c.absence of bladder pain.
d.glomerulation.
e.Hunner lesion.
.Epidemiologic information gathered by the Rand Corporation suggests which of the following?
a.BPS is never familial.
b.BPS may be as common in men as it is in women.
c.A male with BPS should be given a diagnosis of prostatitis.
d.BPS is a rare disease that should qualify for orphan drug classification by the Food and Drug administration.
e.BPS is common in children with urinary frequency.
Answers
1.b. Pain or discomfort related to the bladder. Pain, pressure, or discomfort related to the bladder is necessary to make a diagnosis of bladder pain syndrome. Urgency, frequency, and the presence of glomerulations or
Hunner ulcer on endoscopy are often associated with BPS, but the presence of pain or discomfort is the primary component. IC may form a subgroup of the painful bladder group, but the criteria are not clear, and at this point the terms can be used interchangeably.
2.c. Definition applicable mainly to clinical research studies. The definition of IC proposed by the NIDDK is best considered a definition applicable for use in research studies. It was never meant to define the disease but rather was developed to ensure that patients included in basic and clinical research studies were homogeneous enough that experts could agree on the diagnosis.
3.d. Late occurrence of pain and bowel segment contraction after substitution cystoplasty and continent diversion. Substitution cystoplasty and continent diversion both fail in some BPS patients because of the development of pain in the bowel segment used or contraction of the bowel segment. Some studies have shown histologic changes in bowel segments used in BPS patients similar to those that occur in the IC bladder. Both of these findings provide circumstantial clinical evidence that the urine of BPS patients may have toxicity associated with the symptomatic expression of the disorder. However, data with regard to antiproliferative factor make this evidence suspect.
4.a. Monitor disease progression or regression with or without treatment.
Symptom and problem indices like the one developed by O'Leary and Sant are not intended to diagnose BPS/IC. Like the American Urologic Association Symptom Score for benign prostatic hypertrophy, these indices are designed to evaluate the severity of symptoms and to monitor disease progression or regression and response to treatment.
5.e. Subacute onset with full development of the symptom complex over a relatively short time span. Several epidemiologic studies have concluded that the onset of BPS is commonly subacute rather than insidious. It presents more as one would expect an infectious disorder to present, rather than a chronic disease process. Full development of the classic symptom complex takes place over a relatively short period of time. In the majority of cases, it does not progress continuously but reaches its final stage rapidly and then continues without significant change in overall symptoms.
6.d. The vast majority of reports fail to document an association of BPS/IC with subsequent development of bladder cancer. Until recently, no relationship has ever been shown between BPS and the subsequent development of bladder carcinoma. In the 1970s, the Mayo Clinic documented bladder cancer in 12 of 53 men who had been treated for IC, but the association was the result of incorrect diagnosis rather than progression. Peters and others have noted that patients with bladder cancer can be misdiagnosed with BPS/IC. A recent study from Taiwan reported a 2.95 relative risk compared with controls.
7.a. Cat. The feline urologic syndrome may represent the animal equivalent of BPS/IC. Approximately two thirds of cats with lower urinary tract disease have sterile urine and no evidence of other urinary tract disorders. Some of these cats experience frequency and urgency of urination, pain, and bladder inflammation. Glomerulations have been found in some of these cat bladders. Other findings similar to BPS include bladder mastocytosis, increased histamine excretion, and increased bladder permeability.
8.b. None. Antibiotics are not indicated for the treatment of BPS/IC, nor have they been implicated as a causative factor. An empiric trial of doxycycline is reasonable in patients who have never had an antibiotic trial to treat the symptoms. Numerous studies have concluded that it is unlikely that active infection is involved in the ongoing pathologic process or that antibiotics have a role to play in treatment.
9.c. Mast cell. Mast cells are strategically localized in the urinary bladder close to blood vessels, lymphatics, nerves, and detrusor smooth muscle. BPS
appears to be a syndrome with neural, immune, and endocrine components in which activated mast cells play a central, although not primary, role in many patients.
.e. None of the above. As many as 25% of patients who meet the NIDDK criteria for BPS/IC will have a negative KCl test. It is positive in the majority of patients with radiation cystitis, urinary tract infection, or nonbacterial prostatitis and in women with pelvic pain. It is neither sensitive nor specific for BPS/IC, is uncomfortable for patients, and does not help to guide
therapeutic decisions.
.b. Is generally found in less than 30% of BPS patients. Bladder ulceration (so-called Hunner ulcer) is more appropriately referred to as Hunner lesion and is found in a minority of patients with symptoms of BPS/IC. It
is not a true ulcer, but a "vulnus" or weakness or vulnerable area of the mucosa. A circumscribed red patch that cracks and bleeds with distention is best appreciated with the patient under anesthesia.
.c. Increased diagnostic specificity. Exclusive use of the NIDDK criteria to diagnose BPS would result in increased specificity and decreased sensitivity. Ninety percent of expert clinicians in the NIDDK database study agreed that patients diagnosed with IC by those criteria had IC. However, 60% of patients diagnosed by these clinicians as having BPS/IC did not fulfill the NIDDK criteria. Using the criteria as a basis for diagnosis would probably exclude the majority of patients with this symptom complex from the correct diagnosis.
.b. Diabetes. Fibromyalgia, irritable bowel syndrome, chronic fatigue syndrome, and atopic allergic reactions are overrepresented in the BPS population. Studies are ongoing to find out the reason for such relationships in the NIDDK MAPP (Multidisciplinary Approach to the Study of Chronic Pelvic Pain) 5-year study. Diabetes has never been associated with an
increased prevalence in patients with BPS.
.a. Bladder urothelial cells. APF can be obtained from cultured uroepithelial cells and is not present in renal pelvic urine. It is associated with decreased production of heparin binding epidermal growth factor–like growth factor.
.e. Regulate growth factor production by bladder cells. APF regulates growth factor production by bladder epithelial cells. It has been postulated that any of a variety of injuries to the bladder (infection, trauma, overdistention) in a susceptible individual may result in BPS if APF is present and suppresses production of heparin binding epidermal growth factor–like growth factor.
.d. Rule out other disorders that might be responsible for the symptoms.
The primary value of histopathology in BPS is to rule out other diseases that may account for the symptoms. The differentiation between ulcerative and nonulcerative disease is based on endoscopic features. There is no pathognomonic histologic finding for the disorder, nor can histology predict prognosis. Even a severely abnormal microscopic picture does not necessarily indicate a poor prognosis. At this time, no data suggest that the treatment algorithm can be rationally predicated on the basis of the histologic findings
alone.
.b. Chronic bacterial prostatitis. BPS can be considered one of the pain syndromes of the urogenital and rectal area, all of which are well described but poorly understood. These include vulvodynia, orchialgia,
perineal pain, penile pain, and rectal pain. Bacterial prostatitis is a wellunderstood entity with a known etiology and generally responds to treatment directed at the offending organism. NIH type 1 includes acute bacterial prostatitis and NIH type 2 denotes chronic bacterial prostatitis. Unlike NIH type 3 chronic pelvic pain syndrome/nonbacterial prostatitis, types 1 and 2 have no relationship to BPS.
.d. Decreased capacity and hypersensitivity. Cystometry in conscious BPS patients generally demonstrates normal function, the exception being decreased bladder capacity and hypersensitivity, perhaps exaggerated by the use of carbon dioxide as a medium. Pain on bladder filling, which reproduces the patient's symptoms, is very suggestive of IC. Bladder compliance in patients with IC is normal, as hypersensitivity would prevent the bladder from filling to the point of noncompliance.
.b. Is of no significance in an asymptomatic patient. Glomerulations are not specific for BPS, and only when seen in conjunction with the clinical criteria of pain and frequency can the presence of glomerulations be viewed as potentially significant. Glomerulations can be seen after radiation therapy, in patients with bladder carcinoma, after exposure to toxic chemicals or chemotherapeutic agents, and in patients undergoing dialysis or after urinary diversion when the bladder has not filled for extended periods. They have also been reported in the majority of men with prostate pain syndromes. In the United States and Europe they are not longer viewed as important for
diagnosis or to guide management.
.a. 50%. There is a 50% incidence of temporary remission unrelated to therapy, with a mean duration of 8 months. The clinical course of BPS is
extremely variable, and it can be difficult to differentiate the effects of treatment from the natural history of the disease.
.c. Cystoscopy and low-pressure bladder hydrodistention. Bladder hydrodistention with the patient under anesthesia is a common therapeutic modality used for BPS, frequently as part of the diagnostic evaluation. Its primary value is in diagnosis of a Hunner lesion. Between 30% and 50% of patients experience some short-term relief in symptoms after the procedure. If a Hunner lesion is present, therapeutic response to resection or fulguration is excellent in many patients. About 30% of patients will note a brief exacerbation in their symptoms following hydrodistention. A bladder capacity
under anesthesia of less than 200 mL is a sign of poor prognosis.
.a. Sodium pentosan polysulfate. The target of sodium pentosan polysulfate therapy is the glycosaminoglycan (GAG) layer of the urothelium. This agent is an oral analogue of heparin. About 6% of an ingested dose is excreted in the urine. The proposed mechanism of action is the correction of a GAG dysfunction, thus presumably reversing the abnormal epithelial permeability. It is marginally effective in about 30% of patients in placebo-controlled trials.
.e. None of the above. None of these treatments has been proven efficacious for BPS in double-blind placebo-controlled trials. Hyaluronic acid in both high and low concentrations and BCG have recently failed to show significant efficacy in large, multicenter American trials.
.b. They can make patients physically dependent on them. Narcotic analgesics can be very useful in a subset of BPS patients with severe disease. Unlike other classes of analgesics, they have no therapeutic ceiling, dosing being limited by tolerance of side effects. They tend to cause constipation and can cause some sedation. Physical dependence is unavoidable, but physical addiction, a chronic disorder characterized by the compulsive use of a
substance resulting in physical, psychological, or social harm to the user and the continued use despite that harm, is rare.
.a. Transurethral fulguration of Hunner lesion. Transurethral fulguration or laser irradiation of a Hunner lesion can provide symptomatic relief. None of the other procedures listed have any place in the treatment of BPS.
.b. Patient education. Patient education is the most important step in the initial treatment of BPS. This condition is chronic, the symptoms wax and wane, and remissions are not uncommon. It lends itself to practitioner abuse, and the uninformed, desperate patient is easy prey. Treatment is symptom-driven, and an informed patient makes the best decisions.
.e. None of the above. Clinically insignificant detrusor overactivity may be seen in 15% of patients with BPS, a rate of involuntary contractions that has been reported in normal patients undergoing ambulatory urodynamics. The finding does not rule out the diagnosis of BPS, and treatment of this finding
would be unlikely to result in improvement of the patient's bladder pain.
.e. All of the above. BPS should be considered in the differential diagnosis of voiding disorders in men accompanied by irritative symptoms and pelvic pain. A rigorous BPS evaluation can be useful in differentiating BPS from bladder carcinoma in situ, functional or anatomic bladder outlet obstruction, and bacterial prostatitis. Many men with BPS have undergone what has proved to
be unnecessary and ill-founded bladder neck surgery.
.e. Examine the chronic pelvic pain syndrome in men and BPS along with associated syndromes to better characterize the relationship among these disorders and enhance future diagnosis and treatment efforts. The question as to whether chronic pelvic pain syndrome in men (CPPS III), previously referred to as "nonbacterial prostatitis," and BPS are two different disorders or manifestations of one pathologic process forms part of the goal of the MAPP. Other goals are to outline the relationship of the urologic chronic pelvic pain syndromes with other chronic pain syndromes and learn why such syndromes tend to be associated clinically in the same patients. (http://www.mappnetwork.org/)
.a. Risk factors for bladder pain syndrome. Emotional, sexual, and physical abuse was shown to be a risk factor in the Boston Area Community Health Survey, and this has been borne out in other studies. A Michigan study compared a control group of 464 women with 215 BPS/IC patients and found that 22% of the control group had experienced abuse versus 37% of the patient group. Those with a history of sexual abuse may present with more
pain and fewer voiding symptoms. How reliable these data are is not clear, and it would be wrong to jump to any conclusions about abuse in an individual patient. However, practitioners need to have sensitivity for the possibility of an abusive relationship history in all pain patients, and BPS patients in particular. When patients are found to have multiple diagnoses, the rate of previous abuse also increases, and these patients may need referral for further counseling at a traumatic stress center.
.e. Hunner lesion. Patients with Hunner lesions form a distinct subset of those with bladder pain syndrome. They have identifiable endoscopic and pathologic findings, are less likely to have comorbid conditions, tend to be
older, and respond clinically to bladder fulguration and local steroid injection into the lesions.
.b. BPS may be as common in men as it is in women. The Rand Corporation high specificity criteria data show a male prevalence of BPS of 1.9% compared with a 1.8% prevalence of nonbacterial prostatitis/chronic pelvic pain syndrome. Thus, the prevalence of BPS in men approaches that in women, suggesting that many men previously diagnosed with "prostatitis" actually have BPS as it is currently defined. The overlap of BPS and chronic pelvic pain syndrome was 17%.
Chapter review
1.Bladder pain syndrome/interstitial cystitis (BPS/IC) is a condition that is diagnosed on a clinical basis and consists of chronic pelvic pain often exacerbated by bladder filling and associated with urinary frequency. This is a diagnosis of exclusion because there is no specific test or marker that is diagnostic. Interstitial cystitis may be a subgroup of this population that has typical histologic and cystoscopic features; however, those specific features are still subject to debate.
2.Patients with bladder pain syndrome have a 10-fold higher incidence of childhood voiding problems than do patients without the syndrome.
3.A childhood presentation is extremely rare. The average age of onset is 40 years.
4.Antiproliferative factor (APF) is secreted by bladder epithelial cells, inhibits bladder epithelial cell proliferation, and is used as a marker of the disease. It may be the primary cause of syndrome in some patients. Urine APF appears to have the highest sensitivity and specificity of the markers studied for this disease.
5.Numerous studies indicate a role for increased sympathetic activity in interstitial cystitis. Whether this is a cause or effect is unknown.
6.Cross-sensitization among pelvic structures may contribute to chronic pain syndromes because this may result in alteration in function of adjacent pelvic organs.
7.Bladder compliance in patients with interstitial cystitis is normal.
8.Many patients find their symptoms adversely affected by certain food groups.
9.Amitriptyline, a tricyclic antidepressant, is the staple of oral treatment. Histamine-2 blockers such as cimetidine have shown some efficacy.
10.Intravesical agents such as silver nitrate, oxychlorosene (Clorpactin), dimethyl sulfoxide (DMSO), and sodium pentosan polysulfate (repairs the glycosaminoglycan layer) have all been used with limited success.
11.Long-term appropriate use of pain medication is an integral part of treatment of this disease.
12.Surgical treatment of this disease other than fulguration of a Hunner ulcer or hydrodistention should be an absolute last resort. Removal of the bladder or portions of the bladder has met with extremely limited success and is only rarely appropriate in highly selected circumstances. If frequency is a major symptom, it may be helped; however, relief of pain is unlikely to occur. Moreover, if intermittent catheterization is required, it may be very poorly tolerated.
13.Patient education, dietary manipulation, nonprescription analgesics, and pelvic floor relaxation sensation techniques constitute the initial treatment of BPS.
14.Sexual dysfunction is not uncommon in these patients.
15.A subpopulation of patients may have increased bladder mucosal permeability.
16.Pain memory in the spinal cord may be what causes the patient to become refractory to different therapies.
17.There may be a genetic component to the disease.
18.Urgency, frequency, and the presence of glomerulations or Hunner ulcer on endoscopy are often associated with BPS, but the presence of pain or discomfort is the primary component.
19.Substitution cystoplasty and continent diversion both fail in some BPS patients because of the development of pain in the bowel segment used or contraction of the bowel segment.
20.BPS appears to be a syndrome with neural, immune, and endocrine components in which activated mast cells play a central, although not primary, role in many patients.
21.Fibromyalgia, irritable bowel syndrome, chronic fatigue syndrome, and atopic allergic reactions are overrepresented in the BPS population.
22.Pain syndromes of the urogenital and rectal area include vulvodynia, orchialgia, perineal pain, penile pain, and rectal pain.
23.Cystometry in conscious BPS patients generally demonstrates normal function, the exception being decreased bladder capacity and hypersensitivity.
24.Glomerulations are not specific for BPS.
25.BPS is chronic, the symptoms wax and wane, and remissions are not uncommon.
26.The prevalence of BPS in men approaches that in women, suggesting that many men previously diagnosed with "prostatitis" actually have BPS as it is currently defined.