Márcio Augusto Averbeck: Thank you, Professor Wein. And first of all, hello everyone. And today, we're going to discuss some of the topics related to sacral neuromodulation and other non-invasive neuromodulation techniques for patients with neurological diseases. So, the first point to address is whether the neuromodulation would make sense in patients with neurogenic lower urinary tract dysfunction. And if you take a look at the Incontinence book, in the first-line medical treatment for neurogenic DDO, we have the antimuscarinics. However, over the last decade, several papers have been published online linking the usage, the chronic use of anticholinergics to cognitive disorders. So, as you can see here in PubMed, this is somehow trendy nowadays. We can discuss whether there is a causal relationship or there's an association, but there is a link. So, the current trends for patients with neurogenic lower urinary tract dysfunction would include non-invasive techniques, and also invasive techniques such as sacral neuromodulation. And we are going to tackle as well some future directions. So let's start with non-invasive techniques.
We have plenty of options that have been addressed beforehand, but I would like to bring you some evidence on tibial nerve for neurogenic lower urinary tract dysfunction. So, we have this paper, which is a review, showing that in most of the published papers, we have either patients with multiple sclerosis or Parkinson's disease as the major groups that have undergone tibial nerve stimulation. If we look more carefully to the evidences of PTNS, percutaneous tibial nerve stimulation, for Parkinson's disease, we have some trials published, but in fact, with limited number of patients included, lack of comparative studies, and as well as restricted follow-up, so that the level of evidence for patients with neurogenic lower urinary tract dysfunction is not that high. What about sacral neuromodulation? We usually consider sacral neuromodulation for patients with refractory neurogenic DO in some cases. So, if we take a look at the ICI algorithm, we can see very clearly that neuromodulation techniques are listed here. So, with a grade of recommendation B. Something that is important to be emphasized is that botulinum toxin has a high level of evidence to treat a neurogenic DO in this context. However, the long-term compliance with botulinum toxin, according to this real-life study, was only 25%. Among patients with neurological diseases, perhaps a little bit higher, but this is a strong limitation.
So, this is a point in favor of more chronic treatments such as sacral neuromodulation. So, what do the international guidelines recommend? If you take a look at the ICS white paper, we can see that sacral neuromodulation could only be or should be only indicated for patients with neurogenic lower urinary dysfunction whenever the risk for upper urinary tract deterioration is low. This is a take-home message I'd like to bring to you. If we take a look at the AUA/SUFU guidelines that have been published, for the first time in 2021, we have that sacral neuromodulation could be offered for patients with urgency frequency and urgency urinary incontinence. I mean, according to the current ICS terminology published by Gajewski et al in 2017, it would be called as neurogenic overactive bladder. I mean, for patients with partially preserved sensations in the lower urinary tract. However, the AUA/SUFU guidelines do not recommend sacral neuromodulation for patients with spinal cord injury or spina bifida. We have some systematic reviews of the literature addressing the outcomes of SNM in patients of different neurological diseases, such as this one that was initially published in 2010 on European Urology by Kessler et al, showing that the success rate for the test phase, and the success rate for the IPG implant were somehow similar to what we get from patients without neurological diseases.
The overall success rate was 68% for the trial phase, and only 2% for the patients who received the implant. And the conclusion was that SNM may be effective and safe for the patients of neurogenic lower urinary tract dysfunction. There were some obstacles to implement sacral neuromodulation in the clinical practice, and one that should be acknowledged is the lack of compatibility of MRI that has been overcome over the last years of the development with compatible electrodes and IPGs. And the limitations of the available studies somehow reflect what they get from the older studies, in which we had, according to this review, I had a chance to publish with my working group on the International Brazilian Journal of Urology. As you can easily see, the number of included patients were quite low, and we had some evidences showing that the outcomes for patients with spina bifida were not good. Some insights and the evidences of SNM for patients with multiple sclerosis. In the case of increased PVR, most probably the outcomes would be a little bit better for those patients with DSD in comparison to those with neurogenic detrusor underactivity, somehow debatable due to the fact its level of evidence three and four.
But more recently, we had the publication of the first 1B study, randomized controlled study of sacral neuromodulation for neurogenic lower urinary tract dysfunction, which has been published by the group of Balgrist University from Switzerland, which included ultimately 60 patients with neurogenic lower urinary tract dysfunction, very heterogeneous group in which the patients were randomly assigned to an IPG on and an IPG off after the initial implant. And they could have demonstrated that the on group had a successful rate much higher than the off group, which looks like somehow simplistic, but it's the first time that we have such a demonstration of effectiveness in a randomized controlled trial. So the problem here is how to define which patient groups would benefit the most of SNM. So, the future directions, I would like to bring some insights of pudendal nerve stimulation. This is a study published by Peters that does not apply to the context of neurogenic lower urinary tract dysfunction, but these patients with idiopathic dysfunctions, most of these patients did prefer pudendal nerve stimulation. This is still to be confirmed in other trials by other groups, but look somehow interestingly fine. And the tibial nerve, the implantable devices may somehow overcome the inherent limitation of chronic treatment for those patients that required repeat sessions of percutaneous tibial nerve stimulation or transcutaneous stimulation, which is somehow demanding and time-consuming. And we often hear from the patients that they don't want to keep on this treatment without an implantable device.
So for the patients with neurological diseases still to be proven whether the implantable tibial nerve devices could be of benefit. As my take-home message, SNM seems a promising therapy for neurogenic lower urinary tract dysfunction in carefully selected patients with incomplete lesions and a lower risk for upper urinary tract deterioration. Alan, I come back to you for the discussion. Thank you very much for your attention.
Alan Wein: Great, thank you very much, Márcio. So, let me ask you the question about the guidelines that recommend, according to the guideline, a lower risk for upper tract deterioration in selecting these patients. Are the guidelines implying that you should have urodynamics on them and that the storage pressures should be normal? Or are they saying that these patients should have normal upper tracts as judged radiologically and normal kidney function? Tell us exactly what that means.
Márcio Augusto Averbeck: Yes, thanks for this question. You're completely right. I think this is a great point. So, in fact, the guidelines suggest that prior to the indication of these treatments, and this is a clear position by the ICS as well for patients with refractory neurogenic lower urinary tract dysfunction due to the fact it could bring harm to the patient depending on the pressures within the bladder. So, the ICS, the AUA/SUFU, they recommend that we have to perform urodynamics to assess the upper urinary tract risk. So that the patients presenting end-filling pressures above 40 centimeters of water, which is somehow an arbitrary point. But we have to take something as a reference point. So, for patients presenting high-risk findings in urodynamics or upper urinary tract dilatation, then these patients should be considered very carefully. So, this is a way that we could somehow give a try in more challenging situations for the patients, but then we should tailor this more appropriately in case we proceed with a trial phase, and then afterwards, we should follow these patients very closely at the longer-term to assess whether the condition is getting worsening with time or not.
And that is particularly important for patients presenting detrusor sphincter dyssynergia. So that in these patients, we do require treatment that could more rapidly reduce the pressures within the bladder. And we assume that these patients have a degree of neurological disease that is more severe. In these regards, we don't have the pathways which would be required for the SNM to be effective. And we don't have time to wait to check over time whether these patients would benefit off of sacral neuromodulation. If the patients present renal dilatation or an increase of creatinine, the function of the proofs of renal function, then we have to act more rapidly to avoid a chronic damage to the kidney. So, I guess this is the more important point.
Alan Wein: So it sounds like for that type of patient, that Botox would be a more logical solution with the risk of having to self-catheterize. Is that...
Márcio Augusto Averbeck: We can never forget the chances of indicating bladder augmentation, which is also a definitive treatment for these patients. I know that morbidity of such a procedure is somehow to be considered, but nowadays, if the implementation of robotic-assisted bladder augmentation, perhaps this is somehow easy for the patients as well, more easy than it was beforehand.
Alan Wein: So, it sounds like in order for this to be successful, there has to at least be some cerebral connection. In other words, it can't be a complete lesion, which would suggest that some of the activity of the sacral neuromodulation in those patients is really mediated through the brain. In other words, there are changes that occur, and if the sensory patterns are shut off, that that's not going to be a suitable alternative. Is that a reasonable statement?
Márcio Augusto Averbeck: Quite reasonable. And I completely agree with you. It reminds me of the studies that have been carried out by Professor Clare Fowler at the Queen Square in London with young women with chronic urinary retention, which is nowadays somehow called Fowler Syndrome. In which they perform a functional MRI. And then afterwards of these studies, functional MRI that have been carried out both in the United States and also in Europe, particularly by block in which they could have demonstrated that there are some areas within the brain that are more related to the control of the lower urinary tract. So, we can reestablish the connections and the areas which should be working properly in these patients with chronic lower urinary tract dysfunctions. Most of these patients that underwent this proof-of-concept trial of functional MRI did not have relevant neurological diseases, but these studies were key for us to better understand how SNM works in terms of pathophysiology as well.
Alan Wein: Do you think that with the implantable devices that will ever reach the level of efficacy that we get with sacral neuromodulation, or not?
Márcio Augusto Averbeck: I will open my heart, and I'll not be just with an indefinite position. I don't believe that the tibial nerve stimulation is like a panacea, like something that could be big deals for all the patients. And nowadays, there's quite a hype on the usage of these newer implantable devices to the tibial nerve. So, the companies are pushing hard to implement these studies to increase the levels of evidence for this modality of treatment. And I truly believe that the most important thing behind the development of implantable tibial nerve devices is the compliance, the adherence to the treatment, and the maintenance of treatment at the longer-term. As we all know, after the first cycle of treatment with tibial nerve stimulation, if we consider the percutaneous approach, then we have a residual effect, and from time to time, the patient should undergo a maintenance treatment in the long-term.
So that with the implantable devices, this is somehow overcome. This barrier is overcome. So this is important. I guess there is a role, there's room for implantable tibial nerve devices for these patients, particularly the ones with idiopathic OAB and refractory symptoms to the first-line and second-line therapies, but this is still to be proven whether the implantable tibial nerve devices could be of benefit for specific groups of patients, particularly the ones with neurological diseases.
Alan Wein: So, the ideal patient, then for neuromodulation, let's say a patient that has neurologic disease, what type of neurologic disease would represent the ideal candidate for neuromodulation?
Márcio Augusto Averbeck: Oh, this is the one-million-dollar question, huh? I'll share my insights. I don't know if what I'm going to tell you, Alan, today is not going to be changed over the next years, but I truly believe based on the available literature that this is a patient with a stable neurological condition, should not be a progressive condition, should be a patient with a lower risk of upper urinary tract deterioration so that the urodynamics would be important in this setting due to the fact we should check the bladder pressures. And this is not true for most of the patients with idiopathic OAB, for instance, that are candidates for sacral neuromodulation, because several studies showed beforehand that urodynamics do not predict the response to SNM in most cases. So this is something specifically recommended for neurological patients. We should check the bladder pressures, and the bladder pressure should be at a lower condition. So that non-progressive neurological disease, stable condition, lower urinary tract dysfunction in which there is no higher pressures within the bladder, the patient should understand the chronic nature of the stimulation and the need for a trial phase because we have to establish a benchmark.
Without a benchmark, we cannot proceed with the IPG procedure. So this is something that sometimes we hear very frequently from the patients that the patients are not that comfortable or satisfied with the outcomes at the longer term. But when we have a benchmark, and we bring this benchmark for comparison in the longer term, we can see that the benefit may be maintained at the longer term, but the patient should not be seeing SNM as a resolution or something that can solve all their problems at once for forever. So that this is important in terms of the alignment of patient's expectations concerning what we can expect from SNM. And coming to the neurological subgroups, I believe that for a patient that is a walker, most probably with a stable disease, with partial neurological lesion, I could cite multiple sclerosis without any signs of progression over several months. In this regard, it's important to have a clear and open way to have a conversation with the neurologist, the attending neurologist, perhaps as the evidence is a little bit lower, but also for selected patients with Parkinson's disease, somehow could be of interest. Patients with peripheral neuropathy, I can cite some diabetic patients with diabetic bladder or cystopathy, as we called beforehand, with a more stable disease.
Whenever the diabetes is under control, we can have a more stable disease over time, and then I can come to somehow more difficult to establish, but perhaps if a patient had a partial spinal cord lesion and still have bladder problems, bowel problems, it's always important to assess whether the patient is presenting with fecal incontinence because these patients may also present some benefits out of the chronic stimulation of S3 root so that we always should ask the patients whether a bowel dysfunction is present in this context, just to sum up.
Alan Wein: That's a great summary. And listen, we really appreciate your time. Great discussion, great answers to the questions. Hope to see you in person sometime real soon. Take care.
Márcio Augusto Averbeck: Thank you, Professor Wein. Thank you. And for the UroToday, attendees and viewers from all over the world. See you next time. Bye-bye.
Alan Wein: Thanks, Márcio.