All right, welcome to the AUGS urogynecology webinar series. I'm Sarah Ashmore, a member of the AUGS Education Committee and the moderator for today's webinar. Today's webinar is titled Diagnosis and Treatment of Interstitial Cystitis, Bladder Pain Syndrome, a Phenotype-Driven Approach. Our speaker today is Dr. Henry Lai. Dr. Lai is an endowed professor of urologic surgery, professor of anesthesiology, and director of urologic research at Washington University School of Medicine. He is a clinician scientist with clinical, translational, and basic research focused on benign lower urinary tract disorders, including interstitial cystitis, chronic prostatitis, overactive bladder, and urinary incontinence. He has been continuously funded by the NIH for over a decade. He is the PI and chair of the NIDTK Symptoms of Lower Urinary Tract Dysfunction Research Network, studying the clinical phenotypes of lower urinary tract disorders, including overactive bladder and urinary urgency. He is also the PI of the NIDTK Multidisciplinary Approach to the Study of Chronic Pelvic Pain Research Network, studying the clinical phenotypes of interstitial cystitis and chronic prostatitis. He is also the PI of the Urinary Stone Disease Research Network. He has a solid track record of publication and has authored about 160 papers. He was the recipient of the Rising Stars in Urology Research Award from the AUA and the Paul Zimskin Award from SUFU. Just a reminder, this presentation will run about 45 minutes. The last 15 minutes of the webinar will be dedicated to Q&A. Before we begin, I'd like to review some housekeeping items. AUGS designates this live activity for a maximum of 1.0 AMA PRA Category 1 credit. To claim your CME credit, you must log into the AUGS eLearning Portal and complete the evaluation following the completion of the webinar. This webinar is being recorded and live streamed. A recording of the webinar will be made available in the AUGS eLearning Portal. Please use the Q&A feature of the Zoom webinar to ask the speaker questions. We will answer them at the end of the presentation. Use the chat feature if you have any technical issues. AUGS staff will be monitoring the chat and can assist. All right, Dr. Lai, you may begin. Thank you. Sarah, can you hear me okay? Yep, I can hear you. Wonderful. The reason I was asking and people noticed that I haven't dressed up is because I'm actually on vacation this week. When I signed up for the webinar, actually, I ended up scheduling vacation on the same week. So, I'm here in the beautiful state of Hawaii. Aloha, everybody. Good evening and good afternoon. That's why I didn't dress up. So, welcome. Welcome, everybody. So, it's really a pleasure to be invited to talk about ICBPS. I really thank all of you to spend your afternoon and evening listening to the talk. But thank you very much. So, these are my disclosures. I'm going to have two parts of the talk. The first part will be a little bit shorter. I'm going to tell everybody a little bit about the updated AUA guidelines to treat and to diagnose ICBPS. But most of the talk will be geared towards the phenotype-driven approach or how we're going to identify subgroups of ICBPS patients and treat them accordingly based on their phenotypes. ...treatment of ICBPS since 2012. The guideline was updated in 2014. But eight years later, last year, we updated the AUA guideline again on the topics bringing in new evidence. So, I'm going to spend a few minutes to update people who's familiar with the guideline, what are the changes in the 2022 guideline. You can see the guideline at the AUA website from American Urological Association. It's also published in the Journal of Urology. So, first of all, the diagnosis of ICBPS remains the same in the 2022 guideline. It's essentially still a symptom-based diagnosis. In other words, ICBPS is a clinical syndrome. What we are looking for in a patient to be consistent with this diagnosis is a complaint of unpleasant sensation. So, it doesn't have to be pain. It could be pressure or discomfort perceived to be related to the bladder, associated LUTs of more than six weeks duration, in the absence of infection and other identifiable causes. So, it's a little cryptic if you look at the definition. So, what do you mean when you say your pain, pressure, discomfort is related to the bladder? Basically, it means the pain cycle with bladder filling or bladder emptying and their associated LUTs. So, a lot of times to distinguish ICBPS from other causes of pelvic pain, we ask patients specifically regarding pain with bladder filling. A lot of the IC patients will have what we call painful bladder filling. That means when the bladder starts to fill up and it's on stretch, the pain level increases. That's very characteristic for ICBPS. The other thing that people typically will complain is that I have a strong, constant urge to go to the bathroom. And we ask them, why do they go to the bathroom that often? They would typically say, well, when the bladder starts to fill up, I get really uncomfortable. So, I need to go to the bathroom to relieve my urine, to relieve my pressure and the pain. Now, these kind of strong, constant urge is actually quite different from what you typically hear from overactive bladder patients. They may be doing okay, and all of a sudden, when they got to go, I got to go, they rush to the bathroom. This is different. This is almost like a constant, annoying urge in the bladder. The other thing people complaining about is LUTs. You know, you ask for urinary frequency, you ask about the nocturia. It's not uncommon. They go to the bathroom every hour to urinate, daytime and nighttime. So, a patient come with you with pelvic pain, but it doesn't have LUTs. You think, well, maybe it's not really ICBPS. It's also relatively uncommon for an ICBPS patient to have urgency urinary incontinence. So, it's one of the other features you could distinguish from overactive bladder. The pain can be anywhere in the pelvis. It's typically in the suprapubic area, or if you do a pelvic examination, it'll be on the anterior vaginal wall towards the trigon area. Patient coming to you with isolated dysuria, the only complaint they have is burning when they urinate, may not have ICBPS. The other part of the definition I think everybody realized is that it is a diagnosis of exclusion. In other words, you've got to make sure they don't have urinary tract infection, what we call other confusable disease that may mimic ICBPS, but in fact they have something else. There's a long laundry list of confusable disease, anything from overactive bladder to UTI to urethral diverticulum to mesh complications to high-stage prolapse, et cetera. So, you need to be aware of that. Now, this is the algorithm in the AUA guideline. Everybody start with what we call basic assessment or basic evaluation. It includes history, physical examination, frequency, volume, tract. Patient typically will have high urinary frequency and small volume. You could do a PVR, pulmonary residual volume with a bladder scanner. We typically will send both urinary analysis and urine culture. You can assess the IC symptoms using standard questionnaires, and you could also evaluate the pain using pain questionnaires. Most patients are not complicated in terms of the clinical presentation, and you can go ahead and start to treat them. But again, as I mentioned earlier, the key to the diagnosis and management is to route confusable diseases. So, if you're concerned that something else is going on, you could do imaging, you could do cystoscopy, you can consider urodynamic testing. For example, if they have high post-life residual volume, they have weak stream, and they have other urologic surgery or gynecologic surgery in the past, urodynamics might be reasonable. Nephroscopy to look for endometriosis and other referrals. Now, one of the new things we emphasize in the new AUA guideline is the role of cystoscopy. In the past, cystoscopy is optional, but now we think that we recommend cystoscopy in patients who you think might have Hunter's lesion, and we'll spend more time talking about Hunter's lesion later on. But essentially, men and women over the age of 50 have a higher risk of having Hunter's lesion. You should consider doing cystoscopy on them. The other reason, as I mentioned earlier, to do cystoscopy is to route other conditions. For example, this could be part of the microscopic hematuria workup, where patients have high smoking history, with irritated bladder symptoms. You might want to make sure they don't have a bladder tumor or CIS. This is a new part of the algorithm in the AUA guideline. If you suspect them to have Hunter's lesion, that means men and women over the age of 50, consider doing cystoscopy. If you see a Hunter's lesion, there are a tailored treatment for Hunter's lesion that consists of filtration of the lesion and injection of time-synanol, which is a steroid solution, directly into the bladder tissue endoscopically for your cystoscopy. And if they fail, you can consider oral cycles for an A. And we'll spend a little bit more time later on to talk more about this. The other new thing on the guideline is that we move away from the old system, where we describe first-line treatment, second-line treatment, third-line treatment. So in the past, we typically would start with behavior therapy, stress reduction, self-help strategies. If that fails, you go to oral treatment or intravascular therapy. And if that fails, you go to a third line, which is procedures, hydrodystension, Hunter's lesion treatment. If that fails, you go to your fourth line, which is Botox and neumodulation. And then cyclosporine goes to the fifth line, and then major diversion surgery goes to the sixth-line treatment. Now we get rid of this tier system. You don't necessarily have to fail first-line treatment. Before you go to the third line, I think our emphasis is on shared decision-making. Each of those treatment modalities have different pros and cons and potential complications and benefit ratio. And depending on the severity of the symptoms and where the patient is and what they want to achieve in terms of improving the quality of life, it is okay to do multimodal treatment. That means you could combine different modalities simultaneously to manage the patients. Or you could skip treatment. If you think somebody had more severe symptoms, you want to move to a higher tier that was described in the past, that's okay. But the emphasis here is shared decision-making. You talk to the patients, and then you guys decide what would be the best when the patient will see. Of course, we always reserve surgery as the last resource, so it's always put at the very, very end at the bottom. And one last major update to AUA guidelines is we bring to attention the risk of using pentosine polysulfate, which is Amiron. We say that clinicians should counsel patients who's considering Amiron treatment the potential risk of macular damage and visual-related injuries. Originally, it was some case report, but then the case report becomes case series. And now there's multiple case series of patient who has taken Amiron and pentosine polysulfate over time might develop pigmentary maculopathy, which give them blurred vision and visual problems in the eyes. Now, the prevalence or the risk of having this definitely increases with cumulative exposure to the medications, but it can certainly can happen to any patients at any time. We just don't know exactly how widespread this problem is. So there's even a black box warning on the drugs now. If you want to continue the patient on the medication, let's start them on this medication. We can talk a little bit more about this on the Q&A if you're interested, but this is potentially irreversible. That means even if you stop the medication, some of the visual problems, including blindness in the severe cases, can persist even after you stop the medication. So those are the updates, but we will focus a lot of our talk on phenotype-driven approach to manage the condition. And some of the things I talked about earlier from the guideline will come up again. So we'll spend a little bit more time going over this. I'm going to spend a few minutes to talk about this. This is my summary slide. This is the take-home slide. If you start to fall asleep at this point, I just focus on this slide, and then you can go ahead. I think this summarizes what I'm going to talk about for the next 30 minutes pretty well. Everybody who has treated ICPPS realized this is a heterogeneous patient population. Even though a lot of patients come with very similar symptoms of bladder pain or discomfort, they have LUTs and they don't have infection, da-da-da-da, you realize that within everybody that presents with similar clinical symptoms, or within what we call the umbrella term, ICPPS as a clinical syndrome, there are different subgroups of patients and they are not the same. And there's already literature building up that if you could identify the different subtypes of ICPPS patient, we actually have evidence in the literature that certain treatment benefits certain subtype better than other subtypes. For example, if you look at the right side of the slide, if the patient has Hunter's lesion, and we'll show you some pictures and what that means, we consider them having bladder-centric symptoms, or ICPPS, and they respond well to foundation and transsominal treatment. If patient responds well to installation local anesthetics in the bladder, we think that they have a bladder-centric phenotype because the pain is localized in the bladder or the pain generated is in the bladder. They may respond well with intravascular installation therapy for locals. If patient have high tone pelvic floor dysfunction or tender pelvic floor, so we are on the left upper corner, they may respond better to pelvic floor physical therapy. And there's randomized control trial data to support that. And lastly, we'll talk about the concept of what we call widespread pain. These are the people, the pain is not restricted to the pelvis alone. They actually pain in a number of different regions in the body. They are considered to have what we call a centralized pain phenotype and they may respond better to more global systemic therapy. And we'll go over that later on. So we'll start with the right upper corner, patient with Hunter's lesion. Those are easier. The guidelines say if Hunter's lesion are present, infiltration or injection with transsominal should be performed. There is strong evidence for that and is considered a treatment recommendation on the guidelines. So Hunter's lesion really, I mean, there's been a lot of studies trying to identify Hunter's lesion with our cystoscopy, you know, the people will look at biomarkers, look at the urine. But at the end of the day, the only reliable way to diagnose Hunter's lesion is to do a cystoscopy. There are two ways to do a cystoscopy. You could do this in the office. And for men and women, I think office cystoscopy is very well tolerated if you're able to have access to a flexible camera. Even ICU patients really don't have much discomfort when you do a flexible, gentle cystoscopy in the office. And you can actually see most of these Hunter's lesion without doing a hydrostension. So that means if the patient comes in, you could do a simple office flexible cystoscopy. You immediately know whether or not the patient has Hunter's lesion or not without scheduling them for surgery or having anesthesia or, you know, doing all that. It's a very simple way in the office of phenotype patient with respect to Hunter's lesion. Since most of them responded well to a specific treatment, it's important to identify them early because you don't want to start them on DMSO and amitriptyline and nortriptyline and antihistamine and go through all this to find out, okay, the actual Hunter's lesion. Maybe we should treat them differently. So that's why early cystoscopy is recommended for a lot of the patients that you think might have Hunter's lesion. Again, why do we say men and women over the age of 50 are at higher risk? Because of the data. There's a lot of data from different studies. I'm just showing you a few studies. So this is a MAP-2 data. This is a research population of men and women with incisal status and chronic pelvic pain. We look at the medical record and see what percent of the people have cystoscopy. And among the people that have cystoscopy, what's the prevalence of having Hunter's lesion when you do a cystoscopy on them? If you look at it, after the age of 50, your risk of identifying Hunter's lesion in the population is 20% or higher. So you may score one of five or more. And actually, if they're older, a lot of the patients actually have Hunter's lesion. That's why these people, I think you can start with a cystoscopy to see if they have Hunter's lesion, because knowing that is going to change the treatment algorithm quite dramatically for these people. This is another set of series that I quote. This is actually a different group of patients. These are the clinical populations that we actually treat in our office. We ask the question, how often do they have Hunter's lesion? You can see that it happens in men and women. And the prevalence of Hunter's lesion increases with age. Once you hit the age of 50s or 40s, there is a good risk of seeing Hunter's lesion. Now, obviously, if they have failed other conventional ICPPS treatment and they have never had a cystoscopy before, you should take a look at it. Maybe they have Hunter's lesion, need to change strategies. You have concerns that the patient actually may or may not have IC, because cystoscopy is reasonable to rule out other confusable diseases. Or if a patient has cystoscopy, that's pretty common. They said, well, somebody did a cystoscopy on me and they saw something. And you ask them, what did they see? Well, I have no idea what they saw. And they didn't have a picture and they didn't have anything to show you. It's probably reasonable to do one. So just visualize and see directly what other people may have seen in the past. They may have Hunter's lesion, they may have something else. This is how Hunter's lesion look like. They're actually different description of a Hunter's lesion. And we actually published an atlas. And you can look at the paper from Neo-Urology and Urodynamics in 2020, which is quite different appearance of Hunter's lesion when you do a cystoscopy. The classic one start with almost like a starburst appearance, you have a central dot of redness and you've got this vessels radiating to the side, it's like a starburst appearance. It increases the vascularity, the area can look pretty inflamed. So that's the top four rows that you see over there. Now, the top four pictures you see on the top, some of them looks a little less apparent, they may look a little whitish. And when you start distending the bladder, a red spot start to appear. So those are the two pictures on the bottom left. Sometimes the Hunter's lesion can be conjoined and they have scar tissue in between them. So that's another way it can look. It is different from glomerulation. So the picture A is what we call glomerulation. This is not Hunter's lesion. These are some mucosal hemorrhage that happens after the bladder has been over distended. These are glomerulation, they're not diagnostic for ICD-PS and you could find it with a number of conditions. Any bladder that is over distended will have it or they could have it after radiation or chemotherapy, et cetera. But these are not to be confused with Hunter's lesion, what you saw in picture A. Hunter's lesion can also be more apparent when you start to distend the bladder under anesthesia. So you see picture one, two, and three. When you start to distend the bladder or do a hydro distension under general anesthesia, you will see that the lesion start to crack open and it start to bleed. And sometimes you have what we call a waterfall pattern going from one to three. So that's another good way to identify Hunter's lesion. Treatment for Hunter's lesion, we do filtration and trimesomal treatment. There have been many, many different studies. For example, you can see some of the summary over here. There is actually quite a dramatic improvement of the pain level after either filtration and trimesomal. I don't think one is necessarily better than the other. We did a systematic analysis and what was published in the literature, it looks like the retreatment was seven to 12 months for trimesomal injections, a little longer, 11 to 29 months for filtration treatment. Symptoms will almost always come back. These lesions, given enough time, will start to reappear in the bladder and the pain and the frequency and the urgency that you bring down with the treatment will eventually start to creep back up to where they were. And so you counsel the patient that retreatment is often necessary over time. A lot of my patients will do this every 12 months or so. And that's quite a predictable cycle for a lot of the patients, although it varies from patient to patient, obviously. So we are done with the hardness lesion people. Again, those are patients with bladder-centric phenotypes. You do a cystoscopy on them, even office cystoscopy, you identify the hardness lesion and you drive them to filtration and trimesomal treatment instead of some of the other treatment that we mentioned earlier. Now, we're gonna go to the left upper corner. So a patient with high-tone pelvic floor dysfunction or tender pelvic floor on physical examination, they have pelvic floor-centric phenotype. We think they should undergo pelvic floor physical therapy. This is an actual guideline statement. It says that manual physical therapy, basically things that you would do to relax the pelvic muscle or the tension or the contractures and release the myofascial tissue restriction will be appropriate if they have pelvic floor tenderness on the pelvic examination. We stay in the guideline that they should not be doing anything to strengthen the pelvic muscle, such as Kegel exercises. A lot of you is aware of this result of the randomized control trial where women with myofascial pain on pelvic examination undergo randomization. Half of the group get myofascial physical therapy or the pelvic floor, the other group get global massage and the group that get myofascial PT did a lot better. So a lot of people is aware of this particular randomized control trial. This remains one of the best, I think there are very few positive level one randomized control trial for ICBPS and this is one of those that is very well conducted. Now that brings back to the question, how do you identify women with pelvic floor tenderness? We advocate that people should do a standardized pelvic examination. There are more than one papers describing how to do that, but this is one of those that we describe in the MAP research network where we standardize pelvic examination across six clinical sites enrolling ICBPS patients in the MAP study. So essentially we do a pelvic examination through the vaginal opening. We identify six spots in the levator muscle to examine. So that will correspond two, three, five, seven, nine, and 10. You palpate the anterior levator muscle, the pupil coccygeus at position two and 10 on the left and on the right side in the lathotomy position. Then you palpate up to the internist muscle at position three and nine on the left and the right side laterally, go behind the pubic bone to assess for the presence of tenderness. And you assess seven and five at iliococcygeus muscle on the posterior levator muscle. You can also assess for tenderness on the perineum area, which is point number six and the suprapubic area point number 12. Obviously the goal is to relax the pelvic muscle, but you really, we don't want to do is to have them strengthen the pelvic muscle and do Kegel exercises because that will actually exacerbate the pain. So I think a lot of people is familiar with pelvic floor PT to manage the conditions. The reality is that the majority of the ICPPS patient actually have pelvic floor tenderness. I think the literature rate is 60 to 80%. That's very close to what we observe in our research studies. So it is very important when somebody come to you with chronic pelvic pain, with what you suspect to have ICPPS, do a good pelvic examination and to see if they have pelvic floor tenderness because the randomized control trial data suggest that some of these patients will benefit from pelvic floor PT. So that's our second phenotype that will drive your treatment algorithm. Now, the third one is relatively straightforward. The guideline says some of the intravascular therapy, lidocaine, maracaine, heparin, DMSO, or any combination of that, which we call the cocktail treatment may be administered at intravascular treatment options. So who are the people that benefit the best from these? Those are the people where you put lidocaine inside the bladder for a diagnostic trial, they got better. So those are the ones that respond the best. That's kind of intuitive, even though the guideline didn't say anything specific to that. So what's the role of local anesthetic challenges? It really does two things. One is diagnostic. It helps you to see if the bladder is the source of the pain. So you instill local anesthetics inside the bladder lumen. You ask the patient to rate the pain and discomfort before, and let's say, you know, 15, 20 minutes after the installation to see if there's any improvement of the pain. If the pain improved after intravascular installation of local anesthetics, at least you can conclude that perhaps one of the pain generated actually is in the bladder. So numbing the bladder will help. So that is obviously a good diagnostic test to identify or help you to localize which organ is the pain generator. Obviously, patient can have multiple pain generator. Knowing that the bladder contribute to the problem can be quite helpful, but the pelvic floor and other gynecologic organs and the GI tract can also contribute to the pain. So you don't necessarily only have one pain generator. So it's a little more complicated than the way I am trying to sell it to you. But at the same time, you could do local anesthetics after cystoscopy, as mentioned earlier, as a standalone diagnostic test. There are different strategies to do this. There's no right or wrong. People do it differently. I typically would use a combination of Marcane and Lidocaine, so half-strength Marcane plus 2% Lidocaine, put it inside the bladder, 30 cc of total volume. You could try different combinations also. You could just use plain Lidocaine and alkalines of hydrogen bicarbonate. That's also okay. You want to see, obviously, if they have a bladder-centric phenotype that responds to local anesthetics. And of course, if they respond, you could offer long-term intravascular insulation therapy as a strategy. But the absence of response doesn't really tell you that they don't have ICPPS because, again, they can have multiple pain generators, as mentioned earlier. I want to spend a little bit of time talking about widespread phenotype. This is something that I think people who have been taking care of patients and researching in the field recognize over the course of the last decade that there are certain ICPPS patients that might be a little different than the rest of the ICPPS patients, in the sense that they have pain not only in the bladder or the pelvic area or in the pelvic floor. They have a lot of comorbid pain conditions we call chronic overlapping pain conditions. For example, in addition to pelvic pain, they have migraine headache. They may have temporal mandibular disorder. They may have fibromyalgia, give them pain in the joints and the muscles. They may have chronic fatigue syndrome. They may have irritable bowel syndrome. They may have chronic back pain. They may have chronic chest pain that is unexplained. But the underlying theme among these is that a good portion of ICPPS patients have pain outside of the pelvis. For example, we developed this body map pain, a body map that you can see on the left side. So we asked the patient, where is it hurting besides your bladder? So the bladder is the little cross below the white area 14 and 15 on the left side. But this patient obviously had pain in multiple places in the bodies. And they will be what we consider widespread pain phenotype. The underlying hypothesis is that these patient might have a different underlying pathophysiology. Maybe the problem is not in the end organ or the pelvic floor or the bladder itself. Maybe the pathophysiology is some type of systemic process going on, giving rise to pain in different parts of the body. Maybe it is a centrally driven pathophysiology, decreased pain sensitivity. So many different body parts start to hurt when they shouldn't be, or they have hyperajusia or allodynia when they shouldn't be. So these are what we call the widespread pain phenotype. These are what we call the centralized pain phenotype. They may respond better to tricyclic medication, garbapentaloids are more centrally acting. They kind of dial down your nervous system in a central nervous system to reduce your hypersensitivity to pain. They may respond better to multidisciplinary or other systemic therapy. So that's kind of what we're aiming at for this fourth phenotype. But is there any evidence for that? I mean, is it actually true that patient with localized pelvic pain respond better to localized therapy to your bladder or to your pelvic floor? It sounds intuitive, it makes sense, but is there evidence for that? Is it true that patient with widespread pain somehow respond better to systemic therapy such as amitriptyline, nortriptyline, pregabalin, neurontin, et cetera? Is there any evidence of that? It sounds nice. It seems to make sense, but is there any evidence for that? If you would pardon me to give you, kind of walk you through this concept for about five minutes, I'll try to explain to you. So the problem, this applies not only to ICBPS with a lot of different conditions that have different subgroups of patients. The problem of treating a heterogeneous population is the following. That's for hypothetical consideration. There are two subtypes of ICBPS patients. They are patients that have bladder-centric phenotype, and they are patient with centralized pain phenotype. They have widespread pain outside of bladder versus just pain in the bladder or the pelvic floor. Centric treatments such as hydroxazine or pentosyne polysulfate amyloid works better for the bladder-centric patients due to the mechanism of action. It seems to make sense. So if you have a bladder-centric patient, you treat them with bladder-centric treatment, you're going to get good result. If you're a centralized pain patient, you treat them something that's directed at the bladder, you're probably not going to see the results. So the P value is insignificant. If you know these subgroups a priori, you might be geared for a successful clinical trial. The problem is if you don't know the phenotype, you mix everybody up and you subject everybody to a mechanism of action that only targets the bladder or the pelvis, you mix up the results because the positive result from the bladder-centric group is going to be negated by the negative result of the centralized pain group. So the overall clinical trial is negative. If you don't do some analysis, you would not be able to figure it out. There's actually two subgroups of people and one group responded well and the other group doesn't respond that well. Similar concept. If there are two subgroups of ICPPS patient, you give them a medication such as amitriptyline or tricyclic medication. They do well typically on centralized pain phenotype patients. That's hypothetical, that's the assumption. And they don't do well in bladder-centric patients. What happens if you mix them all up? You get a negative overall trial, but it doesn't mean that you don't have subgroup that can respond well. This is a problem with a lot of the ICPPS randomized controlled trial. A lot of these trials was done a decade or more ago. And back then, we don't know better that there are different subgroups of patient, there are different phenotypes. So everybody that fit the diagnosis of ICPPS with the research criteria was randomized to get treatment. Some get amitriptyline, other people get placebo. And unfortunately, this is a negative clinical trial from the amitriptyline trial. Similarly, this is a negative clinical trial for hydroxazine and pentosan polysulfate. Both trials were negative, but we now realize there are different subtypes of ICPPS patients. So what we did as part of the MAP research network is to go back on the raw data on those two clinical trials. So we analyze the results of the two clinical trials that I showed you earlier. But now we analyze the data based on the phenotype because when these patients came in, even though back then they didn't know better, when these people came in, they are tools or instrument that they have filled up that helped them to characterize the patients into two subgroups. One subgroup have what we call the low pain-wise spreadness. The pain is mostly localized to the bladder. There's a second subgroup of patient within these clinical trial that they reported pain outside of the pelvis. So these are the high pain-wise spreadness subgroup. So we separate the results based on the of the clinical trial again and see if they are subgroup responses. So we actually published this paper recently and let me walk you through this. Essentially, this is what we saw with a hydroxysine and pentosine polysulfate. So those are bladder-centric treatment. If you have high-wise spreadness of the pain, the drug doesn't do any better than placebo. So you could see the blue line and the red line overlaps in the clinical trial in terms of results. However, if you come into the clinical studies, you have low-wise spreadness pain to begin with. The patient that have bladder-centric phenotype actually responded better to amitriptyline, I'm sorry, better to hydroxysine and pentosine polysulfate compared to the placebo. You see the blue line and the red line spread out. So this illustrate the concept that we're talking about earlier. If you can identify the phenotype, you might be able to identify the subgroups that responses to the treatment. Not only that, patient with bladder-centric symptoms or phenotype actually responded better to bladder-centric treatment based on the re-analysis of the results. You see a very similar picture when you look at systemic treatment. If the patient have low-wise spreadness of the pain, that means they are mostly localized to the bladder or the pelvic area, there is no separation between the placebo and amitriptyline. So the two, the red and the blue line overlaps. However, patient that have high-wise spreadness of the pain, the separation of the results. The people do better after amitriptyline than placebo in the centralized pain phenotype. So actually the results to these two questions is yes, there's actually evidence that patients with localized pain respond better to localized treatment in the pelvis and people with widespread pain respond better to systemic treatment. Now, this is not a true randomized trial. These are re-analysis of previously conducted clinical trials. You can also consider as almost like a post hoc analysis. These are not like a new clinical trial, but there are strong evidence, I think, with this, and hopefully confirmed with future clinical trials, that perhaps widespread pain people, you don't, you give them tricyclic garbapentanoids, cognitive behavioral therapy, and other things, because they may be different in terms of having a centralized pain phenotype. So I'm going to, oh, about time. So I'm going to stop about here to give you the summary. I think if you are able to incorporate strategies in your clinic to identify the different groups of people and target the treatment based on the phenotype, I think you do better in managing ICD-PS. It gets us one step closer to individualized treatment for ICD-PS. And honestly, a lot of... To see if the patient will have this lesion or not. That's really straightforward, particularly if you have access to a flexible cystoscopy in your office. You could instill local anesthetics into the bladder to see if they have bladder-centric phenotype that responds to local anesthetic. That's pretty straightforward. All you need is a catheter and some lidocaine and marcaine, and give them some time and see if the pain gets better. You can usually do this in the office, maybe even after the cystoscopy. You could easily do a standardized pelvic examination in the office to see if they have high-tone pelvic floor dysfunction or a tender pelvic floor. This is something you could easily do. And I think every woman who come to the office with pelvic pain, you should consider doing a pelvic floor examination to see if they have pelvic floor-centric phenotype. You can give them a body map or ask about other pain conditions that they have to identify people that are at risk of having widespread pain, and maybe they need to be directed differently. So I would argue that there are strategies that you could use in the office today to identify these four phenotypes of ICD-PS patients. And based on the phenotypes, you then tailor the treatment to specific treatment to optimize this strategy. So I think we do better these days than trial and error for ICD-PS. I think you should all incorporate a phenotype-driven approach to treat patient with ICD-PS. So I think that's my last slide. Thank you. Wonderful. Excellent talk, Dr. Lai. Thank you. It's now time for questions. And as a reminder, please use the Q&A feature of the Zoom webinar to ask questions. First, let's start with, for patients who return for repeat hydrodystension and fulguration, we have found more blanched appearing areas, and I've wondered if these are again Hunter's lesions or scar tissue from prior fulguration. Do you have any advice on repeat fulguration for these scenarios? That is a very difficult question. I also noticed part of that. The question you start to ask yourself is they look different, right? They are blanched. They are like non-inflammed looking. So are they truly Hunter's lesion or is it scar tissue that you fulgurated previously in the past? I tend to fulgurate them again and inject trimicillin. One of the things I do is if I see this little whitish patch in your bladder that you suspect, okay, is that a scar tissue? Is it for real? What I do is I do a little hydrodystension. And if they start to bleed and some of them start to bleed, then I say, okay, maybe this is a real Hunter's lesion. It just looks different. Then I would do the treatment. If you start to distend the bladder and nothing really happens, maybe you don't need to. I typically aim after the area that is red and inflamed and is more classic appearance for that. Now, people actually have done serial studies because the other question you're going to ask, okay, if you keep fulgurating your bladder, you know, there's like multiple Hunter's, are you going to, is your bladder going to scar down over time? Is your bladder capacity going to decrease over time? I think there are studies now showing that repeated fulguration doesn't decrease bladder capacity over time. So it's probably not, I would not worry about over time they become a smaller and smaller bladder from the fulguration itself, but that's my personal observation. Do you have any recommendation about timeframe between fulgurations? It varies from patients to patients. Some typically they would go for about a year. That will be a typical time for most of the patients I've seen. Some people can last longer than that. Other people have multiple lesions and will last shorter than that. I actually let the patient decide. I would tell them, you know what, you get better, but this will come back. When you start to get increasingly consistently to the level, you know, back to where you were, give me a call, we'll do another one. So I let them decide how long they want to do it. Perfect. How often, I guess. When you do bladder installations long-term, do you use the same cocktail of bupivacaine and lidocaine you mentioned to test the response or do you increase the volume and duration? I tend to use the same. And honestly, I think the best use for intravascular installation is probably not something you would want to continue forever because it's not practical for them to come to the office like over and over and over again for a sustained period of time or for them to do it on their own. I think a lot of insurance don't cover installation solutions. I think the best use case strategy for these people are flares. People that have flares, you could talk to them maybe even ahead of time. Okay, if you have a flare, we want to make sure you don't have a bladder infection and that's all fair, but you can come to the office for installation. You may do this twice weekly until your flare is under control. Those are the best strategies. So a boost of intravascular installation over the course of several weeks or to manage flare or symptom exacerbation, I think is the best use for this. Probably not something you want to do forever because nobody really going to come back and do this forever. Do you recommend the IC diet? Yes, I do, but you have to do this properly. As many of you know, it is very individualized. That means the hundreds of items on the diet may not apply to the particular patients standing in front of you. So they need to do a bladder diary. They need to be careful they don't lose weight. They need to identify bladder irritants. If it's not a bladder irritant, they are good to consume the food. So it's a little experimental for them. I tell them to keep a bladder diary. I tell them you don't have to go very, very straight on it, maybe initially you can go on a straighter diet and then we introduce substance back into the diet to see if it causes a flare or exacerbation. Usually they will know within 24 hours and write it down on the bladder diary, you know, on your phone or on the notebook. So you know what items you can or should not be doing. It's okay to do it as long as you know how to manage it. I mean, it's all about quality of life. We don't want anybody to be miserable. Are there multi-center clinical trials or registries that are currently recruiting for ICBPS? I think there's probably a lot of studies looking for ICBPS patients. For example, we have a study, if you have any patients at USS, we are actually looking at the pelvic floor dysfunction and using EMG to characterize the pelvic floor and see if we could target the treatment with Botox. So there are different things that we can, we're actually looking patients for. The MAP study is closed. I think we're doing follow-up, but I would hope that there will be a lot more clinical trials coming on board over time, because now that we know the different phenotype, it makes sense to identify the phenotype and look at them more carefully as opposed to be looking across the spectrum. And I think that's why the clinical trials failed is because people fail to identify the different subtypes and the signals get washed out because they're different subtypes. There's just no way that one subtype will overwhelm the negative results of the other subtypes. So we gotta be careful how we design clinical trials in the future for ICBPS or endometriosis or things like that. Of course. In your experience, is there any benefit of hydroxyzine for patients with more allergy or food sensitivities related issues with the histamine response? That's what some people claim and said. I have not find this myself personally. That's one of the questions I always ask. And if they say, yes, I'm more inclined to do it, do I have evidence to show you that? I don't personally from my practice. That's commonly done, commonly asked. Okay. And do you consider patients who have vulvodynia or dysmenorrhea as part of the widespread phenotype or local pain? I think that's part of the local pain. It may be regional. Widespread, I would say you probably have to go outside the pelvis. Okay. And then can you comment on how you use the phenotypes to treat pain flares? Pain flares, the phenotype of pain flares. I don't know. I think locals could be good strategies to manage that. Hunter's lesion, I guess if they have a flare, you would, Hunter's lesion, you either have it or you don't have it. So I don't know if the flare is relevant. One of the very interesting things, and I think that might also point to the widespread people having a different underlying pathophysiology, maybe more of a top-down problem, is that we did a study where we take the patients with widespread pain and localized pain. And then when they have a flare, we asked them about the symptoms. So when these widespread people have flares in the bladder, it's actually not just the bladder that the pain is worse. So if they have fibromyalgia or they have chronic back pain, during a flare, everywhere else hurts more. So again, it tends to point to a different pathophysiology. There's something going on top-down that causes different pain conditions to have flares when they have a flare. So that's an interesting concept, I think. We have data to show that. It's probably not what is showing up in your bladder after you eat certain things, because how would that affect other organs? That's an interesting concept. Wonderful. And then one participant said that they're surprised that DMSO is still considered a treatment option because of low success rates. Have you had success with DMSO? I don't use DMSO. It's listed on the guideline. I think historically people uses it, but I think it makes a lot more sense, honestly, to use intravascular local anesthetics, you know, lidocaine, myocaine mixture, as opposed to be DMSO. The success rate, as you mentioned, isn't that great for DMSO. And a lot of times the initial field installation actually caused the symptoms to get worse. So that's not nice to do to patients before they get better. And it comes with a very strong smell. There are reasons why it's not common to use. I personally don't use it. Not DMSO. Okay. And then how do you treat flares for patients with centralized pain phenotype? I think it is going to be something that will require a multimodal treatment strategies. I'm not sure we know exactly why these people with widespread pain have flares. It may be because they have a stressful events, you know, happening, and they need to reduce the stress level, but trying to get that kind of history is not so easy and trying to control the stress is not so trivial. It may be because, I don't know. It's tough to tell. I have not given people a short course of tricyclics or gabapentin or pregabalin for that purposes. I think stress reduction could be good, could be useful. I think self-help strategies may be useful if for nothing else, just to empower your patient that they are in control, that you try to break the cycle that people could test about, oh, I'm not having a flare. Oh, it's going to be really bad. Oh, there's nothing I can do about it. You try to break away this cycle of catastrophizing and help them to cope with the flares is probably going to be the strategies. I think empowerment is very important. It may not be what exactly you're doing to them that makes them better, but letting them know that they are in control, that makes them better. Do you send centralized pain patients to pain or anesthesia clinics? I have not. Sometimes I do, but I have not. I think you could try to manage it using Tricyclic. Those are people that responded. I think you could try that first if you wanted to. Cognitive behavioral therapy is obviously, you identify this subgroup. We haven't talked about psychosocial issues, but there are people that can benefit from them if they have a lot of psychosocial difficulties. You will probably realize a lot of the patients will have anxiety or depression, or they have high stress level, or they get maybe even PTSD or stress-related issues. So those people you might want to consider refer to psychology so they could help them to manage you, manage the patients. Okay. Bye. Bye. Wonderful. Next question. So the addition of family, the addition of gentamicin or tobramycin to my bladder installation cocktail seems to improve the symptom resolution. Is this something that you have observed? And then how about the addition of heparin? The addition of heparin is commonly do. The addition of gentamicin, some people relax to do it, but I have not done this routinely, but I think different physicians use different cocktails. I honestly think we need some better studies because basically if you do intravascular installation, it seems like everybody is doing something completely different from another person. So I think we need better studies on how to optimize, like what is the best intravascular strategies for people? We need better studies for that yellow box that you see on the slide over here. Okay. And then how do you talk to patients about long-term use of tricyclics given the concern for cumulative impact on cognition? That is an interesting question. We have not really talked to people more about it. So I think the concern comes of anti-masculinic properties, like you would be concerning about OAB patients too. That's an interesting question. I don't think we have talked too much about that. That was a good thought. Maybe something we should pay attention to. Talk more about, yeah. People that go on that. I mean, it's just not just long-term. A lot of the patients, unfortunately, won't be able to stay on the therapy for very long because they are short-term side effects that basically preclude you from using a meaningful dose. And they have side effects too on top of, but that's a good thought, actually, to look at. Good. And then what evidence do you have that oral PPS is actually a local treatment for the bladder? That is based on what people said. I don't know. I think the comment, the comment continues that as an exogenous gag, PPS likely accumulates in many tissues. We now know that it occurs in the macula leading to rare maculopathy, and gags are ubiquitous. So I wonder how much of PPS's effects are due to localized bladder effect versus systemic anti-inflammation. I think that's a good comment. I honestly, I think there is very little, I think you're gonna come up with a strong argument why, given all these other things that you could do to patients, why you want to put a patient on PPS. Like the data isn't that strong. Some of the early randomized trials show more favorable data, but more the recent trials really doesn't show much of a robust effects beyond placebo. So these effectiveness is being questioned and laying on top of that, this side effects that could potentially be irreversible. You got to ask yourself why do I want to put anybody on PPS? It is still on the guideline. We did not take it off because it's still approved, but I will beg to ask the questions that most people probably don't want to consider given all the other options that we have available. That probably works better with other eye problems concerns. Okay, and then another comment was, what are your thoughts about intravesical PPS? That is not something that I would consider either. I think the evidence is even weaker than oral. I don't know of any problem with the eyes, with the intravesical. I personally would stay away from it. Okay, well, on behalf of AUGS, I'd like to thank Dr. Lai for this excellent webinar. We've kind of gone through all of our questions. Thank you, Dr. Lai. For our participants, please be sure to register for our upcoming webinar. On September 13th, Applied Medical will be giving a talk titled Visibility and Accessibility, Why V-Notes Make Sense in My Practice. And on September 20th, Dr. Marlene Korten will be presenting a talk titled Vulvar and Perineal Anatomy with Clinical Applications. Please follow AUGS on Twitter and Instagram or check our website for information on all upcoming webinars. Thank you all for joining and have a great evening. Aloha, Dr. Lai. Bye. Bye.

interstitial cystitis

bladder pain syndrome

subtypes

phenotypes

tailored treatment

transuminal treatment

pelvic floor physical therapy

Hunter's lesions

cystoscopy