C. Lowell Parsons

Epithelial Dysfunction in Nonbacterial Cystitis (Interstitial Cystitis)

Traditional concepts of impermeability of the bladder have centered around unique cellular tight junctions and ion pumps. However, recent data from our laboratory have shown that the bladder epithelium in animals and humans relies primarily on its surface glycosaminoglycans to maintain its impermeability. This study demonstrates the first disease associated with an epithelial dysfunction of the bladder, that is a leaky epithelium. The study consisted of 31 normal subjects and 56 individuals with interstitial cystitis. Interstitial cystitis patients were shown to have a leaky epithelium by placing a solution of concentrated urea into the bladder and measuring the absorption. The normal subjects absorbed 4.3% in 45 minutes, while the interstitial cystitis patients absorbed 25% (difference is highly significant, p less than 0.005). Interstitial cystitis patients with Hunners ulcers (10) had a 34.5% absorption rate, while those without ulcers absorbed 22.8% (46). This difference also was highly significant (p = 0.002) and supports the concept that patients with ulcers have clinically worse disease.

A Quantitatively Controlled Method to Study Prospectively Interstitial Cystitis and Demonstrate the Efficacy of Pentosanpolysulfate

A randomized, prospective, double-blind, placebo-controlled study was conducted at 7 clinical centers on 148 patients. Patients received orally either 100 mg. pentosanpolysulfate (a synthetic polysaccharide) 3 times per day or a placebo. Of the patients on drug therapy 32% showed significant improvement compared to 16% of those on placebo (p = 0.01). This study provides a model to assess this disease quantitatively in a prospective manner using a method whereby the patients globally assess their symptoms as either worse or improved by 0, 25, 50, 75 or 100%. Patients on drug therapy also experienced a significant decrease in pain and urgency (p = 0.04 and 0.01) on analogue scales when compared to placebo and also more drug patients showed an average increase of more than 20 ml. in voided volume than did placebo patients (p = 0.02). All adverse effects were minor, with 7 in the drug group and 10 in the placebo group. The results support the concept that some patients with the interstitial cystitis syndrome may have abnormal bladder surface glycosaminoglycans.

Subclinical infection of the silicone breast implant surface as a possible cause of capsular contracture

In order to reexamine the possible association between bacterial presence and capsular contracture, 55 silicone devices (mammary implants or tissue expanders) were cultured at the time of their removal from 40 patients. Special culture techniques were used in an attempt to recover bacteria adhering to the smooth-surfaced implant and encased in glycocalyx biofilm. Bacteria were detected on 56% (15 of 27) of implants surrounded by contracted capsules and on 18% (5 of 28) of those without capsular contracture (p < 0.05). Only three implants tested positive using routine plating techniques. The predominant isolate was Staphylococcus epidermidis. The concept that capsular contracture is associated with subclinical infection of silicone implants is supported by this study. With changes in the microbiological technique, bacterial recovery and growth occurs at a frequency greater than previously thought.

Successful Therapy of Interstitial Cystitis with Pentosanpolysulfate

Sodium pentosanpolysulfate (Elmiron) is a synthetic, sulfated polysaccharide available in an oral form that is excreted into the urine. This drug was used in a double-blind fashion to evaluate its efficacy in the management of symptoms of interstitial cystitis. A dose of 100 mg. 3 times daily was used for a minimum of 4 months and was continued for longer than 18 months in some individuals. A total of 62 patients was evaluated from 2 different medical centers. Subjective improvements were greater in all parameters when the drug was compared to placebo therapy, with significant improvement in pain, urgency, frequency and nocturia. Objective improvement in average voided volumes was greater with the drug than with placebo (p equals 0.009). No significant difference was found between drug and placebo groups in the average number of daily voiding episodes.

Successful Treatment of Interstitial Cystitis with Sodium pentosanpolysulfate

The surface of the bladder is lined by a layer of sulfonated glycosaminoglycans, of which the nonspecific anti-adherence effect is reproduced by synthetic sulfonated glycosaminoglycans. This mucous layer appears to be the most important line of defense between the transitional cells and all harmful substances in the urine. Many disease states may be associated with a deficiency in the anti-adherence activity of the glycosaminoglycan layer and may benefit from treatment with synthetic glycosaminoglycans. One such disease is interstitial cystitis. We administered oral sodium pentosanpolysulfate (Elmiron), a synthetic analogue of a sulfonated glycosaminoglycan, to 24 patients with interstitial cystitis. Within 4 to 8 weeks of initiation of treatment 20 patients experienced a decrease of at least 80 per cent in pain, urgency and nocturia, and 2 experienced a 50 to 80 per cent decrease in these symptoms. The 22 patients who responded continue to experience progressive improvement with time.

Intravesical potassium sensitivity in patients with interstitial cystitis and urethral syndrome

OBJECTIVES To examine populations with diagnosed clinical interstitial cystitis (IC) and urethral syndrome and normal controls using the potassium sensitivity test (PST), to determine the incidence of PST-provoked pain and/or urgency, and to document the type and location of IC and urethral syndrome pain, association of pain with sexual intercourse, and family history of female urgency/frequency problems. METHODS The PST and a questionnaire were administered to 466 patients with clinical IC, 116 patients with urethral syndrome, and 42 controls. RESULTS The PST was positive in 78% of patients with clinical IC, in 55% of patients with urethral syndrome, and in 0% of the controls. Of the patients with clinical IC, 9% responded to the PST with pain only and 8% with urgency only. Patients with clinical IC reported the pain as dysuria (58%), urethral/vaginal (76%), above the pubic bone (53%), lower abdomen (47%), lower back (35%), vaginal (51%), and inguinal (28%). The results were similar for patients with urethral syndrome. Of the sexually active men and women, 71% with clinical IC and 59% with urethral syndrome reported pain associated with intercourse. Urgency/frequency problems in female relatives were reported by 35% of patients with IC and 33% of those with urethral syndrome. CONCLUSIONS The significant potassium sensitivity in both patients with clinical IC and those with urethral syndrome and the absence of potassium sensitivity in normal controls indicates that a positive PST suggests the presence of an abnormal bladder epithelium. The lower rate of positive PSTs in patients with urethral syndrome reflects the less severe, more intermittent, nature of the symptoms in urethral syndrome (early IC). Pelvic pain of bladder origin may occur anywhere in the pelvis. Finally, IC appears to have a genetic component.

Functional and Structural Characteristics of the Glycosaminoglycans of the Bladder Luminal Surface

The glycosaminoglycan layer of bladder has been proposed to play a crucial role in protecting the bladder from harmful substances in urine. Rats were partially cystectomized to determine whether bladder glycosaminoglycans are routinely eluted from the bladder surface in detectable quantities. Cystectomy produced no detectable qualitative or quantitative changes in excreted GAG thereby showing that most urinary glycosaminoglycan originates in the kidney and not from the bladder. Damaging the glycosaminoglycan layer by a dilute acid wash, however, leads to a consistent decrease in the output of urinary GAG which recovers to normal at the same rate as the layer regenerates. This suggests that the newly exposed sites tightly bind urinary GAG. We suggest that such binding may be a component of the normal physiological defense mechanism of the bladder. The bladder glycosaminoglycan layer was isolated, dilute acid being used to elute ionically-bound material and brief trypsinization to elute intercalated proteoglycans from the luminal surface. The GAG from the luminal surface, which was present at a density of one chain per 50 nm.2 of bladder surface, was quite different in composition from that isolated from the whole bladder.

The role of a leaky epithelium and potassium in the generation of bladder symptoms in interstitial cystitis/overactive bladder, urethral syndrome, prostatitis and gynaecological chronic pelvic pain

What’s known on the subject? and What does the study add?

Prostatitis, interstitial cystitis, chronic pelvic pain, and urethral syndrome share a common pathophysiology: lower urinary dysfunctional epithelium and potassium recycling.

S we fail to “see the forest for the trees.” In recent years, medical science has made substantial advances in understanding the pathophysiology of interstitial cystitis (IC). The disease still goes unrecognized in most affected individuals, however. Of the clinical symptoms of IC, urinary frequency/urgency has an obvious source, but pain can be referred to one or more locations throughout the pelvis in any combination.1–3 Unless the pain is perceived in the bladder or urethra, its origin is more difficult to identify. As a result, the patient who has frequency/urgency and/or pelvic pain may receive any of a variety of diagnoses. An abundance of recent data shows that many patients aged 55 years or younger, male or female, who present to a physician with a complaint of urinary urgency and/or pelvic pain in any combination suffer from one primary pathophysiologic disorder: an epithelial dysfunction in the lower urinary tract.2–6 This disorder can be called “lower urinary dysfunctional epithelium” (LUDE). On the basis of extensive evidence of the biochemical events that trigger symptoms and injure tissue in LUDE, a new paradigm can be constructed for IC that will aid in the diagnosis and treatment of this disease process. The goal of this review was to place new research findings into a broad and evidence-based perspective that will help the physician to diagnose IC readily and to direct therapy that relieves the patient’s symptoms and results in a real impact on disease outcome.

Gynecologic presentation of interstitial cystitis as detected by intravesical potassium sensitivity

OBJECTIVE To document the initial clinical diagnoses, determine the prevalence of urinary symptoms, and test for intravesical potassium sensitivity in gynecologic patients with chronic pelvic pain. METHODS Gynecologists at three United States medical centers administered the Potassium Sensitivity Test to consecutive unselected pelvic pain patients. Before testing, each patient was given an initial clinical diagnosis based on the patients chief symptomatic complaint(s) and surveyed for urologic symptoms. RESULTS Of 134 patients, 114 (85%) had positive potassium sensitivity. Positive potassium sensitivity rates were similar across all three sites and all clinical diagnoses including endometriosis, vulvodynia (vulvar vestibulitis), and pelvic pain. A total of 75% of the subjects reported urologic symptoms, but only 2.9% received an initial diagnosis of interstitial cystitis. CONCLUSION A significant majority of gynecologic patients presenting with pelvic pain have a positive Potassium Sensitivity Test, indicating their pain may have a bladder component (interstitial cystitis). Interstitial cystitis deserves greater consideration in the differential diagnosis of chronic pelvic pain.