Mitchell Goldenberg: Dr. Wein, thank you very much. And thank you for the opportunity. So as you said, we're going to be talking about two conditions that often overlap. So we're going to talk about some of the distinctions between the two, but also what they have in common. Some of the management strategies, again, like you said, can be distinct, but also there may be some common treatment options that we have. And we'll talk about some of the future directions that the field is going and some of the upcoming therapies that may be coming to your office any day.
So we'll start by talking about the definitions. Overactive bladder is a syndrome. It's a clinical diagnosis generally with urinary urgency as the primary symptom. Where bladder compliance is diagnosed on urodynamics and is a change in volume over a change in the pressure of the detrusor itself. Overactive bladder, there's a number of theories as to how it develops, but the urotheliogenic theory is a commonly thought of one where we believe that the lining of the bladder itself has the ability to impact the way that A-delta and C fibers send signals about bladder sensation.
The myogenic theory, which more pertains to bladder compliance, is increased deposition of collagen within the bladder wall and changes in the muscle composition itself. And then neurogenic theory basically implies that the brain has less control over signaling to the bladder itself, which promotes bladder contraction and leads to the classic hallmark symptoms.
Bladder compliance has a number of different causes, and often the cause is not found, but the ones we commonly see in practice is the patient who's had an obstructed bladder for a number of time, and essentially the bladder tends to remodel and change. We think this is mediated by cytokines. And again, the type of collagen is really important with type I collagen being stiffer, and we see more of it in the patients. And the fibroblast to myoblast transition or that process is what tends to lead to that. The definition of normal compliance tends to vary from paper to paper, but abnormal compliance is generally thought to be anything between 10 to 40.
There's a number of different options on how to manage these folks. Behavioral therapy has been commonly ascribed to the non-neurogenic patients. And there really still is a lack of data supporting it as a monotherapy in the neurogenic patients. Pharmacotherapy is commonly used in both groups. Anticholinergics, obviously, over many years have been studied. And we know more recently, this novel group of beta-3 targeted drugs can promote detrusor muscle changes via cyclic AMP.
Both classes have evidence to show that they can improve the compliance and also the ability of the bladder to store. OnabotulinumtoxinA has been available in this country for many years now. It's approved for OAB patients, but it also has a role for the poorly compliant bladder. Its mechanism of action has been well described. It blocks the presynaptic ACH, and it essentially can last on an average about six months in most folks.
It also has an impact on sensory function affecting the purine and TRPV1 aspects of the bladder. The effect, especially at high dose, is to improve bladder compliance, and studies have shown that changes of over 5 ml per centimeters of H2O in certain patients. The injection technique has changed over the years. Originally 20 sites was done commonly. Now, I would expect most sites do 10. The argument about sparing the trigone has been discussed at length and some evidence points to in the poorly compliant bladder that you should include the trigone. Common risks with this therapy have been well described, retention being the primary one that we get concerned about.
Sacral nerve targeted therapies have been approved for almost 30 years. In the OAB population in particular, stimulating the S3 nerve improves bladder control, and the success rates similar, 70 to about 85%. Tibial nerve stim has slightly lower success rates in data. The innervation of the S3 nerve is similar, but it's done through a peripheral needle and can improve bladder signaling. The pudendal nerve has been more thought of as a salvage option, and in patients who have failed primary therapy, the success rate can be quite high up to 60% or so.
Interestingly, sacral nerve stimulation, especially if done after a neurogenic insult such as spinal cord trauma or in a pediatric patient, has actually been shown to prevent deterioration in bladder compliance changes. This is still an emerging field, but the thought is that if you can intervene earlier in these patients with this type of therapy, you might be able to preempt any future trouble.
Surgical therapy is not as commonly used these days, especially more of a destructive approach to the nerves. Rhizotomy is essentially not used anymore. The complication rate is quite high. Changing or being able to reconstruct the bladder wall itself still has a primary role in a lot of these patients, especially in neurogenic patient who you cannot restore bladder compliance with the less-invasive options, reconstruction using a number of different methods, essentially to increase the ability for the bladder to store urine at a pressure that will prevent kidney function problems. Urinary diversion with a conduit is seen as a sort of end-stage treatment in patients who have failed other therapies, but can have a huge improvement on the quality of life in these patients and suprapubic tube placement in a select patient group where a larger surgery may not be the best choice.
In terms of future options, I mentioned the sacral nerve therapies, but there's a number of others that are being studied. I think of interest to me in particular is the transcranial stimulation, which in combination with pelvic floor therapy has been shown to improve symptoms. Antifibrotic changes or therapies that affect collagen within the bladder seems to be a fairly straightforward way to approach this problem, but we're lacking in human data. And stem cell therapy and tissue scaffolding is another promising option, again, still in the preclinical phase. And just recently, USC and UCLA performed the first-in-human bladder transplant, which while obviously very new promises to maybe offer another therapy option for the select patient.
So in summary, these are distinct medical conditions, but there's a lot of overlap in the pathophysiology and also how we treat these patients. Overactive bladder has a primary impact on quality of life, whereas poor bladder compliance, the fear is that will affect kidney function in the future. Like I said, pharmacotherapy is a useful tool for both. And for poor bladder compliance, taking a slightly more aggressive approach may be a desirable option, especially if kidney function is what we are concerned about. Thank you very much.
Alan Wein: Listen, thank you so much. That was a great review of both entities. So tell me, do you think that if any of the... I guess you would call them less-invasive forms of urodynamics are successful, where you can actually do the urodynamics with a more physiologic filling rate, you think that that'll alter our definition of what bad compliance is?
Mitchell Goldenberg: I think it's going to change a lot of what we define currently. I think urodynamics, the way we do it in the office now remains a fairly artificial test. The parameters are tightly controlled. I think certainly we're going to be able to appreciate what people's true bladder pressures are when they're out in the world. I think when we do a urodynamics, we're getting a single snapshot, and it may not tell us the whole story. I think the definition really in terms of the centimeters of water is less important than the clinical impact that has on the patient, but I think generally we're going to understand these patients' bladders a lot better and be able to intervene earlier in a lot of these patients.
Alan Wein: Yeah. So if somebody has both detrusor overactivity and decreased compliance, in other words, and they have the typical symptoms of overactive bladder, but you do a regular urodynamic study, artificial, like you said, because it's not really real, it's a sort of a trumped-up study that we've done for a long time the same way, but it shows pretty significant decreased compliance and overactive bladder, will these treatments treat both at the same time or will they preferentially treat the overactive bladder, leave the compliance alone or vice versa?
Mitchell Goldenberg: I think it depends on when you're intervening with certain patients. I think in the patient who's come to seeing you with a very poorly compliant bladder reflux, sort of the end-stage sequelae, I'm not sure pharmacotherapy alone is going to make a big enough difference. At that point, their bladder has changed in a way that medication alone is not going to really change the collagen deposition. I think more-invasive therapies, I think things like botulinum toxin have a bigger role to play in those patients.
So I think when you think about treating the overactive bladder component, I think pharmacotherapy is fine in a patient with a mildly-impaired compliance. But in the patient that we all think of with the steep rise in their pressure as they're filling with the phasic contractions of the bladder, I don't think the less-invasive therapies play as much of a role. And I think those are the folks where surgical therapy is still the mainstay. I think ultimately you can buy time with some of these therapies, but if their bladder has remodeled to such a degree, you're unlikely to reverse that to a degree that makes a difference on their day-to-day life. I think surgical therapy is still a tool that we need to be able to offer patients.
Alan Wein: So I know I've talked to Indy Gill a number of times about the bladder transplant stuff, which in and of itself is an incredible surgical feat. So my question to him always is, how are we going to get the nerves to grow in there?
Mitchell Goldenberg: Yeah, I think the answer is... We don't know. What's remarkable, I don't have all the data on the patient who underwent a transplant, but there appears to be a response. They appear to be having a voluntary bladder contraction, which... That's a hugely unexpected thing. I don't think we expected that to happen. The nerves themselves... I guess the first question is we don't really understand necessarily 100% what role the nerves play in some of the intrinsic functions of the bladder. And there may be some innate... Within the plexus of the bladder nerves themselves, there may be some functionality there that can come back.
But yeah, as far as I know, there's no current way of grafting. The nerve complex is too complicated to kind of graft back on, but it may be what it's showing us is we don't understand completely what leads to these changes in these patients and the bladder function itself. I think we have a lot of good theories, but I don't know if we necessarily fully appreciate the intrinsic capabilities of the bladder even when it's separated from the spinal cord.
Alan Wein: Thanks so much and look forward to further achievements of yours.
Mitchell Goldenberg: Thank you very much, Dr. Wein.
Alan Wein: Thanks. You bet.