Transcript
Question: What challenges can be associated with recurrent imaging after CSF-venous fistula embolization? I know it’s a concern for a lot of us with multiple sites embolized. Is it possible to definitively rule out a residual or recurrent fistula at a site that was previously embolized with Onyx? And to patients who may not be familiar with the problems that Onyx can present, maybe you could touch on that as well.
Answer:
Dr. Callen: Yeah. Yeah, that’s a great question. So Onyx is a liquid embolic material that, by virtue of its constituents, leaves an artifact on imaging that is very very bright. It looks almost like metal within the veins. And so this is a big problem when patients have recurrence of their symptoms, for example, because we’re always wondering, well, perhaps the fistula is incompletely treated. And if they have a fistula at a different level, we could still find it. I obviously just gave examples of CT myelography, and it’s my sort of tool of choice, but I think this is a place where DSM is better, because we can remove that Onyx artifact with the digital subtraction and see potentially – are there some residual veins? Now, even in those cases, it sometimes can be very very tricky. I think that there are newer liquid embolic agents that are not yet FDA-approved but that are used in Europe that decrease their density over time that are very exciting, that may be much more useful in this situation.
But we have had cases, more than one, where a patient was embolized and we could not prove that there was a residual fistula there on imaging, but yet we didn’t have a better explanation for what was going on. And so after a multidisciplinary discussion and discussion with the patient, they still went to surgical ligation. And those patients, almost all of them, did very very well. And so there probably was still fistulous drainage in those patients. We just couldn’t visualize it because of the Onyx that was still there.
Moderator: Thank you, Dr. Callen.
Question: The next question that we have is one I’ve seen a lot in the patient community the last two years and wanted to get your thoughts on the idea of Spiky-Leaky Syndrome, which was named in a paper published last year, kind of touching on Mast Cell Activation Syndrome and the inflammatory cascade it can cause in the body. And could this syndrome perhaps contribute to recurrent spinal CSF leaks, specifically CSF-venous fistulas, and is there more research being done on intracranial hypertension regardless of cause and a possible predisposition for CVFs and other spontaneous leaks? I saw you touch on that somewhat in your talk, about that we are more likely to have elevated or normal opening pressures, so was wondering about that.
Answer:
Dr. Callen: That’s a great question, and I’ve had a lot of patients ask me about this. I first want to just start by saying it’s so important to remember that in a field where we have to recognize how little we know, that we have to be very open-minded about what could be possible, right? And so we have to keep an open mind to all sorts of possibilities. The idea of this sort of Spiky-Leaky Syndrome is very interesting, but at this point, in terms of science, it really is an idea. So the main publication that was behind it was a hypothesis paper, not really a research study, and there hasn’t been really strong objective evidence to support this mechanism. And the mechanism is basically that intermittent spikes in intracranial pressure could cause these microscopic or transient leaks that are hard to detect on imaging. And so I wouldn’t call it yet an established diagnosis, but more of a very interesting hypothesis.
But the broader question of whether intracranial hypertension in any of its forms could predispose someone to a spinal CSF leak or CSF-venous fistula, that is definitely a field that we have some evidence for, observational evidence for, etc. And so we know that sustained elevations in intracranial pressure can contribute to cranial leaks, for example, and skull base defects. We know also that there is this seeming predisposition that patients with CSF-venous fistulas can have a normal or elevated opening pressure. And so it does seem like there is a relationship there, but the relationship there, and this is an important distinction between that Spiky-Leaky hypothesis, seems to be more of a chronic sustained issue, especially with what we’ve observed on those histopathologic studies, rather than intermittent tiny spikes. But that’s a nuance that warrants further investigation.
So the good news is that this pressure–leak relationship is being studied a lot in legitimate ways across multiple centers, and I think that no idea, including this one, should be tossed out, and we should really just keep an open mind as to what could be going on.
Moderator: Thanks, Dr. Callen. Yeah, as an official patient myself, I know I had a quite high opening pressure of 20, and I’m very interested in what is the cause of CVFs, which I know is a big question in the field right now, and I think we’re all looking forward to hopefully more of that multidisciplinary kind of research in the future. And so I’ll move on to the next question.
Question: In cases where initial imaging is completely negative, so spine, brain, etc., when do you suspect a CSF-venous fistula, and if myelography fails to turn up a CVF, is pure exploratory surgery advisable in some cases? I know you alluded to that in cases of previous Onyx embolization where a known fistula was there before, but if there’s not been a fistula found at any point but one is suspected, is exploratory surgery ever an option, and if not, what other options do patients have?
Answer:
Dr. Callen: Yeah, this is obviously one of the central questions of our entire field. I mean, I think first starting with somebody who has not yet had a myelogram, I think in the appropriate clinical situation where there’s not a better diagnosis to account for their symptoms, that you go looking for a fistula, right? And if the brain is negative, if the spine was negative, also just because the brain is negative, I’ve talked about this before, but I think a lot of these patients who get lumped in as having a normal brain actually did have some subtle findings and the brain wasn’t actually normal, and it shouldn’t be thought of in this way. I think this has caused confusion. But nonetheless, they have a radiology report that says they have a normal MRI of their brain, and so we have to go looking. And it’s important to remember that even on your myelogram, if you do the best possible myelogram, you may be leaving something behind.
There are patients in whom, and I like to parallel my thinking in the imaging-negative patient to the imaging-positive patient. If I have a patient, for example, like the really subtle one I showed, with that tiny little nubbin along their nerve root sleeve, will all doctors doing a myelogram look at a patient’s myelogram the same way if they have a sagging brain and they’re comatose in the ICU versus they’re walkie-talkie but suffering immensely with a normal MRI of the brain? Do we assess it with the same scrutiny? I would say probably not, right? With patients with the positive brain, we know it’s there somewhere and so it must be there. But in patients with the negative brain, you may be just scrolling through and saying, well, this study is going to be negative. This is a bias that we have to fight very strongly against in radiology, to look at everybody with the same level of scrutinization. And not just looking at the myelogram, but also how do we perform the myelogram? When we do the injection, we do it in the lumbar spine, and then we look up towards the head. If we find nothing on both sides, well, what about below the needle, right? What about down into the sacrum?
We think that sacral CSF fistulas are rare, but they can occur and have been described. Have we really looked at everything before we are ready to say that there is nothing here? Of course, we don’t want to repeat exams with more punctures and more radiation over and over again expecting a different result to the consequence of the detriment of the patient. So every step along the way in these situations where patients are, where there’s uncertainty about what’s going on, needs to be a conversation where we say, look, I could try again because I felt like I didn’t get great dense dye coverage over this one part, but the odds are kind of against us, and this is going to be another puncture and more radiation, and is this something that we want to do? And it has to be very, very individualized.
To the point about exploratory surgery, I think that this is something that I have only appreciated by developing a stronger relationship with my neurosurgical colleagues. But I think myself previously, and I think a lot of patients also, sort of conceptualize that surgery is just this thing where we could open you up and look, and there it is, right? There’s the leak or the fistula. It’s got to be right there. I mean, I know it’s in there somewhere, so could someone just sort of flay me open top to bottom and just see it, because I just need it to be fixed. But it’s much more complicated than that.
Even in cases where we have straightforward leaks where I know exactly where it was, it was a ventral tear. I can tell my surgeon, okay, I think it’s half a centimeter above the disc space, just eccentric to the right. There’s the osteophyte. Wow, this is great. I sometimes get a call from the OR, and he’s like, wait a second, I’m not seeing it exactly where you said. And it requires more careful troubleshooting.
And so with more minimally invasive techniques, with careful exposures to reduce morbidity, it’s not like we’re just opening everything, or the surgeon is just opening everything up with it right in front of them. And particularly in the case of CSF-venous fistulas, sometimes the venous anatomy intraoperatively, the gross operative venous anatomy, can look abnormal. There’s big abnormal veins, or maybe one vein that’s different than the rest, but sometimes it just looks like normal veins that are supposed to be there. Remember these are veins that are normal veins that are developing an abnormal connection. And so it’s very hard to look at that intraoperatively and say, oh, it’s obviously right there. But I think I have a much, much lower threshold to, for example, try putting some fibrin glue on an area that looks suspicious or narrowing things down this way. This is also not perfect, but has much less potential morbidity for the patient, where they have to undergo very expensive, lengthy, and potentially morbid surgery without a clear definite outcome, whereas we could do a percutaneous procedure that, of course, does have risks as well but is not necessarily putting them at risk of making them worse than when they started, because that has to be our guiding principle in all this. We have to be willing to push the boundaries, do things that are maybe outside the box, but not ever leave a patient worse than when they came to see us, because that’s the rule number one in medicine.
Moderator: Thank you for that, Dr. Callen.
Question: I think this kind of relates to a little bit your last answer, talking about just the different treatment options and the risks associated with each for the patient. Blood patches for many of us are often offered as a first-line treatment, and with CSF-venous fistulas becoming more commonly found, the question arises what is the effectiveness for that first-line treatment for CSF-venous fistulas? I think some of us have seen papers come out that showed that they may be less effective at sealing fistulas than other types of leaks. Could you maybe speak to the success rates with a blood patch or fibrin patch, or do most of the patients that you see with CVFs need embolization, surgery, kind of the more invasive options?
Answer:
Dr. Callen: Yeah. So I think this is a really important question and one that we have to be really careful about what words we use. So to be clear, I think that it is a very small minority of patients who will have their CSF-venous fistula fixed by even a, you know, what we think of as sort of a non-targeted or empiric blood patch, the run-of-the-mill blood patch done under fluoroscopy in the lumbar spine dorsally, putting in, trying to get in 20 cc’s of blood. I think this will fix almost no one. I think that it will usually, but not always, provide temporary relief. I think that it’s important to remember that it’s not always because it’s not a perfect test, right? That if a patient does not have a response to a blood patch, but they have a fistula, they could still have a fistula. But I think it is probably a minority, but it is not the overwhelming tiny minority.
Then talking about specific treatment options, you know, there are sort of three commonly performed and described in literature methods of treatment. There’s surgical ligation. So either clip ligation of the nerve root sleeve without resection of the nerve root sleeve there, or the surrounding veins if we’re talking about an eloquent nerve root. Luckily most of the thoracic nerve roots are non-eloquent, meaning that they don’t contribute to critical neurologic function, and so sacrifice of that nerve root generally won’t result in profound neurologic deficit.
Then we have transvenous embolization. Right? So we’re going in through a vein in the neck or the groin and getting up to the veins from the inside and closing them off with Onyx. And then we have percutaneous fibrin occlusion. Now the percutaneous fibrin occlusion is different than a patch, right? We don’t really even use the word patch when we talk about using fibrin for a fistula because we’re not using the same technique in terms of where we’re putting our needle. We are not just placing it in the epidural space, which is the way that people could conceptualize appropriately patching. And the reason that I think when this was first tried in fistulas early on there was a very low rate of success. I think that you need to do this under CT after you have a myelogram showing where the fistula is coming off, so we can place that needle at the junction of where the vein is and where the nerve sleeve or the origin of the fistula is. And we did a multisite study on this with 119 patients and found that in a lot of these patients the brain MRI improves, but that is not really what we care about the most. The patient-reported cure rate, so patients saying I am cured, I don’t have symptoms anymore, was about 59% in that study. And that was after a couple different tries, so on about three tries total. This is the downside of the fibrin occlusion, that we sometimes have to try more than once. There’s a study out of Mayo Clinic looking at 100 patients with transvenous embolization that had a very similar patient-reported cure rate of around 58%, but the benefit there is that that was under less attempts per patient, right?
So this is, I think, important to understand our terminology. There’s pros and cons to each. I think that if, you know, for some people and the resources or the patient’s own fatigue with the process of treatment, the idea of potentially having to get more than one of these treatments for fibrin is just, there’s no way I want to do that. Let’s just try the embolization. I have patients also who are saying I don’t like any of these numbers. I don’t like anything below 100%. You know, I just want surgery, which is not also 100% but probably the closest thing we have to it, which is perfectly reasonable too. I think both those numbers of those studies I just reported are probably higher as our techniques get better and better. I could say that observationally our numbers have gotten better at our own center as we’ve done more and more of these cases, but really the treatment approach for a fistula has to be individualized based on the location of the fistula, the comorbid factors related to each potential treatment type, and then the patient’s own desires for their own health.
Moderator: Yeah, thank you for that, Dr. Callen, and I hope that’ll be really helpful for patients to see the landscape of the options and, like you said, ultimately it’s a conversation between the patient and their doctor for what’s their risk tolerance for their case and what they’re comfortable with, which I think is great. We have so many options now versus 10 years ago when we barely had recently discovered CVFs. It’s just incredible to see how the field’s evolved.
Question: I’ve seen this one a lot in the patient community, and I think you may have done some studies on this at your center. Is there any specific symptom manifestation or presentation differences between CVF patients and those with other types of spinal CSF leaks?
Answer:
Dr. Callen: Yeah, I think this is an incredibly important point to make, and we did report on this in a series of our consecutive CSF-venous fistula patients. In that study, we found that about 40% of patients did not have a, in quotes, “classic orthostatic headache”, right? So they did not have a pressure-type headache in the back of their head that was gone when they were flat and worse when they were upright, but they had something else, and it could have been headaches that did not have that classic orthostatic or positional component. And the reason that I keep pausing on that is because I think that there is even misunderstandings when we talk to our patients about is your headache positional? Like what does that mean? Is it when my head’s in a certain position, or when I look from side to side, or I turn my head, or I look up and down, or when I bend over to tie my shoes, or is it when I’m sitting versus standing or laying versus standing, or is it the act of changing positions, which I see in a lot of my CSF-venous fistula patients, that they get symptoms when they go from laying to standing or sitting to standing or even just laying to sitting. And so we have to be very precise in the way that we talk about these symptoms and what they actually mean, because I think you could see a situation where somebody asks that patient that question, and they don’t totally understand, and they provide an answer that to the doctor sounds like oh, well then that’s not a CSF leak.
And even further, we see a lot of patients who say, I can’t tell you the number of times I’ve heard this exact sentence, which is Dr. Callen, I need you to understand it’s not a headache. It’s not a headache. It is a sensation of fill in the blank. It’s either a pressure, a pulling, it is a burning, and it’s not really my head, it’s my neck. It’s the vestibular cochlear symptoms that are more prominent. It’s the dizziness, the ringing in their ears. It is the sort of muffled feeling like they need to pop their ears all the time, or like they’re underwater all the time. Or for some patients, it’s a more systemic manifestation, GI issues, what have you. And so I think that it’s very important that just as we have broadened our understanding of the pathophysiologic mechanisms of leak in general, that we also have a more open mind in terms of the clinical presentations, because all it takes is seeing enough of these patients with CSF-venous fistula in particular to realize this is not just as simple as a headache that all you need to do is lay down and it goes away. This is a full-body disorder that often has headache associated with it, but not always.
Moderator: Thank you. So am I hearing from your answer that, I think, a more significant portion of CVF patients might have some of these less classical orthostatic symptoms? I don’t know if it’s a majority or what the percentage is, but maybe more so than other types of leaks?
Dr. Callen: Yeah. I mean it’s it’s tough to draw, to say directly in terms of a direct conclusion of this, but if you compare, for example, that study to previously published work on SIH in general that focused more on type 1 and 2 CSF leaks related to dural tears, then certainly you would come to that conclusion that these prior studies have showed that upwards of 90% of patients had an orthostatic headache, right, and so if we’re seeing less of that, you know, but maybe the way that we’re defined in terms. Certainly in my experience I think that it’s true. I think that in general that, not always, but in general, when I see people who have a dural tear, their story tends to be a little bit a little bit more sort of classic, I guess, in terms of that sort of sudden onset intense orthostatic headache that completely went away when they laid down, whereas with the fistulas it could be a little bit more insidious in onset, it could be a little bit more vestibular cochlear predominant, very Valsalva-related, bearing down or coughing or sneezing or bending over related, but I think that there needs to be more work in this domain.
Moderator: Thank you.
Question: And I think we got a question as well about overlap between IIH-type symptoms and CVFs. And I’m guessing that’s something that kind of falls into that non-traditional bucket of presentation that you’re alluding to as well.
Answer:
Dr. Callen: Yeah, completely. I mean, I think that another thing that’s important to remember is that it’s been well described that the longer you live with a leak, the more atypical the symptoms become. The headache can go from orthostatic to reverse orthostatic, and the same could be true for IIH. So a patient could have this sort of classic IIH clinical picture, and then over time their symptoms can become sort of paradoxical too. So I think that because we understand that there is this intimate and important connection between CSF leak and high-pressure disorders, that we have to be very careful when using the clinical story alone to bin a patient as one or the other, when in reality there’s probably an overlap, and there’s probably so much more we don’t understand in terms of how that manifests symptom-wise.
Moderator: Thanks, Dr. Callen. Yeah, this just is such an interesting field, and I feel like so much that we don’t know, and I’m, as a patient, very excited to see us learn more about the condition as the years go on.
Question: Many patients with CSF-venous fistulas and those of us who have connective tissue disorders like Ehlers-Danlos often seem to have comorbid vascular compression such as Nutcracker Syndrome. Nutcracker Syndrome, for example, has been associated with the formation of collateral veins and even congestion in the epidural venous plexus, which is, as you’ve discussed, a place in the spine from which CVFs can form. Could Nutcracker Syndrome or these similar vascular compressions contribute to the formation of a CVF? And if so, how? Is research being done to investigate a potential causative relationship between these vascular compressions and CSF-venous fistulas?
Answer:
Dr. Callen: Yeah, this is a really important question. I think that more often than not, I have patients who are asking me about this. And so, just so we can sort of define terms for the people who are less familiar, Nutcracker physiology, this is dynamic left renal vein compression which then can cause collateralization, and it can cause epidural venous engorgement just as you mentioned. And so it’s the venous bed that CSF-venous fistulas drain into. I think we would be wrong to just say there’s no potential way that there could be a connection here, right? I mean, the venous drainage is all intimately associated. There’s not a proven causation between those two specific phenomena, but we have this pathophysiologic reasoning that is plausible in terms of the connection of those two in particular.
I think that we are missing something incredibly important on the venous side of things, and we may be sort of looking in the wrong places right now, and I think that could be evidenced by a number of things. Dr. Schievink this past year published a paper on patients with frontotemporal dementia-like-syndrome with brain sag. These patients, in whom we see horrible downward sagging of the brain that looks just like a CSF leak, but in a huge number of these patients we cannot find a CSF leak. And they found that in some of these patients they actually had an azygos vein stenosis, a stenosis of the vein that is this sort of unilateral conduit of venous drainage out of the thoracic spine. And when that stenosis occurred, it actually, contrary to what I think we conceptualize as well, there’s a stenosis, so there’s backing up of that pressure causing intracranial hypertension and then a leak, but rather because that venous drainage is driven by respiration. It was almost like a sump effect and hyper-reabsorption — you could think of hyper-physiologic reabsorption of the CSF. It wasn’t one specific spot that was leaking, but when opening that vein actually led to the patient’s brain popping back up.
And it’s very interesting when it was combined with the observations they made clinically, where these patients would do this sort of frequent breath-holding-like maneuver that was probably distending that azygos vein for them and helping them in their own physiology. And when you combine that with the understanding that rebound intracranial hypertension is closely related to, for example, the morphology and anatomy of our dural venous sinuses and not really related to treatment outcomes, as we’ve shown in several different studies, there’s something about the way that patients are experiencing the symptoms which is tied intimately to the venous system.
But it probably, and this is just my guess, but it probably isn’t as simple as the model that we currently propose, that there is just a simple venous compression somewhere that’s causing hypertension and then causing a leak because of a ballooning effect. That probably is true for some people, particularly in sort of bona fide IIH patients, but I think just like everything, the answer is going to be more nuanced and complicated. But we would be wrong to fully dismiss the venous side of this pathology entirely.
Moderator: Thanks, Dr. Callen. All of this is just so interesting, and I wish that we had an hour more to go through the rest of the questions that came in, because there’s just so much to discuss here. And I hope that in a future Bridging the Gap in a few years that we have answers to some of the things that we’ve discussed today and have been a little bit more gray areas. That’s something I know I’m very excited about. And with that, we’re going to wrap up our Q&A on CSF-venous fistulas and move into our next session.