Interstitial cystitis

Introduction

a treatable but essentially incurable condition occurring in the absence of any known etiology
encompasses a major portion of the "painful bladder" disease complex, which includes a large group of patients with bladder and/or urethral and/or pelvic pain, irritative voiding symptoms (urgency, frequency, nocturia, dysuria), and sterile urine cultures
occurring predominantly in women (10:1), there are striking similarities between IC and the newly coined chronic pelvic pain syndrome in men, a poorly understood symptom complex that was formerly referred to as "nonbacterial prostatitis and prostatodynia
IC is truly a diagnosis of exclusion . It may have multiple causes and represent a final common reaction of the bladder to different types of insult.

Historical perspective

Skene (1887) used the term to describe an inflammation that has "destroyed the mucous membrane partly or wholly and extended to the muscular parietes”
Early in the 20th century, at a New England section meeting of the American Urological Association, Guy Hunner reported on eight women with a history of suprapubic pain, frequency, nocturia, and urgency lasting an average of 17 years. He drew attention to the disease, and the red, bleeding areas he described on the bladder wall came to have the pseudonym "Hunner's ulcer."
Hand (1949) wrote the first comprehensive paper about the disease, seminal
reviewing 223 cases.
three grades of disease, with grade 3 matching the small-capacity, scarred bladder described by Hunner.
Sixty-nine percent of patients were grade 1 and only 13% were grade 3
Messing and Stamey (1978) discussed the "early diagnosis" of IC
They turned attention from looking for an ulcer to make the diagnosis to the concepts that
symptoms and glomerulations found with the patient under anesthesia were the disease hallmarks and the diagnosis was primarily one of exclusion


Diagnostic criteria

NIDDK research criteria too stringent. Thus, IC remains a clinical syndrome defined by chronic symptoms of urgency, frequency, and/or pain in the absence of any other reasonable causation

Epidemiology

In 1987, there were 43,500 (perhaps up to 90,000) diagnosed cases of IC in the United States, approximately twice the prevalence in Finland found by Oravisto 12 years earlier. Median age of onset is 40 years.
No reports have ever documented a relationship to suggest that IC is a premalignant lesion
A large-scale survey of 6783 individuals, diagnosed by their physicians as having IC, studied the incidence of associated disease in this population
Allergies were the most common disorder, with 41% diagnosed with allergies and 45% with allergic symptoms
30% had a diagnosis of irritable bowel syndrome
Fibromyalgia is overrepresented in the IC population
Inflammatory bowel disease was found in over 7% of the IC population (100X that in gen population)
Sjögren's syndrome

Aetiology
Infection
Mast cell involvement
Increased mucosal permeability
Neurogenic mechanisms
Hypoxia, Reflex Sympathetic Dystrophy
Urine abnormalities
Autoimmunity/inflammation
IC is a multifactorial syndrome
Elbadawi and Light (1996) have suggested such a pathogenesis based on a potentially self-perpetuating process of neurogenic inflammation that can trigger a biologically potent cascade of events, including a leaky urothelium and mast cell activation

Epithelial permeability: KCl
Potentially strong evidence for a population with mucosal leak has been reported by Parsons (1994) who showed that KCl provoked 4.5% of normals and 70% of IC patients. Intravesical administration of KCl has since been proposed as a diagnostic test for IC (Parsons et al, 1998).
KCl: Normal bladder epithelium is not absolutely tight, and there is always some leak, however small. The findings of pain with KCl may be due to a hypersensitivity of the sensory nerves in this condition, rather than to pathologic epithelial permeability, at least in some patients


Pathology
One can have pathology consistent with the diagnosis of IC, but there is no microscopic picture pathognomonic of this syndrome
Attempts to definitively diagnose IC by electron microscopy have also been very unsuccessful
The role of histopathology in the diagnosis of IC is primarily one of excluding other possible diagnoses
Johansson and Fall (1990) looked at 64 patients with ulcerative disease and 44 with nonulcerative IC.
Ulcerative group: mucosal ulceration and hemorrhage, granulation tissue, intense inflammatory infiltrate, elevated mast cell counts, and perineural infiltrates.
The nonulcer group had a relatively unaltered mucosa with a sparse inflammatory response, the main feature being multiple, small, mucosal ruptures and suburothelial hemorrhages that were noted in a high proportion of patients.
Because these specimens were almost all taken immediately after hydrodistention, how much of the admittedly minimal findings in the nonulcer group were purely iatrogenic is a matter of speculation
pathologically, the two types of IC may be completely separate entities
mast cell counts per se have no place in the differential diagnosis of this clinical syndrome.
Diagnosis
Frequency and pelvic pain of long duration unrelated to other known causes establish a working diagnosis
One must rule out
infection
carcinoma
eosinophilic cystitis
malakoplakia
schistosomiasis
scleroderma
detrusor endometriosis
Various gynecologic problems even when not directly involving the bladder like pelvic endometriosis, vulvodynia, pelvic infection, urogenital atrophy, and leiomyoma can mimic the pain of IC
Reports of successful treatment of IC symptoms by laparoscopic adhesiolysis or urethral diverticulum excision give credence to the fact that IC is a diagnosis of exclusion. Many drugs, including cyclophosphamide, NSAIDs, and allopurinol, have caused a nonbacterial cystitis that resolves with drug withdrawal

Cystoscopy (under anaesthesia with hydrodistention)
Pain on bladder filling which reproduces the patient's symptoms is very suggestive of IC, allows for sufficient distention of the bladder to afford visualization of either glomerulations or Hunner's ulcers. Glomerulations are not specific for IC and only when seen in conjunction with the clinical criteria of pain and frequency can the finding of glomerulations be viewed as significant. Bladder biopsy is indicated only if necessary to rule out other disorders that might be suggested by the cystoscopic appearance


Treatment:
Treatments are empirical, symptoms can be controlled with one of a variety of treatments in majority, and there is little evidence that treatment does more than improve symptoms, rather than cure the condition.
There is a 50% incidence of temporary remission unrelated to therapy, with a mean duration of 8 months

Hydrodistension
Hydrodistention of the bladder with the patient under anesthesia, although technically a surgical treatment, is frequently the first therapeutic modality employed, often as a part of the diagnostic evaluation
A therapeutic hydraulic distention for 8 minutes after inspection of bladder for glomerulations and ulceration.
Therapeutic responses in patients with a bladder capacity under anesthesia of less than 600 ml showed 26% with an excellent and 29% with a fair result compared with 12% excellent and 43% fair in patients with larger bladder capacities (Hanno and Wein, 1991). Most improvements lasted less than 6 months. A capacity under anesthesia of under 200 ml would not bode well for the likelihood of success of medical therapy.
Reassure patient that disease not life threatening
Explain chronicity of disease and that treatments may not be successful
Empower patients (self help groups, pamphlets)
Lifestyle measures (stress reduction, exercise)

Dietary restrictions
Unsupported by any literature. Many patients find avoiding certain foods helpful (caffeine, alcohol, urine acidifying beverages such as cranberry juice)
Timed voiding/bladder drill
Biofeedback to help relax pelvic floor

Tricyclics
Amitriptyline has become a staple of oral treatment for IC.
The tricyclics possess varying degrees of at least three major pharmacologic actions:
They have central and peripheral anticholinergic actions at some but not all sites
they block the active transport system in the presynaptic nerve ending that is responsible for the re-uptake of the released amine neurotransmitters serotonin and noradrenaline,
they are sedatives, an action that occurs presumably on a central basis but perhaps is related to their antihistaminic properties
Hanno and Wein (1987) first reported a therapeutic response to amitriptyline in one of their patients concurrently being treated for depression

Antihistamines
The use of antihistamines goes back to the late 1950s and stems from work by Simmons
Theoharides (1994) have been the major modern proponents of antihistamine therapy and have shown 30% improvement in symptoms.

Sodium Pentosanpolysulfate (PPS)
Parsons' suggestion that a defect in the GAG layer contributes to the
pathogenesis of IC
synthetic sulfated polysaccharide (PPS) (Elmiron), a heparin analogue available in an oral formulation, 3% to 6% of which is excreted into the urine
100mg tds

Analgesics
The long-term, appropriate use of pain medications forms an integral part of the treatment of a chronic pain condition like IC
Most patients can be helped markedly with medical pain management using pain medications commonly employed for chronic neuropathic pain syndromes including antidepressants, anticonvulsants, and opioids
nonopioid analgesics including nonsteroidal anti-inflammatory drugs (NSAIDs) and even antispasmodic agents have a place in therapy
the use of long-term opioid therapy in the rare patient who has failed all forms of conservative therapy can be considered
Intravesical Therapy
Intravesical lavage with one of variety of preparations has remained a mainstay of treatment in the therapeutic armamentarium of IC
oldest of the intravesical therapies is silver nitrate (Mercier 1855)
DeJuana and Everett (1977) had a 50% response rate in 102 patients.
Clorpactin WCS-90 (O’Connor 1955) their success rate was 72% with an average 6-month duration of response (Messing and Stamey 1978)

DMSO
A mainstay of the intravesical treatment of IC is the instillation of DMSO
DMSO is a product of the wood pulp industry and a derivative of lignin
freely miscible with water, lipids, and organic agents.
Pharmacologic properties include membrane penetration, enhanced drug absorption, anti-inflammatory, analgesic, collagen dissolution, muscle relaxation, and mast cell histamine release.Stewart and associates (1968) were responsible for popularizing intravesical DMSO for IC.
Heparin has also been used, and Parsons advocates the use of 40,000 units of heparin in 20 ml sterile water, self-administered by the patient daily and held for 30 to 60 minutes. Reasonable improvement after 6 months
PPS, another GAG analogue, has been shown to have a modest benefit
Trials with hyaluronic acid have shown response rates of 30 to 70%
Intravesical BCG first reported by Zeidman 1994 showing a 60% response rate compared with a 27% placebo response (Peters et al, 1997)
Well tolerated
It is unclear how BCG achieved this result, but immunologic and/or anti-inflammatory mechanisms have been postulated (Peters et al, 1999).
A small Swedish study failed to substantiate BCG efficacy (Haghsheno et al, 2000; Peeker et al, 2000).

Other intravesical agents
Other possible treatements intravesically include oxybutinin, capsaicin.
TENS has been shown to be helpful. Fall (1980:14 women treated successfully with long-term intravaginal stimulation or TENS)
Sacral neuromodulation of S3 may prove to be effective.

Surgery
The surgical therapy of IC is an option after all trials of conservative treatment have failed
IC is a nonmalignant process with a temporary spontaneous remission rate of 50% that does not directly result in mortality
Transurethral resection of Hunner's ulcer, as initially reported by Kerr (1971), can provide symptomatic relief.
Disappearance of pain and decreased frequency in 21/30 pts (Fall 1985)
Similar results have been attained with the Nd:YAG laser
Extreme caution required
Substitution cystoplasty
Urinary diversion
Substitution cystoplasty

Supratrigonal cystectomy and the formation of an enterovesical anastomosis with bowel segments has been a popular surgical procedure for intractable IC (Worth and Turner-Warwick, 1972)
Flood (1995) reviewed 122 augmentation procedures, 21 of which were done for IC.
Patients with IC had the poorest results of any group, with only 10 having an "excellent" outcome
Webster and Maggio (1989) reviewed their data in 19 patients, and concluded that only patients with a bladder capacity less than 350 ml under anesthesia should undergo substitution cystoplasty
Some advocate diversion and/or total cystourethrectomy if the trigone is "affected" by IC (on biopsy, although biopsy findings are not pathognomonic, and IC tends to affect the whole of the bladder)
There has been a controversy over whether the IC process can occur in a transposed bowel patch. Urinary diversion with or without cystourethrectomy is the ultimate surgical answer to the dilemma of IC. Cystourethrectomy is certainly indicated in patients who not only have failed all other therapies but also have demonstrated chronicity such that remission is considered extremely unlikely.

Risks of failure peculiar to IC include both the development of phantom pain in the pelvis that persists despite the fact that the stimulus that initially activated the nociceptive neurons (diseased bladder) has been removed. Despite all of the problems, many patients will do well after major surgery, and quality of life can measurably improve. The surgical route needs to be persued with extreme amount caution and patient motivation has to be taken into account.