Options for Refractory OAB

Options for Refractory OAB

I’m going to start off and talk a little bit about options for refractory over active bladder. Those are my disclosures. So if you look at the AUA Guidelines they break them up into first, second, third and additional treatments. And so we’ll be talking about third line and beyond. But I don’t want to forget about those first and second lines just because you get to a third line therapy or when they need additional treatments. Doesn’t mean that you might not keep patients on an anticholinergic or that you want them to stop doing pelvic floor exercises.

So I think the point is for these refractory patients there’s nothing wrong with monthly monotherapy. I have a lot of InterStim that still do Kegels and an anticholinergic and an InterStim, whatever it takes to get them some control. So those are the different options here we’ll be starting off and we’ll talk about from here on. So we’ll talk about onabotulinumtoxinA, neuromodulation, and cystolysis. This is kind of a forgotten procedure but I think has a role after auto augmentation and we’ll finish up with augmentation cystoplasty.

So I think the first critical question you have to ask yourself when you evaluating the patient who has refractory overactive bladder is can this patient perform a clean and catheterization or not? Because a number of these therapies carry that as a risk and if the patients can’t do that, then it limits him significantly. We’ll talk about the specifics more but that’s really the first question that I try and answer for myself. If I’m unsure then will teach the patient how to do cath and see if they can demonstrate it. Because the worst thing is somebody that has to cath can’t, and now you’ve got an in-dwelling catheter and that really leads to a clinical disasters. So will start off and we’ll talk about Botox. Botox now has an FDA approved indication for the treatment of overactive bladder.

This was a nice study. Vic Denny was the lead author of the EMBARK study group, which is a phase 3 randomized trial whose placebo-controlled. They used a hundred units of Botox was conducted at the 72 sites in the U.S. and Canada and rolled over 500 patients. They demonstrated almost a 50% reduction from baseline in a daily frequency versus just over 12 for placebo and the complications including UTI, which is usually the most common and most serious in a retention rate of about 5%. I would just say that many of the trials you’ll see retention rates are about 5%. There were a couple of notable exceptions one was the Ruby trial. This was an NIH trial that was actually stopped early because retention rates are as high as 30%.

So I think a lot of that may have to do with entry criteria and the Michalski just published a paper on his series and his retention rates were close to 30% and that was in all comers to practice it at Vanderbilt. So I think you got to say there is someplace between 5% and 30% depending on the characteristics of patients enrolled.

This is a meta-analysis that looked at safety and efficacy was a combination of a number of randomized clinical trials that have over 1300 patients enrolled. You can see very significant decrease in the number of incontinent episodes and the number of micturition for a day compared to a placebo groups. There’s significant increase in the voided volume but again complications included UTI and the need for clean intimate catheterization.

Most of the early data for Botox came from neurogenic bladder patients. Now we’re using it much more in idiopathic patients and Chris Chapels was the lead author on this Phase 3 of placebo-controlled trial that was done in Europe and the U.S. Over 500 patients showed very nice decreases in urge incontinent episodes per day and meaningful improvements in quality life. I’ll show you in that group they had a need for CIC of almost 7%.

So here’s the quality of life improvement compared to placebo. You can see quite impressive at the time to post treatment by week and this is just the same data in a bar graph form showing that that the treatment seems to be pretty durable at least up to three months. So the only comment I would have, sort of a parting comment for Botox, is I think it’s a good therapy. I think it works well but patients in my view need to be able to do CIC or I think that’s off the table for us.

The other comment I would make is there was a recent paper presented at the ICS in Canada from Milwaukee where they don’t inject as many sites, and I started doing that several years ago, and they showed that there was no difference if you did for five sites versus 20 or 30. And how many have injected Botox out there? So you know as you start to try to get the 30 sites it gets pretty bloodied, and is pretty hard to see. After about 10 you’re sort of guessing, are we in the bladder? I think I would say that it’s better to get the stuff in in less sites than to be unsure of where you’re put in or how much is actually getting in.

So let’s talk about some sacral neuromodulation. There are a couple forms – one is a posterior tibial nerve, which is the S3 nerve as you know splits one branch goes to the bladder the other branch comes down the posterior tibial nerve. And this is the current available commercial model for stimulation, spatial acupuncture needles hooked up to this electronic stimulator. You put this in usually once a week for about 20 to 30 minutes for stimulation. We started working with a forerunner of this back in the early 90s. The Stoller Afferent Nerve Stimulator was the first form of this. We actually published the first paper in this area at the ICS in Denver. I think it was in ‘98 or ‘99. So this is what we have currently and this is the ORBIT trial. The results are they enrolled 33 patients and most were followed for six months, with 25 made it out to twelve months. Basically they showed a nice decrease in the number of mean urge incontinent episodes via per day.

And so I think this therapy has merit. I think in my experience it works best in patients that are not terribly severe. It also works pretty well if you combine it with an anticholinergic. So for somebody who really is younger, is motivated, doesn’t mind coming for repeated treatments weekly, then usually try and stretch it out the monthly. I think this is a reasonable therapeutic consideration.

So the question is, do you leave anything in? No you just put the needle in you stimulate 30 minutes. And you kind of get this hangover effect that hopefully last for a week. And then then then longer and it seems that that is indeed the case. Now there’s a number of follow-on’s to this where you would do transcutaneously stimulate. We stimulate the foot but they’re not commercially available right now but there is more coming in this area. The other option for a secular modulation is to actually access the sacral nerve root in the as it exits the sacrum. And that’s the InterStim device this came out in a 1997 with the indication for urge incontinence and urgency frequency syndrome. In 1999 non-obstructive urinary retention was added and in 2011 he got the additional indication for fecal incontinence. So of these are the current indications for the device.

So the first question you have to ask yourself before you consider putting one of these in is is this patient going to be able to handle? Do they understand this and are they going to be able to manipulate this device? Because they’ve got to be able adjusted be able to turn it on turn it off turn it up turn it down. So our friend here Forest might not be the best candidate. Now if you can do the InterStim you have to do some form of the test procedure. It’s mandated by the FDA and there’s actually two forms one is called the PNE or peripheral nerve evaluation and other staged implementation. I’ll show you the difference the PNE basically are doing this in the clinic local anesthesia. So is quite nice from the perspective. And the idea is to navigate this test needle down into the S3 foramen and we’re demonstrating here the anatomical landmarks. At least we think they are we always use fluoroscopic guidance for this. I think it’s a very difficult if you don’t have fluoro. And here we’re got a needle in place we tested were talking to the patient. Where you feel it? We look for muscle responses but most of the time the patients are to clenched up to actually see muscle responses. So when you’re doing to test them in the clinic you’re going mostly by where they tell you they feel it and what they feel. So you’re looking for a vibratory sensation somewhere in the perineum, scrotum, vagina or bladder. And then once you have a needle in your satisfied you near the nerve than you navigate this wire down to the needle and basically tape it to the skin. So there’s nothing that holds on here except Tegaderm and therein lies one of the problems is these things prone to get pulled out.

So there’s certain indications where I would definitely not do this, in an obese patients our cut off is BMI 35. We don’t do patients that have any significant pain components. So if you have somebody with urgency frequency and and pain we don’t do those under local. And we don’t do anybody in urinary retention because we found that it takes longer than the test time you normally get with the percutaneous test. These usually don’t stay in more than three to five days. By then they pull out just from the patient’s moving around or they migrate back. And when we first started putting these in this was the only form of test. So everybody had to get tested like this and we were getting anybody who responded that had retention. And then one time we had one that lasted about 10 days and on about day nine the patient started to void. Which clued us into the fact that retention probably takes longer before you’re going to get a response and so that’s why we say we don’t do these in retention patients. We do rather a staged implant which I’ll describe next.

So this is what things used to look like this is actually us putting an electrode in back in around 1999 which is what I did my first one. When you had to make this humongous incision and I dissect all the way down to the sacrum. And then put the electrode in under vision and then and then suture it. And then in 2001 I along with a couple of other urologist went to Medtronic and helped. We were on the design team for this Tined electrode that using this cellular like technique. You can place through a relatively small skin incision and that has revolutionized the procedure. I think and made it possible to do. This is a close up of the Tined Lead to do stage procedure where you implant the lead and then you connected to a temporary stimulator. So and if you have a successful test stimulation which is a 50% improvement in the the symptoms that are most bothersome then you can implant the device.

So if you if you do a staged one you basically just internalized the entire thing. If you’re doing a PNE or test stimulation in the clinic you just implant the whole device at one sitting once the temporary electrodes are removed. So there’s as with everything else advantages and disadvantages the PNE or office-based testing is no anesthesia, no incision it’s it’s much less expensive at least OR costs. You have problems with wire migration and as I said obese patients it’s really not practical. The stage test it’s a two hour procedure. It’s a little more because of the OR time. But the bottom line is this conversion rate is significantly higher with the stage test it’s about double. So conversion I mean going from a stage I to stage II are having a successful test stimulation, but the infection rate also doubles. Because you have the lead in place and you have access to the skin while the temporary lead is still attached.

So there’s some tips I’d like to give you for successful implementation of this is somewhat nuanced. And we found over the years that these very minor differences in how you implant the lead make huge differences in success. So the the first thing the first challenge is to locate the S3 foramen and when I’m teaching the residence I shown these pictures. And tell them usually S1 looks, like a thumbprint, S2 looks like a jellybean and S3 usually looks incomplete. You barely see the whole S3 foramen. So that’s one way to identify it. Another way is to draw a line across the sciatic notches that usually crosses right at the top of S3 foramen and then you can move your entry point to a couple centimeters higher than that. The other way is just to measure nine centimeters up from the coccyx and that usually is where the S3 is and then go up two centimeters above for your entry point.

So those are several ways to identify it in the lateral in the AP position in the lateral position if you follow the iliac shadow it often points you right at S3. And typically there’s this hillock or bump right over the S3 frame. And so that’s how you can identify it in lateral projection. So this is what a stylized version of what a good placement looks like the lead should curb gently in both AP and lateral projections as it follows the nerve. And here’s one actually in a person showing you that the gentle curve as it is a follows the nerve.

So if you could start this movie this is the of the way we decide if when the right place in the just go back to the thing just click on. There you go. So is is by these responses so this is an ankle response this means you’re stimulating the S2 nerve root and you really don’t want to ever leave if that’s the best response you get. You know that you’re too high if you’re getting at that particular response. Alright can click on this one for me? This is a toe response and the only place to get a toe, you see it’s not the whole foot it’s the big toe. So that’s that’s what you’re looking for is great toe. The only place to get that’s PS3 foramen and then patient’s head is up here, feet are down here. Go ahead and click on that one. This is the so called bellows response. So you see this sort of forced pelvic floor contraction it’s symmetrical it’s not the hip. If you’re getting hip that’s an S2 response you don’t want that. And this can be in S3 or S4 response, okay.

And so if you put all that together we want to be in S3’so if you get a bellows and a toe response then really only place you can be as S3, alright. So that that helps guide you. And then the next thing is, so this is a this is a question here. During a staged testing procedure most desirable muscle responses would be? A toe response at a threshold of one and a bellows at a threshold four, bellows at a threshold of two and a toe at a threshold of four, ankle at a threshold of one and bellows at a threshold of five or bellows at a threshold one an ankle at a threshold of four.

So you always want to have a bellows proceed toe okay? And you want to have some separation between those two and the reason is if you get toe first that that’s can be a troublesome a symptom for the patients if their toe is tapping. And and so you want to have the bellows first. And you want to have you know you wouldn’t want the bellows to occur at a threshold of say 0.3 or 0.5.

I had one to start like a couple weeks ago. The reason is because of the patient find it uncomfortable at that low level of stimulation you’ve got no place to go. You can’t turn it down. So you really want to have it at about 2 so you’ve got room to go down. And you want to have a good separation of about two volts between those two responses and that’s a good lead. So how do we get to that we talked about some of these sensory responses before. So on the PNE in the male you’re looking for a perineum scrotum base of the penis and in the female you’re looking for vagina perineum. And under without any anesthesia just with the patient awake you want to make sure they don’t feel anything in their foot or running down their leg. Otherwise that’s a strong indication you’re going to have a problem.

As I said we wanted to try and avoid thresholds that are too high because if it’s too high you’re going to burn to the battery pretty quickly. One to two is optimal for a best battery life. And if you’re threshold is below one that’s too low and you have to remove the needle and redirected it. If thresholds start over five it likely that the medial lateral placement of the needle is off and there’s too much of a medial to lateral angle. So I will show you a couple of the x-rays here in a minute. So we talked about this bellows followed by toe if bellows and toe occur at the same time that’s a problem. If the whole foot flexes that’s a problem and always a toe before bellows is something you really don’t want to leave. If that’s what you get and good separation this is key.

So let’s say that you’re doing InterStim test and the, you’re getting good responses but only on one electrode. What do you think might be the problem there? Here your only on the let’s say the two electrode is the only place you get responses. What do you do? Do move the needle to a more shallow position, deeper? Reposition more medial to lateral or repositioned with more lateral to medial?

So it’s a three. So typically what’s happening if you get just one response and I’ll show you an x-ray of that. You’re coming in too, from too much of a lateral angle and you’re just crossing the nerve perpendicular and that’s why just one electrode. If you went deeper you would lose the response on that electrode and you gain it on the next one up or if you pulled it back a little bit you did you pick it up on the next one down. But would still only be one electrode. So that’s what this is showing you you want to make sure that you’re perpendicular. This is this is a too much of a medial to lateral and here you’re less likely to get separation. And this is too much of a lateral to medial and here’s where you typically will only get one or maybe two active electrodes. If you leave it that way you still may be okay but you’re going to really limit your programming options, because you’re going to be limited to one or two electrodes.

And then the other pearl here is that if you get bellows and toe at the same time a lot of the time it’s because the angle is a little bit too steep. So this was showing you the S2 framing here the S3 here. This was the lead that we had in at the time and we were getting bellows and toe at the same time. And we just change the angle a little bit aligned it up with the black line then we got separation. So these very subtle differences can make a big difference.

In terms of programming I think you know if you’re putting these in you at least have to be able to do the basic programming. And that it’s not that hard but I’d be careful about relying totally on a nurse or PA or somebody you may not be there when you these patients coming back. So you at least need to be able to do the basic stuff alls it is, is basically a circuit you got the battery you’ve got stimulating electrodes and here’s your side of stimulation between your positive and negative electrode. The only parameters that you’re battering are amplitude pulse width and rate. So rate is number of pulses per second. Amplitude is how much juice you’re pumping through there and the pulse width a high how wide each of these are. Most of the time the pulse width in the rate are pretty much held constant and you’re just varying electrodes and amplitude.

So here’s a unipolar configuration this is where the case is the positive electrode and any of one of these as negative. In this case electrode one and this is a bipolar configuration here you have a negative and a positive action on the lead cases off this is the more common a pattern that we use. So typically you’re going to be programming of some bipolar configuration. And this is the so called managed by fact. These are the first seven configurations and anybody who implants should know these. So the first configuration that you program is zero negative and three positive. The second one is one negative and three positive and then they flip. So if you look at this C1 and C4 are exact opposites. So this zero’s negative 3’s positive and C4 zero’s positive 3’s negative and these are just mirror images.

And then when you go to 5, 6 and 7 all you do is add a second negative electrode. So it’s basically this same configuration you just hot, activate another electrode. This is the same configuration as this but with two active electrodes okay, and this one here same as this with two active electrodes. So it’s pretty easy to to remember those. And that’s the way you should go through them. This is the first program to try this is the second, third fourth, five, six, and seven. If you get to seven and they’re still not responding then that’s the time to get the Medtronic rep, call the engineers at Medtronic and see what they suggest after that.

And this just shows the different areas that we each one of those configurations is is activating. This is where the electric current is flowing as you go through those. So in terms of troubleshooting these things the biggest problem we have is the device is turned off. Aa lot of times this happens at Christmas time the depth detectors will turn these off and so we get a whole bunch of patients after the holidays come in with the device off. So first thing is it on if it’s on turn up the amplitude that’s the second biggest problem. And if you’re not getting appropriate change in their symptoms or inappropriate stimulation then use that managed by fact program I just outline for.

So in terms of turning the thing on a off you got to be able to do this you just highlight the first screen and then you just tap here and it’ll turn it off. So if you get called to the OR and they just discovered somebody as InterStim have to turn the thing off and so that’s all you need to do on that one screen. In terms of efficacy these things have been shown over many years to work well. This is the the index trial. This is our data from back in the early 2000’s that we put in there and you can see for urge incontinence there was a good and sustained benefit for about 75 to 80% of the patients. I think those numbers have actually improved as we’ve gotten better at implanting these. This is for urgency frequency and a lot of IC patients in here about two thirds with either normal voids or better than 50% improvement. And then for retention this is about the same numbers were seeing about 60% of patients will actually get off catheterization usually they can get down to just two caths a day morning and night. They consider that a success.

Now a couple other things I think that to consider this is a bladder denervation procedures. These were pretty, became popular in the in the 80s and there were several attempts at that actually transacting the bladder or partially denervating in a kind of fell out of favor. And then transvesical phenol was tried and the problem was they had some vesicovaginal fistula so that fell out of favor. But this Ingleman-Sundberg Procedure for refractory urge incontinence was described by pretty good group in 2000. Lenaine Westney was the first author and all of the investigators on this paper were very good and experienced investigators in this area. And they described 28 patients that have refractory urge incontinence. And they got a durable response in just over half.

So it’s not what we would like but in a group that’s otherwise refractory it’s pretty good. And the way you do this procedure the idea is that you want interrupt the nerves in the area. The trigonal bladder and which is the densest area of innervation and in a female you can do that fairly easily transvaginal just by raising this vaginally flap. You see here so this is a thick vaginal flap and then you just sew it back in place. So it’s a pretty easy procedure for somebody who isn’t a candidate for Botox can’t cath and it’s something I’d consider. You get these patients just like I do. Well you’ve got to do something. I can’t live like this this is something I consider. Bladder autoaugmentation is another, has anybody out here done any of these bladder autoaugmentations? These are these look simple but they’re actually really difficult technical procedures to do. So here we’e doing one we’re taken the bladder muscle off this is the mucosa and the problem is once you make a hole you’re pretty close to being done because you try and close that hole you make four more wholes. And so you really got to take your time and dissect the muscle back in the idea is that you end up with this sort of antigenic diverticulum here and here we stitched the muscle all the way around the side we let this be diverticulum.

Another thing to keep in mind are the best results in the literature Manfred Stöhrer reported 50 patients improved their compliance significantly. Triple the capacity more than tripled but about half of these end up on CIC so again if they can’t do CIC I think you have to be cautious. And then finally the court of last resort is the augmentation system plasty this is been around for about 100 years now can see a technically it’s a fairly straightforward procedure. So here’s the bladders here’s our augment the success rates in terms of preservation upper tracks treating incontinence are quite good in 85% range. Tt does have some significant side effects not the least of which is neoplasia. So I’ve seen a couple of really bad bladder tumors in in younger patients and these were people who were being screened and followed. It was one had a normal ultrasound upper tracks bladder cysto every was normal six months before and showed up with a big pelvic tumor that was starting a bladder growing outside the bladder. You couldn’t even see it in the bladder but on the on the x-rays in the CT there was this big mess in six months. And that the patients I’ve seen with that are ones that have chronic infections of chronic infection augmentation I think really need close follow-up. But it is for the right patient it’s a, it’s a good procedure that’s really stood the test of time.