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AUA IC Abstract Discussions Update - 2001These 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. Conclusions: We dernonstrate 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. COMMENT: 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 occuring 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 occuring pain killing chemicals. This is really exciting !! NEUROMODULATION TREATMENT FOR REFRACTORY SEVERE INTERSTITIAL CYSTITIS Michael P. Feloney, Daniel J. Culkin. Oklahoma City, OK 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 meausres. 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 wite and 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. COMMENT: 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 Introduction and Objectives:
Interstitial cysititis (11C) in children is considered a rare occurrence.
Children often present in asimilar 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 (nonneurogenic 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. COMMENT: 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 unhown 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. COMMENT: Even though this was a limited study on a very small group of patients, there was significant improvent 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. COMMENT: 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 braod-spectrum antibiotics don't improve. Another thought is why did a control patient test positive? Could there be cross-reactiviety with the polymerase assay? I think studies as this are thought provoking and further evaluation along this avenus is warranted. COMPARATIVE (SALINE VS. 0.2M POTASSIUM CHLORIDE) ASSESSMENT OF MAXIMUM BLADDER CAPACITY: A WELL TOLERATED ALTERNATIVE TO THE OAM POTASS101 SENSITIVITY TEST (PST) Lukas daha, Claus
R. Riedl, Marlies Knoll, Heinz Pflflger. Vienna, Austria; Gero Hohlbrugger.
Innsbruck, AK Austria 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. COMMENT: 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. 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. Comment: Another study reflecting the need for careful evaluation prior to neurostimualtion 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. COMMENT: This device uses an accupuncture-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 doctors 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 challeng 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 review
the chart of 189 patients with a diagnosis of I.C. evalua 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).
The mean duration of symptoms before seeking medical advice wa! 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 patien data on first desire to void is available in 57 patients. The
mean bladder capac 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. COMMENT: 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. 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 COMMENT:
Lidocaine instillation can be used to obtain temporary pain relief for
IC.
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