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IC Updates Archives - American Urological Association (AUA) Meeting Abstracts
IC Update 2001 - American Urological Association (AUA) Meeting Abstracts These abstracts were presented at the annual meeting of the American Urological Association. I have included the more digestible papers and provide a personal comment for each presentation. GENE THERAPY OF VISCERAL BLADDER PAIN WITH RECOMBINANT HERPES SIMPLEX VIRUS EXPRESSING PREPROENKEPHALIN Michael E. Franks, Katsumi Sasaki, Teruhiko Yokoyama, Matthew 0 Fraser, Naoki Yoshimura, James Goss, David J Fink, William Goins, Joseph Glorioso, William C deGroat, Michael B Chancellor. Pittsburgh, PA Introduction and Objectives : interstitial cystitis (IC) and visceral bladder pain are a major challenge to all urologists to understand and treat. We hypothesize that targeted and localized expression of enkephalin in the nerves that innervate the bladder by gene transfer can treat bladder pain. Methods: Cystometric studies under urethane anesthesia were done one week after Sprague Dawley (SD) rat bladders were injected with HSV-I with preproenkephalin cDNA insert, 5 X 10'pfu (SHPE, n=10) or HSV-1 with 1acZ insert, 5 X 10'pfu as control (SHZ, n=10). After baseline bladder activity was established with intravesical saline infusion (0.04cc/minute), continuous intravesical capsaicin (15gM) infusion was used as a bladder irritant, while i.m. naloxone (0.5 mg/kg) was used as an opioid antagonist. Intercontraction intervals (ICI, time between bladder contractions in minutes) were measured at baseline, after capsaicin infusion, and with naloxone administration. The differences in ICI were compared between SHPE and SHZ rats. Results: SHPE injected rats demonstrated a significant increased ICI with baseline saline CMG versus SHZ rats (15.L+3.0 and 6.1 ~0.97 minutes, p=0.009). The reduction in the ICI induced by intravesical injection of capsaicin (1 51uM) was significantly smaller in SHPE rats than SHZ rats (24% versus 35% change, p=0.04), and in SHPE-treated rats, this difference was specifically antagonized by naloxone (decreased ICI), suggesting that enkephalinergic mechanisms were upregulated to suppress capsaicin-induced bladder hyperactivity in SHPE-injected animals. Conclusions: We demonstrate that gene therapy for bladder pain is not only feasible but may suppress nociceptive responses induced by bladder irritation with acute intravesical capsaicin. This technique of gene transfer may be useful for treating IC and other types of visceral pain. Dr. Burstein's Comments : This study shows that gene therapy is not science fiction and will have realistic applications. Hang in there while I explain what was done. Herpes simplex type 1 (HSV-1) is a virus that causes cold sores and shingles. The virus actually infects sensory nerve roots and remain dormant. At some time the virus becomes active and migrates to the nerve endings where they multiply. This causes the typical symptoms of skin rash, ulceration and pain. Now here’s the cool part. The virus used in this study had genes modified to produce enkephlins which are naturally occurring pain-killing chemicals made in the body. So instead of causing release of pain producing chemicals in the nerve tissue, these viruses released pain-relieving chemicals. Wow! The long term significance is that genetically modified virus can be placed in the sensory nerves of the bladder so when they are activated by irritants, like what happens in IC, the virus actually releases naturally occurring pain killing chemicals. This is really exciting!!
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Introduction and Objectives: Severe refractory interstitial cystitis (IC) causes significant deterioration in the quality of life of patients with this disease. Surgical alternatives are of questionable efficacy and are usually categorized as drastic and desperate measures. To assess the potential benefit of neuromodulation in this group, the Medtronic@ peripheral nerve stimulation technology was used in a pilot study. Methods : Seventeen patients with documented severe refractory IC, using NIDDK criteria, underwent percutaneous placement of an S3 electrode wire and variable test period (from 1-6 days)(N = 17). Of those with a very successful testing, 9 underwent surgery for placement of electrode with an internal programmable generator (IPG). The male to female ratio was 2:15. The average age was 48 years old. Results: A successful test, defined as 175% improvement in symptoms, occurred in 60% (9/15). Of these successful tests (N=9), 8 underwent surgery for placement of IPG and electrode wires. Of those who were implanted, 6 have had a durable response at a mean of 18 months (range 6-32 months). Five of these eight patients are off atl medications (62.5%). One patient had persistence of urgency and frequency symptoms with resolution of pain and two patients underwent removal secondary to wound complications. Conclusions: The preliminary data demostrates efficacy with neuromodualtion treatment for severe refractory IC and would support a formal multicenter evaluation. Dr. Burstein's Comments: Pain is subjective and becomes very difficult to asses improvement in pain perception during a study based on objective criteria. The Interstim implant is not a cure for pain and frequency but can significantly improve symptoms for some patients.. There are problems however, such as electrode migration and many patients have even suffered increase frequency and pain. This is not a treatment for everyone with IC and patients considering this option should undergo rigorous evaluation prior to implant. INTERSTITIAL CYSTITIS AS A CAUSE OF VOIDING DYSFUNCTION IN CHILDREN George A. Schuster. Joliet, IL Introductions and Objectives: Interstitial cystitis (IC) in children is considered a rare occurrence. Children often present in a similar manner as adults do with I/C Do children with voiding dysfunction meet modified National Institute of Health (NTH) criteria for I/C? Methods: Forty-nine children who presented with voiding dysfunction (non-neurogenic day/night incontinence, urgency, frequency) were evaluated in a systematic manner consisting of a detailed history, focused physical examination, urinalysis, voiding diary, residual urine plus a cystoscopy and hydraulic distention of their bladder. Twenty-six children completed the evaluation and were available for study. Eighteen of the 26 (69%) also had urodynamics performed Modifications of the NTH minimal criteria for I/C were made as follows to accommodate children: A frequency of urination while awake, of less than eight times per day, was defined as voiding less than 1/3 of their estimated bladder capacity per void. Nocturnal enuresis was equivalent to nocturia. Bladder capacity greater than 350 rod on awake cystometry was defined as more than 80% of estimated bladder capacity (Calculated as age/2 + 6 in ounces). Absence of an intense urge to void with the bladder filled to 150 ml of water during cystometry was defined as an absence of intense urge to void at less than 1/3 bladder capacity Children, like adults, had to have diffuse glomerulations on more than three bladder surfaces. Results: Fourteen of the 26 (54%) met the modified NTH criteria for I/C, Three children failed NTH criteria because they had minimal or no glomerulations noted on cystoscopy. Nine children with glomerulations on cystoscopy failed modified NTH criteria. One child failed because her maximum voided volume exceeded 80% of her expected maximum volume on her voiding diary. Three children failed because they did not have urodynamics performed and did not have a history of pain with bladder filling. Three children failed because they did not have an intense desire to void at less than 1/3 estimated bladder capacity on cystometry. Two children failed because they exceeded 80% of estimated bladder capacity on cystometry. Conclusions: 14/26 (54%) children met stringent modified criteria for I/C Although the nine children with glomerulations failed to meet these stringent criteria, they clinically have I/C. If these nine children were included, then 23126 (88%) of the children in this study have I/C. Interstitial cystitis may be a more common cause of voiding dysfunction in children and may not be as "rare" as the literature would suggest. Dr. Burstein's Comments: IC was once considered a rare disease. We now know that the symptom complex of IC is quite common. The problem with IC has been a failure of early diagnosis and aggressive treatment. Just as in the adult population, children with severe frequency need to be evaluated for IC. I think it is far more common than currently appreciated. TREATMENT OF INTERSTITIAL CYSTITIS WITH A QUERCETIN CONTAINING COMPOUND: A PRELIMINARY, DOUBLE-BLIND PLACEBO CONTROL TRIAL Larissa V. Roddguez, Nicolette Janzen, Shlomo Raz, Floyd Katske, Kim Gangliano, Jacob Raj.fer. Los Angeles, CA; Daniel A Shoskes. Fort Lauderdale, FL Introduction and Objectives: interstitial cystitis (IC) is a chronic condition of unknown etiology characterized by bladder pain, urinary frequency and irritative symptoms. There are few effective therapies for this condition. A complex containing quercetin, a naturally occurring bioflavonoid, has recently been shown to provide significant symptomatic improvement in patients with chronic prostatitis, a condition clinically similar to IC. The purpose of this study was to determine if CystaQ, a quercetin containing complex, could be an effective treatment for IC. Methods: 20 patients who met National Institute of Arthritis, Diabetes and Kidney Disease diagnostic criteria for IC were enlisted in the study. All patients filled pretreatment Interstitial Cystitis Symptom Index (ICSI), Interstitial Cystitis Problem Index (ICPI) and severity questionnaires. In addition, all patients filled a 24-hour voiding diary. The patients were randomized in a double-blind fashion to receive either placebo or CystaQ three times a day for six weeks. At the end of the study the patients answered the ICSI, ICP1 and severity questionnaires and filled another 24-hour voiding diary. At that time, treatment patients were given an option to continue treatment and those in the placebo group were offered CystaQ. All patients who continued treatment were evaluated with ICSI, ICPL and severity questionnaires every month. Results: There were 19 patients available for analysis. One patient dropped out due to lactose intolerance (lactose was in drug and placebo). Both the CystaQ and Placebo groups were well matched in gender, age, and baseline ICSI, ICPI and severity scores. At six weeks. the placebo group had a mean improvement in severity score from 7.1 to 5.6 (21% improvement), ICSI from 11.3 to 9.8 (13%) and ICPI from 11.4 to 9.3 (18%). On the other hand, the CystaQ treatment group had a mean improvement in severity score from 8 to 5.4 (33% improvement, p<0.05), ICSIfirom 11.9 to 7.9 (34%, p<0.05) and ICPI from I I to 8.6 (22%). The effects seen in the CystaQ group were more pronounced with longer treatment time, with mean improvement of 54% in severity score (p<0.05), 51% in ICSI (p<0,05), and 50% in ICP1 (p<0.05) at 12-20 weeks. The voiding diary showed a significant decrease in daily abdominal pain (10% in placebo vs. 47% improvement in CystaQ) and vaginal pain (9% in placebo vs. 50% in CystaQ). Conclusions: Daily therapy with CystaQ, a quercetin containing complex, is well tolerated and provides significant symptomatic improvement in patients with IC.
Dr. Burstein's Comments: Even though this was a limited study on a very small group of patients, there was significant improvement in severity score (21% placebo, 33% quercitin) and more encouraging an improvement in abdominal pain (10% placebo, 50% quercitin). This compound has a good safety profile with minimal side effects (it does contain lactose). I have recommended it to many of my patients.
POTENTIAL ROLE OF CHLAMYDIA PNEUMONIAE IN THE PATHOGENESIS OF INTERSTITIAL CYSTITIS Gregory L Alberts, Charles W Stratton, William M Mitchell, Jenny J Franke. Nashville, TN Introduction and Objectives: Chlamydia pneumoniae is now recognized as an important human pathogen. As an obligate intracellular parasite, it is difficult to detect by routine cultures, can cause chronic infections, and may not elicit an acute inflammatory response. C. pneumoniae is commonly associated with respiratory tract infection, but has also been implicated in the development of coronary artery plaques and chronic inflammatory conditions such as multiple sclerosis. Our recent data using polymerase chain reaction (PCR) analysis of urine revealed that 81 % of patients with interstitial cystitis (IC) and 16% of controls were positive for C. pneumoniae. These data suggest a potential role for this organism in the development of IC. We present our data using tissue culture detection of C. pneumoniae in both control patients and patients with interstitial cystitis to further investigate this association. Methods: Seventeen patients with IC as outlined by NIADDK criteria and 6 control patients underwent bladder biopsy. Selection of control patients was limited to those patients without history of irritative voiding symptoms, transitional cell carcinoma or recurrent urinary tract infection. Biopsy specimens were analyzed for C. pneumoniae using standard tissue culture technique. Results: Of those patients with IC, 82% (14/17) had tissue cultures positive for C pneumoniae. In control patients, 16% (1/6) had tissue cultures positive for C pneumoniae (p=0.009). Conclusions: We found a statistically significant correlation between IC and infection with C. pneumoniae based on tissue culture. These results also parallel those obtained with urine PCR. The possible role of C. pneumoniae in the pathogenesis of IC remains to be determined by further analysis of tissue culture results as well as monitoring patient response to appropriate antimicrobial therapy. Dr. Burstein's Comments: It sure would be great if 82% of IC was caused by an infectious agent such as C. pneumoniae. Then all these patients could be cured with antibiotic therapy. Somehow this conflicts with current experience that patients having multiple courses of broad-spectrum antibiotics don’t improve. Another thought is why did a control patient test positive? Could there be cross-reactivity with the polymerase assay? I think studies as this are thought provoking and further evaluation along this avenue is warranted.
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Introduction and Objectives: An increased urothelial permeability has been proposed to be responsible for the development of interstitial cystitis (IC). Parsons et al. reported that bladder discomfort after instillation of OAM KCI (PST) can indicate increased urothelial permeability (J.Urol., 159:1862, 1998). Since exposure to OAM KCI may be extremely painful in IC patients, we investigated a more convenient alternative. Methods: The study comprised a total of 7 controls and 33 patients. Of these patients, 13 were diagnosed with IC, 5 with neurogenic bladder dysfunction, 6 with urge incontinence and 9 with stress incontinence. Patients bladders were first filled with saline and consecutively with 0.2M KCI, and maximum bladder capaciq (Cmax) was assessed for either solution. Results: Controls and patients with stress incontinence did not show significant change in Cmax. KCI reduced Cmax in 12/13 (92%) patients with 1C, in 3/5 (60%) with neurologic bladders and in 3/6 (50%) with urge incontinence Mean reduction of Cmax with KCI was 27.5 % (8-42 %) in IC, 29 % (26-32 qfl in neurogenic bladders and 18 % (6-34 %) in urge incontinence. The examination was painless in 32/33 patients and moderately painful in I patient. Conclusions: In order to diagnose an increased epithelial permeability comparative assessment of Cmax is a well tolerated alternative to the OAM PST A reduction of Cmax > 20 % can adequately indicate increased urothe1ial permeability. The present data also suggest a permeability problem for score neurologic and urge patients. GAG layer substitution maybe the treatment of choice if increased urothelial permeability is found. Dr. Burstein's Comments: The investigators are trying to make the potassium test for detection of IC less painful. These initial results are encouraging. SACRAL NEUROMODULATION IN PATIENTS WITH INTERSTITIAL CYSTITIS: A MULTI-CENTER CLINICAL TRIAL Kristene E Whitmoret James C Lukban. Philadelphia, PA; Christopher K Payne. Stanford, CA; Ananias C Diokno. Royal Oak, MI Introduction and Objectives: The aim of this study was to determine the clinical benefit of sacral neuromodulation in patients with interstitial cystitis (IC). Methods: Interstitial cystitis patients with severe urinary frequency, urgency and/or pain were identified at three clinical sites, and enrolled as candidates for sacral nerve root test stimulation. Demographic data were collected as was baseline data on previous symptoms and past treatments. Current symptoms were evaluated employing O'Leary-Sant symptom and problem indices in addition to a three-day voiding diary. Test stimulation was performed under local anesthesia with temporary wires placed at S3 or S4 nerve roots bilaterally. An external stimulator was worn for seven days. Results: Twenty-two female patients with IC have been recruited to date with a mean age of 45.4 ± 15.3 years (range 23.2 - 81.4). Statistically significant differences between average baseline and average test stimulation values were seen in the voiding diary parameters of number of voids per day (20.9 vs. 11.6, p=0.0009), bladder discomfort (p=0,003) and force of urinary stream (p=0.008). Although average degree of urgency was not significantly different between baseline and test stimulation (p=0.10), indirect measures of urgency including average volume voided (72 vs. 112 ml), maximum volume voided (171 vs. 259 ml), and feeling of emptiness exhibited statistical significance (p=0.002, 0,02, and 0.04 respectively). The average O'Leary-Sant symptom index score was 16.4 versus 11.0, p=0.0008 and the problem index score was 13.9 versus 9.3, p= 0.002. Fourteen patients (64%) were considered candidates for permanent implant. Conclusions: Sacral nerve root stimulation was shown to provide benefit in IC patients with a significant decrease in urinary frequency and pain in addition to an improvement in IC symptom and problem index scores. These results should be tempered with the understanding that response to test stimulation does not, at present, predict implant success in IC patients. Dr. Burstein's Comments: Another study reflecting the need for careful evaluation prior to neurostimulation implant. Only 64% of patients were considered appropriate for permanent implantation. STOLLER'S AFFERENT NERVE STIMULATOR FOR INTERSTITIAL CYSTITIS: DOES IT WORK? VIVEK KUMAR, Chris Hough, Carolyn Mansfield, Paul P Irwin. Crewe, UK Introduction and Objectives: Standard treatments for interstitial cystitis (IC) are many, however none of which is optimal. We present a trial of Stoller's Afferent Nerve Stimulator (SANS) for symptomatic treatment of IC in conjunction with the standard IC medical therapy. Methods: Seven patients with IC (NIDDK criteria) were enrolled for this prospective study after obtaining ethical committee approval and following counselling and consenting. All patients were on different oral and intravesical drugs but not deriving a significant benefit from them. The posterior tibial nerve (S3), above the medial malleolus, was stimulated using SANS stimulator for 30 minutes on a weekly basis. They filled a symptom score chart before the start of the trial and every week thereafter and maintained a voiding diary. The symptoms that were evaluated were pain, urgency, nocturia and frequency on a scale of 0-5. Results: Five responded very well to the treatment. Of these, three were off all other IC medications after 12 weeks. After 15 weekly treatments, pain scores fell down from 4.2(4-5) to 0.3(0-2), urgency from 4.5(3-5) to 0.2(0-2), nocturia from 4.8(4-5) to 1.8(1-3) and frequency from 4.9(4-5) to 2.8(1-4). The mean voided volumes increased from 84.1(40-100) mls to 122.2(50-150) mls and the average frequency went down from 18,5(10-22) to 13.7(9-16) per day. Conclusions: SANS is a promising addition to the treatment options for this distressing condition and may be used in conjunction with standard medical treatment or alone. 'Once patients have derived the maximum benefit, can they be slowly weaned off?'- still needs addressing. Dr. Burstein's Comments: This device uses an acupuncture-like needle that is placed in the ankle. A small current is then used to stimulate the nerve that travels up the leg which then "connects with" the sacral nerve that reaches the bladder. This is a "sneaky" way to stimulate the bladder sensory nerves without resorting to an implanted electrode. The procedure in this study was done in the doctor's office. This is a very limited study. Larger studies need to be done. PROFILE OF INTERSTITIAL CYSTITIS PATIENTS: A REVII OF 189 CASES AT L'HOTEL-DIEU DE QUEBEC Fred, Liandier, Mireille Gregoire, Alain Naud, Guy Bedard, Louis Locom Quebec, Canada Introduction and Objectives: Interstitial cystitis (I.C.) is still a challenging problem in urology. Despite advancement in the diagnostic methods with the I test and in the therapeutic options with oral pentosan polysulfate sodium, diagnosis remains one of exclusion and the response to treatment v unpredictable. To establish the profile of patients presenting with I.C. with rega to symptom duration, cystometric and cystoscopic findings. To evaluate the clinical response to commonly used treatment: DMSO, Pentosan, Amitryptiline ~ Hydrodistension. To evaluate the prognostic value of the KCI test in relation those treatments. Methods: We reviewed the chart of 189 patients with a diagnosis of I.C. evaluated and/or treated at our hospital. Results: Of the 189 patients with a diagnosis of I.C., 173 were female and male, The mean age for the appearance of the first symptoms was 41 years (16 86 years)... A KCI test was done in 128 patients: the test was positive test in 105 patien negative in 17 and equivocal in 6. Cystometrograms were done in 175 patients; data on first desire to void is available in 57 patients. The mean bladder capacity was 274 ml (68-600 ml) and the mean volume at first sensation to void was 1481 (15-350 ml). 118 patients underwent both a cystoscopy and a KCI test, Results a presented in the Table. With regards to treatment, there was a 38% positive response rate for first time use of DMSO and a 57% positive response rate for second time. Pentosan gave partial or complete relief in 47% of users. Amitryptiline improved symptoms partially or completely in 58% of patients whereas the same was true in 47% of the patients who underwent Hydrodistension. Finally, there was no statistical difference in treatment response between patients who had a KCI + test and those having KCI - test, even for Pentosan. Conclusions: The data we obtained concerning symptoms, KCI test cystometric and cystoscopic findings are consistent with those already published except for Hydrodistension where our patients showed a higher response rate, and for DMSO where the response rate was lower than expected. More importantly, our study did not show any prognostic value for the KCI test. Dr. Burstein's Comments: A large, well done study on a variety of treatments for IC. The frustration of IC is readily apparent ; regardless of individual treatment, the response rate of improvement hovered around 50%. ALKALINZED INTRAVESICAL LIDOCAINE TO TREAT INTERSTITIAL CYSTITIS: ABSORPTION KINETICS IN NORMAL AND INTERSTITIAL CYSTITIS BLADDERS Richard A Henry, J. Curtis Nickel, Lindsay Patterson, Alvaro Morales. KingstoA Ontario, Canada Introduction and Objectives: Local anesthetics are increasingly recognized as having powerful broad-spectrum anti-inflammatory effects, including stabilizing mast cells and blocking histamine release. Theoretically they appear to be ideally suited to suppress the neuroinflammatory cycle occurring in interstitial cystitis. However, ion trapping in the bladder results in poor absorption of local anesthetics, with peak serum lidocaine levels reaching 0. 1 ug/ml. The objective of this study was to investigate the pharmacokinetics of alkalinized intravesical lidocame (All, in healthy volunteers (HV) and patients with interstitial cystitis (IC) in order to determine i) a safe dose of buffered lidocaine, ii) the effect of IC on lidocaine uptake and iii) to evaluate the acute local anesthetic effect on bladder pain of IC patients as a prelude to using AIL to treat IC. Methods: An initial dose-finding study was done on 12 HV at 4, 5 and 6mg/kgl of 5% lidocame buffered with 8.4% sodium bicarbonate. Serial serum levels were measured over three hours. The same procedure was performed in 12 IC patients using 5mg/kg of 5% lidocaine with sodium bicarbonate daily for 3 days. PACO rated their pain (verbal analogue score 1-10) before and after treatment on each day. Results: Both HV and IC groups had similar lidocaine absorption profiles with peak levels occurring at about 30 minutes. The mean peak was 1.06 ug/ml (range of 0.66 to 1.71 ug/ml) for the HV group and 1.6 ug/ml (range of 0.2 to 2.0ug/ml) for IC patients. The mean pain scores in the IC group decreased from a baseline 6.0 to 1.8 on day I and to 0.6 on day 2. Both groups complained of temporary urethral discomfort after voiding the buffered lidocaine. Conclusions: AIL improves lidocame absorption from the bladder, as indicated by therapeutic systemic lidocaine levels in both healthy and IC patients. Further, the decrease in acute pain scores in the IC group indicated sufficient concentration of local anesthetic within the bladder wall to block the sensory neurons within the submucosal plexus. AIL is a promising candidate for the treatment of IC and warrants further investigation. Dr. Burstein's Comments: Lidocaine instillation can be used to obtain temporary pain relief for IC without significant hazard.
IC Update 2000 - American Urological Association (AUA) Meeting Abstracts These abstracts were presented at the annual meeting of the American Urological Association in 2000. I have included the more digestible papers and provide a personal comment for each presentation.
INCREASED PRODUCTION OF BLADDER SURFACE MUCIN DUE TO BLADDER TRAUMA Introduction and Objectives: Bladder surface mucin (BSM) is a heterogeneous substance composed of proteoglycans, glycosaminoglycans, and glycoproteins. There is strong evidence that this layer protects the underlying urothelium from bacterial invasion, tumor implantation, and noxious agents in the urine. Alterations of BSM are associated with urothelial permeability changes and enhancement of bacterial adhesion. This protective film is commonly disrupted during endoscopic and open urological procedures. We hypothesize that the production of BSM is enhanced as a consequence of bladder trauma, thus facilitating bladder repair. In this study, we analyze changes in a high molecular weight urinary glycoprotein component of bladder surface mucin, GP51, prior to and after hydrodistention. Methods: Catheterized urine specimens were obtained from 20 female interstitial cystitis (IC) patients, mean age 55, meeting NIDDK criteria, prior to and immediately following bladder hydrodistention. Urine GP51 concentration was determined using Mab (IgG)/human in an antigen inhibition enzyme-linked immunoabsorbant assay. Urine GP51 levels (mcg/ml) were indexed to urine creatinine (mcg/ml). Six female control patients, mean age 47, submitted urine without hydrodistention. Results: Pre and post-distention indices were 0.12 (SD 0.2615) and 2.4 (SD 2.876), respectively (p<0.0001). Control index was 0.31 (SD 0.2217). Conclusions: Bladder trauma produced by hydrodistention resulted in an immediate increase (mean 28-fold) in urinary GP 51 in all patients, far exceeding the concentration seen in non-IC individuals (IC patients are known to have low urine GP51 concentrations). These data strongly suggest that bladder trauma stimulates the production of at least one component of bladder surface mucin. These findings also suggest that a favorable clinical response to hydrodistention in some IC patients may occur secondary to this phenomenon. Dr. Burstein's Comments: Patients frequently ask why hydrodistension works and I answer by saying that during the process, abnormal surface cells are "torn" which allows healing to occur with normal functioning cells. This may be a grossly simplified answer but it appears, as this study suggests, that "stretching" the bladder releases surface mucins that may restore normal function to the bladder lining.
BCG VS DMSO INSTILLATION THERAPY IN INTERSTITIAL CYSTITIS: A PROSPECTIVE RANDOMISED DOUBLE-BLIND STUDY. Introduction and Objectives: We conducted a prospective double-blind study with cross-over design of intravesical BCG versus DMSO in order to determine whether or not patients with classic and nonulcer interstitial cystitis (IC), respectively, might benefit from either regimen. Methods: Twenty-one patients with IC (11 classic and 10 nonulcer) randomly underwent treatments with intravesical BCG or DMSO and were, if not improved, treated with the other substance after a wash-out period. All 21 patients were evaluated with symptom questionnaires including visual analogue pain scale (VAS) and nutrition diaries. Results: Irrespective of regimen, there was no improvement as to maximal functional capacity. There was a reduction of urinary frequency following DMSO treatment but only in the classic subtype (p<0.05) whereas no reduction was seen following BCG in either subtype. A substantial pain decrease was noticed in classic (p<0.05) as well as nonulcer IC (p<0.05) following DMSO. Pain decrease was also reported after BCG, although not statistically significant (p=0.06). Conclusions: Intravesical BCG has been presented as an encouraging new option for the treatment of IC. The present study fails to demonstrate benefit from intravesical BCG treatment. DMSO had no positive effect on maximal functional capacity but resulted in significant reduction of pain and also reduction of urinary frequency although only for patients with classic IC. Supported by: The Swedish Medical Research Counsil, 09902 and 02235, The Regional Health Authority of West Sweden, The Swedish Society for Medical Research, Gothenburg Medical Society and The Medical Faculty, University of Gothenburg Dr. Burstein's Comments: Apparently DMSO was effective in relieving pain, but most patients received multiple treatments and no placebo group was used. I am not convinced that this study proves BCG has no benefit in treating IC . Unfortunately, there has been a lack of patient interest and a major BCG study has been closed. We will just have to wait to further evaluate the usefulness of BCG.
PLASMA CATECHOLAMINE CONCENTRATIONS IN CATS WITH INTERSTITIAL CYSTITIS. Introduction and Objectives: Interstitial cystitis (IC) is a chronic urologic syndrome affecting humans and domestic cats. We have found increased immunoreactivity to tyrosine hydroxylase, the rate-limiting enzyme of catecholamine synthesis, in the locus coeruleus of cats with IC, and increased in vitro release of norepinephrine (NE) from bladder strips. In humans with IC, increased density of bladder sympathetic fibers, increased spinal sympathetic neuron activity, and increased urine NE excretion all have been reported. Based on these results, we tested the hypothesis that plasma catecholamines and their metabolites would be increased in cats with IC. Methods: 4 healthy cats and 4 cats with IC were anesthetized and catheters were placed in the external jugular vein. 6 hours after recovery, samples were obtained for HPLC analysis of plasma levels of NE, epinephrine (E), dopamine (DA), dihydroxyphenylglocol (DHPG), dihydroxyphenylacetic acid (DOPAC), and dihydroxyphenylalanine (DOPA).
A significant increase in plasma norepinephrine concentration (mean " s.d.) and a trend toward increased epinephrine were found, whereas no effect on the dopaminergic system (DOPA, DA, DOPAC) was identified.
Conclusions: These results support and extend previous studies identifying an increase in sympathetic activity in patients with IC. Dr. Burstein's Comments: This study demonstrated an increase in sympathetic ("the fight or flight" adrenalin) nervous system activity. There is speculation that the pain of IC may be a primary nervous system abnormality distinct from a discreet bladder disease.
SINGLE DOSE OF INTRAVESICAL RESINIFERATOXIN FOR THE TREATMENT OF INTERSTITIAL CYSTITIS-PRELIMINARY Results OF A RANDOMISED CONTROLLED STUDY. Introduction: Intravesical conservative pharmacotherapy remains one of the mainstays in the treatment of Interstitial Cystitis (IC). Recently some clinical effect has been reported by intravesical capsaicin in patients with frequency and nocturia, but it failed to decrease urgency and pain. Here we reported the preliminary results of a single dose of intravesical Resiniferatoxin (RTX), an ultrapotent capsaicin-analogue, used for the treatment of IC in a randomized placebo controlled study. Methods: Twelve female patients (mean age 45.5, range 37 to 60), suffering from IC according the Interstitial Cystitis Data Base Study (ICDBS), were randomized to received 30 cc of a saline solution containing 10-8M RTX or placebo (saline solution). The response to treatment was estimated by voiding pattern and a pain score as previously described after 1 and 3 months. Results: A significant decrease of main pain score was observed at primary (2.16 " 0.40 p<0.01) but not at secondary (4.83 " 0.75) end-points in patients who receive RTX compared to before of the treatment (5.83 " 1.16) and placebo group (4.16 " 1.16 primary end-point). After one month 5 over 6 patients of RTX group reported a significant decrease of frequency, nocturia and urgency; three patients assigned to placebo reported an improvement of frequency and urgency but not of nocturia and pain. After 3 months only two patients, who receive RTX, were moderately satisfactory of their quality of life. No one reported a warm or burning sensation at the soprapubic/urethral level during the infusion of RTX or other significant side effects.
Conclusions: RTX seems to decrease significantly pain and improve symptoms in patients with IC when compared with placebo. It would be an interesting alternative in the treatment of interstitial cystitis even if other studies, performed on a larger number of patients, are necessary to confirm our results. Dr. Burstein's Comments: Capsaicin and related compounds are the actual chemicals that make peppers hot. They have been shown previously to be effective in decreasing bladder contractions in various neurogenic conditions. Repeated exposure of capsaicin depletes substance P and limits the ability of nerves to transmit sensation of pain.
THE EFFICACY OF INTRAVESICAL OXYBUTYNIN AND PENTOSANPOLYSULPHATE IN THE TREATMENT OF INTERSTITIAL CYSTITIS: A PROSPECTIVE, DOUBLE-BLIND TRIAL. Purpose: A previous study demonstrated a 44% intravesical Pentosan-polysulphate (PPS) response compared to a 20% placebo response (Br.J.U. 1997, 79:168-171). The rationale to use intravesical Oxybutynin (OX) is based on its strong local anesthetic and anticholinergic qualities. We report the therapeutic efficacy of intravesical PPS compared to intravesical OX in Interstitial Cystitis (IC) patients. Methods: Consecutive IC patients diagnosed in two institutions, according to the NIH criteria, were enrolled. Patients were randomised and prospective, double-blind treated with either intravesical PPS (300mg in 50ml) or OX (10mg in 50ml), 3 times a week, during at least 6 months. Evaluation was done using the IC symptom score, a 48-hr voiding log and urodynamic investigation. Results: Of 24 (22 female/2 male) eligible patients results were available of 21. Two pts went off-study in the OX group, one in the PPS-group. In the PPS group 4 out of 10 patients (40%) responded (subjective) compared to 6 out of 11 pts (55%) in the OX group. Both instillations were well tolerated.
Conclusions: In this study intravesical OX was well tolerated and efficacious in the treatment of IC and superior to intravesical PPS. This is contrary to the general failure of oral anticholinergics in the treatment of IC. Dr. Burstein's Comments: Some subjective improvement in both groups. Bladder instillation can be done at home using self-catheterization techniques, but notice that the results showed mild, not dramatic improvement.
PSYCHOLOGICAL STRESS, URINARY SYMPTOMS AND HPA AXIS ACTIVATION IN INTERSTITIAL CYSTITIS PATIENTS. Introduction and Objectives: Although symptom exacerbation with stress has been reported in interstitial cystitis (IC), this has not been tested empirically. Because abnormal hypothalamic-pituitary-adrenal (HPA) function has been reported in diseases having high co-morbidity with IC, we hypothesized that the HPA axis response to stress might be hypoactive in IC and contribute to IC pathophysiology. We studied whether mental stress evoked IC symptom exacerbation and adequacy of the HPA response. Methods: Fourteen women with IC (mean age 48) and 14 age-matched controls participated in a laboratory session including a 60 min. post-IV baseline (BL), 25 minutes of mental stressors including a speech task, mental arithmetic and a computer video challenge, and 75 minutes of recovery. Cortisol and ACTH were measured 3 times pre-stressor, and 8 times post-stressor onset. Acute IC symptoms were assessed at 4 voids: 15 minutes pre-stressor, and 25, 70, and 100 minutes post-stressor onset; chronic symptoms were assessed with the IC Data Base symptom survey. Results: Patients reported significantly greater pain and urgency at all 4 voids (p<0.005), increased pain and urgency from baseline to post-stressor (p<0.005), and sustained symptom elevations over BL (p<0.03). Controls showed no symptom changes with stress. Patients and controls showed no differences in maximum elicited ACTH or cortisol (p>0.40). Greater cortisol at 10 and 25 minutes was related to less pain on urination during the reactivity (p<0.03). Patients with greater maximum elicited cortisol reported less pain on bladder filling (p=0.05), less maximum pain (p<0.05), and less urgency over the last 4 weeks (p=0.08). Conclusions: These findings indicate that an acute stressor can elicit pain and urgency in IC patients. Although hypoactivity of the HPA axis to a stress challenge was not observed, cortisol response to a laboratory stressor appears to be related to acute and chronic symptoms. Supported by: RR00059, General Clinical Research Centers, NCRR, NIH Dr. Burstein's Comments: Cortisol is a naturally secreted anti-inflammatory hormone that seems to be produced in abnormally small amounts when patients were exposed to stress. This shows a physiologic reason for pain: "it's not in your head."
NF-kB-DEPENDENT UPREGULATION OF NEUROKININ-1 RECEPTORS IN A MOUSE MODEL OF LPS-INDUCED CYSTITIS. Introduction and Objectives: Several lines of evidence suggest a central role for substance P (SP) and the neurokinin 1 (NK-1) receptor as mediators of bladder inflammation. The proteins which constitute the final common pathway linking receptors on cell surfaces to the inflammatory cascade have recently been identified and cloned. Central to activation of this inflammatory cascade is translocation from cytosol to nucleus of the nuclear transcription factor known as nuclear factor-kappa B (NF-kB). This study provides several lines of evidence that lipopolysaccharide (LPS)-induced inflammation of the mouse urinary bladder is mediated by NF-kB upregulation of NK-1 receptors. Methods: Cystitis was induced in anesthetized female mice by intravesical instillation of 100 micrograms/ml E. coli LPS. One group of mice was sacrificed 60 minutes after LPS instillation for determination of p65 translocation and another group was sacrificed twenty four hours after bladder instillation in order to quantify alterations at morphologic levels. In an additional group (N=8), bladder were removed after saline or LPS treatment, and fixed in 4% paraformaldehyde for confocal microscopy. NK1 receptors were quantified by flow cytometry using a NK1 receptor polyclonal antibody and goat-anti-rabbit phycoerthyrein as secondary antibody. Analysis was performed using CellQuest software. Results: LPS instillation into the mouse bladder resulted in time-dependent cleavage of inhibitory subunit (IkB) and translocation of NF-kB from the cytosol to the nucleus. This was associated with increased expression of an NF-kB dependent inflammatory component, the neurokinin-1 receptor. Pretreatment of mouse bladders with the NF-kB inhibitor, lactacystin, prevented bladder inflammation, cleavage of IkB, and the increase in NK-1 receptor. Hence, NF-kB mediates many features of urinary bladder inflammation induced by LPS.
Conclusions: Experimental cytitis secondary to LPS involves NK-kB-dependent upregulation of substance P receptors. The NF-kB cascade is an important target for anti-inflammatory management of cystitis. Dr. Burstein's Comments: There have been multiple studies regarding the role of substance P stimulation and the pain cascade. This study tries to pinpoint the initiation of the cycle . This would be a logical area to study regarding future drug therapy to block the pain using anti-inflammatory agents.
URINE INDUCED APOPTOSIS IN CULTURED BLADDER CELLS. Introduction and Objectives: An epithelial dysfunction has been recognized in interstitial cystitis (IC ) patients. The cause of this defect is not understood. A urinary role in the pathobiological process has been suspected. However, no definitive cytotoxic factors have been isolated or characterized from patients' urines, although an anti-proliferative factor has been recently described. Urine exposure might influence apoptosis in bladder cells. Inappropriate regulation on even a relatively small, but persistent scale would produce significant effects on bladder mass and function. This study was done to determine if urine from IC patients can influence apoptosis in bladder cells. Methods: Urines (N=15) were collected from patients who fulfilled the NIDDK criteria for IC. Urines were tested undiluted by incubation with urothelial or smooth muscle target cells (1X104/well) for 2-12 hrs. Apoptosis was evaluated by ELISA (anti-histone-nucleosome capture), in-situ staining for fragmented DNA (TUNEL) and staining with annexin-V. Apoptotic urines were further analyzed by dialysis and heat denaturation studies. Results: Fifteen IC urines were evaluated. There was no apoptotic effect on the smooth muscle cells, whereas, the urines (6/15) induced significant apoptosis in the human (or rat) urothelial cells. Immunochemical and annexin V staining confirmed the ELISA data. RNA was extracted from target cells sufficient for RT-PCR analysis.
Conclusions: These findings suggest for the first time that urinary factors effect apoptotic pathway in the bladder mucosa. This would impact significantly on urothelial cell populations in the mucosa and therefore would have significance in regulating urothelial cell turnover in interstitial cystitis where the mucosa is believed to be abnormal. These results are also in concordance with our earlier studies that demonstrated cytotoxic urine factors in IC patients and not in normal control urines. Dr. Burstein's Comments: Apoptsis means programmed cell death. Cytotoxic means cell killing. This study suggests that there is something in the urine of IC patients that damages or kills the lining cells of the bladder.
DO INTRAVESICAL AGENTS USED IN INTERSTITIAL CYSTITIS AND AN OVERACTIVE BLADDER ALTER PERMEABILITY OF NORMAL UROTHELIUM? Introduction and Objectives: Intravesical agents have been advocated for interstitial cystitis and overactive bladders especially in children or those intolerent to oral administration due to side-effects. The direct effects and mechanism of absorption through the urothelium of these agents is unknown. This study was designed to test the effects of these agents on urothelial permeability and transepithelial resistence (TER). MethodsFemale Anesthetized New Zealand rabbits were catheterised and instilled with an agent for one hour. The agents studied were saline (control), Oxybutynin (Ditropan @ 5mg), Tolteradine (Detrol @ 2mg), Pentosan polysulfate sodium (PPS - Elmiron @ 100mg) all of which were made up to 20 mls with normal saline and dimethyl sulfoxide (DMSO) (RIMSO-50 @ 20 mls). The bladder was excised, the muscle dissected free of the urothelium and using an Ussing chamber, water and urea permeability was determined and transepithelial resistance (TER). Results are shown as mean, "SEM."
Dimethyl sulfoxide (P=0.002) is the only agent studied which significantly lowers TER. DMSO also had significantly increased urea permeability (P=0.008) at one hour.
Conclusions: DMSO is the only intravesical agent used in interstitial cystitis that affects permeability. This suggests that this agent may cause further urothelial damage, and thereby interferes with the inflammatory process of interstitial cystitis. The mechanism of this is unknown but as DMSO is radical scavenger, the penetration of DMSO into the underlying mucosa may inhibit inflammation caused by free radical release. The other agents do not appear to significantly alter the permeability of the urothelium, thus do not appear to have any immediate toxic effect on the urothelium. Dr. Burstein's Comments: This abstract gives one explanation of why DMSO works: it crosses through the bladder lining where it acts as an anti-oxidant and binds up damaging free radicals.
ARE GLOMERULATIONS TYPICAL OF INTERSTITIAL CYSTITIS? Introduction and Objectives: Glomerulations on cystoscopy are considered to be the hall marks of interstitial cystitis(IC). This prospective study was done in different groups of patients to find out whether glomerulations are present in patients with frequency, urgency and dysuria (fuds) syndrome only or in others too. Methods: This study was conducted from JUL. 96 to OCT.99.100 patents were included in the study.60 patients were suffering from chronic fuds syndrome,29 from disease of genitourinary system other than fuds and 11 patients were suffering from some disease other than genitourinary system. Out of 60 patients of fuds group 26 were males and 34 females.Rest 40 had 18 males and 22 females. None of the patients had been recently catheterised or irradiated. None of them had acute urinary tract infection .Cystoscopy was done in all the patients with 21 ch scope, bladder was distended to full capacity under gravity with reservoir height being 80 cms, drained and distended again. 2nd distension was maintained for 3 minutes and bladder drained again. Cold cup biopsy was taken. Results: Out of 60 patients of fuds syndrome group 30 had glomerulations involving more than 75% area of bladder surface. Rest 30 did not develop glomerulations at all or had only few glomerulation. Most important finding was that the other 40 cases not belonging to fuds syndrome did not develop glomerulations at all even on second distension or hydrodistension.
Conclusions: This study proves that glomerulations are hall mark of interstitial cystitis. There may be some patients who have similar symptoms of IC but do not develop glomerulations but it is very difficult to find glomerulations in normal persons or persons suffering from other diseases than fuds syndrome. Dr. Burstein's Comments: Glomerulations or pinpoint bladder lining bleeding is still considered the hallmark physical finding in IC.
ANTI-PROLIFERATIVE FACTOR (APF), HEPARIN BINDING EPIDERMAL GROWTH FACTOR-LIKE GROWTH FACTOR (HB-EGF) AND EPIDERMAL GROWTH FACTOR (EGF) ALTERATIONS IN INTERSTITIAL CYSTITIS (IC) CONFIRMED. Introduction and Objectives: Many urine components are reportedly altered in IC, but few have been confirmed by testing a different set of IC patients and controls. One of us (SK) found that the urine specimens from most IC patients had decreased levels of HB-EGF and increased levels of EGF (J Urol 158:1983, 1997), plus a factor (APF) that inhibits growth of cultured bladder epithelial cells (Urol 52:974, 1998). The goal of this study was to confirm these findings. Methods: 40 female IC patients and 40 age-matched female controls were recruited by DE to collect 24-hour urine samples. Urine was kept at 4°C during the collection. Aliquots were centrifuged, and supernatants stored at -70°C until assayed by SK, who was blinded to which aliquots were IC or control. Urine APF was measured using a thymidine incorporation assay (Urol 52:974, 1998). HB-EGF and EGF were measured by ELISA (J Urol 158:1983, 1997). Results: 37 of the 40 IC patients were positive for APF, and one control subject was positive. HB-EGF was decreased and EGF was significantly increased in IC.
Conclusions: This study confirmed the original findings, using a different group of patients and controls. APF may contribute to epithelial dysfunction in IC, by inhibiting bladder epithelial cell growth. It is currently unknown whether the alterations in EGF and HB-EGF contribute to the pathogenesis of IC, or are responses to bladder epithelial cell injury. Dr. Burstein's Comments: Anti-proliferative factor is a protein substance in the urine of patients with IC. In laboratory tests, APF inhibits normal bladder cell growth and repair. Whether APF causes IC or is produced in response to the disease is unknown. But this study confirms that it is present only in urine of IC patients and that it may have potential to be used as a marker to diagnose IC.
INTERSTITIAL CYSTITIS OR PROSTATITIS? PENTOSAN POLYSULFATE THERAPY FOR MALE CHRONIC PELVIC PAIN SYNDROME. Introduction and Objectives: Chronic pelvic pain syndrome (CPPS) in males may not be a specific prostate problem. CPPS in males has similar clinical and perhaps etiological characteristics as interstitial cystitis (IC). The mechanism of action of pentosan polysulfate (PPS), an oral medication indicated for the treatment of IC, is believed to be supplementation of the glycosoaminoglycans of the bladder surface but there is no data to suggest that PPS reaches or is excreted by the prostate. We undertook an open label multi-center phase II pilot study to examine the potential efficacy of PPS in the treatment of CPPS in males, employing outcome tools validated for chronic pelvic pain syndrome in males. Methods: Patients with a diagnosis consistent with NIH CPPS Category IIIA (inflammatory) were treated with PPS, 100 mg tid, for 6 months. Evaluation at baseline, 3 months and 6 months consisted of symptom severity index (SSI), symptom frequency questionnaire (SFQ), a prostatitis pain index (NIH-CPSI), quality of life assessment (QoL) and subjective global assessment (SGA). Results: 32 Patients (mean age 45.5+/-11 yrs; duration of symptoms 9.2+/-12 yrs) were enrolled in 5 centers. 6 patients withdrew from study. Drug related side effects included hair loss (6%), headache (3%), mild jaundice (3%), mild nausea (3%) and skin flushing (3%).
SGA at 6 months confirmed mild improvement in 30%, moderate in 15% and marked improvement in 15%. 40% of patients had >50% improvement in SFQ; 45% had >50% improvement in SSI, NIH-CPSI and QoL.
Conclusions: PPS is well tolerated and appears to have efficacy in reducing severity and frequency of general symptoms, reducing specific pain symptoms and improving quality of life in many male patients with CPPS. The safety and efficacy of PPS should be compared to placebo in a well designed randomized controlled trial. Dr. Burstein's Comments: Chronic Prostatitis as defined in this paper has many symptoms in common with IC. Could it be that it is IC? It would have been interesting to see the results had these patients undergone hyrodistention to diagnose IC.
KJ Propert; C Brensinger and JR Landis; Philadelphia, PA; AJ Schaeffer, Chicago, IL; J Kusek and L Nyberg, Bethesda, MD; and the ICDB Study Group* (Presented by Dr. Propert) Introduction and Objectives: The Interstitial Cystitis Data Base (ICDB) was a prospective longitudinal cohort study of patients with interstitial cystitis (IC) to characterize the natural history of the disease over a four year follow up period. Methods: Data obtained from the full cohort of 637 patients who participated in the ICDB was analyzed for patterns of change over time. Results: Patients tended to be female (91%) and white (93%) with a median age of 43 years. In general, patients presented with moderate to severe symptoms in all three of the primary symptom domains of pain, urinary urgency, and urinary frequency, with the latter two symptoms being somewhat more common. Sixty eight percent of the patients reported that they had urological symptoms for more than five years prior to study entry, although many of these patients had not previously been formally diagnosed as having IC. Cystoscopy and hydro-distention were performed at study entry in 36% of the patients, primarily those who presented with more severe urgency and frequency symptoms. Sixty four percent of the patients were followed up to the end of the study. Patients who withdrew or were lost to follow-up tended to have more severe symptoms at baseline (p0.001). The overall patterns of change over time suggested an initial decrease in symptom severity followed by fairly constant symptom levels long-term. The initial drop has 3 components: "regression to the mean", a "placebo effect" related to the increased follow-up and care for patients enrolled in the cohort, and potential individualized treatment effects. Although there were fluctuations in all symptoms over time, there was no evidence of any long-term change in overall disease severity after the initial improvement. Conclusions: These results support the clinical observation that IC is in general non-progressive, and reflect the current lack of effective treatments for a large majority of patients. These results may be useful in the design and conduct of future clinical trials in IC.
Karan J. Singh and C. Lowell Parsons, San Diego, CA (Presented by Dr. Singh). Introduction: Interstitial cystitis (IC) has been sometimes classified into an "early" (non-ulcer) and "classic" (ulcer) forms that have distinct characteristics. However, it is not clear whether the early form progresses into the classic form. In our study we divided IC patients by age to see if there was any evidence of progression of disease in the older patients. Methods: Three-hundred and sixty eight patients with the diagnosis of IC were divided into either Group 1, those below the age of 40 (145 patients) or Group 2, those above the age of 40 (223 patients). The two groups were then compared in terms of symptoms, voiding profiles, cystometrogram findings, anesthetic bladder capacity and cystoscopic findings. Results: There was no statistical difference between the two groups in their symptoms, voiding profiles or cystometrogram findings. However, the average anesthetic capacity was significantly lower in Group 2 (639.9 ml) versus Group 1 (705.3 ml) with a p value of 0.028. Patients in Group 1 had more glomerulations (p<0.0001) and a bloody effluent after bladder filling (p=0.047). Only 5 (3.4%) patients in Group 1 had Hunner's ulcers versus 34 (15.2%) patients in Group 2 which was a significant difference (p<0.0001). Conclusions: Although the level of symptoms stabilize with time, changes to the bladder are progressive in patients with interstitial cystitis with "ulcers" being manifested primarily in older patients.
THE USE OF INTRAVESICAL BCG IN THE TREATMENT OF INTERSTITIAL CYSTITIS (IC): LONG TERM FOLLOW-UP Kenneth M. Peters, Ananias C. Diokno, Bruce S. Steinert and Jose A. Gonzalez, Royal Oak, MI (Presented by Dr. Peters). Introduction and Objectives: The etiology of interstitial cystitis is unknown and currently there is no cure for this disease. At the 1996 AUA, we presented our experience using TiceÆ BCG in the treatment of interstitial cystitis in a prospective, double-blind, placebo-controlled trial. We reported a 60% BCG response and a 27% placebo response with a minimum of 6 months of follow-up. Our purpose is to report long-term follow-up of the participants in our initial study. Methods: The patients involved in the study were followed with questionnaires and voiding diaries. The patients who received placebo were offered BCG in an open label study. Results: Of the 15 patients who received placebo, 13 elected to be treated with BCG. One patient refused BCG because she continued to have a good response from her placebo treatment. Thus, of the total 4 placebo responders, only one continued to have a favorable response (25%). Of the BCG responders, mean follow-up of 15 months (range 12-21 mo), 7 of 9 patients (78%) continued to have an excellent response in all parameters measured. The global IC survey improved from 20 to 6 points (70%), voids/day decreased from 13 to 9 (31%), mean voided volume increased from 92 cc to 167 cc (81%), pelvic pain decreased from 4.8 to 0.9 (81%), vaginal pain 5.5 to 1.5 (73%), urgency 6.7 to 1.8 (73%), burning 5.7 to 0.8 (86%). Overall well-being improved 61% and the Rand 36-quality of life survey overall improved 65%. No long-term adverse events from BCG were noted. Conclusions: Intravesical TiceÆ BCG is safe and effective in the treatment of IC. Of those patients who received only 6 weekly treatments of BCG and responded favorably, 78% of these patients continue to have an excellent response with a follow-up ranging from 12-21 months.
A RANDOMIZED DOUBLE-BLIND TRIAL OF ORAL L-ARGININE FOR TREATMENT OF INTERSTITIAL CYSTITIS Grace E. Korting, Shannon D. Smith, Marcia A. Wheeler, Harris E. Foster, Jr. and Robert M. Weiss, New Haven, CT (Presented by Dr. Korting). Introduction and Objectives: Nitric oxide synthase (NOS) activity is decreased in the urine of patients with interstitial cystitis (IC) compared to normal controls. In a preliminary trial, oral Larginine increased urinary NOS activity and improved patients' symptoms. This randomized, double-blind, placebo-controlled study further investigates the efficacy of L-arginine treatment for IC. Materials and Methods: Fifty-three patients were assigned to 1500 mg/day of oral L-arginine or placebo for 3 months. IC symptoms were assessed in interviews at 2 weeks, 1 month, 2 months and 3 months. Participants also completed avoiding diary. Results: Forty-six patients completed the trial. Seven patients withdrew after randomization (6 L-arginine: 4 due to increased pain; 1 placebo). Six patients in the L-arginine group (29%) and two patients in the placebo group (8%) were clinically improved by the end of the trial (p<0.07). In response to a questionnaire evaluating changes in symptoms over time, there was a significantly greater improvement in symptoms (p=0.05) in the L-arginine group at 3 months. There was a significant improvement in pain intensity (p=0.04) and a tendency toward improvement in urgency (p=0.06) and pain frequency (p=0.09). There was no significant difference between groups in voiding frequency. Conclusion: Oral L-arginine improves symptoms in some IC patients. Clearly identifying the effectively treated group will aid in successfully treating IC. Source of Funding: NIH Grants DK 47538, DK 02499 and DK 38311.
TREATMENT OF INTERSTITIAL CYSTITIS: THE INTERSTITIAL CYSTITIS DATA BASE (ICDB) STUDY EXPERIENCE Aaron Kirkemo, Detroit, MI, J. Richard Landis, Philadelphia, PA, Yvonne Matthews-Cook, Hershey, PA, David T. Uehling, Madison, WI and Leroy M. Nyberg, Bethesda, MD (Presented by Dr. Kirkemo). Introduction: IC treatment is hampered by many difficulties. IC is usually understood to be an inflammatory disease of the bladder characterized by a constellation of symptoms including urinary urgency, frequency, and bladder pain. However, a strict definition of the disease does not exist and the etiology(ies) of IC remains controversial. This makes it very difficult to create rational pathophysiologically based treatments. This abstract seeks to characterize IC specific treatments reported by patients as they entered the national ICDB Study. Materials and Methods: Medications and treatments reported for the treatment of IC at study entry for an 582 females enrolled in the ICDB Study were reviewed. A specially designed ICDB Medications and Treatments Coding Dictionary Structure was used to classify all therapies. Results: Only 105 (18%) women were receiving no therapy at baseline. Single mode therapy was being given to 196 (33.7%) women and dual mode therapy was seen in 118 (20.3%). Treatments from three or more treatment groups (range 3 to 8) were recorded in 163 (28.0%). A total of 183 different therapies were recorded. The ten most commonly used specific therapies were hydrodistention (192), amitriptyline (98), special diet (54), intravesical heparin (53), hyoscyamine (41), oxybutynin (34), pentosan polysulfate (32), propaxyphene (28), Atrosept (26), and hydroxazine (24). The ten most common treatment groups were: hydrodistention (192), tricyclics (111), intravesical therapies (102), anticholinergic/antispasmodics (88), special diet (54), NSAIDS (39), oral pentosan polysulfate (32), systemic alkalinizers (30), hydroxazine/antihistamines (30), and antibiotics (12). Conclusion: The list of IC treatments is diverse both numerically and mechanistically. The plethora of treatments suggests the need for further a. research in IC to develop rational pathophysiology based treatments.
RESULTS OF SURGICAL TREATMENTS FOR INTERSTITIAL CYSTITIS Ramaiah Indudhara, Anna M. DíAmico, Anton J. Bueschen, Lewis Keith Lloyd, Birmingham, AL (Presented by Dr. Indudhara). Objectives: To evaluate the clinical outcome of various surgical treatments for chronic interstitial cystitis (IC). Patients & Methods: This is a retrospective study (chart review & telephone survey) of 37 patients (F-26, M-11; age: mean 43.6yrs, range-16-75)) who underwent a major surgical procedure. The indications for surgery included symptoms (extreme frequency & pelvic pain) not responding to conservative measures including hydrodistension, intravesical instillation of DMSO, chlorpractin and oral pentosan polysulfate. All patients had undergone initial detailed clinical history and examination, routine laboratory tests including UA, urine culture & cytology; IVP and bladder biopsy. In addition patients were offered detailed behavioral evaluation by a psychotherapist. Results: The median duration of symptoms was 4.2 yrs (range:1.3-9). Frequency of urination ranged from 15-50 times/24 hrs. The pain was described variably in the suprapubic region, perineum or rectum. The surgical procedures performed included ileal conduit urine diversion alone (n=13), cystectomy with ileal conduit (n=8), cystectomy with continent urinary diversion with (n=7), or orthotopic neobladder (n=4), augnmentation cystoplasty (n=3) and cystolysis (n=5). There were 11 reoperations including stoma revision (3), small bowel obstruction (2), cystectomy (3), ileal conduit diversion (1) and collagen injection for incontinence (2). There was no operative death. At a median followup of 3 yrs. (range:1.6-22), 8 of 11 ileal conduit only patients, 6 of 8 cystectomy+ileal conduit group, 4 of 7 pts with cystectomy+continent diversion, 1 0f 4 with orthotopic bladder and 1 of 3 with augmented bladder were free of symptoms. None of the patients undergoing cystolysis (5) had any longterm improvement. Recurrent pouch inflammation was seen in 2 pts with orthotopic neobladder and 1 with continent diversion. Conclusions: Surgical therapy of IC provides long term benefits in severely symptomatic patients. Ileal conduit with/without cystectomy provides the best long term results. Recurrent pouch inflammation is a major problem following orthotopic neobladder and continent diversion in patients with IC.
CHLAMYDIA PNEUMONIAE IN PATIENTS WITH INTERSTITIAL CYSTITIS JJ Franke; CW Stratton and WM Mitchell; Nashville, TN (Presented by Dr. Franke) Introduction and Objectives: Since the identification of Chlamydia pneumoniae there has been evidence to indicate that it is an important human pathogen. Clearly it is associated with respiratory tract infections, but the scope of more disseminated C. pneumoniae infections is yet to be defined. This organism, which is transmitted by fomities, is fairly ubiquitous. Seroepidemiological data indicates that the incidence of previous exposure to C. pneumoniae increases with age. C. pneumoniae has been identified in endothelial cells, macrophages, and smooth muscle cells of atheromatous plaques, and an association with coronary artery disease is being investigated. In all C. pneumoniae infections, it is the secondary inflammatory response which is felt to impact most upon the end organ. Disseminated C. pneumoniae may play a role in the pathogenesis of chronic inflammatory diseases like interstitial cystitis (IC). Our objective is to determine if there is an increased incidence of urinary C. pneumoniae infection in IC patients. Methods: As an obligate intracellular organism, C. pneumoniae can be detected with the use of tissue culture or polymerase chain reaction (PCR) to detect organism-specific DNA such as the major outer membrane protein (MOMP) gene. 32 IC patients and 12 normal volunteers were analyzed by serum and urine PCR to MOMP. 11 IC patients underwent bladder biopsy tissue culture. Results: Serum PCR positivity was 94% for IC patients and 83% for controls. This difference is not statistically significant, which correlates with the increasing sero-positivity with age in the normal population. Urine PCR positivity was 81% for IC patients and 27% for controls, which is significant with a p0.05. In addition, all eleven bladder biopsies obtained from IC patients were tissue culture positive for C. pneumoniae.
Conclusions: There is a statistically significant increase in urine PCR to C. pneumoniae MOMP gene in patients with IC. Further age-matched control data is being obtained to clarify its role in the pathogenesis of IC. In addition, urine PCR to the MOMP gene may be an important marker for the disease.
DECREASED GLYCOSAMINOGLYCAN LEVELS IN INTERSTITIAL CYSTITIS: A REALITY OR MYTH David C. Wei, Victor A. Politano and Vinata B. Lokeshwar, Miami, FL (Presented by Dr. Wei). Introduction and Objectives: Defective glycosaminoglycan (GAG) layer on the urothelium is believed to be one of the causes of IC. Consequently, GAGs such as hyaluronic acid (HA) and some sulfated GAGlike substances are used for treating IC. To examine the involvement of GAGs, sulfated GAGs and HA in IC, we analyzed urinary levels of these substances in normal individuals (n=20), and IC patients (n=25). Methods: All study individuals were in the same age group (30-50 yr). The total GAG (sulfated + non sulfated) and the sulfated GAG levels were measured by the modified carbazole reaction and the dimethyl blue binding assay, respectively. These levels were normalized to urinary creatinine and expressed as ?g/mg creatinine. The urinary HA levels were measured by the HA test, an ELISA-like assay. The cut-off limit for normal urinary HA level is 100 ng/mg protein. Results: IC patients were divided into two groups: group 1, symptomatically improved (n=10) and group 2, symptomatic (n=15). The urinary GAG levels were slightly elevated in group I (34.2±3.4) and markedly elevated in group 2 (76.2±11.5) as compared to normals (22.4±3.3) (p<0.001). The urinary levels of sulfated GAGs were similar in all 3 groups (normals, 1.4±0.15; group 1, 1.28±0.84 and group 2, 1.64±0.17) (p>0.5). Consequently, the ratio of total to sulfated GAGs was significantly higher in group 2 (49.9±6.9) than in normals (17.2±2) and group I (14.4±2) (p<0.001). Urinary HA levels were within normal range for group 1 (108.1±23.6) but were high in group 2 (164.9±23) patients. Interestingly, HA present in IC patients' urine was of higher molecular mass (106 D) than that found in normals (105 D). Conclusions: The GAG levels are not decreased in IC; rather, the ratio of total to sulfated GAGs and the HA levels are elevated in symptomatic IC patients. The high molecular mass HA may be involved in the pathophysiology of IC.
PATIENT PROFILE OF 106 PELVIC AND LOWER ABDOMINAL PAIN PATIENTS SEEN IN THE UROLOGICAL PAIN CLINIC RA Schmidt; J Slocumb and R Slover; Denver, CO and R Doggweiler; Memphis, TN (Presented by Dr. Doggweiler) Introduction: Chronic pelvic pain in the absence of identifiable somatic pathology represents one of the most confounding and challenging problems to the physician. Patients unable to find effective therapies for their debilitating symptoms often become frustrated, angry and demanding. To garner insight into symptom patterns of these patients we have investigated the charts of patients seen in our pelvic pain clinic. Material and Methods: The charts of 106 seen during the past 3 years were reviewed. Each patient had filled out a questionnaire regarding the nature of presenting symptoms at the first visit. This was complemented with a careful medical, gynecological and urological history. Pathologies like cancer, urinary stones or infections were absent from the survey. Results: The average age of these patients is 40.85 year (21 ñ 73 year), 89 females and 17 males. Patients presented with symptomatology of voiding dysfunction (retention, dysuria, and urgency/frequency, urge incontinence). All patients have been seen previously by at least one care center and 87.7% had undergone one or more operations; one had 20 surgical procedures as attempts to control her pelvic pain. A total of 182 surgeries were performed on the 106 patients. These consisted primarily of hysterectomy, laparoscopy and removal of ovarian cysts. Previous diagnosis included urethral syndrome, interstitial cystitis, recurrent UTI, irritable bowel, endometriosis and ovarian cysts in females, prostatitis and epididmitis in males.
Conclusion: Surgeries on any of these organs did not produce long-term relief of symptoms. These data support the trend towards conservative therapeutic approaches to pelvic pain and a move away from the traditional surgically based therapies.
INTERSTITIAL CYSTITIS (IC) IN MALES Ramaiah Indudhara, Lewis Keith Lloyd, Anton Bueschen, John Burns and Donald Urban,Birmingham, AL (Presented by Dr. Indudhara). Objectives: To define the clinical patterns of IC in male patients. Methods: 18 white patients (mean age 41 yrs, range 31-78) with biopsy evidence IC were evaluated. All patients had detailed clinical history and examination, routine biochemical & hematological tests, urinalysis and culture; IVP, urine cytology, cystoscopy & bladder biopsy. Results:The median duration of symptoms was 3 yrs (range: 2-6 yrs). Frequency of urination ranged from 12-50 times in 24 hours. Associated medical conditions included diabetes (4), coronary artery disease (7), depression (5), hypertension (12), migraine (2), multiple allergies (7), pernicious anemia (1) and smoking cigarettes (11). Chronic prostatitis was the initial diagnosis in 6 & had received multiple antibiotics for a median of 6 months. 5 patients had undergone TURP with no significant change in symptoms. Culture positive UTI was seen in 7 patients. Cystoscopy revealed varying degrees of bladder inflammation; classic Hunner's ulcers were seen in 4 instances. The mean bladder capacity was 375cc (range:175-600). Bladder biopsy revealed chronic inflammatory response with mast cells in 11 and nonspecific chronic inflammation in the remaining. All patients had been tried on antibiotics, narcotic and non-narcotic analgesics, & anticholinergics; in addition, morphine pump (in 3) & repeated epidural block with long acting local anaesthetic (in 2). Initial therapy consisted of anesthetic cystoscopy and hydrodistension in all. The median duration of clinical improvement was 3 months (range: 6 weeks to 1 year). Intravesical DMSO was used in 2 patients with minimal improvement. Surgical procedures consisted of ileal conduit urine diversion (3), simple cystectomy with ileal conduit urine diversion (5), cystectomy with orthotopic bladder (2) and augmentation cystoplasty (1). One patient was detected to have carcinoma in situ (CIS) of bladder 2 years after diagnosis of IC & underwent radical cystectomy for recurrent tumor. One patient with ileal conduit diversion required cystectomy 6 months later for persisting pelvic pain. At a median followup of 16 months (range: 9-48), patients following surgery are free of bothersome symptoms except for one patient after cystectomy and ileal diversion who continues to experience significant pelvic pain.
Conclusions: IC has similar clinical presentation in males when compared to females. Most often these patients are treated for chronic prostatitis. A high index of suspicion for IC is necessary in such patients & should rule out CIS. No medical therapy provides long lasting benefit. Simple cystectomy may be required to alleviate persisting pelvic pain.
Another excellent source for IC information is: The Interstitial Cystitis Network
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DeKalb Clinic Urology
217 Franklin St
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