 So, today it's a double on neuro-ophthalmology. So I'm going to just give a really brief update on idiopathic and acrenial hypertension, and I'm going to highlight some controversies along the way. But I'm going to first start with the typical case of a 28-year-old woman who has headaches. They're increasing. They're daily, and they're disabling. And she also has transient visual obscurations. She hears noises or whooshing noises in her head, and she has pain between her shoulder blades. She has good acuity, no afferent defect, her neurologic examination is normal, and her general examination is notable for her obesity. Her visual fields show enlarged blind spots and also some nasal loss. And when you look in the back of her eye, she has bilateral papillodema. So you're thinking she's got some kind of intracranial hypertension. And the first point I want to make is that whenever we see one of these patients, well, you know, she's obese and she looks like she fits the stereotype, we want to be thinking about secondary causes of intracranial hypertension as well as primary causes. Today we're going to talk about primary causes, but it's really important to rule out venous sinus obstruction, look at medical conditions, and consider medications that she could be on like the tetracycline, minocycline, norplant, and so forth. But she had a normal MRI scan, except that there are a few findings, and I tell the residents to always look for dilated optic nurseries on the MRI scan. You may even see the papilla bulging into the globe. You also want to look at a sagittal view because an empty cell is frequently seen. And with many of these cases, we're getting venograms, MR-venograms, which can be done exactly at the same time as the MRI. And one of the findings that is seen sometimes in the venogram is some irregularity of the transverse sinuses, and some people feel like that narrowing of the transverse sinus can actually be a sign of increased intracranial pressure. You can't stop just with the scan. You have to go on and get a lumbar puncture. And her opening pressure was 350, and she had normal protein glucose in cells. So this woman meets the criteria for idiopathic intracranial hypertension. Her symptoms are only those of increased intracranial pressure. Her signs are only those of increased intracranial pressure. You can sometimes see a six-nerve palsy, rarely a seventh-nerve palsy, and sometimes you can see some trigeminal abnormalities. You have to have a documented elevated intracranial pressure, and this is really important. You have to ask how was that pressure obtained? Was the person lying on their side with their legs outstretched or could have been falsely elevated? And that's going to be important when we talk about idiopathic intracranial hypertension without papillodema. The CSF must be normal. If it's not normal, then you've got some other process going on, and you really have to look carefully for other causes on imaging for intracranial hypertension. So what is IIH? As you know, this disorder has undergone a metamorphosis of terms that used to be called meningitis serosa, then it was pseudotumorcerabri, and then it was benign intracranial hypertension, and we're settling on, at the moment, idiopathic intracranial hypertension or primary intracranial hypertension. It really is a disorder of women, six to one. No question about it. About 90% of the people who have this have headaches, about 50% have some kind of visual disturbance or auditory disturbance, and if you ask about wishing, and if you really ask the question, that percentage will go up. Papillodema is almost universal, although there are some cases that don't have papillodema, and it's usually associated with obesity. Now you have to ask yourself, what's at stake here, and why do you even care about it? Well the first point is that there's visual loss, and while acuity is not lost, and blindness is not common, visual field loss is actually present in at least a third of the patients. And about a quarter, when Dr. Corbett went through all of his cases, over 20 years had permanent, severe visual field loss, and despite all of our treatments, even modern day treatments, 14 to 35% of people will have visual function or visual field loss. The second thing is, it's a chronic condition. At Iowa, they reviewed 410 patients, they had 20 people followed for more than 10 years, and about half of them worsened after being stable. So people can be toodling along and be doing really, really well, and then all of a sudden they start having headaches and visual loss, and then they're having the condition back again. And their quality of life is definitely diminished. Julia published in Neurology about 10 years ago, a wonderful article about, and was the first article to show that the quality of life in this condition is very low. And recently, three years ago, the Penn Group published this study, which was actually exactly what we found, they just used some different methods, but showed that the physical quality of life, emotional, so depression, anxiety are higher in this group, and their visual quality of life is also lower. So this is an important condition because it affects people's vision, but it also affects their quality of life. Now I did want to mention a couple new things along the way, one of these is men. Men do get IIH, it's not as common, and this recent paper by Beau Bruce showed that many of the men may have testosterone deficiency, and I think this is a really big one, obstructive sleep apnea is more common in men. So if you see a man with IIH, you should be thinking obstructive sleep apnea. They used two questionnaires to determine that people with IIH and men had a greater incidence of obstructive sleep apnea, and also a higher ratio of androgen abnormalities on a questionnaire. Now there are many controversies, I mean we could spend an hour just talking about the nomenclature of this disorder, we could talk about imaging controversies, but I'm going to highlight basically three. One, I'm going to ask the question, can there be idiopathic intracranial hypertension without papillodema? And I know that there have been more than one patient coming from triage with this question. Then I want to talk a little bit about obesity and the treatment of obesity and a study that we're going to be doing while we are doing. And then talk a little bit about endovascular treatment, which is a pretty hot topic. So let's take that same person that I introduced you to at the beginning of this talk. And she's obese, she has headaches, she has whooshing noises in her head, her MRI scan is normal except she's got a little dilated nurseries, she's got a partially empty cellar, she looks exactly like that person. Only you look in and you see this, she doesn't have any papillodema, okay, neither I. But her lumbar puncture shows an opening pressure properly done of 300 millimeters of CSF. So does this woman have IIH? So the first question you have to ask yourself is, can you have high intracranial pressure without papillodema? And there's some lines of evidence here that I think are pretty clear. First, if you take all people with brain tumors and ask the question, how many of those people get papillodema, they've got space occupying lesions, they've got high intracranial pressure, not all of them get papillodema, probably less than half, okay. Trauma, Jack Selhorst in 1985 sat in an intensive care unit in a busy city hospital looking at everybody's fundus who had had a bad head trauma. And he followed them through their stay in the ICU monitoring their intracranial pressure with bolt monitoring and went to look to see if they developed papillodema. And he followed them for days out. And he found that about half or less developed papillodema, even though he was looking every single day. And these people had documented high intracranial pressure. And then I think another really good line of evidence is we often see people with asymmetric papillodema. So here's the same person and on one side maybe you could make out grade one papillodema, but on the other side you've got grade four with obscuration of all the vessels, 360 degrees. You've got two different grades of papillodema in the same individual with the same high pressure. So this has led people to believe that the pressure is transduced along the optic nerve in the dural space. And that some people's anatomy may not allow for people to have pressure developing behind the globe and giving axoplasmic stasis, which is what papillodema is, axoplasmic stasis. So the answer to this question is yes, there can be high pressure without papillodema. Now the waters became muddied when the headache folks got involved here. And over the last 15 years or so they've been doing lumbar punctures on people with chronic refractory headaches. And in one center they found 15% of people with chronic daily headaches, they just all comers did lumbar punctures and they had pressures up to 450. Now this study was always criticized because they said, oh, you'd never had a neuroophthalmologist looking. You were just looking at an undilated pupil. Maybe all these people were rebound. And so a second study was recently published of 60 people with chronic migraine. And 10% of these people had increased intracranial pressure. And all of them had BMIs greater than 25. And their conclusion was that in patients with BMIs over 30, you should at least consider idiopathic intracranial hypertension if people have a high, have a lot of chronic migraine. So we did a study that we published last year. We took all of our patients with IIH and we chose, we found 20 people who met the criteria of IIH without papillodema. And we matched them to 20 people with papillodema. And all of these people were examined by a neuroophthalmologist. All of them had opening pressures done by Judith or by a neurologist that we trusted. And here's what we found. When we compared, I mean, most of these people were women, obviously. Most of them were obese. The BMI in this group was a mean of 35. They were almost identical. The two differences were the people without papillodema had a slightly lower intracranial pressure mean of 309 versus 373. We didn't pick anybody that wasn't, it had to be higher than 250 millimeters of CSF. The other thing was that these people had more lumbar punctures. Many of them, because nobody believed that that's really what they had, was that they had intracranial hypertension. They both had migraines. They both had depression. And we couldn't find any differences in their symptoms. They all had headaches, visual obscurations. Maybe the IIH with papillodema had a few more visual obscurations. They had the same pulsatile tinnitus, even a few with diplopia. And their headaches were very similar. We really couldn't tell much difference between them. The ones without papillodema maybe had more auras, but otherwise they were very, very comparable. Their acuities were by and large very good. The ones without papillodema did a little bit better. The ones with papillodema had a little fewer. Some of them had decreased acuity. And the visual fields were interesting. So the ones without papillodema, as you would expect, had a normal visual field without an enlarged blind spot and the ones with papillodema had enlarged blind spot. But here's what we didn't expect. We didn't expect this large number of the ones without papillodema to have functional visual loss. So these were people who came in with constricted fields, no papillodema. And at the tangent screen, the one meter, the visual field did not expand from one meter to three meters. So they had functional visual loss. And this has actually been shown also in a large study of IIH, where they found about a 6%, at least a 6% rate of functional visual fields in a large series of people with IIH. So one take home message for us is always to be careful that the visual field is not functionally constricted in this group of individuals. So we know that this is a chronic disorder. Dr. Corbett went and retapped patients 20 years later and found that people tended to have high endocrineal pressure despite no papillodema years after the diagnosis was made. Annette Kessler in Israel has targeted the recurrence rate to be at least 38%. The problem with recurrence is you don't know when it ends. Many of the patients I follow have it for years and years. And if I take them off their diamox, their headaches are back, their symptoms are back, their papillodema gets worse, so it's like it's a chronic condition. And this was corroborated also by others who have looked at this as well. And you have to ask yourself, how many of these patients continue to have increased intercranial pressure without papillodema? And the answer has not really been determined yet. So I think the IIH without papillodema exists. It's probably not common. I don't think it's as common as 10% of every chronic daily headache patient. I see headaches all the time, and it's not 10% of my practice in a headache clinic. But I think it's difficult to diagnose, and I think there's some caveats. We have to be sure that they have truly elevated intercranial pressure, that the pressure was measured properly, that the person wasn't fell selving. They weren't hypoventilating. I think you do have to look, you can look at the MRI scan to help you with these cases. I especially like to look for empty cellar, narrowing of the transfer of sinuses. And then I think we have to watch for constricted fields because they can have functional visual loss. And then I think this point really hasn't been made enough that this really is a chronic condition, and that people can have this condition for years. And while some people can have a self-limited one time event, there's a whole group of these people that have it for a long period of time. So going from IIH without papillodema to why does this occur, there's some work being done about the genetics of this disorder. Judith has given a very nice grand rounds about vitamin E in this disorder. I'm just going to touch on obesity. So I just want you to watch the browning of America, the fattening of America. This is in 2000, 2001, 2002, 2003, 2004, 5, 6, 7, 8. And we in 10 years, in 20 years have really gone from a fairly lean country to a fairly, I mean we're, you know, over half the country is greater than 25 to 30% obese. This is really an epidemic. So does obesity have anything to do with IIH? Well, first of all, the first line of evidence is that 90% of the people who have it are obese. Case control studies show that that's one of the factors that separates out people with this disorder. And if you can lose weight, you can go into remission. And of course, obesity has numerous complications. We've already brought up sleep apnea, but there's insulin resistance and other comorbidities with obesity like polycystic ovarian disease that can make this diagnosis and this condition very difficult for these individuals. It is really clear that the incidence and prevalence increases as you look at obesity. So if you take a normal weight population, the incidence is about 3.5 per 100,000. As soon as you get overweight individuals, it goes up. And when you have obese individuals, it's 20 per 100,000. That's the same incidence as multiple sclerosis. So it's very common, you know, and we, it's pretty common in obesity. Moderate weight gain seems to precipitate this. And Annette Kessler has pointed out, this was I think an ophthalmology just this year, that the patients who have IIH tend to have the pear-shaped body or the lower fat body as opposed to the apple or mid-shape, the one you see often with metabolic syndrome. And there's some rationale for people having obesity causing or being related to increased intracranial pressure. One is some people believe that the abdominal adiposity affects the central venous pressure. And it is true that some individuals do have increased central venous pressure. And we do know that venous hypertension will lead to increased intracranial pressure. And then there's a group that thinks that the inflammatory markers that come with obesity are associated with setting up IIH. Now the first question you have to ask is, does IIH increase the pressure in the brain by itself? And James Corbett did a study where he showed that there was maybe a little bit of elevation of pressure, and so that's when we started adopting pressures have to be greater than 250 in obese people. So this study, which was done in Australia and England, showed kind of a normal distribution of CSF pressures. But these were normal people without papillodema, and even in normal people, you can see that there can be people normals with increased pressure. Then they stratified those people from underweight and normal. And while there was a trend for the overweight and obese people to have a slightly increased incidence of higher pressures, it was not statistically significant. So the normal pressure is in this large study between 10 and 25. Now I don't know if you saw this study, but this came out of Penn just in the New England Journal this year, where they looked at children and asked what's a normal pressure in children. And it was done at a children's hospital, people who were coming in for various reasons for lumbar punctures, and they excluded people with known high entercranial pressure. And look at the normal range in pressures. These were kids with no papillodema going from 80 millimeters to 450 millimeters. And one thing that they found that is, I think, important is that there were some things that caused pressures to be elevated. And one was sedation. So when kids are sedated, they hypoventilate a little bit, and their pressures can be elevated. And so you really can't accept that high pressure in children if they've been sedated. You really have to be careful about that or monitor it carefully. They also found a slight correlation with BMI. As the BMI went up, the opening pressures got a little bit higher, but it wasn't a one-to-one. And the pressure really was all over the place for all ages. So I think this is kind of cool that finally we have a study that actually shows what normal pressure is in children. So how about obesity? Should we say that obesity is the cause of IIH? Well, I think, first of all, we have to explain the non-obese cases. Not everybody's obese. You know, 10 to 20 percent of people are not obese. And in children, 70 percent are not obese. And in many centers across the world, very few people are obese with this condition. So there's a lot of things that we really don't understand. Beau Bruce did a study this year that showed if you take all the non-obese patients, more of them are likely to have medication-related IIH. So in your non-obese patient, you better look a little bit more carefully for a secondary cause. I think the link is there. It's not fully understood. And as we see more obesity in our country, we're more likely to see IIH. And we probably really need to repeat some of the incidents and prevalence studies. Certainly, this is well proven that obesity is linked with headache chronification, meaning that people who have episodic headaches can develop chronic headaches without high pressure due just to having obesity. Now, what about treatments? I'm going to spend a couple minutes now talking about treatment. There really are no double-blind masked controlled trials in this disorder. Data is really case series. And our goals of treatment really should be to resolve the condition, prevent visual loss, treat the headache, improve quality of life, and then get people back to work, because a lot of these people end up not being able to live their lives. Some people would argue you wouldn't even treat somebody who doesn't have symptoms or signs. There can be people who come into the clinic who have papillodema, diagnosed IIH, but have really no headaches, no visual loss, no nothing. You really could argue, do you really need to treat those people? Because you may not. For sure, you should at least think about depression because that's a higher incidence. Ask about sleep apnea using the Berlin questionnaire. And if they're overweight, you have to counsel them about weight loss. Because there have been many studies, Len Johnson and Mark Coopersmith have shown that just losing a modest amount of weight can actually bring about a remission. And the evidence for this really has been known for a long time. Back in the 60s, Greer, who is a kind of a pseudotumorcerabribe, Maven, when it was called Benign Intercranial Hypertension, advocated for weight loss, then Newberg, she was an internist in the 70s. And she had a bunch of these patients and looked in their back of their eyes, some of them she took photographs of, put them on a rice diet, about a 600-calorie rice diet for several months. And she showed that they were able, in three months this person lost their papillodema just by going on this rice diet. So this is the first evidence we had that diet actually worked. Dr. Sugerman in Virginia does bariatric surgery, and he was finding that his bariatric surgery patients who underwent bariatric surgery for their IIH had a definite improvement in their condition. And then Len Johnson and Mark Coopersmith found the same. This summer, this study was published in the British Medical Journal. And this was 25 women with IIH. They followed the women for three months and got a baseline on their headaches, on visual situation, et cetera. They put them on a 425-calorie diet for three months. Can you believe anybody could stay on a 425-calorie diet for three months? That was the most amazing part of this whole study. And then they followed them up after the diet. But this is really incredible. I mean 425-calories. So they lost weight. They did lose weight. So their weights definitely declined. Here they are at the beginning. And then they went on this diet. And then they kept the weight off. So all of them lost weight. And their intercranial pressure went down, which was really remarkable, on average about 80 millimeters or 8 centimeters. And their headaches got better. Their papillodema improved, but only four developed completely normal intercranial pressure at the end of the study. So this is really the first study where they used a case. The cells is a case controlled, but it's the first really prospective cohort study that's ever been done in this condition showing that weight loss really does improve the headaches. It improves the intercranial pressure. It improves papillodema, et cetera. So we're embarking because in the Cochrane review, there's no adequate therapy, no evidence for any adequate therapy. We are embarking on the idiopathic intercranial hypertension trial, IIHTT. And it's a randomized trial with mild visual loss. And it's comparing diet alone versus diet plus acetylzolamide. And the hypothesis is that acetylzolamide plus diet would be superior to diet alone in restoring vision to in people with mild visual loss. But at the same time, we're looking at genetic factors, proteomic, genomic factors. We're looking at metabolism factors and vitamin A in the serum and CSF in these individuals. We're one of 39 sites across the country. As you can see, most of them are on the East Coast. So we're holding up the West Coast and Intermountain area. And this study is just underway. We've enrolled two people into the study. And it's just kind of gaining momentum at right now. Well, aside from weight loss, what else can you do with these folks? Acetylzolamide has been used for, you know, 30, 40 years. And it's not an easy drug to use because it's got a lot of side effects. But for many of us, we feel like it's pretty effective. And the biggest problem is using the correct dose. Most people need at least one gram. Even children need a higher dose than what they're often given. If they can't tolerate acetylzolamide, we also use methazolamide, which has fewer side effects, and sometimes lasix or furosamide can be used. Then there are other medical therapies. Topiramide, which is an anticonvulsant approved by the FDA for migraine, will also in decreased intracranial pressure a little bit because it has some carbonic and hydrazine abition. And in one study, it was as helpful as acetylzolamide. So if you have somebody with a lot of headaches but not so much visual loss, topimaxima or topiramate might be a good choice of medications. Some people think steroids are indicated in this disorder. The problem with steroids is as you withdraw them, there's all kinds of rebound in intracranial pressure. So most people kind of avoid the steroids because there's weight gain and you get diabetes and everything else. So we probably don't use it. For a while, there was some interest in these cardiac glycosides like digoxin, but that's gone out of the favor. Octreotide does work, but it costs a million dollars to put somebody on this so you don't want to do that. And some people with polycystic ovarian syndrome have had benefit from metformin and diet. This is in women. Now, there are surgical treatments if people's vision drops. You may not think about lumbar puncture as a surgical treatment, but there are times when we use lumbar puncture to temporize the situation, get people out of this acute situation. If they're losing vision, get them in the hospital, put a drain in, get that fluid off of the nerve right away. You can do that quite quickly. We don't use sub-temporal decompression. This was a procedure where they actually took the temporal bone off the brain and left the brain swell on the pressure. Well, you can imagine the unsightliness of that. So nobody really wants to do that. The two procedures that are most used are shunts. And the shunts are gaining some popularity, again, because there are adjustable valves where you can actually dial in your pressure of what you want, because some of the problems with these shunts where they'd over drain, under drain, and you could never get the pressure just right. So they're gaining popularity. Optic Nershift Fenestration, we still use that. And I'll show you some data that supports our use of that. And then Gastric Bypass. For some of these people, there's so many new procedures, lap band therapy, et cetera, that are pretty benign, that really do help with weight loss and probably are more curative. And then the new kid on the block is Venus Stents. How many of you have heard of Venus Stents for IIH? Well, good. So you're going to learn something this morning. So Venus Pressures. For years it's been known that if you increase your Venus Pressure, you will increase your Intercranial Pressure. This is 1930s work. Direct Correlation. And so about 15 years ago, John King in Australia noted that people with IIH had Venus Hypertension by measuring their Venus Pressures in their Sagittal Sinus Transverse Sinus. And if he took the fluid off, so let's say he did a lumbar puncture after he measured the pressure, the Venus Pressure would dive down or drop. And so he and a bunch of some of these guys in Australia, they'll try anything, and they did. And they put a stint in these people with sinuses that look like this. Here's this beautiful open sinus. And they found, voila, the Intercranial Pressure went to normal. So they thought, well, we got a new treatment for Intercranial Hypertension. And so they started doing this dramatically and have a large series, which I'll show you. All right. Now, this, however, is just somebody who, I just want to show you kind of somebody who had a lumbar puncture who had a change in their Venus Sinus. So here they are at baseline. They have this kind of tight-looking vein transverse sinus vein. Then they do a lumbar puncture, and that vein actually opens up. They do a second lumbar puncture and lower the pressure even more. It opens up more. And then after the lumbar puncture, they've put in a shunt to keep the pressure down and that vein stays open. So it's clear that getting rid of the spinal fluid also will open up the vein. So you can open up these veins by putting a stent in, or you can just lower the Intercranial Pressure and get those veins to open up in many cases. So here's a case of the stent. And then the problem with these stents is, okay, you put it in and here's one week later the person's already getting a little stenosis right here and the pressure is going back. I mean, you can't keep putting stents in because you get into trouble. Well, I kind of tabulated all these stent cases, and Matt Thertell reported 22 of these. He also was from Australia. Almost, these are all Australia cases. And you can see that they improved. Their papillodema mostly resolved. But there were complications. Many of them had thrombosis. One person got a subdural hemorrhage, restenosis, and now there's been one death in the Australia series. So it's not for everybody. Steve Felden from University of Rochester did a nice meta-analysis of what procedure is the best for vision in IIH. And he covered stent placement, VP shunts, LP shunts, optic nourished heat fenestration, and in both acute and chronic cases. And you can see that 80% of people with the optic nourished heat fenestration did better versus all of these other procedures. And granted this is a meta-analysis retrospective review of other people's outcomes, but at least it gives you some idea that probably optic nourished heat fenestration for visual loss is probably still the procedure of choice. Safety, these stents have serious AEs and at least 20%. And death has been reported now. And you can see that every procedure has serious adverse events. Hopefully not death, but you can see that this can be a problem. And often re-operations. Now bariatric surgery, this is just from one series, but a lot of these people do get problems after the surgery, but they have very few re-operations or needing treatment. So stenting I think is not a first-line option until we understand what causes, in what cases can we have reversibility. So if you take the spinal fluid off, that's a much safer treatment than putting a foreign object in somebody's vein that you can't ever retrieve. And we really need to understand kind of the safety issues. And maybe there are cases where with people with fixed tight stenosis that don't go away with lumbar punctures that are keeping the pressure high, maybe this would be a treatment we can do. And for sure we need more controlled trials. I do want to alert you about this problem, fulminant IIH, because this is the one that gets ophthalmologists sued. It's the only condition in neuroophthalmology where I've been asked multiple times to testify is this fulminant IIH thing. These are people who come in bad papillodema. And the problem is delay in recognition. They've had headaches and they've gone to the ER and they went to their primary care and they went to, and they went finally they get to an ophthalmologist who finds that they have papillodema. You just have to jump on this. This is one of those emergencies that you just take on and say, I'm sitting with this patient until they get inertia fenestration. I've got their fluid under control. I might put a drain in at the same time to get the pressure done. But the problem with this is that even you do all this stuff, even give them 2 grams IV of acetazolamide to lower their pressure, IV methylpredicillone, they still end up blind. And the only plea on this one is just early recognition. And so residents who are going out into practice, I'm just warning you that this is the one condition. You don't just say, hey, come back and see me a couple months. If they've got field loss, you got to jump on this one, okay? Because this is really a bad one. So IIH is a perplexing condition. We really don't understand it. And it's probably more common because of our obesity epidemic. We definitely know there's a venous contribution that can't be ignored, but I don't think it should be stented. And I think this is chronic. There's a lot of people who have a chronic form of this disorder that have elevated pressure for years. I do want to tell you about the novel library. Every chance I get, I advertise this joint project with the University of Utah at Coast Health Sciences Library and the North American Neuroophthalmology Society. And on this website, which is free to everybody in the world, we have a patient portal. And you can go to the patient portal and get brochures for your patients on pseudotumor, many other conditions as well. Some of them are translated into Spanish, Hebrew, German, I can't remember all the languages, but there's like seven languages. And at up-to-date, this will take you to an up-to-date search for the recent five years in PubMed of IIH articles. There's a support group website, and there's some other tools. And then these are all downloadable in large print format as well as regular print format for your patients. And so I have left about four minutes for questions here. We can turn the lights on. It's a whirlwind tour, yeah. You know, I love venous pulsations. I love them, I study them, I adore them, I look for them. But no, you can't use them. Because there are cases with actual documented venous pulsations with an opening pressure of 500. And a documented. Okay, so I mean, you can't use them completely. Now it makes you feel warm and fuzzy when you see those little venous pulsations. There is, you know, if you were going to take people and say venous pulsations are present, how many of those have increased pressure? Probably very few of them would, okay? So you can still kind of use it, but it's not something you want to hang your hat on. If you've got somebody who's obese, chronic headache, no papillodema, but you don't know and they've got whooshing in their ears and maybe they've got pain between their shoulder blades and maybe, you know what I mean, you don't know. You may have to do an intercran- you have to do a lumbar puncture to know for sure. Even though I love that sign, you know. There's some people who believe if you saw them and they went away, then maybe that's a better sign, but you really can't hang your hat on it. Yeah, Randy. So fascinating. But it sounds like this is another moment, because I follow some of you, I've got some of you, and you're right. It's a chronic disease. And they put up with their symptoms of dialogues or they quit because they wanted them and then they get the other symptoms back. I mean, well, they can get a dramatic weight loss. They just smolder and keep going on. And I agree with you 100%. That's what's very exciting about the IIHTT trial doing the proteomics genomics, doing vitamin A, because vitamin A has been associated with it, doing genetic studies. I think this is going to be very helpful and may open this up a little bit. But it is complex. I think this is definitely a complex disorder. It's not a easy schmoozy. Oh, yeah, it's just obesity or it's just this or it's just that. Yeah. I don't know of any long-term sequela to the brain from high pressure, okay? In our study and in the Penn Study Depression, you really have to look for depression because that really exists. And that's a brain disorder too, as you know. So I really feel like I'm alert for depression in these individuals, but I don't know of any brain pathology that's long-term in any of these individuals. So it's not like they're going to have difficulties or anything else. I mean, they're going to have problems with headaches and they've got to get those under control, which can interfere with their ability to go to school and things like that. Yeah, absolutely. And if kids, there's kind of an endpoint with kids. I mean, I've followed kids that have it and they kind of grow out of it and they never have it again. You know what I mean? If you can get them over that hump, you're fine. The older kids can be chronic. But those little kids, they really outgrow it pretty quickly. Yeah. Yeah, that's common. You know, 10, 20 percent. So, yeah. Six nerve palsy is common in this disorder. So diplopia is a common complaint. Yeah. You can see a skew. Complex diplopias have been reported. I saw a kid with bilateral six, bilateral sevens and almost a total ophthalmoplegia. I mean, she could raise her eyes a little bit. I mean, it was just dramatic. She got the lumbar puncture and everything started moving again. It was really phenomenal. I've got a, that case I've got published in one of my articles. Yeah. With, without. Well, I mean, that's, it's not rare. You know, when they come in and they've had tetracycline, minocycline, I mean, those are not rare cases. How many total, I'd have to look at our, you know, data, but I'd say, you know, 10, 20 percent. What would you say, Judith? I don't think that number is known of how many would be medication related. Yeah. So if somebody comes in skinny, go after them. And then you just have to kind of get your list out and say, okay, what have you been on? What have you been doing? Well, you kind of have to say what, and if they take drinks, these drinks now, oh my gosh, some of these drinks have like, oh gee, you know, if you look at the ingredients on these energy drinks and vitamin drinks, oh my goodness, it's like taking 20 multiple vitamins every day. Well, so you really can't, you really have to look at what they're doing. Yeah. What's the etiology of? Acetazolamide. Acetazolamide. Okay, acetazolamide is a carbonic and hydrogen inhibitor. It's, right, it's a mild diuretic. It's not a heavy diuretic, but what it does is it keeps spinal fluid from being made in the brain. So it lowers the CSF production. Well, there's, you're right. And some people wonder about that. That's why this study, IIHTT, there's a placebo so they get acetazolamide or a placebo, okay, they get a placebo. So we'll know whether acetazolamide is doing anything. Everybody's getting weight loss, but the big thing is that it's either acetazolamide or placebo. It does work. It does work to lower the pressure, but obesity is probably one mechanism, or having people lose weight is a mechanism, but that's why this study is going to be important because it's going to answer some of those questions. Great. Well, have a good day, everybody. Thank you.