 I have over time, I have over time, you know, the worst of, you know, keynote speakers for this afternoon, and then we'll go ahead and we'll get started with the start-up on the pediometric entrepreneurial hypertension. Thanks, Nick. Welcome back, everybody. Nick did warn Dr. Felden that he was going to have to deal with the post-prandial type. He's the first batter on Dr. Lunch. But he's going to keep us all awake and update on pediopathic entrepreneurial hypertension. For those of you who don't know, we just recently completed one of the best and biggest multi-center trials in the treatment of pediopathic entrepreneurial hypertension, the IIHT, and those results are continuing to come out and I'm just going to address that. Dr. Felden is the chair at the Department of Ophthalmology at the University of Rochester back in New York. He did his residency at Albert Einstein. Or was that Med School? That's what's going on right now. Okay, and then fellowship with Bill Hoyt in San Francisco. Yeah, there's a neurosurgery fellowship on your bio. What's that about? That was your research in neurosurgery. Okay. Physiology. You weren't like doing transcranial orbitization. We did some transcranial work. Dr. Felden is one of those rare individuals who can combine basic and clinical research, clinical care, surgical care, teaching and administration. We're really delighted to have him with us last night. He gave a fantastic talk, kind of bringing together the clinical care and basic science research around thyroid disease and we're so glad he could be with us this afternoon. It's great to be here and to thank everyone for the invitation. I look at Randy Olson as being one of my mentors and we have a great relationship. And I must say that this is really bringing close to Newcastle because your neural ophthalmology group are much more expert in the path of intracranial hypertension than I am. And usually what happens is that the residents begged me to give them lectures on thyroid eye disease. So I never talked to them about thyroid eye disease. So I'm assuming that there's maybe a little room for some getting caught up on intracranial hypertension even though much of the great work has really come out of this institution and then sort of the mother institution at the University of Iowa that sort of gave rise to the interest of intracranial hypertension. So I hope that I'll get corrected for any misstatements I make and we'll all learn. So it turns out that intracranial hypertension has had a few other names in its history. Pseudotimer cerebri, really nobody liked that term because it's had the word timbre in it and people forgot about Pseudotimer. And then the residents would always get confused between orbital Pseudotimer and Pseudotimer cerebri and they'd use them sort of interchangeably which would be great except the diseases are completely different. And then benign intracranial hypertension was actually popular until really the Iowa group said you know it's not so benign patients are going blind and we really shouldn't sort of color bias the outcome of these patients serious enough by calling it benign. So now we call it IIH which is mouthful and so someone in the eyes could come up with a better name for it and I'm sure there's room to change it once again. I'm going to start out with a case. This patient is a 27 year old 5 foot 3 woman which in my house is tall but in most cases in short and overweight and she had a history of a renal stone actually. She was treated with IV antibiotics including vancomycin but wasn't really treated with tetracycline or anything like that and within nine days she developed blurred vision and her vision as you can see was really reduced 2400 in the right eye, 27 in the left eye and this is like you know the grand fuba of papillodema and this is about as bad as papillodema again so this is not your usual case. A lot of hemorrhage, a lot of dis- swelling in both eyes and the blind spot as you might expect was it was increased in the central scatomas in both eyes and here you can see on goldmonde fields yes we still do goldmonde fields and you can see that there's a bilateral synesthesia in the central scatoma. A bit about the criteria for making a diagnosis of an apathic endocrinal hypertension. So up until very recently it's the modified antichriteria that we have used and so we have to have the right symptoms, headache, nausea, vomiting, transcriptional aspirations or papillodema with no localizing signs but you're allowed to have diplopia from a non-localizing six nerve paracist. Patients otherwise in good shape or awake and alert. There's no evidence of thrombosis on CT MRI and the LP was supposed to be greater than 250, 25 centimeters of water. I used 25, 250 millimeters and 25 centimeters interchangeably so if I slid it's not 10 times the amount of hypertension. And there's no other explanation for the region of pain or pressure. So this is the criteria that we traditionally use. And then it got a little bit more complicated and I won't bring you through all this but this is a new classification with Kathleen being involved and this with Doug Friedman who was my fellow and was at the Palm Island Institute for a long period of time before moving to Southwestern and things began to change in terms of what's included and I'd just like to call attention to the fact that there is such a thing as a pseudo tumor cerebrine syndrome without papillodema and this is kind of a new concept. People had intermittently reported well you can have high pressure and no papillodema. I had always had a little saying I have a number of sort of maxims that I use for optic nerve disease and the maximum that corresponds to this is that the optic discs are not the manometer of the central nervous system and so you don't have like a gauge sitting there at 260 and turns into papillodema and at 240 it goes to you have no papillodema. So different people have different tolerances for different pressures in terms of developing papillodema but there are other things that have to be present to make sure this isn't a different kind of headache for instance empty cella that you can have flattening as opposed to your glow and that you can have a transverse sinus stenosis. So these are things just to be aware of that still in evolution exactly what we mean by elevated intercranial pressure. So what are the hypotheses? Well because we don't know everything you say is plausible. So Dr. Sugarman did a bunch of studies where he said you know these patients are heavy and they have weight on their inferior vena cava and their superior vena cava and so they just can't circulate their blood and you get high venous pressure and this is what the underlying pressure problem is but really it doesn't really fit for most people that this is a logical extension. Sleep apnea is regularly associated with patients who have IIH but it's not the other way around. If you go to sleep clinic you can examine thousands of patients and they don't have IIH nor do they have AION or all the other things. I think that having sleep apnea just means you're more susceptible to just about everything including IIH. Hormonal influences, again you know the vast majority of patients are women why should that be so? Well maybe there's some hormonal influences but no one's really identified what those hormonal influences might be. Of course you can increase CSF production and in certain papillomas that involve the coriaplexus you can actually get increased CSF production and overcome the absorption system. This is like overproduction. This is the clock with the brain I'm sure that you've heard that term before. Decrease CSF absorption is probably what's going on most of the time but we don't know exactly why. I did see one interesting article just recently we haven't had time to read in detail yet talking about aqua porn 4 defects being associated with IIH so it'll be interesting to follow up to see whether that has any validity. And then there's a lot been said about functional or mechanical destruction of venous sinuses. So if you raise somebody's intracranial pressure the tissue pressure collapses or can collapse segments of the venous system. On the other hand if you collapse a segment of the venous system then you get higher venous pressure which often has to be higher intracranial pressure. So these are some of the ideas but the fact of the matter is that we just don't know. And we were hoping that the study I'm going to talk to you about today was going to give us some more clues and it has not been satisfying as one would. So the clinical presentation as I've already alluded to is obesity on women usually with a recent weight gain and headaches that are often constant horizontal binocular diplopia at distance because they have abducting a paracet transient obscurations of vision which are usually postural induced in the last seconds at a time they can be in one eye or both. Some patients do get nausea and vomiting in association with it which really makes it confusing for patients who may be treated for migraine for a period of time because they have nausea, vomiting, and headache and here's another syndrome with nausea, vomiting, and headache. Pulsatile tinnitus is the noise in the ear this is not the high-pitched sort of wine that is common but rather this is a whooshing sound that is sometimes pulsing a mild stiff neck because of increased pressure but there are no localizing symptoms. So of course you always want to see if we can find a cause so if you eat polar bear liver then you are in fact at some risk to develop hyperbiderminosis A which can give you papillohemus you know at least all the third-year residents know all about Nalodixic acid and tetracycline I've never seen Nalodixic acid used as an antibiotic in my entire career but Cypro is an analog of Nalodixic acid and can cause the syndrome so that's just a little purlin. Cortico is steroid use either coming on or coming off so it's really complicated and it's used by some people in the treatment of IAH so it really becomes complicated and we try not to use cortico steroids closed head trauma probably from venous stenosis or temporary venous stenosis and then history of waggulopathies again we think about venous stenosis maybe perhaps associated with the signs so the vision can be fine and often is fine but as a matter of fact the IAH treatment trial had patients who didn't have much vision loss and that's one of the strengths and one of the weaknesses of that study and we'll get to it in a little bit they can have acquired dyschromatopsin after in people area defect visual field defects of any type and as I said they can have amnesis peresis the papillodema is usually bilateral and symmetric and I'll show you some evidence for that later the neurologic exam there has been some thought about with all that elevated venous pressure the arterial circulation must be affected in some way and perhaps the core of profusion is compromised but very few patients we see are confused or somnolent or anything like that so we want to do some tests the first thing we do is to get an imaging test so I would say imaging first and then L.P you wouldn't want to image something and find that the pseudo tumor was really not pseudo and that you end up causing complications by doing an L.P when you meet each other so we get MRIs and MRVs in our institution if the patient is the typical onset we usually don't get MRVs we just get MRIs some places do both all the time anybody who's atypical should have an MRV or now I guess they're getting CTVs as well lumbar puncture so I used to do them all myself and the problem was about four hours a week I was doing L.P's and then they found out I didn't have hospital privileges to do L.P's because I'm an ophthalmologist so I had to go back and get privileges and prove that I actually didn't paralyze anybody in doing the L.P's but now we have a PA who does them under fluoroscopy and I can tell you that it's just a wonderful thing to have when you know that person's doing them right because doing them wrong is a real problem you can't say anything about how that patient is what that patient's opening pressure is if they're sitting up squeezing there's a hundred ways to do it wrong they're all equally easy as doing it right but if you do it right to get a pressure you can rely on and I do a test in those cases of happiness, pharmacosis we like to make sure that there's no underlying cause for menace so Lars Friesen who happened to be a fellow with Bill Hoyt when I was a medical student didn't got to know him extremely well very very detailed and individual who is truly brilliant and has done a lot to help us with our understanding of optic nerve he was sort of the premier disc-gazer for decades and he came up with a system of Patholedema that allowed us all to talk about the same things and so this was what was used in the IHGT study so just to review briefly, basically stage zero is a normal disc or a not normal disc but with no C-shaped halo that's very confusing and it causes a lot of consternation amongst all of us and I'll show you why when we get to the results of the trial stage one is the C-shaped halo and it doesn't always project well but basically what it is is you see white a white fuzzy area that doesn't include the macular-capular bundle so if you see white around the disc but it doesn't include the macular-capular bundle then that is stage one stage two is that the halo goes all the way around there's elevation and there's the border there's no major vessel observation so zero, one, two all depend upon what the nerve fiber layer around the disc looks like three, four, and five talk about vessels so in three there has to be at least partial obscuration of one vessel and four you have to have some obscuration of all vessels and in five you have to have complete obscuration of at least one vessel on the disc and again you can say there's room for interpretation with all these things but in general it turned out to be fairly reliable and in the study we were both judged by the principal investigator at the site as well as by photography which is where my so this is what we did in addition to looking at the qualitative classification we actually we can stereo the disc we can blow them up so the size of the beach ball which allows you to see a lot of detail and stereo and we can do a lot of things that help us to actually calculate the area that is involved and when we do that we came up with two different areas and so we came up with what we call the area of white which is the halo so the halo goes all the way around and we looked at the vertical and the horizontal and we calculate the area of the halo and then we calculate the area which we call the dark zone and you can see that on the hill of the apple edema outside the white zone it's still elevated off the surface of the retina and so it comes out as a dark shadow and it also is the inflection point of the vessels and so you can then get an area of dark and we looked at both of these separately and it goes together and so what happens when you try to do a treatment trial but here we actually here's an example from the patient in the IHDP and here here's what they look like at baseline so this is pretty much all the way around there are several vessels obscuring this was called a level 4 and then one month into the study you can see that it still got halo all the way around but now you can see the vessels you couldn't see well before and now it's a 2 and then you look back at month 8 and it was still a 2 and then 2 into a 1 at 9 months so this is a really nice case study of how you can follow Abla Dema look at response to treatment and if you now look at it from the standpoint of the area of white you can see the area of white goes down mostly at the beginning and then it slows down and similarly the total area also continues to go down and then flatten and so in other words this disc size is not very much different than this or this disc size but is different from this one from the first one so we have a nice correlation between the qualitative and the quantitative then we took this quantitative assessment and we started looking at it against other parameters and the reason I show you this is that first of all it's published if you're really interested in the data it's all there but the really there are a lot of things that really didn't help us very much and so you can see that the curves really are not too exciting there's a lot of scatter when you're trying to correlate it with visual fields, visual acuity, color vision all those things it doesn't always correlate as well as you might want it to so what are the management principles of IAH traditionally we have a few things available to us we have medical therapy of which weight loss is the mainstay and we all recommend the patients lose weight of course it's easier said than done in the IHTT we actually had an obesity specialist group work with each individual in role to lose weight and they actually lost a lot of weight which was helpful and then Dymox his own mind has always been the mainstay of treatment for 40-50 years but never shown in a class 1 level study, no perspective study that demonstrated was useful but everybody tended to use it a lesser known drug when I find very useful for patients who are not tolerant Dymox is neptazine so if you're doing 25 250 milligrams of Dymox twice a day which is really low dose you'd be doing 25 milligrams of neptazine twice a day so it has 10 times the potentity but it also seems to have less side effects and so I use it in patients who seem to be sensitive to pyramid there are no clinical studies but it is a mild carbonic amyloid inhibitor it's really good because it gets rid of their headache it helps their headache and it's also a hunger suppressant so it really decreases people's appetite and so they lose weight so a lot of people they don't tolerate Dymox they'll go into pyramid remember that it is pyramid that can cause swelling so every once in a while you can compound your difficulties with the pyramid Lasix is interesting Lasix is sort of the fallback drug they can't tolerate Dymox oh they're pregnant, oh they're this and so we put them on Lasix there's really no good studies that demonstrate that Lasix is really effective patients really don't like it it makes them pee all the time and you have to watch their potassium and it's more complicated patients don't like it so as I mentioned before we want to avoid steroids if at all possible because of rebound on tapering and because the side effects include weight gain and we know that steroids can either start with the onset of using corticosteroids or IH can start as you discontinue it so it's really hard to manage if you have a vision loss you can sometimes rescue their vision for a period of time with a short course of steroids so surgery is generally used when medical therapy fails and the surgical therapies that have come about have been usually optic nerve fenestration and there's one eye or both eyes that take LP shunts which are trying not to use anymore because even though they work about 50 to 60% will have some complication soon after they have the LP shunt put in they get infected, they get disconnected your lower back was just never made total of the shunt so ventricular perineal shunting it takes a little bit more skill you have to stereotactically place the catheter you can get intergranular hemorrhages you can get swelling so it's not completely without problems it has the same effectiveness in the LP shunt and even though the initial success rate is high they also have substantial failure rate so it's certainly not a panacea and we and the neurosurgeons hate doing them so it's not like you have to convince them you want to do an optic nerve fenestration they're sending them to us won't you please do an optic nerve fenestration we have to tell them no it's not indicated you really need to do this shunt so optic nerve fenestration there are really two ways to approach it I still use the medial approach that was first standardized in the ischemic optic neuropathy decompression trial I think you're looking at under as much power as you want in a microscope and this is very early on I think John Kelpner in the 70's published this shunt that occurs between the subarachnoid space and the interorbital space demonstrating fluid but there's also been some demonstrations the scarring takes place and some people feel that the scarring takes place may protect the nerve from swelling but also cause further vision loss down the line because the pressure on the nerve back and the disc is still there and you haven't really done anything for the pressure so I don't know if this is going to work or not I don't think it will work but it was just a 10 seconds showing you a gush of CSF from a super sharp blade so a long time ago now I guess almost 10 years ago I wanted to look at what the effectiveness of surgery for IH was because nobody had actually done any systematic research and literature there's much more data on looking at optic nerve sheath fenestration because ophthalmologists were seeing those patients and got visual fields but if you're being referred from a neurologist to a neurosurgeon or to a neuroradiologist they somehow never stopped in the ophthalmologist's office and so most of them just had subjective my vision's better my vision's not better or thus they had a visual acuity on them which has been a very good measure but basically what it demonstrated is that we really don't have too much data on many of the surgical procedures except for optic nerve sheath fenestration which has like an 80% effectiveness so this is in terms of vision improvement 80% so it's a pretty good thing to do if the patient's having vision loss there's not that much to say about it relative to headache because of course ophthalmologists never send their patients to a neurologist so they can ask about whether their headache is better and so we don't really know much about the effect of optic nerve sheath fenestration on headache so let me go through these are my wall slides so these are the part of the official slide set or the IHTT and this has all been published now and I'm going to show you a few things that haven't been published or have been published in subsequent in subsequent to the initial data so here's the steering committee and you can see that we have really good representation from Jim Corbett, Deb Friedman and Mark Coopersmith, Mike Wall all people who have really invested interest in IAH over their entire careers and here is the study basically it was diet plus placebo or diet plus acetazolamide and the acetazolamide could go up to 4 grams so the deal was if they could drag themselves in the office and they weren't complaining too much you increase the dose and you kept increasing the dose and normally I would say the clinical idea was you got to 2 grams and you pretty much stopped but now we feel much more comfortable about going up to 4 grams in order to get effectiveness and so then you monitored them and the perimetry was the outcome measure and this photos were taken at regular intervals and at 6 months there was statistical comparison of these two groups here are the centers and you can see that I don't think you're that far north I think you're kind of more like there you're right you're there well you can see that it's heavily east coast based I guess we have more patients that have the disease or something but Rochester was one of the centers and he was another center but there was involvement across the country and actually in Canada what was the the BMI and this cohort and it was hefty so I think the definition of obesity is greater than 25 is that correct so these people were obese, obese or an obeseist the initial symptoms of IAH headache and vision loss with the first two headache plus vision loss pulsatile tinnitus and then there were a few that were asymptomatic look how what a small percentage actually had diplopia so I think it's overemphasized that you should have diplopia we just don't see that many and the frequency of symptoms again headache and TBLs are the most frequent interestingly back pain turned up we don't know if this is back pain before or after the LP but certainly one of the complaints pulsatile tinnitus dizziness which is interesting because one wouldn't expect necessarily them to be busy, photophobia perhaps related to headache and again neck pain vision loss so you can see the relative frequency of many symptoms that occur some expected and some unexpected so John Kaltener tells us that this is the most common field effect that's experienced which looks kind of like an archaea interestingly the lower field seems to be more susceptible than the upper field in many of these patients how about the severity of apoledema well you know this is a nice bell shaped curve remember that these patients really didn't have more than a couple of dBs of depression on their visual field and so we are seeing only the mild IIH cases and it's interesting that it's sort of a bell shaped curve around grade 2 to grade 3 and almost no grade 5 and of course there are virtually no grade 0s in the study eye there were some in the non-study eye one of the things that I wasn't published is what was the symmetry between the eyes so this is a calculation that I've performed in my lab looking at symmetry and because unilateral apoledema is always in differential diagnosis you know is this ischemicopic neuropathy or papillopathy of some sort or is it apicneuritis or is this IIH and so it turns out that virtually almost all but 5% had within one grade the either direction of the study eye and that's really helpful to us because you know the more advanced IIH patients they almost always have bilateral disease but even in the milder disease bilateral bilaterality is certainly the rule and again we looked at the relationship of apoledema and visual loss we'd really like to say well the less edema you have the better your pressure and the better your vision didn't look out that way at all seems to be completely random and similarly we said well you know if the metometer of the central nervous system really is the object of this then there should be a really good relationship with the CSF pressure and with mediation and that didn't work out either however what did work out is that we found to the .05 level that there was a benefit to using a cytosolamine and in doing it by increasing the doses in the way that I just described and most of the effect took place in the first three months and so after that you can see that these lines are almost parallel between the placebo group and the cytosolamine group but what you see is that you've got an improvement immediately in the cytosolamine group within a month but not in the placebo group and that accounts for most of the difference what about symptoms well you can see here that the cytosolamine plus diet seem to improve TBOs post-alternatives, dizziness, photophobia, neck pain and visual loss very nicely the diet seem to improve the diet along with placebo seem to improve some more vague symptoms like Pogba's dysfunction and the particular pain so that's not too unexpected percent improvement difference over six months you can see that with these cytosolamine that you got tremendous improvement in the transfer of visual obscuration some improvement in headache severity and some improvement in the frequency of headaches so what was the average dose of medication? well it turns out that if you you needed a lot more placebo to get an effect if there was one so that's not too surprising what was surprising I think to most of us is that people tolerated 2.5 on average and many people were actually on four grams a day and the effect of cytosolamine on freezing grade was fairly significant the effect of placebo courses in the other direction so how many treatment failures were there? there were seven treatment failures in this whole study which basically says you can leave most of these pages alone to define on the other hand since we wanted to find out if cytosolamine would actually help it turns out that there is a significant difference between the treatment and the placebo oh by the way I guess I should point out that all the patients who failed had high degrees on freezing scale this just shows you the change in path of emigrate in the worst eye over time and you can see that the placebo's did pretty well they gradually got better but they never got down to where the cytosolamine group is and this is just to remind you again the progression from grade zero to grade five what is interesting is to look at baseline in six months so here's the baseline up here and you can see this sort of as I already showed you kind of a distribution in both the baseline of both the study group and the cytosolamine group but then when you look at six months you can see that the lower numbers zero and one are predominant at the cytosolamine group but you're still somewhat normally distributed in the placebo group this is again something that isn't in the study it's just a little study I did which says well what's the all those disc hemorrhages mean and what you find out is that the patients who failed have a lot more disc hemorrhages but on the other hand there were also higher grades of papillodema and so when you have higher grade of papillodema you're probably more likely to have disc hemorrhages I'm not quite sure what it means but I now know that disc hemorrhage is not a good thing one of the sub studies was to look at OCT and to look at OCT volumes of the nerve so here you see papillodema grades from zero to grade four they didn't have any grade fives in the subgroup they couldn't measure them and here you see the OCT and you can see that it's a pretty good correlation that as you go up in papillodema grade you get more and more volume and this is the three dimensional reconstruction of those curves so it's very free and it may allow us to be more quantitative moving forward and here you can see over time this is volume over time and the placebo and you see the zolomite groups and you can again see that you can use disc-volumism measurement to demonstrate the differences between the zolomite and the placebo there's also a very interesting phenomena where so this is getting back to umbilical science so we have the RPE that comes in in papillodema and then as it gets better and you treat them then it reflects posteriorly and then you come out of these so this may be a sign to tell you whether papillodema is progressing or regressing um we did look at disc area versus disc volume and it is an amazingly good correlation which I guess one would expect but what it really means is the z-axis doesn't add much in terms of understanding if you can quantitate the difference is OCT is much easier to quantitate than taking measurements using big screens but the correlation is just amazing between total area and OCT volume and the baseline baseline non-study odd and in six months study on non-study odd so very tight correlations and that's I guess reassuring but stay tuned because we didn't address a whole bunch of problems especially we didn't address patients with it really worried us with more severe symptoms and signs of high age and we didn't look at any of the surgical arms so we started two other studies in the light study which I think is a conclusion now and the light study was just to continue those same patients in group one to see what happened to them long term basically what happened to them is they got bored and didn't show up for their follow-up appointments um and in the surgical side we now have the site and the site is we'll find out probably within a few weeks whenever October we'll find out whether they're going to fund this project which is a natural extension and the site study is looking again at parametric mean deviation but these are patients who have from minus 8 to minus 30 to be lost on the visual field instead of like 0 to 6 and they're going to be randomized into a zolomide and this is medical treatment optic nursing fenestration or CSF shunt technique and we're going to try to figure out what maximum medical therapy does and this is the same thing that we just talked about versus doing surgery they're going to be monitored in the visual field and now OCT is the other outcome measure and then we're going to look at the results and see how they fare so let's get back to that patient I should so what did we do with this patient I've given you all this data and talked all about this disease but here you have this patient in front of you in front of you has 20 terrible vision in both eyes and is really probably the clock is really ticking so what did we do the patient had already been taking 1.5 grams per day of diamonds at the time she was referred so I really didn't think we had a whole lot of time to figure out whether or not maybe going to 2 grams or 2.5 grams is going to be effective so she went and had a right optic fenestration and I mean this is great 2040 vision remember that was just a really bad 2400 vision pre-operatively she comes back first post-operative visit 2040 and left drive we didn't touch hand motion so I think we have an idea what happened operated on the wrong eye so what happened to this patient here's the visual field so in the right eye there's just this big blind spot but overall pretty good and this is the left eye I mean just disastrous probably going to skip it well did she have an ATV now? that was one of my thoughts my other thought was it was the resident's fault well the resident the resident then said it was the medical student's fault is there an APD? yeah there is an APD but it's sort of but not the one you think about so here's what happened this patient had a vitreous hemorrhage probably because of hyper-revalation during the time of surgery and it's one of the very few patients I've seen with IIH develop a breakthrough of hemorrhage into the vitreous and when I last saw the patient after one of my retina colleagues cleaned all this up the visual field was 2030 in the right eye 2100 in the left eye it wasn't completely resolved there was no APD at that time and the color plates were back to normal so just to show you when you think you've seen everything then you get to see one more so thank you very much for the opportunity how many have missed this when you were going through there did they follow weight loss compared to the placebo comparison was there a difference? yeah interestingly there was a difference but it wasn't due to the use of the diamox a very sophisticated system but the patients on diamox because it takes away your appetite because it makes coca-cola taste bad your tongue is vibrating all the time so when you took away the dependent variables looked at them as independent variables there was no difference due to the weight about the same thank you Dr. Fowler for a great presentation we have two questions for you so question number one you mentioned a series of online 250 milligrams so do you prefer to use 250 milligrams tablets or 500 milligrams capsules and a second question so what do you usually do when you have a patient with kidney stones medications wise so the first question if I heard it correctly is that correct 250 milligrams 250 versus 500 yeah so of course they went in 250 milligram increments for the purposes of the study but I use the long release 500 milligram capsules and as I increase it what I do is I ask the patient are they more symptomatic from the diamox in the evening and as I build up I'll give them I'll give them more when they're less symptomatic from their diamox related effects but I don't know that anybody again there's no study that shows that one's better than the other but you can almost depend upon patients trying to take medication four times a day aren't going to take it four times a day so you're very fortunate if you take it twice a day and the other question oh kidney stones so we had one patient who had kidney stones the patient here who had the history of kidney stones it turns out that even if they had a kidney stone that you can put them back on and they probably do fine you have to make sure that they're look at their urine from time to time make sure there aren't much oxalic crystals that are forming but in general you can put them back on and this patient tolerated without any recurrences so I noticed in your review from 2007 you had the stent placements as a treatment but you didn't mention that it's been kind of hot in the press in the last five years are you guys doing stenting a lot? so we're not doing stenting not because they don't want to do stenting but I have serious concerns about stenting and the stents the time that I published this back in 2007 there were only about 30 published cases of stents now of course there are probably hundreds these are venous stents yeah venous stents so they go right into the transverse sinus so it's like taking a nail and sticking it in somebody's transverse and a holiday there were initially a lot of complications and there were serious complications like hemorrhages I think the procedure is about to save for over the years and people are more skilled at putting them in and the shunts are better but the problem is that most centers are not making a really good differentiation between stenosis true stenosis and secondary narrowing and so they're all going to get better if you if you take care of the narrowing then you've taken care of part of the circle the vision cycle so it's going to help it get better but if they truly have stenosis it's not going to get better really until you do that or until you have a permanent shunt solution so I didn't emphasize in this talking it's not part of the site so there wasn't not a lot of enthusiasm putting this into the other study what's your experience here we don't do it very often there are certain centers Australia likes to do them if you're south of the equator there's a different fluid dynamic than we expect any other questions thanks again there are certain centers