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Selected Abstracts on IC from American Urological Association (AUA) Meetings
IC Update 2006 - AUA Meeting Abstracts SAFETY AND EFFICACY OF HYPERBARIC OXYGEN THERAPY FOR THE
TREATMENT OF INTERSTITIAL CYSTITIS: A RANDOMIZED, SHAMCONTROLLED, DOUBLE-BLIND TRIAL
INTRODUCTION AND OBJECTIVE: In a recent pilot study, serving as "proof-of-principle", we Reported the therapeutic potential of hyperbaric oxygenation (HBO) for interstitial cystitis (IC) suggesting that HBO has promise as a treatment modality for IC. This study was designed to further evaluate the safety, efficacy and feasibility of HBO for IC. METHODS: We conducted a prospective, randomized, double-blind, sham-controlled study with 21 patients suffering from IC. Patients were randomized to 90 minutes treatment in a multiplace hyperbaric chamber pressurized with 100% O2 to 2.4 atmosphere absolute (ata.) for 30 treatments sessions or 1.3ata. breathing normal air in the control group. Allocation to sham or verum treatment followed a 1:2 distribution. Patients reporting improvement in a Global Response Assessment questionnaire were defined as treatment responders (primary outcomes). Secondary measurements included changes of pain and urgency, functional bladder capacity and frequency. Changes in the O'Leary-Sant IC index and rating of overall satisfaction with the therapeutic outcome were reported as well.The code was broken after evaluation at 3 months, efficacy of treatment was assessed at the end of treatment and after a follow-up interval of 1, 3, 6, 9 and 12 months. RESLUTS: 2 verum patients dropped-out of the study. 8 out of 12 verum patients and none of the control patients were identified as responders (p<0.001). At 12 months follow-up 5 verum patients (41.6%) still reported response to HBO treatment. HBO resulted in a decrease of urgency intensity from 60.2 ± 15.0mm. at baseline to 49.4 ± 23.9mm. at 3 months and decrease of pain intensity from 43.1 ± 20.5mm. to 29.0 ± 22.4mm. respectively (p<0.05). The O'Leary/Sant index sum dropped from 25.7 points to 19.6 points in the verum patients. Sham treatment did not result in improvement of any baseline parameters. CONCLUSIONS: 30 treatment sessions of HBO appear to be a safe, efficacious and feasible therapeutic approach to IC. In the treatment responders, application of HBO resulted in a sustained decrease of IC symptoms with a discordant profile regarding the peak amelioration of the various IC symptoms compared with a normobaric, normoxic sham treatment. Dr. Burstein's Comment: Normal oxygen pressure at sea level is measured as one atmosphere. By increasing the pressure more than two-fold (2.4 atmospheres) patients in this study received significant improvement in IC symptoms. Hyperbaric treatment has been shown to improve wound healing and is currently being utilized for a variety of disorders including autism. . The treatment is cumbersome, requiring multiple, relatively long sessions in a sealed chamber. The mechanism of action is thought to be a reduction in cellular inflammation by increasing the local oxygen concentration. This is the first appearance of a properly controlled study utilizing hyperbaric treatment for IC patients and hopefully, further studies will confirm these findings
BOTULINUM TOXIN TYPE A INHIBITS SUBSTANCE P RELEASE IN
INFLAMMATORY RAT BLADDER MODEL
INTRODUCTION AND OBJECTIVE: An increasing body of evidence suggests that neurogenic inflammation originating from afferent bladder neurons may play a role in urinary tract disorders such as interstitial cystitis. We sought to determine the effect of botulinum toxin type A (BTX-A) on the release of the nociceptive neurotransmitter, substance P (SP), in a bladder model of chronic inflammation. We hypothesized that BTX-A administration would suppress SP release. METHODS: Adult male Sprague-Dawley rats underwent intraperitoneal injection of cyclophosphamide (CYP) (75 mg/kg) every third day for ten days. Control animals received a corresponding volume of saline. Whole organ bladder specimens were obtained from all animals on day ten and mounted on polystyrene rods. Bladders were incubated (15 min per incubation) in two tissue baths (1.0 ml) containing physiologic salt solution (PSS) to allow for equilibration. The bladders were then transferred to another bath (PSS, 1.0 ml) and incubated for 15 min. These samples were collected and used as a measure of basal SP release. To measure the effect of BTX-A on release of SP, bladders were incubated (6 hrs) in an organ bath containing BTX-A (50 •M) or vehicle following equilibration. SP release was determined by radioimmunoassay. RESULTS: Basal release of SP was 245 ± 45 pg/g in control group. Basal SP release in the CYP-treated group increased to 430 ± 155 pg/g, representing a 76% increase over control (p<0.05). Bladder histology following CYP application revealed atrophic epithelium, cytologic atypia, and hemorrhagic lamina propria. BTX-A application reduced SP release to 293 ± 155 pg/g, representing a 32% reduction in basal release of SP as compared to the inflammatory model. Basal SP release in CYP group pre-treated with BTX-A demonstrated no statistical difference from control animals (p=0.21). CONCLUSIONS: Application of BTX-A inhibits release of SP from nerve terminals in an inflammatory rat bladder model. This finding suggests a potential clinical benefit of BTX-A application in the treatment of neurogenic inflammation that may underlie bladder disorders such as interstitial cystitis. SOURCE OF FUNDING: None Dr. Burstein's Comment: Limited clinical studies have shown Botox (botulinum toxin) bladder injection therapy to be effective in treating refractory urge incontinence and severe urinary frequency. Unfortunately, this is currently not an FDA approved use. Several studies are underway to help establish botox as an appropriate option for severe, unrelenting cases. However currently, its use is essentially "experimental" and is not reimbursed by insurance carriers. This animal study supports a possible mechanism of action of botox on a "clinical basic science" level. It also supports the need for further evaluation of the use of Botox for painful bladder.
INSTILLATION OF LIPOSOMES IS SUPERIOR TO DMSO OR PENTOSAN
POLYSULFATE IN REDUCING BLADDER HYPERACTIVITY INTRODUCTION AND OBJECTIVE: To compare effect of intravesical liposomes (LPs), dimethyl sulfoxide (DMSO), and pentosan polysulfate (PPS) on a model of chemically-induced overactive bladder in the rat. Previously, our lab has demonstrated partial reversal of protamine sulfate (PS) and potassium chloride (KCL) -induced bladder hyperactivity by intravesical LP. The relative impact of LP versus other agents used in the clinic for treatment of IC is unknown. METHODS: Bladder reflex activity of female SD rats (250300g) was evaluated by continuous cystometry under urethane anesthesia (1.2g/kg). A transurethral bladder catheter (PE-50) connected by three-way stopcock to a pressure transducer and syringe pump used to record intravesical pressure. A control cystometrogram (CMG) was obtained by slow filling with normal saline (0.04mL/min) for 2h. Bladder hyperactivity was then induced by 1 hour infusion of PS (Sigma Chemical, 10 mg/mL) followed by a 1 hour infusion of KCl (500mM). Animals were then infused with KCl-based preparations containing either 50% DMSO (n=5), pentosan polysulfate (300mg in 50mL, n=5), or liposomes (Lipella Pharmaceutical, n=5) for 2h. The parameters measured included the intercontraction interval (ICI) and pressure threshold (PT) as well as baseline pressure (BP) which is representative of the post- contraction pressure nadir. RESULTS: After induction of hyperactive bladder, there was no significant difference in ICI, PT, or BP among groups. No statistically significant increase in ICI was observed with DMSO infusion. ICI was increased following infusion of PPS (109.3% increase, p<0.005) and LP (185.7% increase, p=0.005) (Figure 1). PT was not significantly affected by LP infusion but showed a small increase with PPS (12.4% increase, p<0.05). A large and significant increase in PT was elicited by DMSO (116.5% increase, p<0.005). BP was increased with DMSO (119.6%, p=0.005) but not with LP or PPS. CONCLUSIONS: Intravesical instillation of DMSO did not have a beneficial effect in a PS/KCL bladder hyperactivity model while both PPS and liposome did with the intravesical liposome achieving nearly doubling of the intercontraction interval above PPS. Intravesical liposome may be considered a new therapy for interstitial cystitis. Dr. Burstein's Comment: This is an animal study that compared the effect of 3 different bladder instillation (irrigation) therapies on a model of chemically-induced overactive bladder in the rat. Dimethyl sulfoxide (DMSO), and pentosan polysulfate (Elmiron) are two well-known treatments that are FDA approved for IC. Liposomes are a novel approach to treat and deliver drugs. They are the lipid (fatty) portions of animal cell walls that form into a hollow sphere in the presence of a water solution. A liposome can be thought of as an empty ball of fat. Drugs can be inserted inside them and then used as a "drug delivery system". In this study only "empty" liposomes were used and surprisingly had the most beneficial effect on bladder hyperactivity compared to Elmiron and DMSO.
EFFECT OF IP-751, AJULEMIC ACID, AGAINST ACETIC ACID INDUCED
BLADDER PAIN RESPONSES IN RATS 24H AFTER INTRAVESICAL
ADMINISTRATION
INTRODUCTION AND OBJECTIVE: Ajulemic acid (IP-751) is a potent analog of tetrahydrocannabinol (THC)-11-oic acid, which is a major metabolite of THC, the principal psychotropic constituent of Cannabis. Studies on isolated tissue strips of various species have shown inhibitory role of CB agonists on neuronally evoked contractions of bladder. Thus, we hypothesized that IP751 is effective to suppress urinary frequency and bladder pain responses in bladder hypersensitive disorders such as interstitial cystitis. The aqueous insolublity of Ajulemic acid (cannabinoid receptor agonist IP-751) prompted its formulations into liposomes for its evaluation after intravesical administration to determine the duration of biological activity against acute bladder irritation induced in rats. METHODS: The cannabinoid agonist IP-751 was formulated into liposomes with lipid and drug in 2:1 molar ratio and a final drug concentration of 0.8mg/ml. Female Sprague Dawley rats were instilled 0.5ml of either saline or liposomal IP-751 for 30min under halothane anesthesia. Liposomes in absence of drug were also instilled in control rats. 24h after instillation, continuous cystometrograms were performed under urethane anesthesia by filling the bladder (0.04 ml per min) with saline, followed by 0.125% acetic acid. Decrease in intercontraction intervals (ICI) of each rat by acetic acid over its baseline value was calculated as percent reduction. Results: Rats instilled with saline 24h earlier showed a decrease in ICI after intravesical instillation of acetic acid (83+6.4% decrease, n=5). However, rats instilled with liposomal IP-751 showed a significantly decreased response (percent decrease of ICI 24.7+ 6.4%, n=5) to acetic acid infusion (p<0.05, unpaired t-test) as compared to control groups. Rats instilled with inert liposomes devoid of drug showed ICI similar to saline treated rats. CONCLUSIONS: This is the first report evaluating the effect of a cannabinoid agonist after intravesical administration. Liposomal formulation of IP-751 can suppress bladder nociceptive responses induced by bladder irritation. A 30 minute instillation has sustained biological activity of at least 24 hours. Liposome can effectively deliver hydrophobic drugs such as IP-751 and further studies are warranted to determine the mechanism of its action by this new route of administration. Intravesical liposomal formulation of ajulemic acid may be a promising treatment in patients with painful bladder syndrome/interstitial cystitis. Dr. Burstein's Comment: This study evaluated the effect of liposomes on bladder pain response whereas the previous study evaluated the effect on bladder overactivity. It compared the result of "empty" liposomes to that of liposomes full of ajulemic acid, which is an analog of cannabis. The authors conclude that cannabinoid formulated liposomes were more effective in suppressing pain responses when compared to either "empty" liposomes or saline (salt) solution. Cannabis is known to have several medicinal properties including relief of pain, relief of nausea and appetite stimulation. The use of liposomes as a drug delivery system is certainly "cutting edge" and investigation of the use of cannabinoids for pain control is well overdue. SEXUAL FUNCTIONING AS A DETERMINANT OF POOR QUALITY OF LIFE
IN INTERSTITIAL CYSTITIS
INTRODUCTION AND OBJECTIVE: Interstitial cystitis (IC) significantly impacts patients' quality of life (QoL). If interventions are to be developed with comprehensive empirical support, a better understanding of the disease components affecting QoL is needed. This study examines the interrelationship of IC symptoms and associated bother, employment, and sexual function on QoL in a sample of patients with moderate to severe IC of long duration. METHODS: Baseline (pre-treatment) data were evaluated from women with moderate/severe IC enrolled in the Interstitial Cystitis Clinical Trials Group randomized controlled trial of BCG versus placebo. Demographic data and responses to the following questionnaires were evaluated: O'Leary-Sant IC Symptom Index (ICSI; 0-20) and Problem Index (ICPI; 0-20), University of Wisconsin IC Inventory (WICI; 0-42), MOS Sexual Functioning Index (SexFn; 0-12), and the Physical Composite (PCS) and Mental Composite (MCS) Scales of the MOS SF-36 (both 0-100). Three composite indices (all 0-20) were constructed from individual symptom scale items, pain and urgency Likert scales, and voiding frequency from a 24-hour diary to document the severity, frequency and bother of pain (CPain), urinary urgency (CUrg), and frequency (CFreq). Linear regression was used to evaluate predictors of MCS and PCS. SexFn data were available for 163 of the 217 women in the trial. RESULTS: The median age was 46 years. Patients reported moderate/severe symptoms on the constructed indices (medians CPain=15.6, CUrg=15.7, CFreq=11.5) and validated questionnaires (medians WICI=34; ICSI=15; ICPI=13). PCS (median 36) and MCS (median 42) were lower than a standard population value of 50. Univariate models showed strong associations (p<.001) for PCS with employment, WICI, ICSI and ICPI, CPain, CFreq, and SexFn, and a weak association with CUrg (p=.026). Strong associations were also exhibited for the MCS with CPain and SexFn, with weaker associations with employment, WICI, and ICPI. However, multivariate models showed that only employment, CPain, and SexFn (all p<.001) independently predicted PCS while only SexFn (p<0.001) remained a strong predictor of MCS. CONCLUSIONS: This study identifies sexual functioning as a strong predictor of both mental and physical QoL. The nature of these relationships remains unstudied. Sexual functioning, employment, and pain issues may be therapeutic targets in a multifaceted approach to treatment of IC patients. SOURCE OF FUNDING: National Institutes of Health Dr. Burstein's Comment: The most important objective of treating patients with long-term, chronic disease is to improve their quality of life. Although pain and frequency may not be "cured" it is imperative that IC patients maintain or regain near-normal lifestyles including employment, adequate relief or suppression of pain, and healthy social and family activities. Validated questionnaires such as those used in this study are very helpful in establishing baseline quality of life issues and for documenting progress during treatment. However, in clinical practice they can be cumbersome and time consuming. The conclusion from this study that is most impressive is that overall quality of life is highly associated with quality of sexual functioning. In other words, the single most relevant question I can ask a patient to determine their relative quality of life is " How satisfactory is your sex life?" Fulfillment with intimacy is the most significant issue that determines a patient’s quality of life. EFFECTS OF COMESTIBLES ON SYMPTOMS OF INTERSTITIAL CYSTITIS
INTRODUCTION AND OBJECTIVE: Dietary changes seem to improve symptoms of individuals afflicted with painful bladder syndrom (PBS)/interstitial cystitis (IC). Since most of the data gathered on diet as it affects IC symptoms is anecdotal, we developed a validated questionnaire in order to determine if certain foods, beverages and/or dietary supplements are perceived as affecting symptoms of IC. METHODS: A questionnaire designed to detect whether food, beverages and/or supplements have an effect on bladder symptoms was developed, validated and administered to patients meeting NIDDK criteria for IC (n=37). In addition to answering general questions about the effect of comestibles on IC symptoms, subjects were asked to indicate whether each of over 150 individual items worsens symptoms, slightly worsens symptoms, has no effect, slightly improves symptoms, improves symptoms, or the item is not eaten by the subject; responses were recorded as -2, -1, 0, +1, +2, DE, respectively. RESULTS: Consumption of comestibles caused exacerbation of symptoms in 73% of IC patients; 5% indicated no exacerbation of symptoms and 22% didn’t know. 18% of the subjects indicated that consumption of certain items reduced symptoms. Of those reporting exacerbation of symptoms, 75% reported exacerbation of symptoms after ingestion of coffee, cola, grapefruit and vinegar; 50-75% reported exacerbation of IC symptoms after ingestion of spicy foods, pizza, alcoholic beverages, strawberries, tomatoes. Subjects tended to avoid the most bothersome foods, indicating that they did not eat chili (50%), orange juice (41%), lemons (41%), spicy foods (41%), pineapple (36%), decaffeinated coffee (36%), grapefruit (32%), alcoholic beverages (32%), coffee (27%), oranges (27%), cola (27%), vinegar (27%). The rank order of specific comestibles which exacerbated symptoms is coffee, grapefruit, cola, vinegar, alcoholic beverages, tomatoes, tomato products,lemons, orange juice, chili, strawberries, pineapple, oranges, onions, pizza,chocolate, decaffeinated coffee, apples; coffee was the most bothersome with a mean value of -1.85. CONCLUSIONS: There is a large cohort of IC patients whose symptoms are exacerbated by ingestion of specific comestibles. The most frequently reported and the most bothersome comestibles include items containing caffeine, citrus fruits and juices, tomatoes and tomato products, items containing vinegar, and alcoholic beverages. SOURCE OF FUNDING: None Dr. Burstein's Comment: Although patients frequently state that their symptoms of IC are affected by diet, these reports are considered as "anecdotal" information based on secondhand accounts rather than firsthand knowledge or scientific investigation. This is the first study that I am aware of that statistically validates the significance of diet on the symptoms of IC. This study confirms that 73% reported worsening of symptoms with the consumption of specific foodstuffs (comestibles) and that the most common offenders were coffee, citrus products and tomatoes. Nothing earthshakingly new but we now know that the effects of diet on IC symptoms can be scientifically validated.
PAINFUL SYMTOMS EVALUATED BY NIH-CPSI ARE HIGHLY
ASSCOSIATED WITH CYSTOSCOPIC FINDINGS CONSISTENT WITH
INTERSTITIAL CYSTITIS IN ELDERLY MALE PATIENTS UNDERGOING
PROSTATE BIOPSY
INTRODUCTION AND OBJECTIVE: Glomerulation has been considered as one of criteria for the diagnosis of interstitial cystitis (IC). Its specificity, however, still remains to be clarified. The present study was conducted to reveal the prevalence of glomerulation in male selected population and to correlate with clinical parameters available including symptoms as evaluated by National Institutes of Health Chronic Prostatitis Symptom Index (NIH-CPSI). METHODS: Informed consent was obtained from all patients. Hydrodistention was performed in 78 elderly male patients (52-86 years old, mean 69) under spinal anesthesia, in whom transperineal systematic prostate biopsy was performed because of abnormally elevated serum PSA levels (4.1 to 95.0ng/ml). Cystoscopy was performed with drip infusion of saline by gravity from a height of 60 cm and hydrodistention was stopped when 500ml of saline was infused. Vascular events were examined during the filling and emptying phases. Cystoscopic findings were compared with conventional clinical parameters and symptoms as evaluated by NIH-CPSI and IPSS. RESULTS: Out of 78 patients evaluated, prostate cancer was detected in 35 (44.9%), and glomerulation was recognized in 8 (10.3%). Glomeruration was recognized in 4 (11.4%) out of 35 patients with positive biopsy and 4 (9.3%) out of 43 with negative one. There was no difference in age, prostate volume, serum PSA levels between patients with and without glomerulation. Interestingly, statistically significant difference was noted in painful scores as evaluated with NIH-CPSI between patients with and without glomerulation (5.5 vs 1.5, p<0.005). The frequency of glomerulation increased as painful scores did from 3.2% (2 out of 62) in patients with painful scores of 0 to 4 to 37.5% (6 out of 16) in those of 5 or more. On the other hand, there was no difference in LUTS- related symptoms as evaluated with IPSS. CONCLUSIONS: The present study first demonstrated that glomerulation was highly associated with painful symptoms as evaluated by NIH-CPSI in elderly men. These results suggest strongly the high prevalence of IC among elderly male patients complaining pains. Further studies are needed to clarify the clinical significance of IC among elderly male patients treated as clinical benign prostatic hyperplasia or overactive bladder. SOURCE OF FUNDING: None Dr. Burstein's Comment: 78 men being evaluated for prostate cancer were screened with hydrodistension for the presence of glomerulations and a presumptive diagnosis of IC. Interestingly, there was a statistical difference between men with higher pain scores and those who had glomerulations. Although there was no association with prostate cancer, in this highly selected population IC was detected in 8 out of 78 patients for a relatively high incidence of almost 10%. IC has always been considered a disease of women with a female to male ratio of 10 to 1. The main reason the diagnosis of IC is infrequently made in the male is because the prostate "gets in the way" resulting in most men with pelvic pain and frequency to be assigned the diagnosis of prostatitis. This study suggests that men should not be presumed to have prostatitis and the diagnosis of IC by hydrodistension should a consideration in the evaluation of pelvic pain.
LONG-TERM EFFICACY OF SACRAL NEUROMODULATION (INTERSTIM)
IN PATIENTS WITH REFRACTORY INTERSTITIAL CYSTITIS (IC) SHOWS
TENDENCY TO DECREASE
INTRODUCTION AND OBJECTIVE: Our IC clinic in the Bernhoven hospital serves as a national reference centre for IC patients. We employ sacral neuromodulation since December 2001 in IC patients who exhausted oral and intravesical therapies as a third line, surgical treatment. We investigate the long-term efficacy of permanent sacral nerve modulation (Interstim device; Medtronic) in an open, prospective study. METHODS: Percutaneous test stimulation (PNE under local, later Tined Lead under general anesthesia) was done in 41 end-stage IC patients (31F,4M). All fulfilled the NIDKK research criteria. In 21 (17F,1M), 55% a permanent Interstim device was implanted under general anesthesia. The electrode was located at the S3 nerve, either right or left. Data were collected from analogue pain- and urgency scales (0- 10 score), the O’Leary-Sant IC Symptom index (ICSI), Follow-up scores (0-100%) and voiding diaries. Results: At 3 months 18 out of 21 (85%) patients reported a subjective improvement of 50% or more. At present 18 patients exceeded 1 year follow-up. At an average f/u of 25 m., only 8 out of these 18 (45%) patients reported an improvement of 50% or more. Meanwhile 6 patients de-activated the device after an average of 10 months. Three of these 6 received an Indiana pouch. COMPLICATIONS: one surgical reposition and one explantation due to infection during PNE. CONCLUSIONS: Despite a positive Percutaneous Nerve Evaluation a substantial IC symptom remission (of 50% or more) in implanted patients reduced from 85% at 3 months follow- up to 45% at 25 months. All failures ocurred in the first year after final implant. This is in line with the long-term results for other indications. In conclusion: Sacral Neuromodulation provided a sustained symptom remission in 8 severe IC patients (45%). SOURCE OF FUNDING: None Dr. Burstein's Comment: In selected patients, permanent sacral nerve modulation can produce dramatic long-term results, but success overall is limited and results can only be measured in terms of "improved" rather than "cured." IC Update 2005 - AUA Meeting Abstracts
LONG TERM RESULTS OF AMITRIPTYLINE TREATMENT FOR INTERSTITIAL CYSTITIS INTRODUCTION AND OBJECTIVE: We recently reported a randomized controlled trial showing the significant improvement of interstitial cystitis (IC) symptoms under amitriptyline (AMI) treatment [van Ophoven et al., J. Urol. 172, 533]. We now present the long term results of a prospective observational study on the safety and efficacy of AMI for IC. METHODS: The study enrolled 94 IC patients (82 women, 12 men) between October 2001 and September 2004 of whom 59 (63%) met the symptom criteria of the National Institute of Diabetes, Digestive and Kidney Diseases (NIDDK) for IC. The drug was taken strictly at bedtime following an established self-titration protocol without a limitation of the maximum daily dosage. Patients reporting improvement of symptoms on a 7-point centered scale were defined as treatment responders. RESULTS: The mean follow up was 19 months and the mean treatment duration was 16 months. Response to treatment was observed in 60 patients (64%). Overall mean dosage was 55mg (range 12.5 - 150mg). Anticholinergic side effects occurred in 79 patients (84%) (dry mouth: 79%, weight gain: 59%). Patient overall satisfaction with the therapeutic result was either excellent or good in 47 patients (50%) (excellent satisfaction: 15%, good: 35%). Fair satisfaction due to minor response correlated with or without side effects was reported by 13 patients (14%). The drop-out rate was 27% (25 patients) after a mean treatment period of 6 weeks at a mean dosage of 70mg. Non-response to treatment was the primary reason for drop-out in all cases, side effects contributed to drop-out in 22 patients (88% of all drop-outs). The following symptoms improved statistically significant compared with baseline: Pain intensity (-22.1mm. on visual analogue scale, p=0.002), urgency (-19.7mm., p=0.004), 24-hr frequency (-6.9 voids/d, p=0.021), functional bladder volume (+32.9ml, p=0.039). The O'Leary/Sant score dropped by 7.9 points under treatment (p=0.004). Response rates and extent of symptom improvement did not differ significantly between the patients fulfilling NIDDK criteria and those with the "clinical diagnosis" of IC. Response to the drug was independent of IC subtype (classic vs. non-ulcerative type). CONCLUSIONS: Long term AMI therapy is feasible, safe and effective for treating IC. Anticholinergic side effects are a key co-factor for treatment termination and constitute the major drawback of AMI treatment. Dr. Burstein's Comment: AMI has been used for years for symptomatic relief, however it has only last year that this group of investigators demonstrated its benefit when compared to placebo in a controlled, randomized study. This current study further supports statistical evidence of symptom relief and patient satisfaction. Unfortunately, as stated in this study, the side effects of this class of medication can significantly limit its use. This further supports the use of amitriptyline as evidence based therapy.
INTRODUCTION AND OBJECTIVE: We estimated the direct costs of interstitial cystitis (IC) and painful bladder syndrome (PBS) in a large sample of the employed United States work force. METHODS: The INGENIX claims-based dataset includes claims for utilization of medical services for employees and dependents of 75 large employers including 1.8 million covered lives. Data from 1999 were reviewed. Patients were defined as having Interstitial Cystitis/Painful Bladder Syndrome (IC/PBS) when given the ICD-9 diagnosis code for IC (595.1) or the combination of codes for urinary frequency/urgency (788.41) and pelvic pain (625.8 or 625.9 for women, 788.09 for men). Estimated annual expenditures were derived from multivariate models that control for age, gender, work status (active/retired), median household income (based on zip code), urban/rural residence, medical and drug plan characteristics (managed care, deductible, co-insurance/co-payments), and 17 disease conditions such as diabetes, asthma, and hypertension. RESULTS: Of 331,605 individuals who filed claims, 285 were classified as having IC/PBS. The mean annual cost associated with IC/PBS was $7,597, more than double that spent on those without the disorder. The cost is disproportionately associated with younger women. CONCLUSIONS: This is the first ever investigation of the cost of IC/PBS to society. It does not include the non-medical economic and non-economic costs of the disease such as missed work, lost productivity, and poor quality of life. Nevertheless, this study suggests that the medical costs alone present a huge burden to the public with $2 spent on IC/PBS patients for every dollar spent on those without the disease. Further investigation to evaluate the nature and effectiveness of the expenditures and to improve disease management is warranted. Dr. Burstein's Comment: Funding for IC research has been difficult to obtain. More Studies, such as this one that demonstrates the high cost to individuals and society, are needed to help promote and attract further research dollars.
INTRODUCTION AND OBJECTIVE: The National Health and Nutrition Examination Surveys (NHANES), conducted by the Centers for Disease Control, are designed to assess the health and nutritional status of adults and children in the United States through interviews and direct physical examinations. NHANES provides a representative snapshot of the non-institutionalized US population but does not include any longitudinal observations. We estimated the prevalence of self-reported interstitial cystitis (IC) in the NHANES III survey participants. METHODS: NHANES III was carried out during the years 1988-1994. Participants were asked, "Have you ever had symptoms of a bladder infection (such as pain in your bladder and frequent urination) that lasted more than 3 months?" Those who answered 'yes' were then asked, "When you had this condition, were you told that you had interstitial cystitis or painful bladder syndrome?" Those who answered yes to both questions were classified as having IC. RESULTS: The prevalence of self-reported IC was 0.47% (0.06% in men and 0.85% in women). Demographics for patients with and without IC are presented in the Table. CONCLUSIONS: In this nationally representative sample, approximately 1:120 women and 1:1700 men report a history of IC. This estimate is strikingly similar to the female prevalence estimate of 0.865% (1:116 women) obtained as part of the 1989 National Household Interview Survey, which utilized the same definition to identify IC patients (Jones, 1994). Although it is likely that a degree of misclassification is present due to inaccurate patient recall and confusion between IC and other forms of cystitis, these results indicate that chronic painful bladder symptoms are a common occurrence in the U.S. population. Dr. Burstein's Comment: the number of people estimated to have IC depends on its definition. By strict research criteria there are about 500,000 to 800,000 with the diagnosis of IC. If less stringent clinical symptoms are used, then up to 2 million are estimated to have IC.
INTRODUCTION AND OBJECTIVE: Interstitial cystitis (IC) often times requires a multimodality approach for ultimate success. In our refractory patient population with overactive bladder (OAB) with pain, we consider sacral neuromodulation therapy (SNT) an option for patients with dominant OAB symptoms who have failed all other more conservative management schemes. The purpose of this study was to retrospectively evaluate the outcome of SNT therapy in a cohort of patients treated with IC at our institution. METHODS: Between April 2002 to July 2004, 27 patients who met the NIDDK criteria for IC were treated with SNT. Operative charts and medical records were reviewed for demographic characteristics, success rates, failure rates, revision rates, and number of programming visits. The status of the patient in relation to the presence of the interstim and its utility and perceived help at last follow up was also extracted. RESULTS: 89% (24/27 patients) were women, 11% (3/27) men (ages range 19-78, mean 49.7 years). All patients underwent stage one interstim using the tined lead approach, 22 patients (81.5%) progressed to stage 2 based on > 50% improvement in overall clinical status. After a minimum follow up of 3 months, 5 devices were explanted (3 for failure to maintain efficacy and 2 for infection). Among those patients who still carry the device, 13 expressed continued benefit and 4 complained of loss of efficacy. Therefore, our overall clinical success rate with SNT for IC is 13/27 (48%). CONCLUSIONS: Despite, the encouraging high success of progression to stage two in this patient population, the long term follow up revealed a significant decrease in clinical success reaching an overall of 48%. The exact reason for this decline in long term success is unclear. This is an important finding for proper counseling of IC patients undergoing this form of therapy. Dr. Burstein's Comment: The initial response rate for sacral neuromodulation therapy was impressive and was thought to perhaps be a definitive "cure" for those suffering severe frequency. Unfortunately, time has shown a significant failure rate and while SNT remains a treatment option, it must be chosen with care and reasonable expectations.
INTRODUCTION AND OBJECTIVE: Several lines of evidence suggest that the bladder epithelial barrier may be compromised in interstitial cystitis (IC). Antiproliferative factor (APF) is a small glycoprotein made specifically by bladder epithelial cells from IC patients that induces changes in expression of certain cell proteins and profoundly inhibits cell growth. We determined whether APF also affects cell production of two tight junction proteins (occludin and ZO-1) and paracellular permeability in bladder epithelial cell monolayers shown to express tight junctions containing these two proteins. METHODS: Normal bladder epithelial cell monolayers were treated with HPLC-purified APF at concentrations found in IC patient urine specimens, or similar quantities of a mock APF preparation. The amounts of occludin, ZO-1, E-cadherin, and beta actin proteins were determined by Western blot and immunofluorescence assay. Paracellular permeability was determined by measuring flux of 14C-mannitol and 3H-inulin between confluent monolayers on Transwell culture plates. RESULTS: APF specifically and significantly decreased production of occludin and ZO-1 proteins by Western blot, while increasing E-cadherin production and causing no change in beta actin production when normalized to total cell protein content. APF also resulted in attenuation of tight junctions by IFA as compared to mock APF. Within only 2 hours of treatment, APF significantly increased paracellular permeability of both 14C-mannitol (13.2 ± 2.3% vs. 3.2 ± 1.7%, p = 0.039) and 3H-inulin (6.3 ± 0.5% vs. 2.5 ± 0.9%, p = 0.035), in normal bladder epithelial cell monolayers as compared to mock APF. CONCLUSIONS: APF significantly inhibits bladder epithelial cell production of tight junction proteins and rapidly increases paracellular permeability in vitro, and may therefore contribute to the leakiness of the bladder epithelial barrier seen in IC. Dr. Burstein's Comment: Continued studies show that APF is specific to IC. It may help to explain the cause and symptoms of the disease and can hopefully be developed into a marker for early and definitive diagnosis. IC Update 2004 - AUA Meeting Abstracts A PROSPECTIVE, DOUBLE BLIND, RANDOMIZED CROSS OVER STUDY EVALUATING URINARY PH ALTERATION FOR THE RELIEF OF SYMPTOMS OF INTERSTITIAL CYSTITIS
INTRODUCTION AND OBJECTIVE: Anecdotally, the use of alkalinizing agents in the management of cystitis-like symptoms (frequency, urgency, dysuria) have been used over the past 20 years or longer. Up to 50% of patients presenting with cystitis-like symptoms will have abacteriuria on urine culture. In the past, these patients have been offered treatment with potassium citrate, sodium citrate, or sodium bicarbonate generally on the basis of anecdotal evidence and with a quoted symptom improvement rate of up to 80%. Our study seeks to determine the effects of altering intravesical pH on the symptoms of known interstitial cystitis patients. A neutral buffered solution consisting of sodium phosphate will be compared to an acetic acid buffered solution in this study. This will be a point-study for possible further investigations in the area of pH in relation to clinical IC and as such seeks to maximize effect by directly administering both an acidic saline solution (pH 5.0) and a neutral buffered saline solution (pH 7.5) as a cross over design trial. METHODS: A prospective, randomized, double blind cross over study was conducted with 26 female patients with interstitial cystitis over the period 2000-02, consisting of cross over instillations of urine-physiologic pH (5.0) and neutral buffered pH (NaH2PO4 buffered to pH7.5). The outcome measured was the subjective symptom of pain via a visual-analog scale at baseline, following initial solution instillation, washout, and post crossover instillation. Data were analyzed using repeated measures analysis of variance. RESULTS: No statistically significant difference between the mean change from baseline pain scores following instillation of neutral buffered solution (0.50 ± 2.78), compared to acidic solution (0.33 ± 3.43) [F(1,24) = 0.04, p = 0.85] could be identified. Secondary outcomes were analyzed including baseline variability and treatment order effects. Neither were found to be significantly different between groups studied. CONCLUSIONS: A statistically significant difference in subjective pain scores on instillations of urine-physiologic pH versus sodium phosphate buffered saline in this population of IC patients was not demonstrated. Further work is required to define the role, if any, of urinary pH in the pathophysiology of interstitial cystitis. Dr. Burstein's COMMENT: Diet modification has shown to be very effective in controlling symptoms in many IC patients. It is thought that acidic foods produce irritation by its effects on the damaged bladder lining. Common sense would lead to the conclusion that countering this acidity by alkalinizing (buffering) the urine would result in symptomatic relief. Surprisingly, this study showed no significant difference in pain scores in those whose urine was alkalinized. Perhaps there is a different reason that IC pain responds to dietary changes.
INTRODUCTION AND OBJECTIVE: We conducted a prospective study to examine the safety and efficacy of the tricyclic antidepressant amitriptylin (AMI) in patients with interstitial cystitis (IC). Although AMI is one of the most common prescribed oral drugs for IC (Rovner et al) its efficacy has never been assessed in a randomized, double-blind, placebo-controlled study. METHODS: The study comprised 50 patients (42 women, 8 men) who all met the symptom criteria of the National Institute of Diabetes, Digestive and Kidney Diseases for IC. The patients were randomly assigned to AMI or placebo. Patients were prospectively treated for 4 months with a self-titration protocol that allowed them to escalate drug dosage in 25mg increments in 1 week-intervals (maximum dosage 100 mg). The change from baseline in the IC symptom and problem score (OLLeary et al) was the primary outcome parameter for this study. Changes in functional bladder capacity and frequency (48-hours voiding log) and intensity of pain and urgency (visual analog scales) were chosen as secondary outcome parameters. RESULTS: 2 patients (1 AMI, 1 placebo patient) dropped out of the study due to side effects. The data of 48 patients (24 patients in each group) were thus available for evaluation. The mean symptom score decreased from 28.0 to 20.5 in the AMI group compared with 28.5 to 24.5 in the placebo group (p = 0.005). Of the patients in the AMI group, 42% had a greater than 30% decrease in the symptom score compared with 13% in the placebo group (p < 0.001). Both pain and urgency intensity improved statistically significant in the AMI group compared with the placebo group (p < 0.001). The frequency and functional bladder capacity improved to a much greater degree in the AMI group, but the differences were statistically not significant (p = 0.06, p = 0.08). At the end of 4 months treatment 37.5% of AMI patients took 50 mg of the drug (25 mg: 29%, 75 mg: 21%, 100 mg: 12.5%). Anticholinergic side effects were noted by all except 2 patients in the AMI group (85%) and by 5 patients in the placebo group (21%). A dry mouth was the most frequent side effect in the AMI group (86%). CONCLUSIONS: 4 months of AMI therapy is safe and effective in treating IC. A statistically significant change in the symptom score and statistically significant improvement of pain and urgency intensity compared with placebo was observed. Anticholinergic side effects constitute the major drawback of AMI treatment for IC. Dr. Burstein's COMMENT: This is the first study that has demonstrated amitriptyline to improve symptom scores in IC patients in a double blind, randomized, placebo controlled fashion. Improvement in both pain and urgency were statistically significant.
INTRODUCTION AND OBJECTIVE: Interstitial cystitis (IC) is a chronic bladder condition resulting in urinary urgency, frequency, and pelvic pain in the face of no identifiable etiology. There is no single test currently available to confirm the diagnosis of IC. The gold standard has been refractory symptoms and hydrodistension of the bladder under anesthesia demonstrating diffuse glomerulations or Hunner's ulcers. There has been a recent trend to diagnose IC in a non-invasive way using a potassium sensitivity test (KCl test) and a pelvic pain, urgency, and frequency questionnaire (PUF questionnaire). The benefit is that patients may be more readily diagnosed and have early initiation of treatment. The concern is that significant pathology causing their symptoms may be missed, such as transitional cell carcinoma. The purpose of our study is to present our experience of patients who have been labeled as having IC, who truly had cancer as the cause of their irritative symptoms. METHODS: A retrospective review of patients seen in our IC center was performed from 1998 to 2002. A total of 600 patients were seen with the diagnosis of interstitial cystitis. Patients referred to our center already diagnosed with IC had a thorough history, physical and review of medical records. Additional diagnostic evaluation was tailored based on this work-up. RESULTS: Six patients (1%) previously diagnosed as having IC were found to have transitional cell carcinoma as the cause of their symptoms. Ages ranged from 39 to 78 years old. Four of six patients (67%) had no hematuria and 50% were non-smokers. The pathology included carcinoma in situ,a Ta grade I lesion, a T1 grade II lesion, and T2 grade III lesions. Treatments for the TCC included intravesical therapy, bladder tumor resections, nephroureterectomy and radical cystectomy. Irritative bladder symptoms resolved after identifying and treating their malignancy. CONCLUSIONS: Patients with irritative voiding symptoms require a thorough work-up that may include cystoscopy, cytology, and upper tract imaging. Hematuria was not a good predictor of cancer in this series. In the era prior to widespread use of minimally invasive means to diagnose IC (i.e. KCL test, PUF questionnaire), one-percent of patients that were labeled with IC actually had transitional cell cancer as the cause of their symptoms. One would expect that this number would increase if the criteria to diagnose IC were oversimplified. Interstitial cystitis remains a diagnosis of exclusion. Dr. Burstein's COMMENT: This abstract was included to stress the need of a complete evaluation for patients complaining of the irritative symptoms of urgency and frequency. A vital aspect of IC is that it is diagnosed by excluding all other causes of symptoms including the rare possibility of bladder cancer.
INTRODUCTION AND OBJECTIVE: Interstitial cystitis (IC) is a chronic bladder disorder characterized by thinning or ulceration of the epithelium; its etiology is unknown. We previously showed that bladder epithelial cells from IC patients produce an "antiproliferative factor" (APF) that profoundly inhibits bladder cell proliferation via regulation of gene expression and alterations in production of specific growth factors (including HB-EGF and EGF). Treatment of normal bladder cells with purified APF causes the same changes in gene expression and proliferation seen in IC cells, suggesting that this factor plays a critical role in the pathogenesis of IC. We have now determined the structure of APF and carried out its synthesis. METHODS: APF was harvested from the supernatant of IC patient bladder epithelial cell explants and purified using molecular weight fractionation, ion exchange chromatography, hydrophobic interaction chromatography, reversed-phase high performance liquid chromatography (HPLC), and microcapillary reversed-phase LC. The structure was deduced using ion trap mass spectrometry, lectin affinity chromatography, and enzymatic digestion. APF was synthesized by solid phase methods using protected threonine-N-acetyllactosamine and enzymatic sialylation. All intermediates and the final product were verified by mass spectrometry. RESULTS: APF was determined to be an acidic, heat stable sialoglycopeptide, consisting of only 9 amino acid residues (TVPAAVVVA) with a 2,3 sialylated N-acetyl lactosamine unit ¿-O-linked to the N-terminal residue [viz. Neu5Ac¿(2,3)-GalÀ(1,4)-GlcNAc¿-O-Thr]. The peptide chain of APF has 100% homology to the putative 6th transmembrane domain of frizzled 8, a G-protein coupled receptor whose natural ligand is Wnt. The structure of APF was confirmed by total synthesis and measurement of biological activity. Like native APF, synthetic APF profoundly inhibited bladder epithelial cell proliferation (IC50 = 0.4 nM) and HB-EGF production, while stimulating EGF production. Synthetic APF was also shown to inhibit the proliferation of bladder carcinoma cells that are sensitive to native APF. Initial structure-activity analysis indicated that APF does not require sialic acid for maximal activity, but is remarkably sensitive to structural changes in the N-terminal glycan. CONCLUSIONS: APF is a modified peptide related to the frizzled 8 transmembrane receptor, and is the first small sialoglycopeptide growth inhibitor to be completely characterized. Dr. Burstein's COMMENT: APF is produced by the lining cells of the bladder and is found only in the urine of IC patients. Hopefully a simple office lab test can be developed that would identify APF and lead to earlier diagnosis of IC.
INTRODUCTION AND OBJECTIVE: We evaluated the efficacy of sacral neuromodulation for the treatment of symptoms in patients with refractory interstitial cystitis. METHODS: Twenty-seven patients (mean age 47 years) with refractory interstitial cystitis were prospectively evaluated with a trial of sacral nerve stimulation. All patients had failed dietary modification, pharmacotherapy, and hydrodistention. Those individuals who demonstrated 50% improvement in frequency, nocturia, voided volume, and average pain qualified for permanent sacral nerve stimulator implantation. Treatment success was measured by voiding diary, report of average pain, and response to the Interstitial Cystitis Symptom Index and Interstitial Cystitis Problem Index. RESULTS: Nineteen patients qualified for permanent sacral nerve stimulator implantation. At an average of 26 months follow-up, mean daytime frequency and nocturia improved from 17.1 to 11.9 and 4.5 to 2.5, respectively (p<0.01). Mean voided volume increased from 111 ml. to 215 ml. (p<0.01). Report of average pain decreased from 5.8 to 2.6 points on a scale of 0-10 (p<0.01). Interstitial Cystitis Symptom and Problem Index scores decreased from 16.5 to 9.2 and 14.5 to 7.5, respectively, (p<0.01). 15 of 19 patients with a permanent stimulator (79%) demonstrated sustained improvement in all parameters at the last post-operative visit. CONCLUSIONS: Results of this prospective clinical study demonstrate that sacral neuromodulation is a safe and effective treatment for the dysfunctional voiding and pelvic pain in patients with interstitial cystitis who are refractory to other forms of treatment. Dr. Burstein's COMMENT: Neuromodulation is not a "cure-all", but certainly can help improve symptoms in a select subset of IC patients. Further study is needed to tell if these results are durable over time.
INTRODUCTION AND OBJECTIVE: Validated questionnaires for interstitial cystitis (IC) have evolved to monitor patient clinical status and, in some instances, to help formulate a diagnosis. We prospectively studied the value of two frequently used "IC questionnaires" (the Pain, Urgency, Frequency (PUF) questionnaire and the O'Leary-Sant (OS)) to establish a diagnosis of IC in general urological practice. METHODS: 157 patients from an urban urology clinic were administered PUF and OS questionnaires prior to diagnoses. The clinical diagnoses of the patients permitted the assortment of subjects into 10 diagnostic groups (including IC, recurrent urinary tract infection, urinary incontinence, renal calculus disease, prostate cancer, among others) and questionnaire scores between groups were compared by ANOVA and posthoc student's t-test using the Bonferroni correction for multiple comparisons. RESULTS: Both questionnaires were able to distinguish the IC from the other diagnostic groups (ANOVA for each questionnaire, p<0.001 ). However, the mean total score from the PUF questionnaire for patients with IC [19.3 +/- 0.9 (SEM)] was significantly different (p<0.01) from that of patients with urinary incontinence [10.8 +/- 3.2], whereas this difference was not significant for the O'Leary Sant score. Furthermore, both questionnaires were able to distinguish urinary tract infection from IC (PUF p<0.001; O'Leary-Sant, p<0.05). Pairwise comparisons of diagnostic groups other than IC were not distinguishable from each other by either the PUF or the O'Leary-Sant scores. Finally, the total PUF scores, for each of the diagnostic groupings, exhibited less variability than the O'Leary-Sant total scores, as evidenced by smaller standard deviations from the mean. CONCLUSIONS: Both questionnaires were found to be useful in screening for IC, however, neither questionnaire demonstrated enough specificity to reliably diagnose. The PUF demonstrated less variability than the O'Leary-Sant for each diagnostic group, and was better able to distinguish between IC and urinary incontinence. Dr. Burstein's COMMENT: There is no test that can diagnose IC. The benefit of the questionnaires that were evaluated lies in their ability to help screen patients that may need further work-up to validate the diagnosis of IC. These patient oriented questionnaires also make it easier for a physician to obtain important medical history information in a timely and efficient manner.
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DeKalb Clinic Urology
217 Franklin St
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