Okay, welcome to Nashville, everybody. So glad you could all be here, both especially the in-person people, but also I hear there's quite a few people online who are gonna be watching this as well. I'm really excited for the faculty that we've put together for this meeting. I really appreciate them coming, and I really hope you guys enjoy the meeting. We have a pretty good mix of both sort of non-surgical stuff, most of this morning's gonna be non-surgical stuff, but as the course goes on, we'll get more and more surgical stuff. So my name's Miles Murphy. Roger Goldberg and I are the directors for the program, and again, thank you for coming. I don't know about you guys, but when a 55-year-old woman comes in, normal BMI, not on any prescription medications, but she's complaining of leaking when she plays pickleball and when she goes out and laughing with her friends, it's really ruining her life, and you do an exam and she's got little hypermobility, but otherwise no prolapse, and you say, yes, this patient, I'm gonna cure. I'm gonna make this person happy. She's gonna love me. She's gonna think I'm the best thing since sliced bread. And then you get a 78-year-old patient with advanced diabetes, hypertension, morbid obesity, who thinks she has recurrent urinary tract infections, but every time they culture her, she's negative, and she's peeing all the time, going through pads, and you say, this is gonna be a little bit more challenging for me. So this is all about feeling more comfortable when those people come in and knowing how you're gonna help them. These are my disclosures. So we're gonna start talking about overactive bladder syndrome and nocturia. OAB is urgency with or without urgency urinary incontinence, usually with increased daytime frequency or nocturia with no proven infection or other pathology. And sort of the hallmark symptom is this urgency, which is an urge to urinate which is difficult to defer. That's the main thing you have to have to have overactive bladder syndrome. I always tell my patients, a normal bladder should be compliant. It should be able to increase in volume without increasing in pressure. And it's constantly communicating with your brain. Bladder's telling your brain, hey brain, I'm starting to get full. Brain sends a signal back, say I hear what you're saying bladder, but we're just gonna keep storing and keep storing. And eventually, after sending all those signals, your brain takes you over to the bathroom, you sit on the toilet. It causes your urethra to relax and your bladder to contract and you void normally. When you have overactive bladder, that communication between the brain and the bladder is just not so good. And brain, the bladder just decides, doesn't care what the brain's gonna do. It's just gonna contract on its own and that's when you have these symptoms. There's no exact known etiology for this, but there are risk factors as you all are aware. Age, advancing age, female gender, menopause, higher BMI, declining cognitive function. And you have to rule out local abnormalities with your basic diagnostic evaluation, which I'm sure many of you are well aware of. Getting a 24-hour bladder diary can be very effective and it can be educational for the patients. They didn't realize, maybe I shouldn't be drinking those five Diet Cokes a day. We like to use severity and domain-specific quality of life measures. That's helpful just to compare how severe a condition is across different patients and it can be helpful if you ever end up wanting to do retrospective studies. Certainly wanna get a urine specimen to rule out hematuria and infection. Check a post-void residual, especially in people with risk for retention like diabetic patients, prolapse patients. Obviously do an exam. And you may consider cystoscopy. It's not routine, but if there's hematuria or other risk factors for bladder cancer, might be a good idea if they've had prior reconstructive surgery. And then whether or not you choose to do urodynamics is kind of up to you. I mostly use it as a preoperative test and a postoperative test if things haven't gone the way I want. I put this slide up here not because I expect you to be able to read everything, but just so you know, Sufu has put out this overactive bladder clinical care pathway that's a pretty effective thing to have at your disposal. It talks about basic diagnostic approaches, patient education, first and second line therapies, and then over on the second page is all about advanced therapy. This talk is not gonna touch on, but we'll get to that later in the course. So first line therapy, behavioral interventions can be quite helpful and you need to give it at least a good four to eight week trial for this, but obviously it's not gonna fix everybody. But knowing what's gonna irritate the bladder, how you're drinking, what you're drinking, all those things. Bladder training, doing schedule avoiding, urge suppression, and pelvic muscle exercise is usually in combination with this. And there's actually some pretty good data. Dr. Richter has done some of the study on some of these devices. Obviously pelvic floor physical therapy is great, but sometimes people don't wanna be leaving the home to do that, so there's some in-home products that can be used to really help with this. And then sometimes it's just something as simple as getting someone a bedside commode, someone who has difficulty ambulating and in the middle of the night to save them from having to get to the bathroom, they just have a commode right by them. And obviously these first line therapies can be done in conjunction with medications or second line therapy. Second line therapy, again, this Sufu guide recommends a four to eight week trial of medications. If you look at most studies that get drugs FDA approved, you'll see that there's generally an increase in efficacy for the first eight weeks. It sort of tapers off to 12 weeks, but there's still usually some improvement from eight to 12 weeks. So I tend to do more like a 12 week trial, but for some people, four to eight weeks is adequate if they're just not getting any response at all. There's two classes of medications. Anticholinergic medications include both oral and transdermal options, and then beta agonist medications, which is of course only an oral option at this point. This care pathway suggests that patients need to fail at least one medication before offering third line therapy, but as you all know, oftentimes insurance companies are not gonna cover these third line therapies unless they've tried at least two medications, and oftentimes they have to have tried one from both class. And then there's other things you can do in terms of second line therapy before moving on to third line, like dose escalation, dual drug treatment, especially using one from each class. How do these meds work? So obviously, detrusor contraction is moderated by the parasympathetic nerve system, the neurotransmitters acetylcholine, and there are muscarinic receptors in the detrusor muscle that when stimulated cause contraction, and when blocked causes relaxation. The hypogastric nerve via the sympathetic system using norepinephrine as its neurotransmitter affects beta-adrenergic receptors to relax the detrusor, so beta-adrenergic agonists cause relaxation of the detrusor. And then we don't have medicines that treat this, but the somatic system is gonna innervate that external urinary sphincter, urethral sphincter, and that's mediated by nicotinic receptors. For those of you that are maybe a little bit younger out there, back in the day, about 20 years ago, there was some investigation as to whether using an SSNRI might work for stress incontinence by basically increasing the norepinephrine at those alpha receptors, and people were looking at duloxetine as a possible treatment for stress incontinence, but that never panned out. So there are muscarinic receptors all throughout our body. The ones that are most responsible for detrusor contractility are M3s, and so when these medicines first started coming out, there was a lot of talk about how selective these meds are for M3. Also to note, though, they're mostly metabolized hepatically with a cytochrome P450, but if you see here, trospium, whoops, darn it. Trospium is not metabolized in the liver, and also it is a quaternary amine, which is different than all the others, so it's a little bit unique, that trospium. Unfortunately, these anticholinergic medications have a lot of side effects that are not easy for a lot of patients to deal with. And there are contraindications in narrow-angle glaucoma and gastroparesis, and you have to use them in caution with people with renal hepatic insufficiency or myasthenia gravis. In 2019, this sort of landmark study came out in JAMA looking at whether the risk of dementia in patients over 55 was associated with the use of different types of anticholinergic medications. And this was a huge study, lots and lots of patients in a nested case-controlled study where they found statistically significant associations of dementia risk with exposure to anticholinergic medications such as bladder antimuscarinics. And they basically determined that the association observed for specific types of anticholinergic meds suggests that these drugs should be prescribed with caution in middle-aged and older patients. Just a quick note, the blood-brain barrier is the tight junctions between endothelial cells and brain capillaries, and it's the only path through cell membranes of endothelial and glial cells. And lipophilic drugs will pass through it easily, of which tertiary means are this way. But quaternary means, which are highly ionized, don't cross. So there's a question of is this, is trospium, that specific anticholinergic a little bit different in regards to that risk? Unfortunately, there's not a lot of good data to tell us whether or not that sort of theoretical benefit is true or not. So what does Oggs say about all this? So in 2017, Oggs put out a statement about anticholinergic medications in these at-risk patients. And they updated this after that JAMA article. And so in 2020, sort of this highlighted area was changed. And it said, given the available evidence, which has shown significant associations between anticholinergic medication use and increased risk of cognitive impairment and dementia, providers should counsel on the associated risks, prescribe the lowest effective dose, and consider alternative medications for patients at risk. So the medications that we're talking about that don't have these risk factors are their beta-3-adrenergic agonists. The one that's been around the longest is mirabegron. It stimulates beta-3-adrenergic receptors and relaxes bladder smooth muscle, and obviously doesn't have anticholinergic side effects. You do have to use it in caution with people with poorly controlled high blood pressure. It does have two doses, a 25 and a 50. But really, the risk of these hypertension side effects doesn't increase with the higher dose. So I generally will start people straight at the 50 milligram dose. The newer medication, vibegron, it only has one dose, same mechanism basically as mirabegron, but it does not have the caution with hypertension. So it's a nice option, but unfortunately, as you all, I'm sure, have experienced, you get poor coverage from Medicare. So it's very frustrating when you wanna do the right thing by your patients, but what they can afford is dictated by their insurance companies. And oftentimes, they won't pay for these medications. And then, of course, you get the patient, comes into your office, you do all this great counseling, you spend all this time, tell him to avoid caffeine, tell him to go to pelvic floor physical therapy, talk to him about the options of drugs, give him a script. They come back two months later, say, Doc, my symptoms are the same. I said, oh, you know, did you take that caffeine out of your diet? Oh, no, you can't make me give up my coffee. And I said, did you do your kegels? I hate doing those things. I can't be bothered going to a physical therapist. And, well, did you take the medication? No, I read that package insert. I don't want all those side effects. So basically, they didn't do anything, and they have the same symptoms, and they're wondering why. So we do have this amazing product in our office. It's the OAB wand. So that always helps. But in any event, it can be challenging to treat, and luckily, we do have third-line therapies, and tomorrow, Dr. Siddiqui's gonna be covering those. So just a little branch or sub-portion of overactive bladder has to do with nocturia, which is defined as waking at night to void and then going back to bed. And the WHO classifies this as two or more voids per night. And when you have nocturia, it can be due to just, it's just a product of polyuria throughout the 24-hour cycle, which we see up here. But then, for nocturia that's specific to the nighttime, you can have nocturnal polyurea, which is designed, excuse me, defined as greater than 1 3rd of your urine output at night. It can be just an offshoot of 24-hour detrusor overactivity or instability, but it can also be caused by sleep disorders. So if you have noct, if the patient has nocturnal polyuria, there are certain things you can do behaviorally to try and help with this. You can do evening fluid restriction. You can do time diuretics. You can do afternoon naps. I always tell my patients, you know, as we age, our blood vessels, our kidneys, our heart don't work as efficiently as they used to, and if you're standing or sitting during the day, fluid tends to collect in your legs, and then when you lay down at night, it's easier for your body to process that fluid, and you're actually making more urine at night than you are during the day. So if you get those legs up above the level of your heart for a half an hour, once in the late morning, once in the late afternoon, that might help you process some of that fluid during the day so you're not doing it at night. And then there's medical therapy. There have been, over the years, there have been quite a few preparations of DD-AVP. To the best of my knowledge, there's only one formulation now. It's a sublingual tab called Nocturna, and it has a dosage for female patients and for male patients that are different. It does have the black box warning for life-threatening hyponatremia. This is an older study of DD-AVP for nocturia in the elderly, and it really does show that about 2 1⁄3 of patients have a greater than 50% reduction in their nocturia on DD-AVP. But unfortunately, 5% will develop this hyponatremia. So if you do prescribe these medications, you do have to monitor these patients closely. If it's just a nighttime extension of overactive bladder syndrome, you treat it as you would for daytime problems, anticholinergic, beta agonists. Sometimes you can do different dosing, so taking it in the evening instead of in the morning. Sometimes I'll, you know, if I have someone on a beta agonist that they take in the morning, I'll do a low-dose, immediate-release anticholinergic before bed at night to help with that. And then you can also consider low-dose at-night tricyclic antidepressants. These tend to have the side effect of drowsiness, which can be beneficial for patients that have sort of a light trigger to wake up with urge, so it kind of helps them sleep a little bit better. But if you do, you have to tell them about the risk of drowsiness that's gonna, you know, carry on to the day, and if that's too much and they wanna stop, you do wanna taper slowly off these medications. You don't wanna stop them cold turkey. If sleep apnea is the cause, why does that happen? Well, when you have obstructive sleep apnea, it causes increased airway resistance, hypoxia, which leads to pulmonary vasoconstriction, and release of atrial natriuretic peptide, which acts like a diuretic and actually causes the kidneys to excrete more urine in the nighttime hours than during the day. And you're going to treat that. Well, you're going to diagnose this by having a high suspicion with risk factors of people who have obesity or are increased in age. If their partner comes to the consultation, you can talk to them. Does your partner snore? And if they have these risk factors, you can refer them to a sleep study clinic. There is pretty good data that shows that CPAP can definitely decrease frequency of nocturia in addition to all the other good things it does for people in terms of daytime energy. All right. So we're going to switch now to female bladder pain syndrome. This has lots of different names. But just recently, just this year, IUGA and AUGS put out this white paper. And they've coined this term female bladder pain syndrome, or FBPS. For just to make this lecture go a little bit more quickly, I'm probably still going to say IC, because you all know what it means. But that's the official term that AUGS would like us to use. So it's a chronic intermittent condition of at least three months duration affecting women involving symptoms of pain or discomfort localized to the bladder, often with bladder filling. And it's not attributed to other pathology. Again, don't expect you to read this. But just so you know, this is the white paper from AUGS and IUGA that was published in the International Journal this year. And then in 2022, the AUA put out a similar diagnosis and treatment of interstitial cystitis white paper. So these are valuable documents for you to have at your disposal to read if you're treating these patients. In this white paper from AUGS, IUGA, they coined, or at least sort of solidified, some terms and their definitions. But traditionally, we think of these triad of symptoms with IC. The two basic symptoms are very similar to overactive bladder patients. You have that imperative urinary urgency. You have high urinary frequency. But the thing that really differentiates these people from your overactive bladder patients is this bladder pain. So if you look at the demographics of this, there's lots of this sort of conflicting information. But in general, it's a diagnosis that's often made a little bit younger than a lot of your overactive bladder patients. It is definitely more common in women than men. Some people, some data suggests it's more common in white individuals. But this may reflect a lack of diversity in studies. But for sure, there are a lot of undiagnosed cases out there. We don't know why people get this condition. But there are some theories as to what causes this. And I like to think of these because it just helps me think about what are the options for treating these patients. And the first putative etiologic factor might be a defect in this glycosaminoglycan layer of the bladder lining. And those defects can lead to activation of inflammatory mast cells. And that can cause inflammation of C-fiber nerves. There's also some thought that maybe this is a type of autoimmune process. Maybe it's an infectious process. I'm looking forward to Dr. Siddiqui's talk about the urinary microbiome. Because I'm sure you guys all have these patients that say they're having a flare. They take Macrobid for a week, even though their culture was negative. And they say they feel better. I don't know. Is that just a placebo effect? Is there something that we just fully don't understand yet? Also, there's this question of, is there a heralding event that leads to this? A bad urinary tract infections, a traumatic vaginal delivery, a sexual assault, something like that that triggered and started this process in motion. Again, the theory here is that there's this normal glycosaminoglycan layer that covers the urothelium. Stained here is chondroitin sulfate. And that protects the underlying urothelial cells from stimuli in the urine. But when this layer breaks down, as is shown here, the potassium ions within urine and other noxious stimuli irritate the lining of the bladder. And this increased permeability allows inflow of potassium ions and other noxious substances into the bladder, urothelium, and muscle. That can lead to involuntary detrusor contractions and a sense of urinary urgency that can be voluntarily suppressed, but often results in painful urgency. This increased permeability can also trigger an inflammatory response with mast cell degranulation. And these mast cells are full of mediators such as histamine, prostaglandins, leukotrienes, cytokines. And this just triggers more of an inflammatory response. And that, in turn, irritates the nerves within the bladder, particularly these C-fiber nerves. So it's this vicious cycle of bladder insult, epithelial layer damage, leaking of potassium into the interstitium, activation of C-fibers, release of histamines, more injury, and a vicious cycle. How do we diagnose it? Well, unfortunately, we're not great at diagnosing it. I'm sure you've experienced people who often go to a number of different providers before they finally end up getting this diagnosis. But it's mostly based on symptoms and history. But a good workup will include, in addition to the H&P, urinalysis and culture, kind of similar to OAB, maybe urine cytology, depending on risk factors, frequency and volume charts, and again, less commonly, urodynamic testing, cystoscopy with or without hydrodistension. Some people are fans of bladder biopsy. Potassium-sensitive testing is no longer recommended as a routine part of diagnosis. But that used to be something that we used. And even though alternative diagnoses need to be ruled out, many patients also have comorbid somatic disorders like IBS and fibromyalgia. If you have them do a bladder diary and you see that they are only voiding six, seven times a day, the chance that they have IC is pretty unlikely. These patients more typically have 10 to 20 voids per day. You can use some validated instruments out there. If you see a lot of these patients, again, similar to overactive bladder, there are some instruments that can be helpful in managing and diagnosing these patients. Cystoscopy with hydrodistension is somewhat controversial. But it is something that I do do. Generally, I do not recommend it. Generally, you're going to hang a bag of fluid 60 to 80 centimeters above the bladder. I use 80. And you let the water flow in until it starts to come out around the scope. It can be both diagnostic and therapeutic. Again, not the highest levels of data, but some observational studies have shown that up to 50% of people can at least get a temporary relief from their symptoms. And I have experienced that with my patient population. And there's not a lot of adverse events associated with it. Once you've filled them, you drain and look for terminal hematuria, measure bladder capacity, reinsert the scope, and look for bladder wall changes. Consider fulguration or injection of Hunter's lesions with Triamcinolone if you see Hunter's lesions. This does not rule in or rule out 100% IC, but it can be very helpful. This is a patient that was sent to me. An outside provider had worried that she had interstitial cystitis. And this is what her bladder looked with hydrodistension, looked pretty darn normal. So again, it's not that you don't say, well, you don't have any symptoms. You don't have the condition. We're not going to help you. You still treat these patients, but you can at least reassure them that they don't have an advanced condition. Whereas a patient like this, who has much more typical findings on cystoscopy with hydrodistension, is another one of my patients. These pictures are from the Augs Ayuga white paper. And it's showing three different stages of Hunter's lesions. The first is this reddened mucosal area with vessels radiating towards the central scar. As you fill, the ureotheal layer splits with distension. And then finally, the submucosal hemorrhagic infiltration, usually with this waterfall bleeding pattern. Only 5% to 10% of patients who you consider having this condition will have Hunter's lesions on cystoscopy. But if you find it, it's considered pathognomonic for the condition. Again, if you do cystoscopy with hydrodistension and you're able to get in 1,200 cc's, chances this person has advanced IC is very unlikely. But a lot of these patients will have a volume of more like 500. So how do you help these people? Well, there's no cure. So you tell them, my goal is to improve your quality of life. And I always am straight up with them. I say, listen, Western medicine is not great at treating this like other chronic pain syndromes. We're going to work together to try and make your life better. Is everything we do going to be perfect? No. But if you stick with me, I'll stick with you. And set these expectations. Tell them, listen, I'm going to try something. It may work. It may not. If it doesn't, it doesn't mean we should give up. We're going to try different things until we get to where we need to be. And if they want to try acupuncture, I'm all for it. I'm a fan. Let's do that in addition to all the other things I'm going to do to help you. But again, sort of traditionally, the steps that you're looking to do are minimize insult to the bladder, repair epithelial dysfunction, modulate neural activity, and stabilize mast cells. How do you do that? Well, you start with avoiding things in the diet that are going to exacerbate the condition. And there's a million different lists of these. You're going to try to rebuild that gag layer in whatever manner you can. You're going to try to help calm the nerves within the bladder with low-dose tricyclic antidepressants. And you're going to try and minimize that mast cell degranulation by giving antihistamines. There's only two US FDA-approved treatments. The first is pentosin polysulfate, or Elmeron. It's an oral medication. It's a polysaccharide ester, similar to heparin. It has anti-inflammatory and fibrinolytic effects that can rebuild the gag layer. It's usually prescribed three times a day. But I know it's hard for people to take medication three times a day, so I will often do two tabs twice a day. And I always tell people it can take three to six months before it's really going to start to make a difference. The other FDA-approved treatment is DMSO, which is intravesical installation. Unfortunately, it also gets secreted through the lungs and skin and can have a garlic-like odor. As I'm sure most of you are aware, unfortunately, about five years ago, this paper came out reporting on side effects from long-term pentosin polysulfate, or Elmeron use. Shows that you can get a pigmentary maculopathy, and it can affect vision with difficulty reading, slow adjustments to low or reduced light, blurred vision. And unfortunately, those changes, to my understanding, are permanent. They're non-reversible. When they looked at it at five years, there was no difference between people who used it and people who were unexposed. But at seven years, that's when we really started seeing an increased risk of this. So if you are going to give Elmeron, I would not suggest giving it for more than a few years and probably avoid it altogether, unfortunately. Obviously, there's off-label drugs that can be used for this. We talked about trying to decrease mass cell degranulation with antihistamines. Common ones are hydroxyzine and cimetidine. You can use tricyclic antidepressants, which we'll talk a little bit more in just a minute. Well, here we go. So there was an RCT in 2010 looking at amitriptyline in these patients. Big study, where they followed people for 12 weeks. And there was a standard education behavioral modification alone. And then the treatment group was that plus amitriptyline. And it allowed for titration. Started at 10 milligrams and allowed for titration up to 75 milligrams. And there was no difference. There was a trend. But there was no difference in the, oh, my laser's dead. Anyway, oh, there it goes. So a trend, but no significant difference between groups. But when they did a sub-analysis of people that were able to get up to a dose of 50 milligrams, there was a statistically significant difference. Unfortunately, 50 milligrams of amitriptyline will often cause drowsiness. But if someone can tolerate that, you try and get them up there to get the full effect. So again, this is from the white paper from Augs and Iyuga. And it shows all the different options for treatments and the grade recommendation and the level of evidence behind them. Unfortunately, not a ton of awesome options. Best things, or one of the best things is just patient education, behavioral and dietary modifications. Amitriptyline does have pretty decent data behind it. But the best recommendation, grade A, level one evidence, was physical therapy. I have had two patients in the last 20 years which I felt the only treatment available for them was sort of drastic treatment like removal of their bladder. Both of them have chosen not to do that. But I have had two patients that were just terrible bladders. Very recently, after that white paper was published, Kate Merriweather and her group published this randomized trial in the Green Journal. It's just a couple of months ago. And it was an RCT of almost 100 women with standard care behavioral changes or medications recommended by the AUA versus that. In addition, they were given mind-body care with self-administered treatment with a meditation app and a yoga tutorial video, easy for me to say. And they looked at a global response assessment at 12 weeks between responders and non-responders and also some secondary outcomes of some domain-specific symptom indexes. And all the outcomes, both the primary and the secondary, showed significant benefit with the yoga and the meditation across the board and sort of got stronger as time went on. So really valuable, good level one data. When you look at the people that have this condition, this is a case control study that showed that compared to controls, patients with IC reported significantly more pain, worse physical quality of life, increased sleep dysfunction, depression, anxiety, stress. And the question then, of course, is which is the chicken and which is the egg? Are they this way because of IC? Or are people with these types of psychosocial phenotyping just more likely to get the condition? In my mind, who cares? We've got to treat them. We've got to help these people. But it can be a frustrating thing to do. You just have to know that you try. You do the best you can. You be straight up with people. And you can really make some people's lives better. But you can't please all the people all the time. So thanks very much.

Nashville conference

bladder function

overactive bladder syndrome

female bladder pain syndrome

treatment strategies

patient education

mind-body interventions