Transcript
Question: So, thank you all for your excellent talks. I had a question for Dr. Wolf about the rebound headache because I find it difficult to decide when to start treatments and if there’s a specific population who’s at risk for rebound headache. We had several cases where they had papilledema and even some visual decrease. And I find it difficult to find who’s most at risk for this.
Answer:
Dr. Wolf: I think we probably should have a survey just how we all do it. I’ve heard about different approaches. I can just tell you how we do it. Many, many patients have a slight rebound hypertension and [inaudible] that’s good. Now we are going and now that’s the start of you healing and most of them are fine within the next few days. So usually we don’t treat them in the first place. If they are symptomatic already like they cannot sleep and they cannot really handle the symptoms and then we start with acetazolamide and usually we can table this up in a few days. I actually am surprised. I have very, very few cases with papilledema and all of them are rare IIH types. So I think that’s probably something again we need to look into. With some patients I think we like in the first place we okay they might have come from IIH then we are more we tend to treat earlier and follow up and also I would also like to hear some of your opinions and we try to get them as soon as possible on GLP-1 receptor agonist because also has some effect on the blood-brain barrier to reduce CSF production and it reduces the weight to prevent going back and forth between the CSF loss and the hypertension. So that’s something we try to do but we are sometimes like it’s very difficult with our insurances. I would really like to hear your opinion from your centers. I guess probably everybody has their own.
Dr. Friedman: I can’t say that the patients I see recover as quickly as your patients do. And even when you look at the literature most of them do not have papilledema but some do. And I’ve seen it happen recently in a person who had absolutely no risk factors for having IIH before. So I will generally use acetazolamide. I found that it is not tolerated very well by a lot of people, in which case I will either switch to methazolamide or I may even try topiramate because it probably works better for the headaches as well as lowering CSF pressure. Studies actually indicate that topiramate may be more effective than acetazolamide in lowering CSF pressure. And since I’m a neuro-ophthalmologist I can also follow their visual function, which is convenient for the patient I guess. The only study that I know of which looked at predictive factors is from Wouter, yeah? Looking at the pre-procedure MRI, that you found that a lot of these people that got rebound intracranial hypertension had signs of elevated CSF pressure on their brain MRI. Wasn’t that you?
Dr. Schievink: Basically what we looked at in a group of patients, we looked at their pre-op. Most of them had surgery for their leak. We looked at their MR venogram, and the patients who had bilateral transverse sinus stenosis are at much, much higher risk than any other type of patient. So it wasn’t so much the duration of the leak, it wasn’t so much the type of the leak, but this was done quite a few years ago. So we didn’t have that many fistula patients, but it mostly seemed to depend on whether or not there was a pre-existing transverse sinus stenosis.
Question: I have a two-part question. The first is for any of the surgeons: when you’re operating on ventral leaks, how often—because I don’t think it’s published—do you think you have visible xanthochromia at the time of surgery?
Answer:
Dr. Beck: 10%? Just an estimate.
Question: And then the second follow-up to that is, in brain sag dementia, do you often see superficial siderosis, because I don’t think that’s been published either?
Answer:
Dr. Schievink: Well, patients who have really severe brain sagging with frontal temporal dementia-type symptoms, none of them had superficial siderosis. But again, I think we’ve seen maybe 70 now, and only one of them had a ventral leak. Half of them we never were able to find a leak on, so maybe there was a different reason for their lack of spinal CSF.
Question: I have a question from our virtual audience. I would like to ask Dr. Jürgen Beck to comment on the role of CSF ferritin in superficial siderosis in SIH.
Answer:
Dr. Beck: Little is known. It could be a marker of siderosis that is about to come. Probably we should look at this more often, because as I tried to mention during my talk, once we see full-blown siderosis, it’s too late. There’s a lot of damage that already happened. So probably we should just measure ferritin each time we withdraw CSF. We don’t do it, we are sloppy, but probably we should do it, and we should clearly put more research in biomarkers for SIH and also for superficial siderosis. So I think it’s a good question, and we should be doing our homework better.
Dr. Schievink: Unfortunately, in the US, in both the west coast and the east coast, it’s impossible to measure ferritin in CSF. But in Europe apparently it’s pretty easily done.
Dr. Beck: It’s not easily done—it was a project in Bern—but it’s doable.
Question: And then there was a follow-up question for you, Dr. Beck, from the same individual. Is there any role for routine usage in current practice, measuring ferritin, or is this just an obvious curiosity?
Answer:
Dr. Beck: Usage of what?
Dr. Schievink: To measure ferritin.
Dr. Beck: Again, it’s a single study. There is no scientific evidence to do it. But again, I would clearly encourage to do more biomarker research, and not only for superficial superficial siderosis, also for spinal leaks per se. And when we touch the topic of post-dural puncture headache tomorrow, even in this disease we do not really know whether it’s all a physical fluid thing, whether it’s all low pressure, low volume. We discussed this a lot, and you get to know more and more data that the volume is probably normal, that the pressure is probably normal. So what about that? At least part of SIH and part of chronic post-dural puncture headache is a metabolic syndrome, is something deranged in the functioning of all the transmitters, of all the toxins in the brain. Now we have iron because it’s so easily visible, but what’s with all the other stuff? I think we should do proteomic studies. We should do single-cell sequencing of the glial cells. We should do single-cell sequencing of the inflammatory cells in the CSF. We don’t do that, so we don’t know. I don’t have an answer to this question, but I strongly believe, because this is such a multifaceted disease, that we should not ignore this side of the spectrum.
Question: I have a question. I also wanted to make a comment on Dr. Beck’s comments just now. My question was about retrograde flow across the fistula, as you mentioned in CVF possibly causing superficial siderosis. There’s been one documented case of retrograde flow across a CSF lymphatic fistula, and as a CSF lymphatic fistula patient I clinically experienced that and treated it, and it responds to the theory but isn’t currently in a peer-reviewed paper. My question is should we also be looking for lymphatic biomarkers in CSF, as you suggest looking for ferritin in CSF, and what might be the long-term complications similar to superficial siderosis in patients who have CSF lymphatic fistula with retrograde flow. I know that’s another curly question, apology. The other thing, where you’re talking about biomarkers for disease and deranged metabolic conditions, one of the things I’m considering—
Answer:
Dr. Beck: The question is excellent, I’m just not able to answer it sufficiently. Probably you, Marcus, or anyone has an idea. Katarina, right, neurologist.
Dr. Friedman: Not for lymphatics, but there, and that’s just not my idea. This is the same as Dr. Andrew White. He did his neuroradiology fellowship at UT Southwestern, and he was wondering if Beta-2-transferrin in the serum could be a marker for CSF-venous fistulas. I thought that was a pretty cool idea. We measured it in one patient. We only had N of one. It was kind of a hassle. We had to send the blood somewhere where they could do it, and it came out negative. But I don’t know if that was just the fact that there’s not enough to measure when it gets circulated throughout the entire system. But I thought it was pretty intriguing.
Question: One of the curious things I’ve noticed is that 56% of patients with a diagnosis of ME/CFS, chronic fatigue, have brain sag visible on their MRI imagery. And I’m considering whether possibly they are a missing group of CSF leakers, and potentially are some of them leaking into the lymphatic system, because as a CSF lymphatic fistula leaker, headache is not the primary symptom. Fatigue is quite noticeable as a symptom. So perhaps that’s a group of patients we’re missing. There is a lot of research in the ME/CFS space about other potential biomarkers. So if there is a crossover of a patient group, is there an existing body of research that we could tap into for these potential markers? They’re looking at mitochondrial dysfunction and other potential markers that way.
Answer:
Dr. Wolf: I think I can just continue that currently we don’t know, but I think what we can pick up of this is not just the CSF lymphatic drainage, which now occurred to exist via the nasal mucosa, and that we get this lymphatic drive that we still need to investigate and see how that is regulated, which we will hear talk of by Horst Urbach tomorrow about glymphatics and all we know about the regulations from the [inaudible] group. So I think that’s also something we need to keep in mind and connect this, and also I hope for somebody getting down with a mouse model or something with a spinal model and to look into how the lymphatic train and the venous train look like there. And I think we’re still at baby steps. We’re talking about huge science, something we still don’t understand. So just aligning a few things would probably help us to get maybe one or two ideas.
Question: I really, I really would love if you helped me to understand why the craniotomy or the defect in the head skull causes brain sag.
Answer:
Question: I have another audience question also for Dr. Beck. It says, “Have you experienced a patient developing superficial siderosis in the year following ventral spinal CSF leak surgical repair?”
Answer:
Dr. Beck: No, I personally haven’t, but there is a report from Cedars that at least a couple of patients developed it early. If I read your paper right, I’m not aware that it continues after surgery. Then I would suspect that the leak hasn’t been sufficiently closed. But this is also speculative, and we don’t really have large numbers. Usually, as a rule of thumb, it takes time. There are exceptions that after one year, or even I think there was one patient in your paper after a couple of weeks, there’s superficial siderosis. But as a rule of thumb, the longer, the higher the risk of superficial siderosis. And once the leak is sealed it should at least stop—hopefully it gets a little bit better.
Dr. Schievink: Yeah, I think this was more about the situation where you have a patient who does not have superficial siderosis. You repair the leak, the leak is repaired. What is the risk of developing superficial siderosis after fixing the leak, thinking that all those years the person has been leaking? Might it be like a delayed radiographic appearance of superficial siderosis?
Dr. Beck: Good reasoning. I don’t have a case. I don’t know. Good reasoning.
Question: I’ve noticed in many of my myelograms, maybe 20 or even 30% of patients investigated for CSF leaks, that they have ossification of the ligamentum flavum in patches through the thoracic spine principally. Has anyone else noticed that? And what does it mean?
Answer:
Dr. Lützen: To be honest, I haven’t looked at this too. I mean sometimes in the dorsolateral leaks we have the big facet joint that probably makes a leak, but calcification on the ligament I never really looked at this in detail.
Dr. Beck: So to give you an answer, if you force me to, I have not observed during surgery that the ligament — that there was ossification, no.
Dr. Schievink: Let’s ask your neurosurgeon what he thinks.
Dr. Stoodley: We went through a phase of wondering whether that might cause dural tear, and we did explore a couple and did not find them. So I’ve not seen, but we see the calcification. Yeah. I guess it would be fair to say we’ve reduced our emphasis on the likelihood that it’s related.
Question: I have a question about airplane flights. A lot of patients ask if they can fly after their leak is sealed or with an active leak, and the evidence is scarce and somewhat contradictory. I know of the study from the Danish Headache Center that published a case series of some SIH patients that worsened or first experienced symptoms after airplane flights. But I’ve seen myself many, many patients who have been flying with active leaks with no problems whatsoever. So I really don’t discourage it, but I’m interested to hear your opinion on this.
Answer:
Dr. Schievink: I generally encourage patients to fly to wherever they need to go for a leak, rather than driving 12 hours. And we once, we’ve never published it, we once did a survey. I don’t remember how many patients, 30 or 40. And I think 70% there was no change in their symptoms. But taking into account that they would not be sitting, they’d be flying either first class, business class, or they would take a red-eye and could just lay on a couple of seats. About 20% felt actually better during the flight, and 10% felt worse. Right? So, except people who might fly out on a private little jet, all commercial airliners are pressurized to at least 7,000–8,000 feet. The Boeing Dreamliner to 3,000 feet. So, yeah, generally that’s not an issue.
Dr. Friedman: I have the same experience. It’s one of the questions I ask my patients when I’m thinking about whether or not they have a leak, is how do you feel in the airplane? And in general, I find that patients who have SIH feel either just as good or just as bad when they’re on the airplane, or better. Most of them, I find, get better. They get better on the airplane. Conversely, patients who have IIH feel worse at altitude. The other thing that SIH patients tell me is they feel better in the swimming pool. So, I ask that one too.
Question: I’m an interventional neuroradiologist. I work in Paris and it’s a question about pathophysiology. I was in one of our conferences several months ago and there was Nick Higgins. Nick Higgins is an interventional neurologist, the first one who put a stent in the venous sinus to treat IIH. He pointed out that there are several clinical situations that share several common features like chronic fatigue, IIH, SIH, or normal pressure hydrocephalus. He pointed out that there are now several case reports that found there is a common feature, this venous stenosis in the cervical region. He advanced a hypothesis that can unify some cases where this venous stenosis, both in the dural sinus and also in the cervical region, in the presence of this stenosis we can have different clinical situations according to compensation processes. So you can have a skull-based leak and you can have a normal hydrocephalus but symptomatic for spontaneous CSF [leak], or you can have a leak at the spinal level. So you can have an SIH, or you can have another patient that doesn’t compensate with glymphatic or lymphatic system and then develop a clinical IIH. The common point is this venous stenosis. There are some case reports now that, for example, there’s a spontaneous spinal leak that was treated by a stent, or I don’t remember if a stent in the jugular, or they decompressed the bone impression on the venous , and the hypertension just went away, the clinical situation. Or a patient with chronic fatigue that was in bed for several months, they stented the vein and the patient just healed. So can you comment on that? Do you think it’s a valid hypothesis, something we can look into or not?
Answer:
Dr. Stoodley: So look, I think it’s perfectly reasonable to connect intracranial venous stenosis with impaired CSF absorption leading to increased intracranial pressure that then manifests either as IIH or increases the propensity for developing a CSF leak. I think treating intracranial stenosis in that setting is perfectly reasonable. But I would emphasize that it’s really the intracranial pressure that’s the problem. It’s not the venous flow itself. It’s only if it causes a pressure problem. The difficulty I have with the extracranial, so cervical venous stenosis, is that in the normal situation the venous outflow from the brain goes through the internal jugular veins when we are supine. When we are erect, the jugular veins collapse because they’re actually under negative pressure, and the venous outflow is actually through the spinal epidural veins. It’s not actually through the jugular. And so I have difficulty connecting a jugular venous stenosis with the same pathophysiology as intracranial venous sinus stenosis unless it is demonstrated that there is an impact on intracranial pressure. Now a lot of these patients, you find that there’s a lot of—when they do have an extracranial venous stenosis—there are a lot of collaterals that develop. You see them on MR venography. But there are a lot of patients who come to us saying that I’m symptomatic from this, and they think that it’s the blood flow that’s the problem. But I’m still of the view that it can only be a problem if it affects intracranial pressure. So if you measured intracranial pressure and it’s normal, then the venous stenosis in the neck is not problematic unless it has caused intracranial hypertension and a CSF leak in the past, which is pretty uncommon.
Question: Thank you very much, and I just want to highlight a patient I had recently who had superficial siderosis infratentorial. And, as we know, we expected durapathy, and to my surprise, when I did the myelogram, I actually saw CSF-venous fistulas. And then I had the same problem with Dr. Beck—reading your paper, I just wish it was in tabulated form, Dr. Schievink there. No, no, I’m just joking. But my question is, what was your experience with those five patients with the CSF-venous fistulas with siderosis? Did they get much better? What was your ultimate hypothesis in the end? Was it leaking back from the fistula, or was there some other durapathy? I wonder if I should be looking for something else in those patients.
Answer:
Dr. Schievink: No, I think there’s pretty good evidence that there can be bidirectional flow through a CSF-venous fistula. It was pretty straightforward to say that their leak was gone, and I don’t remember exactly, but either two or three out of those five patients also had other MRI features of SIH, and that went away after surgery. None of those patients had had other SIH symptoms. So the other ones we’ve just been following with serial MRIs, but it’s a little bit difficult, right? Particularly the patient with a really high hemosiderin load on their MRI. I mean, it probably can get 10 times worse before we would see it on an MRI scan. And of course, we would follow their symptoms of superficial siderosis.
Question: Which brings me to our next question from the virtual audience, and I think I will ask Dr. Wolf: which should be the end point to treatment success? Only clinical and whole CNS MRI might not be enough, especially in oligosymptomatic patients—for instance, residual intermittent auditory symptoms, no headache.
Answer:
Dr. Wolf: Absolutely agreed. I would yet say that in this disease we have a kind of ground truth that there’s an open leak and a closed leak. I think we always should make sure that this is the case, and in the long run, all of our data shows that there is something that changes in between. I think there’s the complexity of the system. It’s like defining a syndrome and working from there. I think we are now, in these days, we have so many more options. We really need to go into biomarkers as well. We need to take quality of life measures, symptom measures. We all want to end up helping the patient finally healing and getting better. But endpoints chosen at this time that just marker the clinical outcome, I think that draws us back. We have now this perfect disease actually in a research way. We really need to look into biomarker measurements and try and understand and possibly even get better in other diseases, spread out, translate this to other headache disorders. Why does migraine react to changes in pressures and so on? Why can you tell by the weather that migraine starts? So I think we should come up with more questions and not try and confine things. What do you think?
Dr. Schievink: Well, actually, I was going to ask Dr. Beck what he does on his patients with superficial siderosis. Let’s say they have a ventral leak, you repair the leak, the post-op MRI shows the leak is gone, symptoms remain the same. Do you do postoperative CSF analysis after a period of time to show that the red cell count is low, xanthochromia has resolved?
Dr. Beck: Unfortunately not. No, we do surveillance together with neurology, only clinical and imaging based, not based on blood or CSF biomarkers.
Unknown Speaker: I have not wanted to dominate microphone time, but just to touch base on the barometric pressure question, particularly about flying, but also atmospheric pressure and the impact on patients with CSF leak. I’ve been monitoring barometric pressure change every two minutes for the last 18 months and its influence on my symptoms, and initially the data was showing that it wasn’t an absolute measure of barometric pressure, and it wasn’t particularly high pressure or low pressure that impacted it. It was the rate of change. So if the barometric pressure changed more than 0.8 of a hectopascal per hour, it would instigate an acute neurological event related to my symptoms. Conservatively managing connective tissue integrity has improved that to the point where I now only have an acute neurological event with barometric pressure change of two hectopascals per hour, which happens less frequently. So I have fewer acute neurological events. I’m in discussions with other patients about barometric impacts on their particular symptoms. They notice it as well. Driving in mountains, for example, you’ll find patients that can’t handle being in a car. I’m particularly interested in talking to doctors and patients about creating collaborative research projects where we can ask the right questions, collect the right data, and find ways of understanding this particular aspect of this particular disease. But I’m not sure whether anybody else here has any suggestions for how to fund this research or plan this research or do this research, and how we can collaborate and start understanding these bits better.
Unknown Speaker: I’ll second the observation with what my daughters were patients. A change in barometric pressure seems to affect their symptoms more than any absolute pressure.
Dr. Friedman: That’s not unique to SIH or IIH, and it happens with migraine as well.
Unknown Speaker: There’s a crossover of misdiagnosis. I was misdiagnosed with severe constant migraine with neurological manifestations when it was CSF-related. So a lot of the things that are understood, a lot of the problems I’m finding in the epistemology of these conditions is how do we define what the condition is? How do we diagnose them? And how do we deal with separating people into the diagnostic boxes? So I think there’s a lot of confusion across there.
Question: I have a question to Wouter and Niklas Lützen. These lateral tiny little leaks, do you think Niklas would have found it with ultra-high beam cone beam resolution CT fistulas? And a second, are they all better? So after you—27 patients is a lot—after you closed them, the SIH was gone. That’s a really good question.
Answer:
Dr. Schievink: About 40% of those patients had a normal brain MRI, which is quite a bit higher than the average patient with a CSF leak, and the resolution of symptoms was less frequent than what we see in patients with a more obvious leak. I do think that a dynamic CT myelogram would have shown that. As a matter of fact, there were four people that we operated on who also had a dynamic CT myelogram done at another institution, and you could see it on their myelogram too. On our myelogram, we do a digital myelogram. We pay a lot of attention to that. Then they go to the CT scanner just supine, and we only saw it on our post-myelogram CT in two out of those 31 patients.
One question to that. You said you haven’t seen them drain into the veins, these small tiny leaks we are talking about. What do you think, why this happens? Why do we not see them draining into the veins when they are CSF-venous fistulas?
Dr. Schievink: I mean, I don’t have a perfect answer for that either, but it certainly looks like part of it has to do with the volume of the leak, right? They seem to be smaller veins. Obviously you don’t see the vein on the digital subtraction myelogram. So I do think there’s a relationship between the volume of the leak and what we see on a scan, or how severe the symptoms are, or how obvious the brain MRI is affected by it. And then sometimes we think, boy, maybe is this like a physiologic CSF-venous fistula. That’s possible, right? But when we’ve done studies on other patients with, for example, normal brain MRIs but just orthostatic headaches, we don’t usually see that.
Dr. Beck: These are super interesting observations, Wouter. Also these tiny little leaks. And maybe, if I remember correctly, see these very nice images done by Marcel, are done under general anesthesia. So you have positive pressure over ventilation. This could be one explanation. This is why I was asking, because you are doing the CT myelograms, ultra high resolution cone beams with spontaneous respiration. And this is the same what I mentioned. Why do you see a vessel-like heartbeat-like flow of contrast into the vein, and during surgery with positive airway respiration, patient lying on the belly, it’s tough to see. It’s a huge difference. And maybe these tiny little findings, you nicely have shown in your latest submission, could be visible in spontaneous respiration. And then there is the topic, what’s physiological? This is so super interesting. We’ll see. Very good observations.
Question: I have one more question. I would like to come back to the CSF-venous fistula and the associated siderosis. Can you please explain why do you think we have good evidence that the flow is going in both directions? There’s a new publication from Ian Mark who was looking at 100 patients after embolization, and Onyx never migrated into the intrathecal space. So this would be a good argument to say the flow is only going in one way and not into the other way.
Answer:
Dr. Schievink: Yeah, I don’t think that’s a very good argument, because I don’t know if you’ve ever seen post-embolization scans from the Mayo Clinic in Rochester. They’re really, really conservative. No, I’m kidding. They inject an enormous amount of Onyx. But Onyx basically is rubber, it’s not a liquid. So I think it’s just a totally different situation.
Unknown Speaker: But it’s interesting, because when you go with the microcatheter into this place, you sometimes have high pressure when you inject Onyx and then do another contrast injection. This is sometimes high pressure. So I would expect, if there’s a two-directional way, I would expect to see it going into the intrathecal sac. So what is your argument to say that we have good indications that it is flowing in both directions?
Dr. Schievink: Well, because they develop superficial siderosis, right? The longer the CSF-venous fistulas are present, the higher the frequency is of finding superficial siderosis. And obviously when you cut the vein it usually bleeds pretty profusely.
Unknown Speaker: Just going back to the case that I had in my superficial siderosis case, going back to what Niklas was saying, with that case I was curious to see if the Onyx would go intrathecally. And I was very thorough, extremely, tons of Onyx, and I had not seen a case yet where the Onyx will go intrathecal. Injecting contrast, it doesn’t go intrathecal. Now after almost 100 cases. So that’s why I was just curious to see what you see in the surgery. Maybe there’s something else going on. But yeah, it’s very curious. I mean, I also use the thin Onyx. We have two different preparations of Onyx, 18 and 34. I use the thin one to make sure it penetrated thoroughly and it doesn’t go intrathecal. I think in Ian’s paper there is certainly a valve phenomenon there. Why that is, I don’t know 100%.
Unknown Speaker: And even more, sometimes we also use a balloon, right, so?
Unknown Speaker: Oh, yeah. Each one of mine I’m extremely sure we put a lot of pressure while we are injecting. I don’t know.
Dr. Stoodley: I just like to point out that CSF drainage into the venous system in the spine is normal, as it is into lymphatics. It’s part of the normal absorption process of CSF. Just the same as in the head, there are arachnoid villi that we think are the main pathway for CSF to get into the intracranial venous sinuses. Those structures are around spinal nerve roots and probably—I mean, we don’t know—but they may well be the basis for anatomical formation of a fistula. So, whatever the valvular mechanism that’s underpinning that normal process is probably still there to some degree for most cases, which would explain whatever that valvular mechanism is. And that’s controversial, but whatever it is, that probably explains why it is a one-way flow. But there would be circumstances where that valvular mechanism would be overwhelmed, and then blood could come back through, right? But that’s the minority of cases, isn’t it?
Dr. Beck: We cut out several veins, CSF- venous fistulas, sent them to pathology, and found no valves. We found no mechanical obstruction of any flow back and forth.
Unknown Speaker: Just wanted to mention our observation about flow in CSF-venous fistula, and it is incredibly intermittent in our experience. We can do a DSM myelogram, and what we do is we proceed straight to high-resolution cone beam CT while the patient’s on the table. And if you do it quickly, you will see the paraspinal vein opacified. And if you delay or try to complete the DSM study before going to a cone beam study, you may miss it. So the flow of these things is just so incredibly intermittent.
Dr. Wolf: Maybe one argument for the both-wave flows might be that at the time you pressurize the vein, it may collapse, same as the jugular vein, and just cause a collapsing resistance, and that’s why it doesn’t transduce into the CSF space. That was just one thought. I think it hadn’t been discussed that it might also be the hypermobility within the intrathecal space causing microbleeding. I think this was not an idea I came. I think I’ve heard it before. But probably Marcus can tell us whether this is true or not, because do you see siderosis in any Chiaris? I think I’ve heard the argument before that the siderosis might be caused by the hypermobility of the brain within the intrathecal space, which we know occurs in SIH and in Chiari. So, causing microbleeds because of some mechanic stress to the subarachnoid small vessels. But the main argument could be your observation for many many Chiari, who show exceedingly high hindbrain motion. And so my question to you is, have you ever seen siderosis in those? Because that would be the argument, is that not within?
Dr. Stoodley: That’s a great question. I’ve never seen.
Unknown Speaker: I just wanted to say that there’s some original research from, I think, the 1970s and 1980s on CSF resorption and spinal nerve root arachnoid granulations is through vesicular transport, so it’s not a mechanical bulk flow valvular-type mechanism. It’s vesicles.
Dr. Stoodley: I skirted around that because it’s probably that at least in the head it’s a transcellular flow, and it’s probably not just vesicular. The channel opens up the whole way through the cell, so it’s not a pinocytotic vesicle that goes through the cell and opens up on the other side. It’s the channel that opens up through the whole cell, and CSF goes directly through.
Question: I’ve got a question that’s just been touched on already, but how sure are we that the bleeding in superficial siderosis is coming from the dural defect or the fistula there? And could it conceivably be due to brain sagging and traction on veins around the cerebellum, or mechanical distortion of venous structures around the brain that then bleed?
Answer:
Dr. Schievink: That’s certainly possible. And early on, we kind of struggled with that. As you probably know, if you do a high-volume lumbar puncture or you put in a lumbar drain and you remove an excessive amount of spinal fluid, you can get what we call a remote cerebellar hemorrhage. But that’s usually not in the typical location of infratentorial superficial siderosis. It’s not the superior cerebellar vermis, but it’s more in the cerebellar hemisphere.
Dr. Beck: I only can tell you what I’ve read in the last days in preparing on this talk. And one theory is that it is a kind of a cloaque [cesspool] that the CSF turn-around is always passing the vermis, and this is just the place where the most CSF flows by, and this is just the place where the most iron and hemosiderin and ferritin is deposited. So that’s at least what I’ve read in the papers, but Horst probably knows more.
Dr. Urbach: Yeah, I think because the Bergmann clears the Purkinje cells are extremely susceptible to brain iron, and maybe they suck the iron from below. We know the blood comes from below, and we have the most atrophy in the upper vermis where these cells are located. So that may be the reason. We do not really know the normal CSF flow from downwards upwards, but I think the stability of the Purkinje cells are the reason why there is so much atrophy. What we don’t see is the layering on the seven and eight nerves, because that’s the hearing difficulties, and we have a high — and if you have a higher amount of superficial siderosis we also see it in the hippocampal layer in the sulcus hippocampi. So we only see the tip of the iceberg, and we only see it in the cells that are extremely susceptible to that iron overload.
And another question that I have, or the idea that comes to me, we are now facing the problem of superficial siderosis associated with Lecanemab treatment for Alzheimer disease, and that is related to the amyloid depositions of amyloid 42 and 40. Would we have ferritin increase, ferritin in this situation? Does anybody know that? Is there a difference in ferritin in infratentorial hemosiderosis compared to Alzheimer disease-related CAA and CAA-related inflammation? It would be interesting to find out for the future. Does it take the CSF from below, which we do in patients looking for amyloid in Alzheimer’s disease? So that is a — maybe we can differentiate or separate both entities, Why is there ferritin in both patient groups?