My name is Danny Koh, I'm a third year OB resident at Ameda Health in Chicago suburbs. Glad to be here for the next few days. I wanted to take a moment to introduce Dr. Zevlin Koop. He's going to be our speaker for this upcoming session and also the session right afterwards. So it will be the back-to-back sessions. Dr. Koop is currently a third year urogynecology fellow at the University of Louisville. He actually went to the College of William & Mary initially for undergraduate and pretty cool history, but he played basketball Division I there and also played across seas and had an outstanding career. And then he went on to pursue medicine at LECOM on the Erie campus and finishes OB joint residency at Michigan State University, part of Spectrum Health. He won several awards, teaching and surgical and clinical performance, and he's currently now again in his third year of urogynecology fellowship at University of Louisville. So if you would please join me in welcoming him as he comes up to present us about painful bladder syndrome, interstitial cystitis. Dr. Koop. Can you guys hear me okay? Yeah. I think I'm tall enough, so I'm probably just going to be down here while I do this, one, because I'm a pacer, and two, it's just, I feel so lonely up there so far from you guys. So with that being said, I have this wonderful and delightfully intimidating opportunity to present in front of all of you wonderful people, painful bladder syndrome. Our objectives today, we're going to go over the history, epidemiology, etiology, and learn how to diagnose and treat. We're going to explore future research as well. So overall, I see painful bladder syndrome, bladder pain syndrome belongs to a group of hypersensitivity or sensory disorders. Every specialty has these things. This just tends to be ours. A main component of any of these disorders is pain. When we talk about definitions, which have been kind of difficult to do with IC, we start in 1987 with the NIH having this definition that was very restrictive, potentially missing up to 60% of women. I know everybody can read this because they have great eyes in the back row, right? So part of the restrictions is you had to have diffuse glomulations, at least 10 per quadrant and at least three quadrants of the bladder already. And then you had to have pain associated with the bladder. The exclusion criteria alone ended up missing those 60% of those patients. We move forward to 2002 with International Continence Society said it was a complaint of suprapubic pain related to bladder filling accompanied by symptoms such as frequency and the absence of some other proven pathology. They reserved the term interstitial cystitis for typical findings you see on cystoscopy and histology. Going forward, the European Society for the Study of Interstitial Cystitis in 2008 proposed bladder pain syndrome, which was chronic pelvic pain, pressure, discomfort, perceived to be related to the urinary bladder accompanied by at least one other urinary symptoms. And they added the timeframe of six months in there. SUFU took this, which is the urogyne portion of FPMRS for urology, excuse me, and they said bladder pain syndrome is going to be an unpleasant sensation, pain, pressure, discomfort, perceived to be related to the urinary bladder and associated with a lower urinary tract symptom. And they said six weeks instead of six months, allowing us to start treating these patients a little bit earlier clinically. They also kept the further classification on cystoscopy and the morphological features of the biopsy for their definition. With that being said, because it's difficult to find, the epidemiology would follow that it's difficult to know who has what. So overall, up to 12.6 of all people may have IC, bladder pain syndrome, painful bladder syndrome. But regardless, we find that women tend to be affected twice as often as men. How do we come upon these epidemiological studies? Well, there were three main types, self-report studies, symptom assessments, and then the clinician diagnosis. The self-report studies from the 80s and early 90s found the population prevalence in women about 865 per 100,000. That translated to about 83,000 men and 1.2 million women across the United States. When we go to the symptom assessments, we have some international studies like the FINISH study, which show a low prevalence of 0.45. But we have some studies from 2011 that found up to 6.5% of all adults may have one of those three definitions for IC. With the clinician diagnosis, most notably, we have Kaiser Permanente, who just looked at ICD codes and found the prevalence of 197 per 100,000 women. Regardless, there's a lot of people that are affected by this. Etiology. I should say proposed etiology, because we kind of still don't know. So I'm going to highlight a couple of these, but I do want to take a moment and see. The first one up there is genetics. It says the first degree relative is, if you have a first degree relative with IC, you're 17 times more likely to have the disease. Moving forward to some of the ones that we're going to talk about here, infectious agents. This started in 1950 with Hunter, of Hunter lesions, who suggested hematogenously disseminated bacterial cystitis as etiology. With that being said, throughout the history of IC, we've never been able to find a single bacterium, virus, fungus, organism identified as the etiologic factor. So the deficiency in the GAG layer, which used to be the reason you did the potassium test to diagnose it, this used to be the leading theory, which said the deficiency allowing toxic urophilial substances to affect the bladder and cause some injury, has kind of given way to like the ultra structural abnormalities, in which we find that in all layers, for patients who have IC, they have an abnormality after hydro distension. For example, all of these, lymphocytes, mast cells, extracellular tissue, glomerulations, urine from the IC patients. So the urine tends to have a level of heparin binding epidermal growth-like factor increased for those patients. That's important because one of the treatments that we can offer is sacral neuromodulation, and we find that that normalizes afterwards, as does it tend to move towards normal after hydro distension as well. Mast cells themselves have been proposed as both a diagnostic marker for IC, because they tend to be found in places of inflammation associated with the nerve fibers and terminals in the suburban urophilium. So this is kind of where we are, most notably where we keep maybe the reason etiology for IC. It's kind of a cycle that goes through, you can have bacterial cystitis, elevated estrogen, endogenous exogenous toxins, and potent mediators like histamine. We have a little cartoon graph here, and it shows maybe some bladder injury, some bladder insult starts, leading to activation of C-fiber substance, P5 release. It can go back and forth, leading to more bladder insult, or it can move on to the mast cell activation, epithelial later damage, potassium leak, and then more injury. In essence, the neurogenic inflammation theory incorporates all those other theories to what we know today. So now we're going to walk through the basic assessment, and then diagnosis and treatment of IC using the American Urological Association framework. I know everybody can read that, especially in the back row, but no, we're going to go step by step through it. Any basic assessment starts with the history and physical. An important part of this history is going to be the evaluation of pain. When does it start? How often is it there? And what alleviates it? Objectively, any patient that comes in with this, it's wise to do a post-void residual, a UA, culture is indicated, and a cytology for people with a smoking history to rule out potential for bladder cancer. IC, PBS, BPS, it's a diagnosis of exclusion. So you have to rule out all these other things before you, or you should rule out all these other things before you start treatment. Infectious cystitis, tenofoherpes, vaginitis, urethritis. It's not uncommon that you may find a UTI. Even after you treat it, come back and reassess to see if they need some other treatment forms. In this workup, you may come up with some complicated patients or things that should prompt further evaluation. Things like hematuria, sterile pyuria, GI signs, and signs of a continence, which may lead you to do further investigation with a urodynamic study, cystoscopy, and even laparoscopy as needed. Again, once you do that, symptoms persist, come back to this algorithm to start working with it. Once all these things are ruled out, you can apply some basic clinical management. Summarizing this basic table here, in general, we're going to start with the most conservative and go to the least conservative. You can try simultaneous treatments. Pain management should be considered throughout, and of course, reconsider the diagnosis of no improvement within a clinically meaningful time frame. Walking through the first line treatments, first line, we're going to find basic patient education, avoidance, awareness of triggers, stress management, and pain control. At just about every level, if there's a research opportunity to try another drug that's under a research trial, you can institute that, because more or less, we don't have a very definitive treatment for IC. This is a patient education form that you can get from the American Urogyne Society from their website. This can begin the patient education form right here. You can go to augs.org to find this. It's one of the things that we can give from a doctor's office so the patients get some education. In that education are triggers. I often tell patients about the four C's and the A to summarize it. So all the fun things in life that you can't have, chocolate, caffeine, carbonated drinks, cigarettes, and alcohol. How significant is this? So in patients that had IC and PBS, we find that they had an exacerbation of symptoms 41% of the time with chocolate, 53% of the time with alcohol, 57% of the time with carbonated drinks, coffee 60%, tomato 62%. Again, education. This is the IC Smart Diet. Patient is like, what should I eat in greater detail? You can get this straight off. You can find these in many different places. It just talks about different foods that may be better or worse for you. That little box here says typically avoiding foods high in acid and potassium as well as beverages containing caffeine and alcohol is a good idea. Stress management, complementary alternative medications, things like acupuncture and mindful meditation have actually done well in randomized controlled trials to manage some of the symptoms of IC. When we talk about pain control, at this level, we're over the counter with Prusertin, Prerelief, and Azo. Azo is a very popular one. You have to be careful with patients with G6PD for hemoglobinemia because it can exacerbate your symptoms. So this wonderful person that's appearing on the screen, this is a nurse practitioner that works in our office. She's Elise Abram. She is Nurse Practitioner of the Year in the great state of Kentucky. In our office, she exclusively sees IC and chronic pain patients. God bless her soul. And she's been doing that in our office for the past 10 years. And before that, she worked with another provider doing that for 10 years. She's in the process of writing a book of management with some of the leading authorities for IC. And so some of the stuff that I will talk about will be keys from her. So once again, so some of the things that have worked with her patients, CystoRenew, Cytoprotect, Desert Harvest Aloe Vera, these things you can find on Amazon and have worked for her. If that's too much, you can try eight ounces of water with a tablespoon of baking soda when you're symptomatic, and that tends to work very well also. Second line, we're going to physical therapy, more oral medications. We start to get invasive treatment with intervestigal installations. Again, we can use research trials if it's available. So just a note about pelvic floor physical therapy, not all pelvic floor physical therapy is equal. One of the things that we do is we vet our pelvic floor physical therapy. There are actual different proficiencies that they may receive. Simply sending someone to pelvic floor PT and expecting them to say, do some Kegels is absolutely the wrong thing to do. Absolutely the wrong thing to do, especially for IC patients who may exacerbate some of their symptoms. I'll talk a little bit more about this in my next presentation about pelvic organ prolapse. Again, Elise Abram, she went and she vetted, she spoke to all the pelvic floor physical therapists in town, and we actually have just a few that we send our patients to. The medications, amitriptyline, in some studies it showed improvement in 63% of patients, has a significant side effect of 80% of them are a little bit drowsy. Cimetidine or Tagamet, about 50% showed improvement on some studies, can have interactions with other drugs. And hydroxyzine, Vistaril, in a randomized controlled trial, it showed no difference. In observational studies, it showed 92% improved. Again, you have a side effect of potential sedation. So Amaranth, pentosine polysulfate sodium, PPS, sure many of you heard of this, a heparin like sulfated polysaccharide. The idea is to reconstitute the gag layer, the significant adverse effects, hair loss, nausea, diarrhea, retinal pigment maculopathy, and that's a picture of what that is there. So in studies have correlated that seven to 15 years of use increased odds of maculopathy, leading to $4 billion recovered from lawsuits from super lawyers, that's what just popped up there. So I will say this, if you find an IC or IC patient that has found something that works for them after years of being tormented by their symptoms, it's really hard to try to talk them into not doing what that thing was. So we talk with our patients, we say, look, this is what it is. We say, if you want to continue with this medication every six months to a year, you're going to have to get an eye exam. If you notice anything different, we have them sign another waiver. A large majority of them did stop using this, because we found another thing that could work equally as well, but we do still have some patients that use it. DMSO is one of the bladder installations. It's anti-inflammatory and it has the unusual property that if it touches your tissue, you're going to taste garlic. You're not going to smell it, but it's going to taste garlic. And it, for a while, was the hot new kid on the block for a little bit, thinking to hopefully help some of these patients with IC. There was a multi-center randomized controlled trial in 2016 that wanted to evaluate two different types of bladder installations. One was hyaluronic acid, chondroitin sulfate, that's the HACS that you see up there, and then DMSO. Their primary outcome was a measure on the visual analog scale to see that their pain had reduced significantly. They called the responder at least 50% reduction in pain from their baseline. They also evaluated the economic impact, namely, which one was cheaper to do. So the way that they did it, also 13 weekly installations, three months, then they did nothing for three months, and then re-evaluated their pain to see if there had persistence of relief. Inclusion criteria, they used the definition by the European Society for BPS. And they also had patients who, when they came into the clinic for the first time, their symptoms were consistent with IC, they ruled out some other things, and they said, all right, we're gonna enter you into this trial. And then they also had patients with a known history of IC. So first observation and response of first liners. It was pretty equal in each group. Comparable demographics. However, the DMSO group did have increased frequency and bladder capacity compared to the HACS group. They did find significant difference between groups. So the hyaluronic acid group had greater reduction in their pain, and they had more responders to that. The secondary outcomes, most notably, I'm gonna talk about bladder capacity increased in both groups, and it was not significant between groups for that. When they evaluated the overall cost, it was 1,000 euros cheaper compared to the DMSO, but both were effective. No serious adverse effects in either group. And basically at the end of this, they concluded that they had sustained improvement in symptoms following treatment of BPS IC with hyaluronic acid. I think the point of this is, if you're treating IC patients, and you're doing bladder installations, it's okay to kind of experiment with what you're doing. If it's not working for them, whether you're using some bicarb or lidocaine, or what your heparin is, or you wanna try this, if it's not working for them, experimenting with them is okay, as long as they know that you're experimenting with them, of course. When we get to third line, we have invasive treatments with cystoscopy and hydrodistension. I'm not gonna get too much into that. Again, research is able to be used at this level as well. Fourth line, we're gonna consider sacral neuromodulation. Research is able. So if you don't want the sacral neuromodulation, the pacemaker for the bladder that's used for OAV, fecal incontinence, constipation, chronic pelvic pain in some cases, if you don't want the permanent implant, or if someone is like, I don't know if that's gonna help my IC, or they don't have a concomitant symptom where the sacral neuromodulation is for them, one of the things you can use is a TENS unit. So again, this is Elise Abrams coming through with a recommendation. And so she has patients that apply TENS units at various places on their abdomen, and some of them have great results. It has showed promising results in randomized controlled trials as well. Here, we're gonna see the immunosuppressant cyclosporine and intravesical Botox that's considered. Cyclosporine immunosuppressant. In some of the studies, it was 75% improved compared to Elmeron, 91% and some others. This is where you wanna know your compounding pharmacy. So if you're going to do this and treat some of these IC patients at a deeper level, you're gonna need a compounding pharmacy at some time, or your patient is gonna need a compounding pharmacy. In the studies that use cyclosporine, there was varying doses, and varying doses might work with your patient. They actually crushed up pills and added 25 milligrams here, 80 milligrams here. Overall, the patients that respond best are those with Hunter's ulcers. So they already had a cystoscopy and were evaluated. In the most recent study that I'm aware of, the adverse events that's always discussed with cyclosporine, hypertension, elevated creatinine, and gross hematuria, no patients had any of that. So intravesical Botox, is it effective for the treatment of IC? So 2016 study, multicenter randomized control double-blind placebo study, they went to test the actual therapeutic efficacy of Botox for IC patients. The thought process being it inhibits the neuroplasticity of sensory fibers. Again, primary outcome was the VAS scale, and the treatment outcome was assessed by the GRA, which is the Global Response Assessment. Secondary outcomes, voiding diary, urodynamic study, looking at bladder capacity and post-void residual, and the IC symptom score. They used inclusion criteria that had diagnosis of IC based on characteristic symptoms and cystoscopic findings of glomerulations, fatigue, and mucosal fissures after hydrodyspension. Glomerulations are bladder hemorrhages, and this is just an image from cystoscopy showing some of those glomerulations, opposed to the Hunter's lesions, which is a circumferential area with mucosal reddening with small vessels pointing to a central scar. So here's like that central scar. Here's a little central scar. As you can see here, it can be darker, or it can be completely white. Hunter's lesions can be BOVI, biopsied if necessary. Lots of stuff for the exclusion criteria. One of the things I do want to highlight though is if these patients had a PBR greater than 150 milliliters, they were not able to participate in the Botox study because we know that Botox is a risk factor for urinary retention. 10-point VAS, three-day voiding diary, and a video urodynamic was used. And they also used the symptom score on the O'Leary ST. So the O'Leary ST is a way that you can grab a base. God bless you. The O'Leary ST is a way that you can grab a baseline of pain or where your patient is at. It has two sides. I know, and I apologize for how small the writing is. It has a symptom side and a problem side. You can have a total of 20 on this side, a total of 16 on this side, so a maximum of 36. So you can use this, have them fill it out, begin whatever treatment that you have, have them fill it out afterwards, and you can monitor in a more objective way how they're feeling or the progress of their symptoms. They used 100 units, 20 injections, one millimeter deep, none in the trigone. The normal saline cohort or the placebo, 20 injections of normal saline. They did a lot extra in this study as well. They also performed hydro distension to 80 centimeters, had an indwelling Foley overnight, and used Keflex as a prophylactic antibiotics for seven days. They had their symptoms assessed at two, four, and eight weeks and video urodynamic at eight weeks. The results showed a significant between group difference. The Botox group had a greater reduction in their visual analog scale and their mean bladder capacity. So the mean bladder capacity on average went up about 70 milliliters from a baseline of 264. Everybody has great eyes, can read that. Opposed to the normal saline group where they actually went backwards after treatment. They actually had a mean reduction of 45 milliliters. So overall reported subjective, wow. Y'all can read that. At three months was 62% for the Botox. So 62% in the Botox group got better opposed to 15% in the normal saline group. Adverse effects, things we know about Botox. Dysuria, 33%, UTI, two and a half percent, and acute urinary retention. Conclusion, intravascular injections of 100 unit Botox effectively reduced pain, symptoms in patients with IC and bladder pain syndrome with an acceptable rate of adverse effects. By the time we get to the sixth line, we're not considering research anymore. This is at the point where we're considering permanent anatomic manipulation. So like diversions therapy. Well, with all that being said and all my talking, let's do a little patient vignette with patient KT. We have a 27 year old G2, P2 comes to a return visit for your clinic. Significant past medical history of seasonal allergies and anxiety. Unremarkable surgical history, social history that reveals occasional alcoholic beverage two to three times a month. Doesn't smoke tobacco and denies drug use. Previously diagnosed with IC after a recent cystoscopy. Largely unremarkable physical exam. Today on her visit, she's going to receive a bladder installation. Medical provider has recently begun enrolling patients in IRB approved experimental research trial with a novel treatment. According to the AUA, guidelines for treatment of IC painful bladder syndrome, when would it be appropriate to offer this novel research medication as part of the patient's management strategy? A, after attempting six weeks of practicing stress reduction techniques without relief. B, after trialing at least two different bladder installation medications. C, after cystoscopy and full duration of Hunter's lesions is performed. D, after trialing oral antihistamines. Or E, enrollment is permitted for all the above. I'm gonna give a second to take off my jacket cause it is warm and then we'll answer this. So if you said E, pat yourself on the back, enrollment is permitted at all levels. So that's that. I wanted to include my little one in this picture because I figured if this went wrong and I didn't have any smiling faces out there, at least this face is gonna help me smile. So with that being said, any questions? I think that's my boo calling out. All right. Well, thank you, I guess. Oh, yes, sir. One quick question. What's your recommended bladder installation like recipe that you use in the office? I think the way we talk about it is like, all right, you're coming in first time, what are we gonna use for everybody at baseline? Unless other indicate it. We use 10,000 units of heparin, 15 milliliters of sodium bicarb. And I don't know why I'm blanking because I was asked the question. Oh, viscous lidocaine, about 10 milliliters of that. Shake it up, wait a while, see what happens. And then again, I feel very great about kind of tweaking some things. Thanks to Elise Abram. Sometimes it doesn't work. Add a little bit more of this, add a little bit more of that. That's where we are. We just, we don't have the answers for IC. So with these patients, you know, patience is a virtue. You know, you talk to them, you say, we're gonna keep working with you. This doesn't work, we have other things we can try. We're gonna get there, just give it some time. So I think, again, compounding pharmacy, discussion with your patients about what we're going to do. And that some of this is we're kind of figuring it out on the fly. Other questions? Wait, I think I'm. I know, it was very awkward in the first row as I'm just standing over you guys. Okay, so I have a patient who is currently actually just found out she's pregnant, but prior to this has terrible IC. She tried Elavil, had severe side effects, didn't tolerate that. I sent her up to urology. So she saw urology, they ended up giving her installations. She did those at home. Sound like the similar cocktail to what you described. At first they helped, but then they stopped working for her. And we've done multiple urine cultures on her, and it's always negative. Just hematuria, negative culture, because I'm always like. You said she had hematuria? Yeah, she had hematuria, but again, every culture's negative for UTI. So she went back to urology. They did a cysto, but they did not do hydrodistension. Told her they didn't see ulcerations, therefore she wouldn't benefit from hydrodistension, and told her just to keep doing installations, but it's not working. So I am a general OBGYN, not urology, so what would you recommend for this patient? If you're not going to do the hydrodistension, or everybody's busy doing their thing, whatever their thing is, if that person doesn't want to do it, is there someone else that you can refer? How about a friendly FPMRS urogyne would be my recommendation. Urologists are fantastic. And I mean, it's different. It tends to be a different clinical experience in my humble, I just started in this medicine business kind of thing, opinion. It's just a different experience, and I would say just maybe go to an office that is used to experimenting more, has the time to experiment more. It takes time to talk to these patients, and that's why Elyse is so beneficial for us. Send her somewhere else. Send her somewhere else, quite simply. Yes, ma'am. Thanks for your lecture. Thank you. Going back to Elmoron, when I tried the research, because I've seen it be very successful in patients over the years, but when I tried to research the dangers of it, it seemed like, and if you can comment on this, it may have been that some of the more severe chronic effects were in patients that were abusing it, not just in the United States, but in other countries, it's used worldwide. So if it's safely used, as the company recommends, because they still have patient programs that help them pay for it if their insurance doesn't, I mean, the company is still very involved with the product, the maker. If it is safely prescribed and the patient uses it as recommended, three to six months, and then follow that up with more alternative therapies when their symptoms are minimized, do you still support its use if prescribed correctly and used correctly, based on the recommendations of the company? And also, what is your opinion about aloe vera? I know there's several studies out on that, successful outcomes on that, but what are your opinions on aloe vera? Thank you for your question. I see patients, when they find the thing that works, they adhere to it. The best that we can do is counsel about what we do know. It happened, right? We know that the macular retinopathy, it's there. We can't ignore it. So we can just educate and inform them. Say, this happens, this may be likely, this is what you can do, eye exams, why, blah, blah, blah. After that, informed discussion. We can try these other therapies while we take this away. And it just goes from there. It's a discussion in our clinic. It's really exciting, or I get excited about it, I don't know what that says, about all the different medications or research trials that are coming out. I was just at a couple of conferences, to your point, about head-to-head randomized control trials that are gonna be coming out in the next six months. I would say, in general, try it. Try whatever, within reason, you can for your patients with that patient education. In the next six months, we'll probably have a little bit more information to provide patients about the success or failure rates of some of the things that we use today. I see, again, just be ready to experiment. Be ready to be patient. You have to think out the box and maybe go out your comfort zone of what is an A-to-B kind of diagnosis and treatment. One more question, then. Yes, ma'am. About DMSO. I've been in two hospitals. They refused to purchase it because of the expense. A patient and I, in an office, looked it up online. It is available at Amazon. Very concentrated. Mm-hmm. Is that where you're, how are you, are you having the patient purchase it, bring it to your office, and then dilute it appropriately for use in them? How are you doing that? We have done a lot of different things because, as you said, it's insurance, pharmacies, and again, compounding pharmacy, compounding pharmacy, compounding pharmacy. You need that for an ICU patient. We've done all of the above. We've done all of the above. Again, you have to think out the box. It's not going to be the typical, oh, run down to CVS and pick this up. You're probably not going to be able to do that for some of the things that you want to provide for these patients. Other questions? All right. You guys look excited for presentation number two. Huh? Huh? Yeah. Woo! Thank you. Thank you. Thank you. Thank you. Oh, thanks. Appreciate it.

painful bladder syndrome

interstitial cystitis

hypersensitivity disorders

bladder pain

diagnosis

treatment options

patient education