% of control women of similar ages [4]. Overlap of defining symptoms of FSSs
Results The literature searches yielded 157 reviews or editorials that discussed functional somatic syndromes and 71 that mentioned all of CFS, FM, and IBS. Of these, eleven articles met inclusion but not exclusion criteria and are listed by publication date in Table 1 [10,13–22]. Each of these referenced CFS, FM, and IBS, an inclusion criterion. The first, by Wessely et al. also listed the following conditions as FSSs: tension headache, TMD, atypical facial pain, atypical chest pain, hyperventilation syndrome, non-ulcer dyspepsia, globus syndrome, premenstrual syndrome, CPP, and multiple chemical sensitivity [13]. Subsequent articles [14,15,17,19–21] added others that those authors considered to be FSSs: insomnia, post-concussion syndrome, tinnitus, dizziness, pseudoseizures, neck pain, chronic whiplash, repetitive strain injury, low back pain, palpitations, mitral valve prolapse, vulvodynia, hypoglycemia, sick building syndrome, chronic Lyme disease, silicone breast implant effects, candidiasis hypersensitivity, food allergy, and Gulf War syndrome. Interestingly, several listed BPS/IC as an FSS [14,15,20,21].
Although this was introduced by Wessely et al. in their seminal article, each such symptom mentioned (abdominal pain, bloating, headache, and fatigue) overlapped ≤8 of the 13 listed syndromes [13]. Moreover, there is no overlap of the symptoms that define two classic FSSs, i.e., CFS [27] and IBS [28]. Hence, this FSS characteristic might not stand the test of time. Nevertheless, because Wessely et al. included abdominal pain as an “overlapping” symptom and the great majority of BPS/IC patients have lower abdominal, i.e., suprapubic, pain [26], BPS/IC appears to possess this characteristic. Co-morbidity with FSSs This is the characteristic that prompted this project. BPS/IC is associated with FSSs, as well as other conditions that are epidemiologically linked to FSSs: FM, CFS, IBS, temporomandibular disorder, CPP, migraine, depression, anxiety, low back pain, allergies, asthma, sicca syndrome, and vulvodynia [4–9].
Characteristics of functional somatic syndromes
Number of FSSs is a risk factor
Table 1 lists 18 characteristics of FSSs that were mentioned in at least one article, ranked as they might emerge during a patient work-up. Each characteristic is noted below, followed by findings from the literature search of that characteristic in BPS/IC patients.
Many BPS/IC patients have numerous FSSs [29]. Indeed, the greater the number of syndromes, the greater the odds of BPS/IC [9,29–32]. Two studies showed that the presence of multiple FSSs preceded and thus was a risk factor for BPS/IC [31,32]. The number of FSSs is by far the most powerful risk factor yet identified for BPS/IC [33].
Table 1 Characteristics stated or implied to be common to functional somatic syndromes (FSSs) in articles meeting inclusion and exclusion criteria Author
Wessely
Aaron
Katon
Sharpe
Mayou
Henningsen
Masuko
Henningsen
Goldenberg
White
Harvey
Year
1999
2001
2001
2001
2002
2003
2007
2007
2010
2013
2013
Reference
[13]
[14]
[15]
[16]
[17]
[18]
[19]
[20]
[21]
[10]
[22]
√ √ √ √ √ √
√
√
√
√
√ √
√
√ √
√ √ √ √
√ √
BPS/IC
Characteristic Female Precipitating event Pain Fatigue FSS symptom overlap FSS co-morbidity No. FSSs = risk factor Non-FSS symptoms Depression Anxiety Adverse experience Familial Normal laboratory Normal pathology Chronic Diagnosis of exclusion Worsened by stress Disability
√
√ √
√ √ √ √ √ √
√ √ √ √ √
√
√ √ √ √
√ √ √
√
√ √
√ √
√ √
√ √
√ √
√ √ √
√ √
√ √
√ √
√ √
√
√ √
√ √
√ √
√ √
√ √
√
√ √ √ √
√ √ √ √
√ √
√ √ √ √
√ √
√
√ √ √ √ √ √ √ √ √ √ √ √ ± ± √ √ √ √
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Presence of other, non-FSS symptoms
Disability
Several studies have reported that more BPS/IC cases than controls report nonbladder symptoms that are not in the definitions of FSSs. Clauw et al. reported numbness, dizziness, dry eyes, dry mouth, fingers sensitive to cold, and problems with balance [4]. Chelimsky et al. found significantly more BPS/IC cases than controls reported syncope and sleep abnormalities [34].
Compared to controls, BPS/IC cases report poorer quality of life, and are less likely to be working full time. BPS/IC patients noted less life satisfaction than patients with end stage renal disease [47]. FSS definitions
History of adverse experiences
Several of these reviews had a statement that could be interpreted as a definition of an FSS: physical symptoms “… that, after appropriate medical assessment, cannot be explained in terms of a conventionally defined medical disease”[13,19]; “… appearing in patients who do not have proportional tissue abnormalities”[15]; “… (without) pathologically defined changes in tissue that designate medical conditions …”[16]; “… for which adequate examination does not reveal sufficiently explanatory structural or other specified pathology” [20]; “… that cannot be explained by organ pathology and currently lack definitive diagnostic tests” [21]; and “… for which medicine cannot find presently a convincing explanation” [10]. It appears that many BPS/IC patients would not meet several of these definitions, or descriptions, of FSSs because of abnormal anatomic pathology (Hunner's lesions and glomerulations) or laboratory tests (hematuria).
Significantly more BPS/IC patients than controls report a history of physical, emotional, and/or sexual abuse [6,35].
Discussion
Depression Compared to controls, significantly more BPS/IC patients have depression [5,7].
Anxiety These studies also assessed anxiety disorders and observed significantly more BPS/IC cases than controls with these diagnoses [5,7].
Familial A demonstration that a disorder is clustered in families is generally the first step in identifying a genetic contribution. Family and twin studies [36–38] of BPS/IC have shown such clustering. The largest and best designed, the Swedish Twin Study, albeit of young participants, suggests that in women about 30% of the susceptibility to BPS/IC is genetic [38].
Normal laboratory tests BPS/IC cases have not been reported to have abnormalities in blood counts, electrolytes, or renal and liver function. However, some BPS/IC patients have microscopic hematuria. A chart review indicated that 60/148 (41%) BPS/IC patients had at least one urinalysis demonstrating hematuria over a mean of 18 months [39]. Hence, a proportion of BPS/IC patients do not have this characteristic of the FSSs.
Normal light microscopic anatomy Visible findings at cystoscopy with hydrodistention under anesthesia suggest that the majority of BPS/IC patients do not manifest this characteristic either. The Interstitial Cystitis Database (ICDB) showed that about 10% of North American patients had Hunner's lesions and about 90% petechial hemorrhages, called glomerulations [23]. However, histopathology tells a different story. In a landmark study of 108 BPS/IC patients, Johansson and Fall showed that abnormal pathology indeed accompanied Hunner's lesions: mucosal hemorrhages, marked mononuclear inflammation, elevated mast cell counts, granulation tissue, and perineural infiltrates. However, they noted that nonHunner's bladders had few pathologic findings except for mucosal hemorrhages, often with mucosal ruptures and thought to be glomerulations from the preceding hydrodistentions [40]. The ICDB used cluster analysis of histopathologic findings in 203 BPS/IC patients and defined three subgroups: 3% had denuded epithelium, lymphoid infiltrate, mastocytosis, granulation tissue, edema, and small nerve proliferation; 8% had isolated denuded epithelium; and fully 88% had none of these pathologic features [41]. These two large studies show that about 90% of BPS/IC patients, generally those without Hunner's lesions, have what Johansson and Fall described as “remarkably meager” histopathological findings. Chronic Longitudinal studies of BPS/IC confirm the clinical impression that BPS/IC in most patients persists for years [42,43].
Diagnosis of exclusion
Of the 18 identified FSS characteristics, BPS/IC patients manifest all but two. The exceptions were that many BPS/IC patients do not have normal light microscopic anatomy and/or normal laboratory tests. Two types of abnormal pathology are found in most BPS/IC patients: 1) a Hunner's lesion with accompanying inflammation, and/or 2) glomerulations, with scant inflammation. The abnormal laboratory test is hematuria. These findings also would preclude most BPS/IC patients from meeting many of the definitions of an FSS. However, close inspection of these exceptions is revealing. Firstly, the 10% of BPS/IC cases that have a Hunner's lesion might have a different disease. Not only do they have more bladder histopathology [40], but also they have a smaller bladder capacity and are significantly older [48] than other BPS/IC patients. And very pertinent to this discussion, patients with Hunner's lesions are less likely than those without to have fibromyalgia, migraine, temporomandibular joint dysfunction, and depression [48]. Of the remaining exceptions, glomerulations and hematuria are probably related. Glomerulations appear during hydrodistention and their numbers are directly associated with the appearance of bloody effluent [49]. Glomerulations and bloody effluent are each inversely correlated with bladder capacity [49], yet scattergrams constructed from patient diaries show maximal voided volumes often exceed the volume at which pain occurs, sometimes by a multiple of 2 or 3 [Fig. 4 in [50]]. In aggregate, these observations suggest that over-distention of a chronically small bladder with consequent glomerulations and hematuria likely occur during the normal day in many BPS/IC patients. Additionally thousands of cystoscopies have not revealed another cause of hematuria in BPS/IC patients without a Hunner's lesion. This reasoning suggests that in the absence of bladder distention, there is no light microscopic pathology or abnormal laboratory tests in non-Hunner's BPS/IC patients. If this reasoning is correct, then 90% of BPS/IC patients have all the characteristics and meet all the proffered definitions of an FSS. Other BPS/IC characteristics found in FSSs
The first generally accepted definition of BPS/IC listed a dozen other diseases that would exclude the diagnosis [44]. The more recent American Urological Association definition merely states “… in the absence of infection or other identifiable causes” [1].
BPS/IC as an FSS predicts positive comparisons in the opposite direction, i.e., additional characteristics of BPS/IC would be found in the FSSs. BPS/IC has a number of other features, described below and followed by findings in the best studied FSSs, i.e., FM, CFS and IBS.
Worsened by stress
BPS/IC has a prodrome
Of BPS/IC patients, 60% report that stress exacerbated their symptoms and those with the most stress had quantitatively worse pain and urgency [45]. An experimental study of BPS/IC patients showed that acute mental stress elicited transient increases in pain and urgency [46].
For a median of 22 years before onset of BPS/IC, more cases than controls had urinary symptoms that appeared not to meet the definition of BPS/IC [51]. Studies of CFS, FM, and IBS also have revealed apparently
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relevant symptoms years before onset of the syndrome. A large medical database revealed that more CFS patients than controls had prior visits for lethargy and other symptoms over the 15 years before diagnosis of CFS [52]. A prospective study over 4 years showed that baseline regional pain was a risk factor for FM [53]. Another prospective study over 12 years demonstrated that abdominal pain was a risk factor for IBS [54]. Bladder filling exacerbates BPS/IC This is one of the features of BPS/IC that causes the patient to describe the bladder as the source of pain [55] and is described by a large majority of BPS/IC patients [26]. IBS is the only classic FSS in which a luminal organ is central. In a landmark study, Ritchie showed that IBS patients felt pain at smaller volumes of balloons inflated in the colon than controls [56]. BPS/IC is associated with surgical operations Patients with BPS/IC had more non-bladder surgeries than controls; the number of FSSs correlated with the number of operations [57]. Similarly, patients with FM [58] and with IBS [59], syndromes that are not indications for surgery, had more operations than controls, and in IBS multiple FSSs were associated with multiple procedures [59]. BPS/IC prognosis is predicted by severity and FSSs at baseline At onset of BPS/IC, its severity and the presence of FSSs predicted its poor prognosis [60]. For CFS, FM and IBS, baseline severity plus symptoms and pain elsewhere have been shown to be prognostic factors [61,62]. BPS/IC is heterogeneous Many investigators have compared those with Hunner's lesions to those without [40,48]. Related work has examined differences in histopathology [41]. Other investigators have used clinical presentations to distinguish BPS/IC subgroups [63]. Regarding FSSs, a variety of methods have used symptoms, signs, laboratory tests, and physiologic findings to show heterogeneity in each of CFS, FM and IBS [[64–66] and reviewed in [67]]. A useful approach? Accumulating experts' opinions of FSS characteristics and showing that BPS/IC has these features is a tedious and untested process for concluding that BPS/IC is an FSS. In a general way, one can estimate the sensitivity and specificity of this method by its ability to capture other FSSs and exclude non-FSSs. A perusal of the list of disorders noted as FSSs by these experts (first paragraph of Results) suggests that most of these conditions have most of these characteristics. But what about diseases that are clearly not FSSs? As measured by the World Health Organization, the top ten disabling disorders In the United States are ischemic heart disease, chronic obstructive pulmonary disease, low back pain, respiratory cancer, depression, other musculoskeletal disorders, stroke, diabetes mellitus, road-traffic injury, and drug-use disorders [68]. Three of these have already been noted as possible FSSs in some patients (low back pain and “other musculoskeletal disorders”) or as epidemiologically associated with the FSSs (depression). The other seven indeed have some characteristics of FSSs: they were chosen as chronic, disabling diseases, many are familial and accompanied by fatigue, some by pain, and a few are precipitated by an acute event. However, most are not epidemiologically linked to FSSs (although FM can follow automobile accidents) nor are numerous FSSs a risk factor (except possibly drug-use disorders). None are predominantly in women. And most importantly (with the inconstant exception of drug use), all are accompanied by abnormal laboratory tests and/or pathology.
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Not every feature of BPS/IC should be expected to be found in FSSs, just as every characteristic of, say, IBS, is manifest by other FSSs. This is of course because each syndrome has been distinguished clinically as a result of certain symptoms that differentiate it from other disorders. And it is likely that not all cases of BPS/IC are an FSS. As noted, BPS/IC is probably heterogeneous, which means among other things that it might have several pathogeneses. BPS/IC with the pathogenesis of an FSS would be more likely in patients with numerous FSSs [32]. And it might be more likely in the 90% without Hunner's lesions or in the 10% who have neither Hunner's lesions nor glomerulations [49]. This paper does not itself test the hypothesis that BPS/IC is an FSS but it is a useful exercise because it reveals research and clinical possibilities that can be explored even while the pathogeneses of FSSs and BPS/IC are being pursued. Regarding research, there are only two ways that one syndrome can be significantly associated with another: either the first syndrome initiates a process that leads to the second, or an underlying process leads to both. Therefore, explorations of the processes that connect FSSs could expose a pathogenesis of BPS/IC. Candidate processes found in patients with FSSs include pain amplification, abnormalities in the hypothalamus–pituitary–adrenal axis, and dysfunctions of the autonomic nervous system [69]. Indeed, some of these pathophysiologies have been identified in BPS/IC patients [34,70,71]. The possibility that in some patients, BPS/IC might best be understood as an FSS has clinical implications as well. Therapies that are successful among FSSs [20,72,73] might be applicable to BPS/IC. Patients with FSSs, particularly those with many syndromes, comprise a high risk group for BPS/IC [31,32]; as the process(es) that lead to BPS/IC are revealed, this group might benefit from as yet unknown preventive techniques. This investigation has several weaknesses. Foremost is that there is no precedent for this methodology. But neither has there been suggested a better approach to classify a disorder as an FSS. To date the identification of a syndrome as an FSS has been the prerogative of the authors of a given article. It is interesting to note that some authors of the identified articles have already listed BPS/IC as an FSS [14,15,20, 21]. The most persuasive classification technique almost certainly will require an understanding of the pathogenesis(es) of the FSSs. Another limitation of this study is the use of only one database, restriction to English, and the absence of informal searches. A third is that the list of FSS characteristics does not attempt to rank them in importance. The presence of normal anatomy and laboratory tests are arguably the most critical characteristics of FSSs; were these findings abnormal, another disease would be diagnosed. Finally, the discussion of glomerulations and hematuria during the routine day of a BPS/IC patient, although consistent with extant data, is primarily an exercise in common sense. There are strengths. The most important was that the study was a systematic, unbiased approach to identifying characteristics of FSSs as expressed by experts in this group of syndromes. The review focused on those most widely accepted as FSSs, i.e., CFS, FM and IBS, rather than on more contested syndromes such as multiple chemical sensitivity. A third was its face value: clinicians skilled in FSSs would recognize this list as reflecting features of these syndromes in their patients. Finally, BPS/IC as an FSS had predictive utility: several additional features of BPS/IC were found to be present in the most widely recognized FSSs, i.e., CFS, FM and IBS. Conflict of interest The author has no competing interests to report. References [1] Hanno PM, Burks DA, Clemens JQ, Dmochowski RR, Erickson D, Fitzgerald MP, et al. AUA guideline for the diagnosis and treatment of interstitial cystitis/bladder pain syndrome. J Urol Jun 2011;185:2162–70. [2] Berry SH, Elliott MN, Suttorp M, Bogart LM, Stoto MA, Eggers P, et al. Prevalence of symptoms of bladder pain syndrome/interstitial cystitis among adult females in the United States. J Urol Aug 2011;186:540–4.
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