And last, but certainly not least, we have Zaman Mirzadeh, who will be presenting to us about, is pain relief efficacy after singulotomy dependent on lesion number? OK. So thanks. So this was some work that we did during the Oakley Fellowship as part of the joint section. And I spent some time with Bill Rosenberg, because what the joint section has done is have this NREF-funded fellowship so that for neurosurgery residents in most programs, like in my program, where I trained at BNI, we didn't have someone really dedicated to pain. And so about as much pain as you see is sort of the really routine stuff that all the spine guys do, like put in stimulators. But then when it gets to more nuanced things, like treating cancer pain, or how do you use drug pumps and combination therapy, and what are all the kind of things like we've heard today, you don't really get exposure to that as a neurosurgery resident, I don't think, unless you're at one of these programs that happens to have a person that's really dedicated to that. So the pain section made this really cool fellowship that just gives you some money to travel for a few months after you're done residency. So that's what I did for those two or three months, and I basically spent some time with Bill Rosenberg. I spent some time with Ashwin Viswanathan, with Nandan Ladd, and sort of picked up what those guys tend to do in pain. And so now I feel much more equipped to help patients in ways that my partners at BNI have no idea what to do. And it's nice, because it makes you kind of special. But anyway, this work came out of the time that I spent with Bill. He had done a couple of sinulotomies and said, hey, we should look at this. It's only a couple patients, but it gives us a chance to at least just talk about neuroblation for cancer pain. So the more commonly performed neuroblative techniques that are done for cancer pain are actually done at the level of the spinal cord, usually the high cervical spinal cord, either a chordotomy or a myelotomy, where the goal is to disrupt descending pain tracts, either for midline visceral pain, in the case of myelotomy, or unilateral nociceptive pain, in the case of chordotomy, like a metastasis to the arm or to the leg. Or for visceral pain, it's like a pancreatic cancer. And then there's trigeminal nuclear tractotomy for head and face cancers that also targets the spinal cord. But then for today's talk, we're going to be focusing on the supertentorial targets, which are a little less commonly performed, as I'll show you in the data, but still can be very effective. These are used for indications where the chordotomy or myelotomy might not be as effective. So for example, if you have diffuse pain from widely metastatic disease, then you can't really do a chordotomy. And also, again, these are diffusely metastatic. So myelotomy, which targets really midline visceral structures, also probably won't work. So that's really the mainstay for singulotomy, is for diffusely metastatic cancer with diffuse pain. And primarily, also, ideal would be if it has a psychological component or significant affective component, suffering component to the pain. You know, in often patients with cancer, advanced stages, there's a high comorbidity with depression and anxiety. So it's a nice treatment for that reason. Now, singulotomy for pain was actually sort of a serendipitous discovery back in the days of doing lots of ablative procedures for psychiatric illness, where they noticed that patients, even if their, let's say, their psychiatric disease didn't get better, they were relieved of maybe a comorbid pain condition. And so that's where it actually developed. Now we have nice evidence, physiological evidence, that it makes sense that it works, because we now understand the cingulum as sort of a target of ascending pain pathways, and then also able to provide descending modulation. So this is some work. This is actually a meta-analysis done of many, many studies that had fMRI or PET data. And they're basically localizing in the red areas that showed increased cerebral blood flow in response to pain in healthy subjects, or increased cerebral blood flow in the setting of clinical pain in patients with chronic pain. And then down below, again, healthy subjects' response to the pain, and then compared to subjects undergoing analgesic interventions, like an anesthetic block. This is work from Dr. Lenz's lab, or I don't know if it's from his lab, but it's work that Dr. Lenz did, I guess, 20 years ago now, but where in epilepsy patients, they put subdural grids along the medial surface of the cingulum and recorded, while inducing a cutaneous heat stimulation over the contralateral face, and they saw these evoked responses in the cingulum. So that's, as I said, a little bit of what we understand about the anterior cingular cortex and what it does physiologically. And as I said, there's this rich history in psychiatric surgery with those early studies that really pointed to the cingulum as a target for pain. And then this is what I was alluding to earlier about the number of these cases that are done. So obviously everything that's done is not published, but as far as the published literature goes, looking at case series of, you know, patients undergoing cingulotomy for cancer pain, that, you know, a couple years ago, a review came out that showed eight unique case series with a total of 87 patients. So not a lot of patients. You compare that to chordotomy, where there's been like, you know, over 3,600 published cases. But the pain relief seems to be okay. Now, this is not, these are terminally ill, you know, cancer patients, but, you know, pain relief of, you know, usually in, you know, on average around the 50%, anywhere between 30% and 80% in the published reports, relatively low complication rate. And the complications that you get tend to be transient with, you know, decreases in attention or apathy, and the patients are said to just kind of, you know, lie there for a few days. So the traditional, or sort of the usual technical approach to these, in the past it was with an air ventricular gram, and essentially the targets have varied, but tend to be within four centimeters of the frontal horn pole. Currently, you know, this is done with stereotactic MRI guidance. Again, now with stereotactic MRI and some of the data that I presented before, the target's been refined to now two centimeters behind the frontal horn pole, essentially right in the middle of the cingulum bundle, just above the corpus callosum, and you lesion with an RF probe with a 10 millimeter exposed tip, and usually two lesions are created along a single trajectory, and you get an image that looks kind of like this. So now in the time since I, you know, since we submitted this abstract on these two patients that I'll present to you in a second, Ito Strauss from Israel published this really nice paper where he had 13 patients, sort of essentially kind of saying the same kind of point as what we were trying to suggest with our two patients, which is that maybe a little bit more is better in terms of the pain relief you can get with this approach. And so he did a double anterior stereotactic cingulotomy, so you see compared to the picture I showed before, essentially his targets straddle the other target I just told you. So he's got one, 1.6, and the other one at 2.4 behind the frontal horn pole. So he's kind of making just a larger lesion in that area, and presumably the variability in those studies, or if it's going to work better, it might be from misses or not enough of the cingulum being damaged to have a beneficial effect. So in his paper, there's 13 patients with metastatic cancer and tractable pain. All of them reported substantial pain relief immediately. Three of them, three of six bedridden patients were ambulating. I mean, this is, you know, it's really like gratifying to be able to make this kind of a difference. And then you see here his VAS scores over the course of three months, and then these are BPI scores over one month showing a significant benefit. Of course, the downside to these treatments, which is why they're primarily really indicated just in terminally ill cancer patients, is because they're not long-lasting. The pain tends to come back, you know, maybe from what I've heard, I mean, I haven't been doing this long enough, but, you know, one year, two years, you know, max in terms of the durability of the pain relief. He also had some data on neuropsych testing showing that, you know, increasing the lesion didn't seem to make too much of an effect in terms of cognitive decline or the adverse events. And so this was, you know, our two patients, and essentially what we did is what's done for doing an anterior cingulate cortex lesion for OCD. And so it's three lesions in tandem along the cingulum bundle. The most posterior one is two centimeters behind the frontal pole, and then each successive one in front of that goes seven millimeters anterior to that, you know, so you're basically creating a lesion and then another lesion right next to it based on the heating, the spread of the heat. The rationale for this, as I said, was based on the OCD literature suggesting that a little bit more might be better in the case of OCD, so we applied it to pain. These are our two patients showing, this is their VAS score, so you see, you know, and this is obviously limited data. We analyzed the, based on their pain diary, where they were reporting their VAS for what percentage of the day in the pre-op week compared to the post-op week, and you see this dramatic decline in both patients, also with a dramatic reduction in their morphine equivalents, with also the caveat that these are actually weaning doses, so they were actually going lower, and we had no adverse events in either of those patients. That's it for cinguloma. Thank you very much.

Zaman Mirzadeh

pain relief

singulotomy

lesion number

neuroablative technique