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17. Chronic Prostatitis/Chronic Pelvic Pain Syndrome
Keywords
Chronic prostatitisChronic pelvic pain syndromePhenotypically directed multimodal therapyMicrobiomeEvaluationManagementUnderstanding an Enigmatic Urologic Pain Syndrome
Urologic chronic pain is a real condition with at times a debilitating impact on patients, a significant burden on society, and it will be us as Urologists that these challenging patients seek out for diagnosis and management. And it is a common affliction—up to 10% of men will experience pelvic or genitourinary (GU) pain (chronic prostatitits/chronic pelvic pain syndrome or CP/CPPS) over the course of 1 year. It is a fact that numerous excellent studies examining the etiology, diagnosis and management of CP/CPPS have been published resulting in textbook chapters (and even whole books), comprehensive reviews, meta-analyses, and guidelines dedicated to outlining diagnostic and management strategies. Despite this, chronic urologic pain in men remains an enigmatic condition with elusive treatments and the practitioner is often left frustrated and confused, the patients even more so.
It is the goal of this chapter to explore one of the most common urologic chronic pain conditions—chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS)—Category III of the prostatitis syndromes (see section “Definition and Classification”). It is without a doubt the most prevalent of the prostatitis syndromes, responsible for 90–95% of prostatitis diagnoses [8]. We aim to provide an up to date review of the etiology, diagnosis and treatment options, arming those tasked with treating this condition with a realistic, practical approach driven by current evidence and extensive clinical experience in treating the disease.
Definition and Classification
In reference to a diagnosis of “prostatitis” it is generally accepted that one is referring to any one of a collection of syndromes, defined on a spectrum of involvement of three main contributors: (1) bacterial infection of the prostate, (2) GU pain, and/or (3) involvement of lower urinary tract symptoms (LUTS). Prostatitis is a clinical diagnosis, relying on thorough history, physical examination and although there is no single diagnostic laboratory test, several investigations can help contribute to arriving at an appropriate diagnosis (see section “Evaluation”).
Following their pioneering work, studying the urine cytology and bacterial localization of the urinary tract which culminated in their classic four-glass test of the urine [1], Meares and Stamey first recognized that a definition of “prostatitis” was far too simple and suggested a more nuanced classification of the disease based on findings from their research: acute and chronic bacterial prostatitis, nonbacterial prostatitis and prostatodynia [2]. This was the first “official” acknowledgement in the literature of a group of patients with symptoms reminiscent of bacterial prostatic infection, but where no identifiable infection could be found.
NIH category | Clinical presentation |
|---|---|
I: Acute Bacterial Prostatitis | Acute symptoms of UTI, general malaise, fever. bacteriuria, pyuria |
II: Chronic Bacterial Prostatitis | Recurrent episodes of bacterial UTIs; C&S reveals infection with same organism; evidence of bacterial infection of prostate between symptomatic episodes |
III: Chronic Prostatitis/Chronic Pelvic Pain Syndrome | Primary complaint of pain in GU tract with no identifiable bacterial infection |
(a) Inflammatory | Leukocytes present in expressed prostatic secretions, post-prostate massage urine, or semen |
(b) Noninflammatory | No leukocytes present in expressed prostatic secretion, post-prostate massage urine, or semen |
IV: Asymptomatic Inflammatory Prostatitis | No history of GU symptoms; but with leukocytes present in expressed prostatic secretion, post-prostate massafe urine, or semen; incidental diagnosis |
This possibly noninfectious category acknowledged that most symptomatic “prostatitis” patients—up to 95%—ultimately have a diagnosis of CP/CPPS, and recognized that their pain may be complex and related to structures in the pelvis other than the prostate. They further sub-classified Category III into Category IIIA—known as the inflammatory subtype—and Category IIIB—the noninflammatory subtype—based on the presence or absence of leukocytes in the expressed prostatic secretion (EPS) or post-prostate massage urine (VB3) specimens of the four-glass test (see section “Urine Studies”) or leukocytes in the semen. Finally, Category IV—representing those who were asymptomatic but with findings suggestive of prostate inflammation on investigation—was introduced and not previously described in the in the Meares-Stamey classification system.
Epidemiology
Kreiger et al. [4] proposed a collection of epidemiological study characteristics they suggested would act as a desirable set of criteria for including a specific study in any review evaluating the epidemiology of chronic prostatitis. These characteristics included: (1) population-based studies. The authors point out that population-based studies are preferable to case series and studies based on referral to tertiary care centers, as population-based studies are more likely to be representative of the population as whole. Secondly, the authors suggest a (2) clear case definition for chronic prostatitis should be apparent in the study. Furthermore, they go on to intimate that ideally, this case definition would bear a relationship to those patients seen in routine clinical practice. Thirdly, a (3) survey strategy to ensure an adequate sample of the population was acquired while employing methods of ensuring identified cases met the case definition of the study. Ideally, a (4) standardized instrument—the authors favour the NIH-Chronic Prostatitis Symptom Index (NIH-CPSI; see section “Chronic Prostatitis Symptom Index”)—should be employed to identify cases in a reliable, consistent manner. Another desirable study characteristic is (5) that the population studied would be large to have an acceptable statistical power for any subsequent analyses. Finally, (6) the study ideally would be published in a peer-reviewed journal.
There are a number of reviews of epidemiologic studies analyzing the prevalence of prostatitis—the first by Kreiger et al. [4] was performed in 2003, where the Kreiger criteria was first introduced, and later updated in 2008 [5]. The 2008 study by Krieger et al. identified 10 studies that met their inclusion criteria—7 from North America, 2 Asian and 1 European study. Of the studies where prevalence could be determined, 873 men met criteria for symptoms of prostatitis out of 10,617 men surveyed, yielding a prevalence rate of 8.3%—this varied from 2.2 to 9.7% amongst the included studies.
More recently, Nickel et al. [6] used the Krieger criteria and identified 24 studies for inclusion in a epidemiologic review of prostatitis. Their analysis yielded 13 North American studies, six studies from Asia, two European, two African and one Australian study. The results represented a much larger patient population of 336,846 participants with a prevalence of prostatitis of 7.1%, ranging from 2.2 to 16% amongst the individual studies.
Clearly there are limitations to considering an accurate prevalence of prostatitis by collating studies as in the above, described manner: the baseline characteristics are not well-described in many of these studies, definitions of prostatitis varied amongst the studies and importantly, the methods of determining a diagnosis of prostatitis varied from physician diagnosis—both by urologist and general practitioner—to self-reported diagnosis, to determination from survey responses. Despite these limitations, the studies do suggest that prostatitis is a commonly encountered patient problem. Though most studies do not distinguish categories of prostatitis diagnosis, Clemens et al. [7] used an administrative health care database and determined that Category III CP/CPPS made up the majority of prostatitis diagnoses using the NIH-CPSI definitions of prostatitis diagnosis.
Health-Related Quality of Life
There has been increased interest in patient-centered care in medicine in general, in recent years and contingent upon this has been an uptake in research of patient-reported outcomes (PROMs). When evaluating health in general, several PROMs tools exist. The Sickness Impact Profile (SIP), which evaluates sickness-related dysfunction in 12 different life areas—eating, work, sleep and rest, household management, recreation, pastimes, ambulation, mobility, body care and movement, social interaction, emotional behavior, alertness behavior, and communication—has been used to study PROMs in CP/CPPS patients: Wenninger et al. [9], using the SIP total score, found that chronic prostatitis patients suffer to a similar degree in terms of quality of life (QOL) as patients with myocardial infarction, angina and Crohn’s disease.
Another common PROMs tool used to measure health in general is the Short Form 12 (SF-12). This tool evaluates a variety of QOL domains including bodily pain, general health, physical functioning, vitality, mental health and emotional problems, role limitations, and social functioning. McNaughton Collins et al. [10], in their NIH-supported Chronic Prostatitis Cohort Study, described SF-12 scores of CP/CPPS patients and revealed they suffer in both the physical and mental subscales of the SF-12, on a severity worse than similar patients suffering from other chronic diseases including diabetes mellitus and congestive heart failure.
Urology has seen an abundance of PROMs tools introduced specific to various urologic diseases [15] and CP/CPPS has a validated PROM tool of its own—the NIH-CPSI (see section “Chronic Prostatitis Symptom Index”)—which includes questions specific to QOL. Though helpful for purposes of stratifying disease severity and following response to treatment over time, it should not be relied upon solely as a diagnostic tool. The questions specific to QOL again, although helpful in following CP/CPPS symptoms and QOL impact over time, is not overly thorough in this domain.
Several studies have evaluated the QOL of CP/CPPS patients in more depth, including comprehensive assessments of mental health, disability and coping strategies amongst this patient population. Patients with CP/CPPS have been shown to exhibit worse depression [11] symptoms and diagnoses than their healthy peers. Those CP/CPPS patients who exhibit worse catastrophizing behaviors have been shown to have worse prostatitis-related pain [12], highlighting the importance of biopsychosocial factors in this disease process.
Krsmanovic et al. [13] have furthermore shown that both catastrophizing and illness-focused coping fully mediated the relationship between pain and mental QOL in CP/CPPS patients. These findings again highlight the importance of patients’ perceptions of self and that their cognitive strategies for managing their disabilities are not simply secondary to their disease, but inherent in it and even associated with the severity of their physical pelvic disease in some instances.
Not only are the patient’s QOL negatively impacted by their disease, but their spouses’ QOL measures have been shown to similarly be affected. In a study following CP/CPPS patients and their spouses over a 2-year period, both patients’ and their spouses’ depression, disability, pain and catastrophizing behavior remained stable over a 2-year FU period [14] regardless of the type of treatment they received. These QOL studies have demonstrated the crucial attention to biopsychosocial factors that must be paid in these patients.
Etiology
The etiology and pathogenesis of CP/CPPS is not well understood. Perhaps the most broadly accepted working hypothesis is that it is a disease process that is most likely multifactorial, involving several bodily systems including genetic, immunologic, endocrine, neurologic, musculoskeletal, and psychological pathways [6]. Though investigators have failed to discover the smoking gun for a diagnosis of CP/CPPS, it has not been due to a lack of trying. Much research has been devoted to understanding the etiology of this enigmatic disease and below follows an exploration through some of what we know about the etiology of CP/CPPS.
Microbiome
Though by definition , Category III Chronic Prostatitis/Chronic Pelvic Pain Syndrome does not have an identified bacterial causative agent, many have believed that we are simply limited by our current culture-based microbiology techniques—it is not that CP/CPPS lacks a bacterial cause, but that we have not been able find it.
More recently, investigations into the microbiome of the lower urinary tract inspired by this theory have provided additional insights into our understanding of a possible role of bacterial pathogenicity in CP/CPPS. We know the majority of bacteria species, resistant to current culture methods, exist in a “biofilm” mode of growth [16] within the urinary tract and prostate—an area that was previously thought of as a sterile tract. Though this finding of bacteria previously undiscovered in these areas to this degree has been a breakthrough, it remains to be known which of these culture-resistant bacteria are actual pathogens.
Leading the way in this concept of the GU microbiome and its role in CP/CPPS pathogenicity has been the Multi-Disciplinary Approach to the Study of Chronic Pelvic Pain (MAPP) Research Network. In their 2015 publication [17] where they used a novel, state-of-the-art culture independent method of characterizing GU bacteria in CP/CPPS patients and healthy male controls, Nickel et al. showed that CP/CPPS patients exhibit a GU microbiota distinct from healthy controls. Specifically, they found higher concentrations of Burkholderia cenocepaciaens in CP/CPPS patients compared to their matched asymptomatic male controls.
Later in 2016, Shoskes et al. [18]—using the 16S rRNA-gene amplification method to detect bacteria in urine specimens—performed an analysis of 25 CP/CPPS patients and compared their urinary microbiomes to healthy controls. They similarly found a unique GU microbiome in the CP/CPPS group: higher phylogenetic diversity and higher counts of Clostridia species in CP/CPPS patients compared to healthy male controls. Using similar methods in a subsequent study [19], the same research group demonstrated that the microbiome uniqueness of CP/CPPS patient was not limited to the GU tract—they showed significantly less microbiome diversity and decreased prevalence of Prevotella species in the gut microbiota amongst CP/CPPS patients compared to controls. Though all these findings are hypothesis-generating, their clinical significance remains unclear and further research is required. It will likely turn out that there will not be a single causative organism but rather a dysbiosis or ecological disruption of the microbiome that impacts symptoms of some patients with CP/CPPS.
Dysfunctional Voiding/Pelvic Floor Dysfunction
Dysfunctional voiding involving abnormalities of the pelvic floor, where there is some degree of neural-motor dysregulation may suggest an underlying abnormality of pelvic neural-sensory pathways. Intuitively, this could lead to a dysfunctional state, manifested as chronic pain. Indeed, investigators have demonstrated these mechanisms. Blacklock [20, 21] showed that abnormal prostate anatomy, urethral and bladder neck abnormalities, leading to high-pressure voiding may have a role in the pathogenesis of prostatitis syndromes.
Furthermore, pelvic floor tenderness has emerged as an important target in CP/CPPS patients. Chronic prostatitis/chronic pelvic pain syndrome patients presenting with the tenderness domain through evaluation using the UPOINT phenotyping tool (see section “UPOINT Phenotyping”) is common, reported by Doiron et al. [22] as being present in close to 50% of patients in a large cohort of CP/CPPS patients followed for over 15 years. It remains unclear whether the pelvic floor abnormalities lead to pelvic floor tenderness and then the chronic pain syndrome or vice versa, but it represents an important acknowledgement by those assessing CP/CPPS patients, as targeting the pelvic floor with interventions has been shown to be beneficial (see section “Management”).
Immunologic Alterations
It has been well-established that CP/CPPS patients have markers of heightened immune sensitivity [23, 24]. The clinical correlation, though has not been established and a causal linkage is still lacking. The observation by various investigators [25–27] that in those with bacterial infection of the prostate who receive adequate treatment, the immunologic cascade remains activated despite eradication of the bacteria has focused research efforts in this domain.
Neural Sensitization
Men with CP/CPPS have been shown to have altered autonomic nervous system responses [28, 29], which may suggest a role of the central nervous system in the development of chronic pelvic pain. Furthermore, neural cross-sensitization continues to be investigated [30–32] as a possible mechanism for neural dysfunction and sensitization as an etiology of the establishment of chronic pain in these patients. Though a relatively recent concept and its research has mostly been in animal models to date, this concept of neural cross-sensitization represents an active area of investigation.
Psychosocial Associations
It has been well established that patients with CP/CPPS suffer from an inordinate level of psychological stress and poor mental health. What remains unclear is the causal relationship. Investigators have shown that those CP/CPPS patients who suffer worse from psychosocial perspective often suffer worse in terms of their physical symptoms and have worse quality of life. Furthermore, psychosocial factors have been shown to modulate the experience and perception of the disease. So although a causal link has yet to be established, recognizing the importance of this domain of the disease in terms of outcomes make it a desirable area to continue investigation and develop interventions.
Evaluation
As Urologists, we are first clinicians, and it is those clinical skills on which we must draw to appropriately evaluate a patient being considered with a diagnosis of prostatitis. Though the task of evaluating a patient for a possible diagnosis of a chronic pain condition may seem daunting at times, we have the skill set as clinicians and tools necessary available to us in the outpatient clinic to evaluate and diagnose CP/CPPS.
The evaluation should begin with a thorough history. The history should be directed in a way so as to rule out other confusable diseases in the differential diagnosis. In considering a diagnosis of CP/CPPS, most patients will present with some sort of pain, localized to GU tract—perineal, penile, scrotal, suprapubic—and the onset and duration of their pain should be determined. For those with more acute symptoms, one might be considering a diagnosis of acute bacterial prostatitis, as CP/CPPS is by definition, chronic in nature.
Chronic Prostatitis Symptom Index
The National Institute of Health Chronic Prostatitis Collaborative Research Network—the same collaboration that lead to the current classification system of prostatitis—introduced a symptom index tool in 1999 [33] to aide in the evaluation of CP/CPPS patients. The Chronic Prostatitis Symptom Index (NIH-CPSI), later validated amongst a large cohort of CP/CPPS patients using a placebo-controlled randomized study [34], quantified a patient’s symptom experience through a series of 9 questions, addressing 3 domains: physical symptoms of pain and urinary function are covered in the first 6 questions, while the final 3 questions inquire about QOL and the impact of the patient’s symptoms more broadly.
The tool has proven useful in clinical evaluation of patients, as it can be administered within minutes to a patient in the waiting room. Though it should not be considered a stand-alone diagnostic tool, it can useful as an adjunct to an otherwise thorough history and physical, and the quantification of a patient’s symptoms—pain severity categories were recently developed for the pain domain [35] with a score of 0–7 considered as mild, 8–13 moderate, and 14–21 is considered severe pain—can assess severity of symptoms and allow for patients to be followed over time. This can be helpful to assess response to treatments—the NIH-CPSI represents the most commonly used outcome measure in CP/CPPS clinical trials.
Physical Examination
Physical examination is instrumental in the evaluation of a patient being considered with a diagnosis of CP/CPPS. A focused physical examination including a pelvic exam and digital rectal exam (DRE), should be considered mandatory in their assessment. The authors prefer to perform the pelvic exam prior to DRE as those with significant prostate tenderness, a common finding amongst CP/CPPS patients, may refuse further physical examination following palpation of an exquisitely tender gland. Furthermore, it is important that prior to DRE or any manipulation of the GU tract, midstream urine specimens be collected for culture and sensitivity so as not to interfere with any attempts at bacterial localization (see section “Urine Studies”).
In terms of the pelvic examination, it has been the authors’ experience that pelvic examination in lithotomy position allows for a more thorough exam (but examination in the left decubitus position is acceptable) inspecting for pelvic floor muscle tenderness, spasticity and trigger points. Digital rectal exam should follow careful pelvic exam. Investigators with the Multidisciplinary Approach to the study of Chronic Pelvic Pain (MAPP) have recently described an extended GU exam [36] that may be useful in those with a confirmed CP/CPPS diagnosis to further subcategorize and phenotype CP/CPPS patients in terms of physical exam findings. Their extended exam includes a thorough assessment for tenderness of the pelvic floor, including palpation of the perineal body, levator, obturator and urogenital diaphragm muscles, an examination of extrapelvic regions including abdomen, flank and back, as well as sensory and motor function examination of the pudendal nerve. Clearly this extended exam is not practical as an assessment for all patients presenting with symptoms of CP/CPPS, but may prove useful for a patient who screens positive for pelvic floor tenderness.
Urine Studies
The goal of urine studies as part of an evaluation of patients with symptoms of CP/CPPS is to identify bacterial infection in the case of Category II patients, while the presence or absence of WBCs from prostate specific specimens can differentiate between the inflammatory (IIIA) and non-inflammatory subtype (IIIB) of Category III patients. For practical purposes, the differentiation of patients into these two subcategories has not proven helpful—that may change with the introduction of better inflammatory biomarkers.
The gold standard for bacterial localization and cytologic examination of the urine in prostatitis patients remains the classic four-glass test developed by Meares and Stamey [1]. Though the test is practically challenging for many clinicians to perform in an outpatient setting [37], and some have questioned the clinical usefulness of the finding of leukocytes in urine specimens [38, 39], the authors feel the findings may still prove helpful in selected cases and the potential role of molecularly phenotyping our patients is under study.
The first specimen in the four-glass test—voided bladder 1 (VB1)—is the initial 10 cc of urine from a collection, corresponding to the urethra. The second specimen—VB2 or midstream collection—represents urine in the bladder. The expressed prostatic secretion specimen (EPS) is collected during prostate massage while the VB3 or post prostatic massage specimen is the first 10 cc of urine collected immediately following prostatic massage and represents an alternative prostate-specific specimen. The results provide a ctyologic and bacteriologic roadmap of the lower urinary tract.
Given the practical challenges of the four-glass test, a more practical screening test introduced in 1985 [40], is a two-glass screening test, which consists of a pre- and post-prostatic massage urinary specimen. Investigators have shown the two-glass test to be as diagnostically robust as the four-glass test in terms of diagnosis, when in a study of 353 patients enrolled in the NIH Chronic Prostatitis Cohort study comparing the two-glass test to the four, the same diagnosis was achieved regardless of what urine test was used over 95% of the time [41].
Imaging and Cystoscopy
Current clinical practice guidelines do not recommend any routine imaging studies in the evaluation of a patient suspected of a diagnosis of CP/CPPS [42, 43]. Imaging’s primary role in the evaluation of these patients lies in ruling out confusable disease and should be employed on a case-by-case basis.
Ultrasound can be helpful in evaluation of the prostate, determining post-void residuals in those men with obstructive voiding symptoms, and can rule out a host of confusable diseases, such as obstructed seminal vesicles, prostatic abscess, and prostatic calculi. However, it has little role in diagnosing CP/CPPS directly. Although the role of MRI in prostate cancer has grown significantly in recent years, its role in the evaluation of patients with symptoms of CP/CPPS is limited and should be considered only when specific indications are present.
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