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Interstitial Cystitis

Diagnostic overview and management update of bladder pain syndrome

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Interstitial cystitis (IC), also referred to as bladder pain syndrome (BPS), is a challenging disease for both patients and clinicians.1 Affecting mostly women, IC/BPS is characterized by bladder pain with lower urinary tract symptoms (LUTS) and negative urine culture results.­2 Patients presenting with chronic pelvic pain or recurrent aseptic LUTS should be evaluated for IC/BPS.

The exact etiology of IC/BPS is unknown.3 IC/BPS commonly resembles other conditions making it difficult for clinicians to identify. Patients can go several years before being given a diagnosis of IC/BPS.4 The goal of treatment is to minimize symptoms and improve quality of life.5

The American Urological Association (AUA) defines IC/BPS as "An unpleasant sensation (pain, pressure or discomfort) perceived to be related to the urinary bladder, associated with lower urinary tract symptoms of more than six weeks duration, in the absence of infection or other identifiable causes."5 LUTS, such as painful bladder filling relieved temporarily by voiding; urinary frequency and urgency; nocturia; and diffuse pelvic pain or pressure are commonly associated with IC/BPS.3 IC/BPS begins insidiously with mild symptoms that may go unnoticed and slowly progress. Symptoms will usually stabilize within one to two years and then become chronic.4

Epidemiology
Two large scale self-report studies estimate that 1.2 million women and 83,000 men living in the United States are currently suffering from IC/BPS.5 Diagnosis is most commonly made in the fourth decade of life or after with no significant variations noted between ethnicities.5

The incidence of IC/BPS is often associated with other urogenital diagnoses due to an extensive symptom overlap. This causes clinicians to lean toward a diagnosis with a better understood pathology. Conditions such as UTIs, vulvodynia, vaginitis, endometriosis, chronic prostatitis, chronic pelvic pain and overactive bladder (OAB) are often confused with IC/BPS.4

 Other conditions that commonly coexist with IC/BPS include anxiety and depression, chronic fatigue syndrome, fibromyalgia and irritable bowel syndrome (IBS), suggesting the presence of systemic dysfunction.5

Pathophysiology
The pathogenesis of IC/BPS is not completely understood. Believed to be multifactorial, suggested theories include glycosaminoglycan (GAG) layer defect, autoimmune mechanisms, pelvic floor dysfunction, and genetic predisposition. Due to mounting evidence, GAG layer defect is the most accepted hypothesis. GAG proteins are molecules found within the urothelium of the bladder which prevent bacterial adherence and secrete mucous that forms an impermeable barrier to urine. 4 In many IC/BPS patients, damage to the GAG layer allows urine to infiltrate the underlying layers of the bladder wall. This leads to inflammation and the activation and proliferation of mast cells.2 Mast cells secrete pro-inflammatory and nociceptive substances such as histamine, prostaglandins, and substance P (SP). These substances cause up-regulation of sensory innervation in the bladder to produce neuropathic pain, which results in hypersensitivity and pain with distension of the bladder.1

woman in painWith neurogenic inflammation, potassium molecules permeate the bladder wall and depolarize nerves and muscles, leading to tissue injury. This process causes excess activation of spinal cord neurons, resulting in pelvic pain. Excess stimulation of the central nervous system (CNS) leads to associated symptoms within the pelvic floor, gastrointestinal tract and other surrounding areas. This chronic inflammation can lead to fibrosis of the bladder wall causing altered bladder function due to decreased capacity.1

Symptomatology
The sensation of pain (pressure and discomfort) within the bladder upon filling which is relieved temporarily by voiding is seen in most patients who suffer from IC/BPS. Pain is mainly located in the suprapubic region, but can also be felt throughout the pelvis including the urethra, vulva, vagina and rectum.2 In some patients, pain may be felt in extra genital locations, such as the lower abdomen and lower back.1 Patients with IC/BPS commonly complain of urinary urgency, frequency and nocturia. Incontinence is not typically seen; the presence of this symptom can be used to distinguish IC/BPS from overactive bladder.5

Diagnostic Testing
The diagnosis of IC/BPS begins with a thorough history and physical examination. Extensive investigation of the patient's urologic, gastrointestinal, gynecologic and sexual history should be obtained and evaluated. Questionnaires are often used to identify the symptomatology patients present with and distinguish IC/BPS from other urologic etiologies.

The O'leary-Sant IC/BPS Symptom and Problem Index was originally created to evaluate the management of IC/BPS, but is now used as a diagnostic tool. It is composed of two scales. The symptom index measures severity of pain and level of urgency and the problem index measures the patient's experience with each symptom.  A minimum score of six points on each index is indicative of IC/BPS.2

The role of laboratory diagnostic studies in the evaluation of IC/BPS focuses on excluding other etiologies. Urinalysis with reflex to urine culture should be ordered to rule out infection. Positive symptomatic urine culture should be treated with appropriate antimicrobial therapy; the patient should be reassessed upon completion of treatment. In a patient with hematuria or a history of tobacco use, urine cytology should be ordered.1 Post void residual measurement can also be helpful to exclude urinary retention. While cystoscopy is not required for the diagnosis of uncomplicated IC/BPS, it is commonly ordered by clinicians to rule out other pathology. Common cystoscopic findings include glomerulations, pinpoint hemorrhages, pain during hydrodistention, and decreased bladder capacity.2 

Treatment
In 2014 the AUA restructured the treatment of IC/BPS into a six step algorithm. Each line of treatment is recommended based on its efficacy, potential benefits, potential adverse effects and the level of invasiveness. The hierarchy is not based on evidence strength alone.5 Pain management should be incorporated into each line of treatment tailored to the individual patients' needs.

 First Line Treatment - First-line treatment should begin with lifestyle changes and behavior modifications. Certain foods can irritate the bladder and exacerbate symptoms in patients with IC/BPS and should be limited. Acidic foods, specifically those high in citric acid, have been shown to intensify bladder pain. Conversely, alkalinizing agents have been shown to provide symptomatic relief. Refer to Table 1 for a list of dietary substances that may aggravate or alleviate IC/BPS symptoms.6 Improving emotional health through relaxation and stress management may also decrease symptoms. Bladder training which involves performing timed voids at progressively increasing intervals can increase bladder capacity improving urgency and frequency.1 For many patients, first-line treatment is successful and no further treatment is neccessary.3

 Second Line Treatment - Second-line therapy includes oral medications, physical therapy, and intravesical treatments. The goal of physical therapy is to manually relax the pelvic floor musculature.2 Physical therapy sessions should focused on relaxing trigger points, lengthening muscles contractures, and releasing painful connective tissue restrictions. Patients with IC/BPS do not have a weakened pelvic floor and therefore pelvic floor strengthening exercises are not recommended.5


The only oral medication that is FDA approved for IC/BPS is pentosan polysulfate sodium (PPS). PPS acts as[DB1]  a synthetic GAG layer and improves symptoms of pain and urgency.7 Amitriptyline  a tricyclic antidepressant, acts as an anticholinergic which results in bladder relaxation.2 Hydroxyzine is a histamine-1-receptor antagonist that blocks mast cell degranulation to prevent histamine release, which decreases nocturia, frequency and bladder pain.8 Cimetidine, a histamine-2-receptor antagonist, has been shown to decrease symptomatology in IC/BPS patients due to its antihistaminic mechanism of action.2[P2] 


The first choice for intravesical therapy is dimethyl sulfoxide; it is thought to have anti-inflammatory, analgesic and neuromodulatory properties. It is the only FDA approved medication for intravesical treatment. Another option for patients with IC/BPS is intravesical heparin, which is thought to help restore the damaged GAG layer. Intravesical alkalinized lidocaine can also be used to provide symptomatic relief by downregulating bladder sensory innervation.2

 Third Line Treatment - In patients with significant symptoms or those who have had an unsatisfactory response to first and second line treatment, cystoscopy with hydro distention may be recommended. During this outpatient procedure, the bladder is filled to capacity under relatively high pressure. This expansion of the bladder wall disrupts sensory innervation to decrease pain. This procedure may also stimulate GAG layer regrowth.2 Hunner's lesions, which are present in a small number of patients, can be identified during this procedure and fulgurated.9

 Fourth Line Treatment - If prior-line treatments are refractory, intradetrusor botulinum toxin A (BTX-A) may be administered. The main mechanism of action of BTX-A is relaxation of the bladder musculature which reduces pain upon filling. There is a risk of urinary retention associated with BTX-A, so patients who undergo this procedure should be aware of the possible need for intermittent catheterization post-treatment.5 An additional fourth-line option for patients is a trial electrical nerve stimulator, or neuromodulator. This device is thought to improve pain and urinary function via stimulation of the sacral or pudendal nerves. If this trial proves to be successful, a permanent device can be implanted.5, 10

 Fifth Line Treatment - The AUA suggests oral Cyclosporine A (CyA) as the fifth-line treatment option. CyA, an immunosuppressive agent, inhibits calcineurin, which halts the activation of T cells, leading to decreased bladder inflammation. Patients with Hunner lesions usually respond better to CyA therapy. Patients should be advised on the potential toxic side effects and that it can take up to four months to notice results.11

 Sixth Line Treatment - The last resort for IC/BPS therapy is surgical intervention. Patients with severely limited bladder capacity who have failed all prior lines of treatment may be eligible for a urinary diversion or bladder augmentation surgery. Patients should be counseled that these procedures are irreversible and require lifelong management with either catheterization or ostomy appliance.2

Recommendations for Practice
IC/BPS is often a diagnosis of exclusion with symptoms that can overlap other disease processes. This often presents a diagnostic challenge to clinicians and a delay in treatment. Thorough history and physical examination should be performed in conjunction with laboratory tests to exclude other common urogenital conditions.  First-line management of this condition can be initiated after the diagnosis is suspected. Persistent LUTS and perceived bladder pain upon filling should warrant referral to a urologic specialist for further evaluation and treatment. Achieving satisfactory symptom control is often a multi-step process. Patients should be educated on their treatment options and reevaluated at regular intervals to assess efficacy and patient quality of life.

Whitney Nolan and Natasha Camera are assistant professors and clinical coordinators in the Physician Assistant program at Gannon University in Erie, Pa[DB3] . Allison McDonald is a 2016 graduate from the Gannon University PA program and currently works for Lakeview Urologic Surgeons in Erie, Pa.

References

1. Miller LA, Gardner A. Interstitial cystitis: a current guide to diagnosis and treatment. JAAPA. 2012;25(6):28-32.

2. Gish BA. Interstitial cystitis/bladder pain syndrome. Nurs Womens Health. 2012;15(6):497-507.

3. Anderson R, Zinkgraf K. Use and effectiveness of complementary therapies among women with interstitial cystitis. Urologic Nursing. 2013;33(6):306-311.

4. Martin E, Sheaves C, Childers K. Underlying mechanisms and optimal treatment for interstitial cystitis: a brief overview. Urologic Nursing. 2015;35(3):111-115.

5. Hanno PM, Erickson D, Moldwin R, et al. Diagnosis and treatment of interstitial cystitis/bladder pain syndrome: AUA guideline amendment. J Urol. 2015;193(1):1545-1553.

6. Friedlander JI, Shorter B, Moldwin RM. Diet and its role in interstitial cystitis/bladder pain syndrome (IC/BPS) and comorbid conditions. BJU Int. 2012;109(1):1584-1591.

7.  Pentosan polysulfate sodium. Interstitial Cystitis Association Web site. http://www.ichelp.org/diagnosis-treatment/treatments/pentosan-polysulfate-sodium/. Revised March 25, 2015. Accessed February 5, 2016.

8.  Antihistamines. Interstitial Cystitis Association Web site. http://www.ichelp.org/diagnosis-treatment/treatments/antihistamines/. Revised March 25, 2015. Accessed February 5, 2016.

9.  Payne RA, O'Connor RC, Kressin M, Gurlanick ML. Endoscopic ablation of Hunner's lesions in interstitial cystitis patients. CUAJ. 2009;3(6):473-477.

10.  Neuromodulation. Interstitial Cystitis Association Web site. http://www.ichelp.org/diagnosis-treatment/treatments/neuromodulation/. Revised March 25, 2015. Accessed February 5, 2016.

11. Forrest JB, Payne CK, Erickson DR. Cyclosporine A for refractory interstitial cystitis/bladder pain syndrome: experience of 3 tertiary centers. J Urol. 2012;188(1):1186-1191.

 


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