Transcript

- Colleagues and friends, thank you for joining us for another session of the Virtual Operating Room from "The Neurosurgical Atlas." My name is Aaron Cohen. Today we're very honored to have with us Dr. Mark Hamilton. He's professor of neurosurgery at University of Calgary at Alberta, Canada. He's also the chair of the Adult Hydrocephalus Clinical Research Network. I've known Mark for a long time, and his contributions to neurosurgery are immense, especially to treatment of hydrocephalus, an extremely challenging disease that unfortunately does not get the attention it deserves. Today, he's gonna talk to us about how we can improve the outcome paradigm for patients with suspected idiopathic normal pressure hydrocephalus. Mark, thank you for being with us, and very much look forward to learning from you. Please go ahead.

- Thank you very much, Aaron, and thank you again for the invitation. It's great to be here and it's a real honor to have the opportunity to share this information. So the title, "Changing the Outcome Paradigm for Patients with Suspected iNPH," the meaning will become evident as we work through this. So I'd like to start off by reminding everybody that not all adult hydrocephalus is iNPH. Some people think that all adult hydrocephalus is... You know, if you're seeing patients with subarachnoid hemorrhage, you get a very narrow view of what adult hydrocephalus encompasses. So this is a pragmatic clinical grouping that the Adult Hydrocephalus Clinical Research Network uses. I started using this back in late 2000, and this was done because it reflects not only some clinical groupings for symptoms, but also risks and treatment choices. So there are four groups: Transitional, those are patients treated as a child, and we all know these types of patients, they tend to have... When their shunts fail, they tend to have more complicated courses. And the asterisk refers to potential role for ETV, endoscopic third ventriculostomy. Now, there's what we refer to as unrecognized congenital, so no treatment as a child. This is a big group. It's got many different names used by people, chronic hydrocephalus, SHYMA, LOVA... I think we've tried to take a very neutral term, and just use that to describe it. Also potentially treatable with ETV. Acquired hydrocephalus, we see subarachnoid hemorrhage, trauma, infection, tumors. Also the potential for ETV may come up. And then, there's idiopathic normal pressure hydrocephalus. Now, one proviso for iNPH is that the age should be greater than 60 years. If you're looking at the international guidelines from 2005, you'll see that they talk about secondary NPH, and that goes down to about age 40. So the approach to that has changed a lot, and we generally consider this disorder to be a disease of the elderly, and there are new international guidelines that are being formulated, there's a group of us doing that, and that will become quite clear in the new set of guidelines. There have been three sets of guidelines in Japan that have also clarified the age issue. So to give you an idea of that and to show you, rather, that these patient populations exist, this is the centers in my network, in the Adult Hydrocephalus Clinical Research Network. There's two in Canada, five in the US and one in Bristol. And these are the four groups I mentioned at the top. So this was just from a couple of months ago, the transition, congenital, acquired and iNPH. And we have approximately 2,300 patients in the network now that have been enrolled, and we're collecting reasonably detailed information on these patients. And you can see that all groups are represented. And we find, having done this, and we've reported on this classification mechanism, and it is very useful and very practical. So a good question then following that is we have these different types of hydrocephalus, what's the incidence, what's the prevalence? Incidence is a difficult term in adult hydrocephalus. Incidence can be demonstrated very clearly in hydrocephalus of the newborn, often because of registries, so you know the denominator and you know the denominator over time. So we did this paper in 2008, and there have been others that have focused on different aspects of this, but the prevalence of hydrocephalus in infants was about 88 per 100,000. IN infants, the incidence was about 81 per 100,000. The information on young adults, the group in between, is just terrible. It's very difficult to get any real information to estimate the prevalence. And the prevalence in the elderly ranges from about 175 to 400 per 100,000. We'll come back and talk a bit about that in a minute. So what is iNPH, where did it start? Well, it started back in 1965 when Salomon Hakim, he's the author in the middle there, Dr. Adams at the front, that was his research thesis and it was a syndrome of hydrocephalus with normal pressure. And people do get hung up on the concept of normal pressure. I think the second line of treatable syndrome is almost more important than the normal pressure aspect of it. So it's often referred to as a triad of clinical symptoms. I think of it more as a tetrad. The difficulty that people have in sorting out the disorder is that these symptoms I'm gonna go through are not specific for iNPH, but we do though when you go through a sorting process, that treatment with the shunt improves outcomes. So a gait disorder and a balance disorder. Now, if you lump those together, you've got one. You can almost think of 'em as separate entities. Dementia or cognitive impairment and urinary frequency and urgency, and then, potentially, incontinence. Now, many people think of incontinence as the thing in the triad, but when you ask and talk to patients, it's actually frequency and urgency that precede all this. There's also been some reports about stool incontinence as well. So now, to look more closely at the iNPH prevalence, and again, eliminating the secondary NPH prevalence, these are the numbers that came out from our systematic review and meta-analysis. And the prevalence increases with age. And there are other studies, and I'll show you one in a minute, that show even higher prevalence levels. And this paper from Jaraj in 2014 suggests that over the age of 80, just under 6% of patients had iNPH. Now, compare that to the prevalence data from the Central Brain Tumor Registry in the United States for this interval: Primary brain tumor, 48 per 100,000, GBM, 9.2 per 100,000. So even lowballing it, iNPH is a common disorder. The assessment and management of iNPH is underrepresented in our neurosurgical centers. So this is probably the most interesting of the studies that I've seen. This was a sample in Sweden where they went in and they randomly selected residents of a community over the age of 65, and the prevalence of iNPH was four times higher among those 80 years and older, it was almost 9%, then among those 65 to 79, 2.1%. The 2.1%, that's an important number to think about. Now, they use 65 because the age of 60 is just in the process of being made consistent across multiple locations, so the range 65 and above has been used by others, in case that adds a little element of confusion. Now, what happened with iNPH was, and this is a slide that I borrowed from Michael Williams, a neurologist who's in Seattle, there was this initial exuberance, and it really was irrational. People were shunting everybody who had any of these symptoms and the result was a catastrophe. There was a lot of complications, poor results and that generated skepticism. And the skepticism, to this day, still exists, and it's a significant impediment to treatment. Now, summarizing all of that skepticism was this meta-analysis that was done in 2001 by Hebb and Cusimano, and they're basically giving you a snapshot of how bad things were prior to that. So there were only 59% of patients who improved, and look at the range, 24% to 100%, 29% experienced prolonged improvement, again, incredible variability, and 38% had complications. So what's happened since is that there's been research and, I think, a renaissance, in terms of the approach to idiopathic normal pressure hydrocephalus. This can be reflected in a simple metric, you look at the number of publications for iNPH going back to 1965 when it was first reported, and in 2022 there were 263 papers published. There are some things we're not gonna cover about iNPH, but there are also new things that are happening in terms of trying to understand the etiology of iNPH. The purpose of this talk is to discuss the barriers that prevent people from considering iNPH as a real diagnosis, and I think this is important, because I think it limits access to what is a good therapeutic option. So I've put this into three concerns, and you may not feel that all of these are relevant, but some of them may be relevant, but these are the things that I encounter when I talk to people: The selection process to diagnose patients is poor, treatment risks are high and treatment outcomes are poor. And so I'm gonna go through and address each one of these. So if you have a feeling that there's no good way to diagnose iNPH, let me show you how you start. You have to have a differential diagnosis, that's not foreign to any of us. Ventriculomegaly is not specific to iNPH. Gait, balance, cognitive and bladder issues are not specific to iNPH. So manage the differential diagnosis, but don't forget about iNPH. The radiology is very non-specific. We often talk about the Evans index more as a way to define big ventricles. It's not predictive of a therapeutic response. Disproportionately enlarged subarachnoid hydrocephalus, or DESH, has been reported for a number of years and is used by people as a significant criteria for treatment. Unfortunately, there are numerous studies that show that it is both non-specific and not as sensitive as people think. A decrease in the callosal angle has been reported. I'll show you one issue with the callosal angle, when people do it, that's really relevant. It has to be done in a very specific way. So these and many others are all non-specific. I'd like to point out the Radscale. I'm not gonna go into it in detail. This was proposed a number of years ago in Sweden, and it's trying to combine a number of these radiographic variables. It improves the specificity, but still, it's not as reliable as some of the physiologic tests I'm gonna talk about. This is an example of DESH. So this is somebody with big ventricles. You can see in the center of the axial image, in T1, you see the sylvian fissures are enlarged, there are blebs up high, and so this is a very typical appearance that was often called atrophy, prior to recognizing it as a syndrome. You can see the steep callosal angle in this patient. Now, with the callosal angle, it has to be measured in a certain way, so if you're not using the way that illustrated in this figure, then you're gonna be getting incorrect values. And so it has to be standardized across studies. So we have this patient tetrad, so how do we sort this out? We've ruled out the other things, radiology doesn't tell us a definitive answer. So these are the recommendations from the 2005 guidelines, and Tony Marmarou and others worked on this quite a number of years ago, obviously, it was funny, it was published in 2005. You look on the left, you have degree of certainty of improvement. So if you start over here with clinical exam and imaging, your chances of success, if you treat somebody with a shunt, is terrible. It's about less than 50%. If you go on and you do a large-volume tap, so you remove CSF, and I refer to that as a physiologic test, that improves the specificity quite a bit. And this should actually refer to specificity. So some people fail a lumbar puncture, and will go on to have a drainage procedure and they'll improve with the drainage procedure. So as you go along and you end up down here with lumbar drain, external lumbar drain procedures, the specificity improves quite dramatically and the sensitivity. So you're picking patients who are gonna respond to a shunt. And I think, back then, it was like 80%. We're actually doing even better than that, I think, now. The CSF dynamics tests, you'll see that a lot in Europe. It's done very in frequently in North America, and I'm not gonna cover it this time, but it's a very interesting approach, and some of these are done in complement. So CSF dynamic tests are often done with a large-volume tap. But basically, the summary here is without using some other assessment measures, you might as well flip a coin, in terms of picking patients for surgery. So when I decided to approach this in a systematic way, I decided to be pragmatic. If I was gonna do these tests and patients improved with the tests, then I would offer them a shunt, as long as they didn't have a contraindication. So if you're gonna do these tests, what are you gonna measure around these tests? So what, how and when? So this is not what I expect people to be doing, I'm gonna show you what the minimum is, but this is what we do in our clinic. So a 10-meter gait velocity in a standardized fashion. We have a video library. We count the steps for a 10-meter walk, we count the steps for a 180-degree turn, and that's the gait. For cognition, we use a MoCA. Many people use an MMSE. It is not as sensitive for the subcortical frontal issues associated with hydrocephalus, and most centers have are switching to MoCA, Montreal Cognitive Assessment. We've added the symbol digit modalities test. We do BDI-II, a depression inventory, 'cause that can skew the MoCA or SDMT. We look at the Lawton Activities of Daily Living, and we do a OAB-Q short form, which is a bladder questionnaire. Since I started this, we've also added a Timed Up and Go, quality of life evaluation, Frailty Scale, Tinetti balance and gait scale. The Tinetti balance and gait scale is a very interesting tool to apply and to look at, 'cause it makes you think of balance as almost being separate from gait, but it really makes you focus on the balance issue. And you have to use standardized methods. It's not complicated to do that, but you still have to be standardized. So this is the minimum I think people need to do: A 10-meter gait velocity, and I'll show you how the reliability of gait velocity is a predictor of shunt response in a few minutes. We count the steps and we count the steps to turn. The Timed Up and Go is a nice thing to add. It helps with people who are more impaired, because they need to be able to do that, and it shows them getting up out of a chair and walking three meters and then back. If they can't walk 10 meters, you may miss some improvements. And then for cognition, at least the MoCA. This is a very useful test, and there are standardized ways to do the MoCA and you have to vary the MoCA. There are a number of different versions. It's available in many, many languages. So now I'm gonna show you what to expect from a lumbar puncture, large-volume tap or a lumbar drain for these patients. Now, we looked at this a couple of years ago, and we're just updating it to do a more in-depth evaluation. This is almost 300 patient, and you see the age, about 77, and you see this skew towards male patients. I don't understand exactly why that is, but that is very commonly reported in registries and in other clinical studies. Now, just a summary, you can see that we did LPs in 91. Our clinic, if you have a negative LP, we offer you an ELD. If you have a positive LP, we offer you a shunt. Again, we've already sorted out, hopefully, that there are no contraindications for a surgery option before we do these. You can see that of the people who had a negative lumbar puncture, 33, almost three quarters, had a negative follow-up EVD, and about 20% went on to a shunt. So for the ELDs, 104 were negative, so just about half, and I'll show you what this means when they're negative in just a minute. So you see the value in doing this. Now, I can't tell you that I have information on what would happen if I had offered to shunt these 104 patients. Would some of them have responded? Perhaps, but this is the best we can do at this time to sort out and offer patients an operation, giving them a reasonably high predictive score for getting better with the shunt. So here's some values for pre- and post-LP drains. So these are the patients that were positive. You can see that we don't do cognitive assessments after a large-volume tap, we do them after the ELD. So the pre-LP, post-LP, you see that the positive ones, the gait velocity improved, improved in the positive lumbar punctures. MoCA changed a bit in the ELDs, SDMT increased a bit. And we don't have time to go into a a deep talk about reliable change, but the range of MoCA, the amount that it has to increase, varies in the literature from 1.6 to 4.0 as what's required as an increase to be representative of a reliable change, and some of that's dependent on age. So if you use 1.6 or 2.0, which is commonly used, then that would suggest that MoCA improved. So the negative lumbar punctures, you can see gait velocity did not improve, in fact, in many of them, it actually worsens, and the same with the LPs. The one thing you can see here is that the LP patients have a better gait velocity to start with and that is some of the selection bias in doing ELDs. If it doesn't look like we're going to be able to get an improvement with lumbar puncture, we start with an ELD. You see MoCA did not improve, it often worsened, and the same with SDMT. Again, for lumbar punctures, we did not do the cognitive test afterwards. It's generally felt to be too soon to do that kind of reassessment. So then how do we select patients for the shunt? Again, being pragmatic, let's show you what happens when we do these tests, and this is the Calgary experience again. For 164 patients who had a shunt, I've done a non-statistically correct merge of ELD and LP gait velocities, but if you do have somewhere around 0.64, post-LP, it increases to 0.84, post-ELD to 0.88, and with the shunt, it increases to about 1.05 meters per second after shunt. And this can continue on even further. MoCA, again, 21 up to 24 after shunt, SDMT, 20 up to 25 after shunt. So this is... Again, it's one center, it's my center, but it shows you if you do a systematic approach, you can detect changes and select patients who will respond for shunting, so there is a way to diagnose patients. So the second concern is the treatment risks are high. So treatment risks, the only treatment for iNPH at this time is a shunt. Every time one talks about a shunt, this is the thing that strikes us, what's the risk of shunt failure? What are the challenges with shunt failure? Well, it's often perceived as a simple operation. We all know this in our groups. Not a lot has changed in the basics, and if you don't change a lot in the basics and you think of it as a simple operation when it's not really a simple operation, you end up with challenges. So to illustrate that, let me show you this result from Joe Piatt in 2020. Now, he used data from 2015 from the Nationwide Readmissions Database, and this shows you the shunt failure rates. If you look down at the bottom, in days, that's about, you know, barely a little bit more than a year, the shunt failure rates for children, elders, adults and infants out in the entire community of neurosurgical patients is really quite poor. We need to do better, and I think we can do better by approaching this operation in a systematic fashion, and I'm gonna give you a very brief overview of what we do, and hopefully, in other rounds, we can talk about the specifics in more detail. So the issues of shunt failure that I've addressed, or tried to address, are infection, ventricular catheter issues, peritoneal catheter issues and shunt over-drainage. Now, we've published data on this already, a standardized infection prevention bundle for reduction of infections. We should all be familiar with these bundles, they're used in ICUs, they're used in a lot of different surgical specialties and medical specialties. So our bundle involved a number of simple things in the OR, the type of prep, handling of the shunt. And we had data on our shunt infection rate before this. I naively thought that we had a low-end shunt infection rate, but the infection rate was about 6%. We implemented the infection prevention protocol, and it would drop down to about 4%, and then, we changed our skin prep to chlorhexidine with alcohol and started patient to preoperative scrubs, and it dropped down to zero. Now, zero for infection rates always raises questions. Our infections were defined by the Infection Prevention Control Committee, so it wasn't our group, or myself as a surgeon, defining an infection, an independent group did this, and these were all consecutive patients. So when this was last evaluated in 2021, there had been 379 consecutive surgeries with no infections. There have been now about 450 to 500 procedures with one infection. I think it's naive to think that we can eliminate infection, but we can do a lot to reduce it. And this is done without antibiotic-impregnated catheters. This is just trying to focus on technique. So that was a quality improvement protocol. I did another quality improvement protocol looking at how to improve proximal and distal shunt failure. So we did this by using frameless image guidance for selecting the shunt insertion location and passage of the shunt catheter, and using a laparoscopic approach to place the catheter through the falciform ligament, behind the liver, to keep it away from the omentum, which, I think, is a significant cause of shunt obstruction. This shows you our shunt failure rates over time. You can see that we are hovering around 58%, very similar to the graph that came from Joe Piatt's paper. By implementing these protocols, including infection reduction, the number of failures, number of revisions that I've had to do has dropped dramatically. I was at a point in my practice where I was doing more revisions than insertions, and now I do very few revisions in each quarter. So again, focusing on technique, and we'll hopefully have an opportunity to discuss that in more detail. So shunt failure rates can be low if we pay attention to these issues. And the last thing, what might concern you, is that treatment outcomes are poor. "Oh, yeah, so we shunt somebody, but you know, they're not gonna do very well, it doesn't last." These are the arguments that come forward. Well, I think one needs to put things in perspective. Without treatment, the mortality and morbidity rates for iNPH are very high. And as we're going through this, I want you to think about how aggressive we are with patients with glioblastoma multiforme, and that's another part of my practice. I think you lose context, unless you start thinking about what we can do with this disorder and what we already do with another disorder that has potential lethality. Let's look at what happens if the elderly fall. Now, one in three adults over the age of 50 who have a hip hip fracture will die. So 33% of elders, within 12 months, are dead after a hip fracture. I think if balance and falls are a thing with iNPH, that should make you stop and think. This is an interesting paper that came out of a group in Gothenburg, Sweden, and they a large consecutive series, including a small group of untreated patients. When they looked at the five-year mortality in that small group of untreated patients, the hazard ratio for death was almost four. The hazard rate for developing dementia was almost three. Untreated, this is a very bad disorder. During COVID, I had the unpleasant experience of watching patients decline, fall, a number of them had limb fractures, their cognitive scores deteriorated, so I think as we leave these patients untreated, they succumb to the disorder, and some of that damage becomes irreversible. To show you beyond my, you know, single-center reporting, this is from the Adult Hydrocephalus Clinical Research Network, and this is looking at iNPH. And this will show you the the flow, or the process, that we did, and it sort of pulls what we've been talking about into perspective. So if you're coming to a clinic, you tend to start by seeing a fair number of patients. You have to sort out who might have iNPH, might have other types of hydrocephalus, and so we start here... In this registry, we've sorted out there are 581 patients with suspected iNPH. Now, in some patients, you can rule out iNPH very clearly, it's, you know, clear that this is not iNPH, it's Alzheimer's or something else, could be spinal stenosis, and then you get this group of possible iNPH. The 23 on the far left, that's a group that had shunting that was done using some of the other criteria, such as DESH, often when access to CSF drainage was limited. But if we go to the CSF possible group, some of 'em will have CSF drainage, some of them won't, and we might think they have iNPH, but perhaps, they're too good. And if you look further at the group that has CSF drainage, we see that after CSF drainage, just under 50% end up going on to a shunt. And you know, we are following these patients long-term, and over time, we'll have them followed... We'll get more and more long-term follow-up information on them. So this sort of reinforces the approach that I went through, and these are the results. So these are two really, I think, important graphs. So if you look at the one on the left, you look at the access velocity meters per second, now, you can consider one meter per second the lower limit of normal gait velocity in the elderly. You can see, if you look at the bottom axis, you see baseline, pre-CSF drainage, post-CSF drainage, and then zero to four months, four to eight months, eight to 12 months. So basically, between post-CSF drainage and zero to four months, they've been shunted. So their baseline, before they come in for their full assessment, they actually decline. After their baseline assessment, they improve, these are the ones that are gonna go onto a shunt. After they're shunted, they continue to improve. So if we do the amount of change in individuals, we can see that about 80% of that group, in this graph on the right, will have greater than one meter per second improvement, and about 65% will have greater than 0.2 meters per second improvement. These are significant clinical changes, and this doesn't account for all the other things, such as the changes in balance. So I think this reinforces the relevance of gait velocity and the utility of gait velocity as part of the screening process to help select patients for shunt surgery. And in our group complications, we're low. So are the risks of treatment high? No. There was one infection with an ELD. 91% of the patients had no complications, 5.7% had what we called serious complications, and a number of these were actually catheter complications that went away when that site changed using laparoscopic insertion. We also had four deaths in one year. If you look at this age group, that's no different from expected all-cause mortality. So not a high-risk procedure if you select patients properly, and the results, I think we've demonstrated, are good. So in summary, for this part, if you're testing with CSF drainage and you're selecting patients properly, shunt surgery has a high rate of sustained improvement and a low rate of complications. And I think the message to drive home is that the evaluation and treatment of iNPH patients has better outcomes and is safer than many think it is. So again, this is the local data, but reinforcing the fact that, if you go through this process, you will see that there is very high positive predictive values. There's multiple studies that have shown this. We are searching for the non-invasive biomarker, we don't have it at this time. This is the best approach we have at this time. I think that non-invasive biomarkers exist and we will find them in the future, but for right now, we need to offer treatment to patients who have this disorder. And again, to mention that we currently lack reliable negative predictive values. I don't know for sure that all those patients I don't offer a shunt to would not have improved if I offered them a shunt, but the best evidence we have suggests that they don't improve if we offer them a shunt. What are the expected outcomes? All iNPH symptoms can improve, gait, urinary symptoms, incontinence and cognitive symptoms. The perception is that only gait improves in many areas of the community, neurologic and neurosurgical. That is incorrect. You know, I've shown you the data. All of these can improve. This is one of the few types of dementia where there is a treatment for it, and I think that needs to be driven home. The ultimate degree of improvement depends on the contribution of other disorders and the severity of the brain injury associated with hydrocephalus. Hydrocephalus is not a benign entity, whether it's acute or chronic. Damage is occurring, whatever the underlying pathophysiology is, untreated damage becomes permanent and patients reach a point where treatment is not something that will help them. This is a different way to look at it. Also a study that came out of Gothenburg, Sweden, and this was to look at the economics of shunt treatment. So using shunt as a standard treatment in iNPH resulted in a gain of 2.2 life years and 1.7 quality-adjusted life years, with an incremental cost of about 7,500 euros per QALY. There have been other papers looking, in the United States, the Medicare population, at the economics of treatment versus non-treatment. Further data is needed in this area, but this kind of early information suggests that we can eventually find information, do the studies to evaluate this, to prove this. As I'm wrapping up here, I just want to talk about two important studies, and it's basically one study that's gone on to a multi-center, randomized clinical trial that's sponsored by the NIH, PENS and PENS 2 We have already published this pilot study, which was PENS, placebo-controlled effectiveness of idiopathic normal pressure hydrocephalus shunting. So PENS is the acronym. These patients were randomized, the procedure was done in all patients, but some of the patients were randomized to being in an off-position for their valve, virtual off or on. Now, this was using the Integra CERTAS Plus Valve. It's not a study to say that that's the valve we have to use. It was used because it had that feature. This is the flow through this. We had normal processes to select patients, then randomized the offsetting, it was off for four months, and it's not actually 100% off, but really, there's not a lot of CSF flow, and active for four months. And then, we did a mock change, so everybody was open, but neither group knew whether they were previously open. They just knew that, at that time, they all were open, and then we did further evaluations. So we were able to provide blinding to the patients and to the assessors. The only people that knew what the shunt setting was were the neurosurgeons. This is a summary of gait velocity. A small group, so the standard deviations are not insignificant, but the changes were just under the significance level. And if you see here, when all the patients were in placebo, the first group and the open group and the closed group... Sorry, if you look at this as the first interval, the first four months, the control group is blue, and they don't change in their gait velocity. The treatment group, the open group, is the red group, and they do change in their gait velocity. And then, when all are active, the open group continues to improve and the closed group improves actually at a faster rate. And some of this may be because, in these first three months, people are recovering from their surgery, so the rate of improvement here is more reflective of the treatment of just the hydrocephalus, rather than recovering from surgery. But you can see that we are able to create a negative improvement effect by using the closed valve, the setting of 8 on the CERTAS Plus. So PENS 2 is underway. It's got a lot more comprehensive assessments. We're trying to find biomarkers. We're doing CSF analysis, comprehensive neuropsychology, very comprehensive 3T exams, and we've already started looking at trying to do long-term follow-up in this patient population. We have 20 centers that are involved in this trial sponsored by the NIH, and we are approaching about 20% enrollment in this trial. One of the things that the pilot showed us is that we could also do this safely. We did not have a significant increase in falls. We had a data safety monitoring board for the first trial, and of course, we have it this one currently underway. The process is almost identical, except we dropped the time that the valves are different to three months. We discussed this in detail, and decided that the extra month really didn't matter. The first three months was what mattered, based on other clinical practice reports. Now, this I'm gonna show you is the last thing. It's a video, and it's the assessment of a patient with suspected idiopathic normal pressure hydrocephalus, and this video was previously shown in a Human's chapter.

- [Clinician] This video looks at the assessment of a patient with suspected idiopathic normal pressure hydrocephalus. The patient is a 75-year-old male, previously healthy, with two years of progressively worsening gait, short-term memory and bladder incontinence. On his physical examination, assessments of his gait were done with a Timed Up and Go, which was 17 seconds. He walked 10 meters requiring 20 steps in 10 seconds, for a gait velocity of one meter per second, although his gait was unstable. It took five steps for turning 180 degrees, and he had a mild wide-based, low-steppage gait. Assessment of his cognitive function demonstrated a Montreal Cognitive Assessment score of 19 out of 30, SDMT or symbol digit modalities test was 28 out of 110 and the Lawton ADL was zero. Imaging done four years previously demonstrated no ventriculomegaly. His current MRI scan demonstrated ventriculomegaly with an Evans index of 0.41 and a DESH pattern. This following video will give a review of his baseline and then post-lumbar drainage gait. This is his baseline gait assessment prior to the external lumbar drain. It's slightly wide-based, slow, at the upper end of normal, and he took multiple steps to turn. This is his gait assessment 72 hours after the start of his external lumbar drain. His gait is faster and he took fewer steps to turn. He's more steady and the gait is less wide-based. A summary of his testing showed his MoCA improved from 19 to 23, his SDMT improved from 28 to 33. His gait velocity increased from 1 to 1.1 meters per second. He required only three steps to turn, rather than five. His TUG test improved minimally. Because of these overall changes, the patient was offered surgery with the insertion of a VP shunt which was successfully completed. This CT scan shows his placement of the catheter, which was felt to be in good position. This is his post-op lumbar abdominal x-ray, showing the placement of the peritoneal catheter. In this case, the catheter is placed in the space behind the liver, with the tip located in the right paracolic gutter. Postoperatively, about three months later, this is his gait assessment. The video shows a significant increase in velocity, further decrease in the number of steps for a turn and a much more balanced gait. His overall assessment at three months post-VP shunt insertion showed that his MoCA had increased to 25, his SDMT had increased to 28. His gait velocity improved from one meter per second to two meters per second, the steps required to turn dropped from five to two and his TUG test improved from 15 to 12 seconds. Overall, a significant change, and significantly better than even his post-lumbar drain assessment.

- Thank you.

- Really appreciate it, Mark. Well done. Enjoyed the lecture, important topic. Something I wanted to emphasize that you very well mentioned is really the underdiagnosis that goes on in iNPH. I think there are many patients that unfortunately may, by now, not be with us anymore, who could have significantly benefited from a shunt, and they were diagnosed because of getting old, and grandma or grandpa is too old and it's just aging, or the family doctor really didn't recognize, you know, the diagnosis and the patients never had a chance to be better. You know, the pendulum swings. You know, initially we treated too many of them, and suddenly, we overreacted, and now we are very careful about how we treat, and end up leaving a lot of people underdiagnosed. And it's just... It's the sensitivity of our diagnosis, essentially. Are we gonna diagnose people correctly, overdiagnose, underdiagnose? And I think that's something very important. So we gotta keep that in mind, and make sure the referring doctors are also well-educated. The other item is that, really, the indication for shunt. I know patients who have done an LP high-volume tap, and for places that don't have the expertise, and really, the many tests that you discussed today that are so important, for me, for example, that don't have the facilities like you have and the tests, I usually do a lumbar puncture high-volume tap. We remove 35 cc. If the patient has a good response and a favorable response, we'll go with the shunt. However, there are patients that I know, they look so classic, we do the lumbar puncture, they really don't get better, but you know, if you do the shunt, probably, with continuous drainage, they're gonna get better, and they would need a shunt. And I've had a few cases, at least, where I've said, "You know what, the lumbar puncture didn't show a great response and I can't guarantee the shunt will do well, but if you really wanna do it, because your symptoms are so classic, are you willing to consider it?" And we did the shunt and they really got a lot better. So even CSF drainage is not a perfect test, so what do we do in those cases?

- So one of the things that I was trying to illustrate here is that large-volume tap is good for picking people who will respond to a shunt, but it misses people who could respond to a shunt.

- Right.

- I think, by the time you get to lumbar drain, and I've had the opportunity to do a lot of these, we do about 100 lumbar drains a year in our institution, and you see that group that go on to the lumbar drain, about a third of them, a quarter of 'em to a third of them, respond to the lumbar drain. So it demonstrates the lack of sensitivity of a large-volume tap. So I think that ruling people out with a large-volume tap is not necessarily the right choice. But it's a struggle, 'cause lots can't do lumbar drains. If you combine that with a DESH pattern, combine that with a very classic clinical syndrome, you're probably gonna do better than that 50% number I talked about. But it is a challenge. And I, certainly in the past, I used to take the approach where... I did it all the time before 2008. If the patients looked like they might have iNPH, the ventricles are big, I didn't do anything more than just say, "Let us be reasonable, let's take a shunt, but there's a 50-50 chance it'll work." And that ends up being not very gratifying after a while. And then you chase the shunt. Is the shunt working? Is it the patient... So I think that there is this minimum set of things you can do, a lumbar puncture, just video their gait. Anybody can start by to Best Buy, you buy a video camera, you can start doing a lot. And that's what we started. We have a massive video library now. It also gives you a reference point to go back to see how people did earlier, gives you a reference when people come back and they say, "I don't think my shunt's working." You have measurements you can use. So the minimum, I think, is what I described as a 10-meter gait, maybe a TUG and a MoCA. And if all you can do is the gait, then, you know, that's still relevant.

- Yeah. What do you tell people when they get a shunt, we know this is unfortunately a progressive disease, how long the shunt will be effective and when sort of the shunt effect could potentially wear away?

- So that's a really important question. And that was one of the things that, even in Cusimano's systematic review, they had a small fraction of people with long-term effects. So there is some good literature on patients that suggests that, or that shows, not just suggest, shows that if you have working shunts in these people, they can continue to experience the benefits of treatment of their iNPH. And I have patients who I've treated, you know, 10, 11 years ago, who are still going along. However, we all have to remember that the average age of the patients, when you put a shunt in them, the average age is like 78. It's not uncommon to see people in their eighties, so other things creep in. We know that neurodegenerative diseases, Alzheimer's, frontotemporal dementia, all of those things can coexist. But I think to deprive somebody of an opportunity to have... I think they have a better quality of life. There's more information coming out about that. We have to prove that. I think they do have a better quality of life. They don't fall. I've had, you know, a lot of families, a lot of patients, you know, are very thankful that... You know, they often talk about getting their life back. I think we not only undertreat people, we had to recognize this, I think we are still treating people too late. I think we could do a lot better if we get people earlier. And I think we get people earlier, there's less damage, it'll get even longer effects. So all those things together... I mean, knowing that somebody... I have nothing against glioblastoma, but I use it as a frame of reference. We know that we do surgery on glioblastoma patients, they may not get a long term out of that. They may get, you know, nine months, 14 months, 20 months. But we still do it. And I think these patients deserve that kind of treatment approach, because we can give them quality for the short-term, and I think, for the long-term.

- Very well said. I've always said the shunt is one of the absolute most life-saving procedures in neurosurgery, absolutely. At times I think it's the most, to be honest with you, because you really can do magic. You have some incredibly thankful patients and you really gotta pay attention. I think, in neurosurgery, we get so enamored by skull-based surgery, vascular, complex spine, and we all feel like, "Okay, we're doing these operations and we're doing magic." And sometimes that magic is really in that shunt that really brings these people a new life, a new chance at life. Many years of incredible productivity and thankfulness. And just a thankful patient who comes to you after shunt and they feel like you are, you know, Jesus, and you really are saving their family and their lives forever. That feeling is unreplaceable. That feeling is incredibly amazing. And really, that is our duty as a neurosurgeon, to improve the care of our patients, no matter what procedure. So with that, I wanna thank you, Mark. A tremendous contribution to neurosurgery. I've been a huge fan of yours for many years, you know that, for what you have done for hydrocephalus and neurosurgery, many of us commend you as well-deserved, and look forward to seeing you with us for another session soon, as I hear. So thank you, God bless and see you soon.

- Thank you very much.

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