Okay. Next up, I'd like to ask Dr. Ludwig Zunzow to come and give us his experience. Dr. Zunzow is a nurse surgeon at Queen's Square in London and also splits his time in Malta when it's too rainy in London. And he's going to be talking to us about the nurse surgery for OCD, stimulation versus ablation. Okay. So, as that loads up, thank you very much for inviting me to speak over here. The first thing to clarify is there's never been any head-to-head study of stimulation or ablation in terms of neurosurgery for OCD. So, what I'm going to talk about today is really a composite of our own personal experience at Queen's Square with both methods as well as what's recorded by the literature. I think we have to acknowledge that OCD is one of the highest global burdens of psychiatric disability, a lot of which is hidden because patients who are refractory to what's currently available for psychiatric management in terms of SSRIs and cognitive behavioral therapy, these patients often drop off the radar and they end up at home leading rather desperate lives that affect both them and the family around them. And the tragedy of this is that you have unwanted thoughts, desires, or images that cause repetitive behaviors that tend to reduce the anxiety driven by these obsessions. And a large proportion of patients remain significantly impaired. So, we have ample evidence that OCD is a disorder of networks, neural networks, just as movement disorders are. And there's even imaging studies that show that cognitive behavioral therapy that results in improvement in OCD symptoms results in a change or normalization of abnormal function in functional imaging prior to the therapy being instituted. So, this is a fairly good biomarker that neural circuits are involved and can be modulated in various ways, whether it's pharmacological, behavioral, and perhaps even surgical. So, if we run through the list of deep brain stimulation targets that have been used and ablation targets that have been used over the years, on the ablation side, the main targets are those of singulotomy and capsulotomy and a combination of the two, which is subchordate tractotomy. And on the DBS side, we have the ventral capsule, the inferior thalamic peduncle, and the anteromedial subthalamic nucleus. And to add into that, there's also the medial forebrain bundle that Volker will speak to us later about. So, two targets have most evidence for DBS and OCD, and those are the ones I'm going to be concentrating on. And those are the ventral capsule, the anterior limb of the internal capsule, and the anteromedial subthalamic nucleus. And this is a very nice review paper that, if you want to have a look at, Clement Hamani published a few years ago. And if we look at the anteromedial STN, this is a target that really came from an observation that there were a number of Parkinson's patients who had comorbid OCD, where their symptomatology of both their Parkinsonian syndrome symptoms and their OCD improved after DBS. And this is a randomized control trial that was performed in a multi-center fashion in France. And 16 patients were randomized into a crossover study. And what we're seeing was that there was a significant difference between on and off stimulation when you looked at the Y-box score, which is a measure of the severity of OCD. However, the cutoff value for what was termed as a response was used as 25 percent instead of 35 percent, making this rather difficult to look at in terms of comparing to other studies. And sadly, to date, there's been no long-term data published. So although this has been shown to be an effective target in a randomized crossover study, we don't know what the long-term response is. Now, I've been told that the long-term data is good, but until we see that in the literature, that's one of the negative aspects. And this is a study published back in 2008. Moving on to the ventral capsule, there's a lot more patients that have been published with deep brain stimulation of the anterior limb of the internal capsule. And this is one of the larger studies. This is a paper where 16 patients enrolled, but only 14 randomized, with a significant difference between being on and off stimulation. The only difference in the design being that all patients were turned on for the initial phase of the study, lasting quite a number of months. And then were randomly switched off without being informed that they were being switched off. So there is the possibility that patients could feel that they were being stimulated and feel the difference when they were switched off, making the fact that there may be a placebo effect built into this. Interestingly, the paper was termed stimulation of the nucleus accumbens, but when a subsequent paper was published, it was quite clear that the active contact was actually in the ventral capsule. And this seems to be one of those papers where the authors were trying to make the data fit into their theory of what is driving OCD, rather than looking at the actual data. The biggest drawback was this, is that there's a very large current drain to get a significant clinical effect. However, this has been replicated by other groups, and this is Barton et al.'s group looking at, and their targets actually evolved from the ventral capsule to further anteriorly close to the bed nucleus of the anterior terminalis, which is actually very close adjacent to the anterior capsule. And what they noticed was, again, a very significant difference between on and off stimulation, but again, a very high voltage required to get that clinical effect. The other interesting thing that was noticed is that there was a significant improvement, not only in the Y-box scores, but in the depression scores, which is a significant comorbidity in these patients that has an impact on quality of life. For this target, we have several long-term outcome studies with fairly large numbers, so 26 patients, or large-ish numbers for mental health disorders, running up to 31 months, going into a follow-up of 12 months, and more studies here looking at two years, larger numbers of patients, 16 patients, 18 out of 24 patients, with significant improvement in quality in Y-box scores, with roughly two-thirds of patients getting meaningful improvement from stimulation. I just put this slide up as a courtesy for Volker, because he'll be talking to us about medial four-day bundle DBS for depression in the next talk, but he has also reported its successful use in a limited number of patients for OCD. Importantly, we know that cognitive behavioral therapy can enhance the effects of deep brain stimulation, and therefore deep brain stimulation is required, but if you apply DBS and then subsequently perform cognitive behavioral therapy in patients who sometimes could not engage with cognitive behavioral therapy because of the severity of their symptoms before, it provides a synergistic effect. And this is also true for the ablative literature, when you look at the ablative literature. So just to summarize what we know about deep brain stimulation for OCD, we have level one evidence that supports the use of bilateral anteromedial STN, DBS, and OCD, but unfortunately there is no long-term data yet. We have level two evidence that supports bilateral ventral capsule DBS and OCD, and we have long-term follow-up, but there is a requirement for very high energy needs, and a rechargeable IPG is definitely suggested for these. There is a suggestion that ventral capsule may be superior to the anteromedial STN, not in a blinded fashion so far because these are all open-label studies, but suggesting that the improvement in Y-box is more significant with the ventral capsule and the additional benefit in terms of improvement in mood may be a useful thing. And there's very little evidence in favor of DBS of other targets, which are limited to case reports. So with this knowledge in mind, I'd just like to share a bit of data for a randomized controlled trial study that we performed in Queen Square in London. This manuscript is under review. And what we did is recruited six patients and implanted four electrodes, two in the anteromedial STN and two in the ventral capsule, to compare the effects of the stimulation of these two targets with a crossover design. Now these were the worst of the worst patients in the U.K. All of them had extreme OCD with more than 32 on their Y-box score. And what we saw in terms of results was quite remarkable, actually. From the baseline in the extreme range, both targets gave a very significant improvement in the Y-box scores, although no significant difference between the two targets. But a combination of the two targets and then after CBT meant that the Y-box really went into single figures, from a score of over 30 to a score, a mean score of under 10 for the group. Interestingly, when we looked at the depression scores, we found that there was a significant improvement in depression with the capsule, but no significant improvements with the anteromedial STN. So this really confirms what has been shown in the open-label papers. And what I'd like to point out here is that looking at the capsule, we had five out of six responders, which is defined as a more than 35 percent reduction in the Y-box, and a 58 percent improvement in the depression score compared to a 25 percent improvement with STN. So the ventral capsule, both targets are efficient, but the ventral capsule seems more potent. And it's not just symptomatology, it's also quality of life. And if we look at the GAF score for these patients, going from baseline to the prolonged score after CBT, we've gone from a level of a seriously impaired function to really mild symptoms, mild impairment. So that we didn't have any adverse surgical effects, we realized, again, that a large voltage was required for the ventral capsule, and that only a small amount of voltage was required with the anteromedial STN. So to summarize this very small study of six patients, we've learned that both targets are effective in reducing OCD symptoms, but that the ventral capsule is more effective and also helps lift mood. This was accompanied by significant and meaningful improvement in quality of life. Cognitive behavioral therapy is really quite important in maximizing the outcome. You do require high stimulation per act as the VC target. But during this trial, we realized that DBS is an extremely laborious and lifelong therapy, much more engaging than movement disorders. These people have a lot of comorbidities, and they think that every other comorbidity, whether it's their depression, whether it's whatever they go through in life, and if you've had OCD for 20 years, you don't just return to a normal life, they think that DBS can sort it out. So they're always back at your clinic asking for adjustments. And it requires very close follow-up. So I'd like to summarize very quickly the stereotactic ablation for OCD, and I'm going to limit this to singulotomy and capsulotomy. And this is an excellent paper by Samir on the panel here, who really looked at singulotomy and capsulotomy studies where YBOX was well-recorded. And to summarize the paper in a few words, it was suggested that the efficacy of capsulotomy is probably better than the efficacy of singulotomy, but probably the side effects of capsulotomy were slightly higher. I must say, I think this may be biased because of the use of strange techniques for some of the capsulotomy patients where very high gamma knife gray units were used for some patients resulting in side effects, or where a leucotome was used causing bleeds, which is not something that we would use nowadays. But we do have level one evidence for this. So there's a study from Brazil where patients were randomized to being in a gamma knife which was switched on, or being in a sham gamma knife which was not switched on. And when we look at the improvement in YBOX in a double-blinded fashion, we found there's a significant difference between active and sham gamma knife therapy. So there really is, this is the first time we have class one evidence of ablative surgery in a mental disorder. So what we what we wanted to do is look at the literature to see whether the best target for DBS, which seems to be the ventral capsule at the moment, compared to the best target for lesioning could be compared. And as I say, there's no head-to-head study, so we looked at the literature and took all those papers that looked at YBOX, that had at least YBOX before, and one year after surgery, and had also the side effects listed. And what we came out with was just over 100 patients who had had a capsulotomy and 62 patients who had had capsular DBS. To be clear, we're not comparing like with like, because if you look at the duration of OCD, they were much higher in the DBS group, so these are possibly worse affected patients, and the YBOX pre-op was higher, significantly higher. So this is not like with like, it's not a fair trial. But what we did find was that you were just as likely to have the responders or non-responders, whether you were having a capsulotomy or DBS, but you were much more likely to go into remission if you had a capsulotomy. So here we are, suggesting that a cheap therapy, right, it may be actually better than a very expensive, laborious therapy. However, we're not comparing like with like. So in effect, to try and stratify these patients, we took patients according to their baseline OCD, YBOX, sorry. So patients had moderate OCD or severe OCD or extreme OCD, and we looked at their outcome, whether they had a capsulotomy or DBS. And none of the moderate OCD patients had had a DBS, so we can sort of forget that for a while, other than to say that the response rate was it was about 60% after capsulotomy. If we look at severe OCD patients, again, the numbers are small. However, you are much more likely to have a response with capsulotomy than you were with DBS, and you were much more likely to be in remission. So that's another tick for capsulotomy. If we look at the worst effective patients, right, and there's significant numbers here, there wasn't really much significant difference whether you were a responder or non-responder, but your chances of going into remission, which is a YBOX of less than eight, was essentially a lot better if you had a capsulotomy. If we look at the adverse effects, so we've got a feeling that capsulotomy may be better than capsular DBS, but what about the side effects? Really, the only significant difference was a weight gain in the capsulotomy patients, and sometimes this may not be an unwanted effect. And the other problem was that you had a much higher incidence, of course, of equipment breakdown or wound infection. So that's 10%. That's one in 10 patients not being able to have therapy because of a problem with their DBS system. So if I'm going to summarize my opinion, really, based on some reading of the literature and our own experience, is that there's a growing evidence that stereotactic neurosurgery for OCD can help significantly refractory patients. However, this is a huge unseen problem, and until our psychiatry colleagues actually wake up that there is a potential to help the severest of patients, these patients just aren't going to get referred for what we know, with class one evidence, is an effective therapy. We know that there are at least two targets that are very effective in reducing OCD symptoms, but that the VC, the ventral capsule, DBS, may have some advantages in terms of not improving not only the YBOX scores but also mood. We also know that a significant improvement in the YBOX is accompanied by meaningful improvements in quality of life. These aren't just scales, these make real difference to patients' lives. However, from my own personal experience of a very small number of DBS patients, DBS for OCD requires lifelong surgical surveillance, just like movement disorders, but these are much more demanding patients than movement disorder patients. It's not to be taken on lightly. And we should certainly not discount stereotactic ablation. In my experience, the stereotactic ablation is that the patients who do well are actually much better than the patients who do well with DBS because they feel like they're cured. Now, they're never cured, of course. They need psychiatric follow-up and they still have ongoing life issues. However, they don't feel that they need to come and change batteries and have surgical follow-up. They're discharged from the surgical side, but they do require the mental health input. My main point is that there isn't a yes or no answer. We don't have to have ablation is the way forward or DBS is the way forward. Both of these techniques are very powerful. Both of them can be very useful. Patients may have their own preferences, and I think we have to help patients decide, number one, to make them available in our various communities where we can, but also to offer patients informed consent before they decide which way to go. But we do need further trials to understand this better. So this isn't my work. This is together with a huge number of people, both at Queen's Square and through the OCD network in the UK, and that's a summary of the people, the wonderful people I work with in London. So thank you very much. Any questions for Dr. Zunzo? I've got one. So you'd mentioned that the energy requirements on the capsular DBS target remain reasonably high. You know, the Ben Greenberg 2010 paper with the 26 patients, you know, they break it down to these three cohorts over the period of, you know, 10, 12 years as the study progressed, and they saw that their targeting was, as you said, moving more posteriorly towards the anterior commissure. And they also, they did notice that the power requirements were reducing. But are you saying that despite that, I mean, so it's better where it is now, but it's still quite high relative to a more anterior target? So the flip side is Barton Tennis Group has moved more posteriorly, but they still have fairly high voltages, you know, six volts, double monopolar. So it may be better, but you're still requiring a rechargeable battery if you don't want to be changing your IPG every year, essentially, which is not a bad thing. You know, rechargeable batteries are very good, and current technology makes them easier to recharge. But again, it's an extra hassle, it's an extra treatment, and it reminds the patient that they suffer from OCD. And there is a stigma with mental health conditions, and I think a singulotomy, or sorry, a capsulotomy, where you've done it, and there's no recharging, there's no battery maintenance, there's no, there is a certain cleanness to it, where if the results are just as good, and the side effects seem to be fairly comparable, if not better, one asks oneself, why are we submitting patients to this, when we've got a very good therapy, which is quick, effective, safe, and easy? And the main reason why we do DBS in movement disorders is that bilateral lesions in movement disorder targets causes axial symptoms, which are very difficult to manage, and can be fatal. This is just not true of the anterior limb of the internal capsule. So, you know, I agree, we need to pursue studies in both, in DBS, we need to try and optimize the DBS target, and DBS is a very powerful tool by which we can explore new targets before unleashing lesions, permanent lesions on our patients, but I think there's a role for both, and, you know, lesions aren't sadly a dying art in the hand of neurosurgeons. Thank you Ludwig for a very nice presentation. I would just say that I agree with you concerning lesions versus DBS. We have quite good results of DBS for OCD, but we had better results when we were doing lesions, and it takes a lot of time to manage these patients nowadays with DBS, and the only reason why I'm doing DBS instead of lesions, that is because the journalist community are quite unfavorable to lesions in Sweden. Hadn't that been, I would have preferred lesions. Well, it's nice to hear that another fellow neurosurgeon who has experience of both DBS or lesions, commending lesions, and I think our role as neurosurgeons is not just to provide informed consent to our patients, but also to educate the public, and, you know, this is a very heated topic and mental health and neurosurgery sadly have a sad checkered history, but it's our role to try and enlighten the journalists and the people and the communities at large that, you know, lesioning isn't necessarily lobotomy, and that there are advantages, there may be advantages for patients of stereotactic lesions over stereotactic DBS. So at least let's have that discussion. So you're not only educating the journalists, you're educating the psychiatric community, and that's been my biggest, you know, opposition to... You and me both. So back to your comparison between anteromedial STN and ventral capsule. Can you speak to the time course with which the symptoms improved in one versus the other? That's very interesting. So that the block was a three-month crossover study. We actually saw fairly acute symptoms improvement with both, and we saw hypermanic behavior with overstimulation with both, which is interesting because we don't tend to see that with capsulotomy, for example. There is definitely a time course effect. If you look at the literature, if you look at our own experience, you know, when you start stimulation, you get an acute reaction, but it takes time. So with ventral capsule, the mood tends to improve first, and then the OCD tends to improve, whereas with the anteromedial STN, the OCD tends to improve, and there's very little improvement in the mood with time. So there are definitely different networks through which the different targets are modulating the pathophysiological signals, and we've actually got some imaging data, which I haven't shown here, to bear that out. The other thing, just to squeeze it in here, given that topic, is that we looked at measures of cognitive flexibility, which is, of course, rigidity of thought and OCD is a big thing, and we saw improvements with the anteromedial STN, which we didn't see with the ventral capsule. So I think, you know, it's really important to think about this carefully, because although we picked these up in subclinical studies, you know, in psychological studies, they don't come through in everyday life, but it clearly tells us that different access to the different circuit, different parts, is having a different mechanism in terms of improving the symptomatology, and time course has a lot to do with it. Thank you for a great talk, and I applaud the comparison of the lesions to the DBS, and likewise, you know, a lot of experience with both ablative and stimulation procedures, and I completely agree there's a role for both, and it's certainly much easier and nicer to manage the ablative procedures. It would be nice if we had a way to predict who would respond better to one approach or the other, so it wasn't arbitrary or wasn't, you know, by design randomized. Sure. Any thoughts as to observations that you've made beyond the severity of the disease of what might, you know, be balanced? It's a great question. I just don't have the numbers to be able to look at subgroups like that, and I think even if we look at the literature, you know, there are only tentative conclusions that we can make. I think until a few years ago we were still debating whether the paladin or the STN was the better target after 150,000 DBS for Parkinson's disease. I think after a few hundred reported surgeries for OCD, it would be premature to come to conclusions. I think the main obstacle, to come back with what Aviva was saying, is we need psychiatrists to engage with us. We need them to understand that this is an effective therapy. It's a safe therapy, and there are thousands of patients out there who could benefit, and once those patients start getting referred, we should network and make studies to examine what the best surgical therapy is. But until those patients are being referred in large numbers, it's not going to happen.

neurosurgery

OCD

stimulation

ablation

DBS

cognitive behavioral therapy