Now let’s talk a little bit about glaucoma progression and specifically what I’ll do is tell you a little bit about what’s in the literature, some evidence basis and then I’ll show you a number of cases that try to illustrate various aspects of detecting glaucoma progression using OCT and other imaging technologies, basically the tools that we have available to us with a focus specifically on OCT.

First of all in terms of looking at the OCT scan Rob really told you everything about the OCT and how you would detect whether or not there was an abnormality, but one thing I did want to point out is that you need to make sure that the exam is of adequate quality before you accept the results of that exam. So if you don’t have a good exam, the machine will still give you a number and it will still give you colors, but they won’t be right, and so it’s garbage in, garbage out, you need to make sure that the signal strength is good enough, and these are the numbers that you see here on the, on the slide. You have the signal strength for Cirrus, for Spectralis, For Topcon and for RTVue. And then you want to look at the actual scan and make sure that the scan quality is good and that the lines that define the borders of the neurofiber layer do follow the contour of the neurofiber layer.  In other words, that you don’t have algorithm failure that’s giving you the data that you are seeing.

So back in 2005 Gotty Wolstein from our group published this paper where we looked at glaucoma progression and whether it could be diagnosed by OCT or visual field earlier. And what we found in that study was that we had more progression events that were detected by OCT than we did by visual fields. So this is a Kaplan-Meier plot and this is visual fields on top and OCT over here, so more progression events by OCT.  Now do we know for sure that those people actually had progression and that these weren’t false positives?  In other words what’s the specificity of this?  I can’t tell you, I don’t know what the specificity is, I don’t know if any of those are false positives at this point. We are reviewing those data now to see 5 years later whether or not those patients who we identified as having progression events using OCT actually ended up having field progression as well.  And these are the data from that, from that study.

But what I can tell you is that there have been subsequent studies that have looked at progression using OCT that have shown similar findings in different ways.  And what do I mean by that? they haven’t looked at events, it hasn’t been an event analysis but rather a trend analysis, what is the rate at which the test is getting worse? And so what they found in this study, what Felipe Medeiros and his group found in this study was that progression was occurring faster by OCT in the group that was progressing by visual fields or optic nerve head change than in the group who did not have an optic nerve head change.  So the neurofiber layer in other words as OCT measured it was getting worse in a way similar to the optic nerve. 

There haven’t been a lot of studies looking at progression.  One of the other problems that we have is something that people call the Venn Diagram problem.  And so the Venn Diagram problem is that you have data like this where you have change by OCT here, and change by visual fields here.  And the overlap is only 3 eyes.  In other words, you have all of these that are changing by OCT, and all of these that are changing by visual field, and oh, by the way if I also put up another technology like HRT, that Venn Diagram circle would be around here.  There would not be complete overlap with either the OCT group or the visual field group if I were looking at HRT as well.

So why do we have this Venn Diagram problem?  Well the neurofiber layer, the optic never and the visual function as measured by visual field seemed to change at different rates in different ways. And so if you look at the optic nerve head you are going to get a different rate of progression than you do if you look at the neurofiber layer.  Maybe it has to do with the supporting tissue, with lamina cribrosa, with the astroglia that are in the optic nerve head that you don’t have in the same, the same concentration, the same density in the neurofiber layer. And the function of the neural tissue may change in a way different from its thickness.  So maybe when a nerve cell gets sick it doesn’t work as well before it gets thinner, or maybe the other way around, we don’t know.  Nobody knows. So we are doing these studies looking progression, trying to define how the nerve tissue decays and how we can measure it best, but these are the data that we have so far.  In other words OCT can be used to measure progression but it’s not going to change in most cases in the same way that the visual field change or even that other imaging technologies show change.

So here is a case.  A 63 year old woman with normal tension glaucoma, she had had an SLT in the past and she had also had conductive keratoplasty, her best corrected vision was quite good, she had normal thickness corneas, her disc had normal appearing cupping on the right, maybe a little bit of asymmetry and then there was a focal neurofiber layer defect. So let me show that to you.  And here is the optic nerve head in 2000 through 2009 I believe and here you can see in the right eye there doesn’t appear to be any change occurring. In the left eye though well is there change or not?  It’s kind of hard to say. This focal defect is a little bit darker here but it’s a darker image, maybe it’s bigger, maybe it’s not.  Here are the red free photos just to highlight that neurofiber layer defect in the left eye.  The right eye the nerve tissue looks pretty good.  And here is the visual field.  So how many in the room use a Humphrey Perimeter?  Most, all?  How many use Cita?  Okay. And of those who use Cita how many use the GPA program to assess progression?  Okay.

If you can get your hands on the GPA program or on the VFI, which is like the mean deviation but a little less sensitive to the media opacity, these are great tools for determining whether or not progression is occurring using the best statistics that are available today.  So here we see that the VFI, again similar to the mean deviation, is not changing and that the GPA doesn’t really show change. And that was the right eye and here is the left eye.  And here is one analysis and then here is the next time the field is done, and here is another analysis. And the reason that I show both of these is that this one was done first and then this one was done, and they were done very close together in time and this one showed progression and this one showed no progression. So there’s variability on the visual fields, you have to be careful in how you accept the data that the visual fields are showing you.  Also I wanted to show you that there is this superior paracentral defect in the left eye that corresponds to the focal neurofiber layer defect that I showed you in the photos.  The stratus OCT unfortunately does not identify that focal defect.

And this is the stratus OCT progression program and this is really just serial analysis, it’s overlaying the neurofiber layer, the thickness profiles and then plotting the mean neurofiber layer thickness over time and drawing a regression line through it.  I have to tell you I don’t find this, this program particularly helpful. Sometimes it will show me something that’s of value but most often the serial analysis is not something that I find particularly useful.

On the other hand, this is Cirrus from this patient and this is using the 5.0 software for Cirrus.  And the reason I mention that is it does some things that the older software didn’t do.  So for instance, here you have the virtual circumpapillary neurofiber layer thickness sample from this 3 dimensional data cube, but you also have an assessment of the optic nerve head cup and disc size. Those numbers are up here.  And then you have the neuroretinal rim thickness here, and then the neurofiber layer thickness is here. And then you have your usual parameters of quadrants and clock hours.  And this also did not pick up the focal defect if you are looking at the circumpapillary data.  But if you look at that 3-D data set and you are looking at a deviation from normal map here, this where it’s yellow and red is that focal defect. So it does identify an abnormality but that abnormality only becomes evident, in other words the data are only outside of the normal range in the normative data set beyond the point of this circle. And so we have to look beyond the circle now that we have the 3-D data available to us and we can find abnormalities like this.

We can also measure them for progression, and we can do that in several different ways.  One way is to look at the 3-D data and compare it over time. That’s what this, this does. You are looking at the 3-D data sets and looking for change in each super pixel. Here you are looking at mean neurofiber layer thickness, superior neurofiber layer thickness and inferior neurofiber layer thickness. And here you are overlaying the neurofiber layer thickness profiles but unlike the serial analysis if there’s an abnormality, if there’s a statistically significant difference between profiles that will be highlighted, and I’ll show you that in a different case.  In this particular case while OCT could identify the abnormality, it did not identify any change. 

Now this is the RTVue neurofiber layer thickness analysis and with the RTVue actually the data fall in the borderline range in that circumpapillary scan, the virtual circumpapillary scan. So the normative data define whether or not a particular patient’s value is going to be normal, borderline or outside the normal range.  So the normative data are different on RTVue.  RTVue also does this overlay of neurofiber layer thickness profiles and gives you the neurofiber layer thickness data over time, and then it plots out the mean neurofiber layer thickness as you see here, and you can see also by RTVue there’s no change occurring.

This is another printout from RTVue looking at the neurofiber layer and also the optic nerve head, so here is the disc border and here is the cup.  And then this is a, a parameter that RTVue has that the other technologies don’t have at this point, which is called the ganglion cell complex analysis.  So what’s the ganglion cell complex? Actually David Wong and his group are the ones who developed this algorithm. This is looking at the tissue of interest, the relevant tissue in the macula and determining whether or not it is of normal thickness or abnormally thin and whether or not it’s changing. And so in this patient looking at the ganglion cell complex, the macular neurofiber layer, the retinal ganglion cell layer and the inner nuclear layer, so the – I’m sorry, the inner plexiform layer, so you have the axon cell bodies and dendrites of the retinal ganglion cells you can map the thickness of the retinal ganglion cell complex, the ganglion cell complex and you can look for deviation. This is the thickness and this is the significance, the statistical significance of the deviation from normal.  And so you can see in this patient who we saw that little focal neurofiber layer defect that in fact there’s this big abnormality in the macular – in the macula where the retinal ganglion cells are affected. This is the fovea, it’s not the disc. 

And then this is the Heidelberg device, same patient, and in the Heidelberg device normative data again different data set, here this patient falls outside the normal range. So we saw it within the normal range, borderline and outside the normal range, same patient, same day. All depends on the normative data.

And this I show you because the Heidelberg here was used to cut across that focal neurofiber layer defect. So here is the defect, you can see that the neurofiber layer is very thin, and then as you move further away from the optic nerve head the defect broadens and further away still it broadens even more.  So you get very good definition with the Heidelberg device of the retinal layers for visualization. 

This is looking at the macula again with the Heidelberg device, and then this is the macula with the RTVue device if you looked at the total retinal thickness in the macula, right eye, left eye, and so you can see here is that abnormality that we saw with the ganglion cell complex, but it’s only borderline if you look at the entire retinal thickness.  On the other hand, if you look at the ganglion cell complex, it’s outside the normal range.

And then you can look at that over time and in fact this patient is not changing, this, this patient is stable. You can see that there is variability here, I think that there is work to be done in terms of registration of these images so that we can reduce variability, but I wanted to point out that the macula can be a sensitive area for the detection of glaucoma and measuring for progression.

Here is another patient, this is an 80 year old man with pigmentary glaucoma.  He had had a laser iridectomy, he was on a number of medicines, his pressure actually seemed to be okay.  And he had a cup to disc at .8, but when you looked at the visual field that didn’t look so good, and so here are the visual fields and you can see from a number of years ago and from the most recent. And you can see a decline in the VFI, or the mean deviation, so his visual function is going down.  You even have the rate of decay, which is actually fairly high at -4, and then this is the GPA which is showing you the area, the actual spots that are changing and the ones that have changed multiple times in a row.  And so here you can see that this patient is really getting worse.

Here is the patient’s OCT, and this is the OCT of the right eye and left eye.  And you can see the abnormalities, but this is back in 2008.  Here is 2009, and 2010.  2010 again, and here is the progression analysis. So in this patient we’re seeing confirmed progression in the patient’s right eye consistent with the area that was changing on the visual field, so inferior thinning correlating with that superior progression on the visual field.  You can see that in the mean neurofiber layer thickness, a little bit in the superior quadrant, superiorly and even more so inferiorly. And then you can see it also on the neurofiber layer thickness profile where the change is highlighted for you.

I’ll show you this one last case and then I’m going to stop.  This is a 75 year old man who has glaucoma, he has some cataract and you can see his parameters here.  And here are his discs, and that’s back in 2007.  And then here we are in 2008, and 2009.  And I would be hard-pressed to say whether or not there was any change occurring in either of these eyes, but there is one thing, and that is that there is a little disc hemorrhage right up here.  So we’re going to watch that area. 

Here are the visual fields, normal, right eye, no change over time.  Normal in the left eye, no change over time.  Here is the GVX, the right eye is stable, and the left eye just is beginning to show a change inferiorly, consistent with the area where the disc hemorrhage was. Remember the disc hemorrhage occurred to 2007 and this is 2008 and 2009, so you see the neurofiber layer thinning occurring following that disk hemorrhage. 

This is HRT, right eye and left eye.  And again you see that area 2007, this little bit of red indicating change.  More red in that area indicating more change and more still in 2009, again right in the area where the disc hemorrhage occurred, even though this patient has a normal visual field, always had a normal visual field and showed no change on the visual field.

This is the stratus OCT, this is one of the rare cases where the serial analysis actually did show a statistically significant change. And then here is the OCT and here is that area of abnormality consistent with the disc hemorrhage.

This is the macula in that patient, don’t see a whole lot.  Again, the neurofiber layer and on RTVue you can see that the neurofiber layer is outside the normal range in the area of the hemorrhage.  The optic nerve head, the neurofiber layer, and then here is the macula, the ganglion cell complex and you can see that in fact there is progression occurring and you can see it on this plot as well.  You don’t see it when you look at the total retinal thickness.  I’m going to stop there.  I have one more case, we’ll just show that in the cases session.  But I hope that you get a sense for how imaging specifically with OCT can be used to measure progression in our patients with glaucoma and it’s especially helpful if there is correlation but don’t be surprised if there is not.  Thanks very much.

I have been working in the AMD space a long time, and I want to speak to you about some of the things that Carmen touched upon, that is imaging of drusen and age-related macular degeneration.  When we see an eye that comes to us and we look in their fundus you often see patients that have just a few drusen, or those that have a lot more.  And the question is always are the patients that have more drusen, are they at greater risk of developing end stage disease?  It’s not so simple. 

If you look at the – this was a great image I think, this was an electron micrograph from 1987 and this is a patient with AMD, the eye bank and the RPE is peeled over, and what you see here under the RPE layer, this orange is Brook’s membrane, are these drusen.  So the drusen look like crystalline structures and they sit right beneath the RPE, this is really fascinating to me, I have never seen a better image of drusen than this one with scanning EM.

Okay, now I’ve been involved in several age-related eye disease studies, I was one of the principal investigators in AREDS 1, and in those trials in order to qualify for a trial you need to have at least some drusen. So drusen are sort of the semiquinone of AMD.  And if you didn’t have a drusen, even if you had lost vision in the other eye from a previous AMD event you still couldn’t get in a trial.

Now risk factors for progression of disease include several morphological features including clumping of pigment, the number of large drusen, at least historically, the total drusen area, whether you have geographic atrophy and then obviously how long do you follow the patient for?

One of the things that’s interested me is we’ve got this nomenclature about the size of drusen, and large drusen are fairly important, they are always mentioned in articles and they are supposed to be between 100 and 25 and 249 microns, or 250 microns in size.  But one of the things that’s very confounding and very few people really realize it, in fact I didn’t realize it until I dug deep in some of the previous historical papers is this druse, which is 125 microns across is not a large drusen because the way they define it has to do with the minimum diameter, not – or the minimum dimension not the greatest dimension. This is not intuitively obvious, so to me this is just another reason why the, the field is sort of confounded.  But when NEI or these publications regarding AREDS all those publications, they talk about large drusen, they are talking about one whose minimum dimension is 125 or greater.

And then there is these severity scales. If you look at a patient with AMD, dry AMD, you can sort of help predict how they might do by looking for certain features and the features are fairly simple, whether they have the other eye being already affected by an event, whether they have pigment abnormalities or whether they have a large druse.  So these three things are very important in sort of coming up with a guess as to how much at risk your patient is.

And why are risk models of CMD important?  Well, we know as Carmen mentioned we have some pretty nice treatments for wed AMD but they only work if you identify the patient. So if a patient is at high risk, and they don’t notice that they converted to wet, then they are not going to do well. So knowing who is at high risk you are going to see them more often.

Also if you are going to look at strategies that are prophylactic in nature, that is ones that might prevent progression of AMD, in those trials you want to select those subjects that are likely to progress within the time frame you are going to study.  So you want high risk patients, so knowing risk is important in that regard.  And then finally the patient as well as the family members sort of want to know how likely this individual is to develop end stage disease or lose vision.

Now there is some other severity scales that have been defined, I mentioned the very brief one, or very useful one clinically but the ones that were derived very pedantically were derived from the studies of using trained readers. They were reading drusen using overlaid templates on projected photographs. These were really before the days of digital imaging, and they assessed the different regions and they counted up the number of drusen, of different sizes using these templates and they also measured the total drusen area. But the reproducibility of these measurements really isn’t all that great. They were sort of generally on reader, between readers they generally agreed but not, not really spectacularly. Now we know we can image drusen on OCT and we talk about that drusen seemed to  - can change the overlying retinal layer.

This is an image out of the Retinal Physician here, drusen here and you can see that the outer nuclear layer is a little bit thin here. But I’m not sure if that’s because these drusen are actually pushing into the retina, and remember the retina is pretty elastic. Or is it because there’s a problem with nutrition because the drusen are there?  I’m not sure it’s mechanical.

And then the other thing that comes to mind really what is a druse?  How do we define it now?  We know how they look, at least we think we do on color images.  But now that we have OCT do you need some OCT reference to really dictate what a drusen is, what a drusen, or what drusen are.  So this sort of makes things simpler but also confounds things because there’s not an agreed upon definition.

So one of the things I was interested in and still am is doing quantification of drusen over time, and years ago I went to a Greek island actually on a sabbatical, worked with some colleagues and we made a drusen reading program. And we use that to measure drusen and drusen areas. So essentially it’s an algorithm that can take an image such as this and with interactive controls you can define what you think drusen are and the software helps you and then it comes out with the measurement of total drusen area as well as the individual size of all the drusen in the image.  And that’s been published in 2007 and the reason I wanted to do this is if you look at drusen specifically maybe by measuring drusen area for instance over time that might be predictive of risk.

And with respect to how robust is this software, at least between readers there is a very good agreement when you have them read let’s say an image for drusen area, you have a cap of about .86.  So we looked at, we were assessing risk in a bunch of subjects that were participating in previous AMD trials including the AREDS trial and there was also a trial called the Prophylactic Treatment of AMD, which I directed and that was a trial where you use laster to make drusen disappear in an effort to try to see if drusen disappearing was a good thing. It turned out that it didn’t really matter very much, didn’t really help. But in any case we had  a lot of patients that had drusen and we used only the untreated eyes in those PTAMD patients, and we looked at these 513 subjects to look at their baseline data with respect to drusen and some other criteria to see what would be the risk factors that would be predictive of which ones got into trouble.

So we looked at ETDRS visual acuity, presence or absence of wet AMD in the fellow eye, the number of drusen of different sizes, follow-up time and the age and so forth. And we looked at the central 1,000 and 3,000 microns.  And these are the results.  So just bear with me, I’ll just touch upon them.  If the fellow eye is affected it’s really an important risk factor. So if you have a patient that the subject eye – excuse me, the fellow eye has already been toasted by wet AMD they are at high risk.  If you have pigment that also was a significant factor. But surprisingly the total drusen area, at least at baseline, was not significant. But it appeared to be a situation where they needed to have a certain amount to reach threshold to enter into a risky category.  So the idea, at least this is unpublished, but hopefully we’ll get this published, is that more drusen doesn’t necessarily mean more risk, but you need a certain number of drusen in order to have a substantial risk.

Now you can measure drusen area on a color image, but if you measure it on OCT you might actually – and it seems like it’s fairly obvious, you might get quite a different number. And then the whole question, Carmen touched upon drusen volume, well I guess I pose the question if drusen area isn’t so important, if it isn’t really so important how can drusen volume be so important?  Okay.

So we know that we can measure drusen volume using these – we can measure drusen using enface images as well and you’ll stack it all up and look at this sort of the OCT fundus images as it was called.  And just as a matter of reference as how far things have gone, you know this C mode or coronal kind of view, that is looking at the layers directly, hasn’t been around all that long.  And I’m going to show you – this is a patient with drusen and one of the first C modes done I think was done of a patient, this patient. And we have this little movie, you can see how crude this movie is and Herochi Ichikawa and Larry Hageman worked on this, but you know obviously you saw some really elegant movies, but this was not that many years ago. This field moves very, very fast, and you can see where this line comes across all these drusen tops show up and so now we have a way to measure drusen volume.

Okay, so here’s a patient with lots of drusen in the left eye, and here is the enface image.  Now if you are going to measure drusen area based on the projection of this enface image it might be different than looking at a color image. And this is the other eye on the same patient.  But you can use some schemes to detect what you think are drusen in this enface image.  You can do point to point correlations as well.  And Carmen showed you, you can develop these C mode plots or essentially contour maps of the drusen on the Brook’s membrane.  And you can measure their volume.  And this is the same image, this came out of the BGR, I think that’s where it was published. The thing that I wonder though is whether this data is going to be relevant.  

And one of the things that we looked at, myself, Peter Brennan and some of our colleagues at ARBO this year, we, we wanted to compare the drusen area as obtained by looking at this enface images versus ones coming from fundus images.  And just to make a long story short, you know we, we used fairly traditional techniques to measure the drusen area on the color images that is using our program and so let me just show you an example here.

Here is an eye that has a fundus image.  This is the detection of the drusen on that algorithm that’s just used for area of drusen, and then enface you can also use a similar program to measure the total drusen area.  So if you use it, if you measure it in these two ways do they agree? Well, not so well.  If it agreed this line wouldn’t have a slope. So essentially what we found is on the fundus images you are going to see more drusen, there’s going to be greater drusen area than on the enface image.

In fact it might be like 20, 30, 40, 50% more. And that’s actually what was recently published by another group, Cynthia Toth at Duke. She did something very similarly and she found that – she sort of spun it a different way and said the agreement between the enface images and the color images was pretty good, about 80% of the pixels agreed. But if you look at it, for instance of the total area in her paper identified as drusen on fundus images only 80% were identified as drusen on spectral domain OCT.  So there’s not a match here. And it goes right to the point of what exactly is a druse, how are we going to define that?  Then another question that comes up, are changes in drusen area really relevant?  If you  monitor drusen area over time let alone drusen volume, do changes over time have any relevance?   

And we had all these patients, as you know, and we already analyzed them for drusen area so we looked at a bunch of variables that might change over time to see whether there was a signal that might predict when these patients might convert to wet AMD. 

And we used longitudinal regressive, regression analysis to find the risk profile and so forth.  And one of the key things that we found was that temporal changes in drusen area, that is changes in drusen area over time and changes in the number of drusen of a particular size over time didn’t seem to be very relevant, at least in our subset which was quite a few eyes and they were followed for quite a reasonable length of time. So we didn’t find that signal. So there’s a lot of work going to be done on drusen volume, but I’m just saying back up a bit, I have questions as to whether this is going to be relevant.

And I mentioned the, the conundrum we are in as far as how do you define a druse?  Probably going to have to have a group of people come together and decide whether OCT presence has to be used as well.  So I’m just saying I don’t think drusen volume at least at this point we are not really sure whether it’s relevant, but it’s going to be interesting to see those folks that are looking at it.

Just a few other comments, geographic atrophy is another form of end stage AMD, that’s not the wet form but it’s the atrophic form. The reason I mention geographic atrophy is because there are some companies that are making drugs to decrease the progression of geographic atrophy.  One of them is Neurotech, there are others as well.  They, they use a device that’s implanted in the eye, sort of slow release to slow the regression, but that’s not FDA approved. But anyway on geographic atrophy because of the reflectivity on an OCT you really could measure it quite nicely the size of the geographic atrophy and do some serial measurements.

And this – my last slide has to do with there are folks that believe that drusen types of very important.  You’ve heard of soft drusen.  My problem with the definition of soft drusen, the drusen can be soft but if you make it smaller and smaller and smaller, all of a sudden the borders can’t be soft because there’s no – there’s no change in the area.  I mean so I think it’s sort of a construct, but there’s also this called reticular drusen, and here’s just an image came up from Holtz who has a paper this year.  Reticular drusen are ones that you see on fluorescein angiography and they, they show up as dark little spots and if you image those on OCT they look a little bit different than some of the more standard AMD drusen. So anyway you could subcategorize drusen with respect to OCT.

But I guess in closing here I’ll just say OCT has given us so much more information and now how do we use this information because we have so much data that we can look at and so the data manipulation becomes very, very important in any kind of trial. Thank you very much. 

The retinal dystrophies are defined as a group of disorders involving the degeneration of the sensory retinal layers of the retina. But of course it can also involve RPE, Bruch’s membrane, a choroid or a combination of these.  So it’s not very descriptive really.

We’re most familiar with retinitis pigmentosa which is a disease that’s inherited, it’s worldwide incidence of about 1 out of 5000.  Initially effects the photoreceptors but ultimately leads  more to the retinal layers and peripheral pigmentary changes in nerve ____ manifestations.  Now there are different in patterns about RP, I’m not going to go into them really, but there’s autosomal dominance and it serves up the next link.

With respect to patients that come to you with RP, really what can we do for them?  We know they have poor night vision, we know they’re losing their visual field, some of them are on Vitamin A. But then some of them come with central visual loss.  Now that might be due to full receptive RPE loss but there are also a couple of other things that it could be due to.  One would be cystoid macular edema, epiretinal membrane formation or maybe even cataracts.   So you want to make sure that those subjects or patients don’t have those because you can treat some of them.

So here’s a patient with lots of pigment, some RP.  You see a – this big black thing here is a floater that is on the slide field image.  The OCT in patients with RP typically shows a much thinner retina than normal.  And this, it’s a little bit confining because of the floater but the retinal thickness is – it’s not dramatically different in this subject but it can be very thin.

And cystoid macular edema occurs relatively frequently with these  patients with RP. So CME is not rare in RP patients, it  might be 10 to 20 percent of them.  And you can obviously detect CME on      fluorescent angiography but you can also use OCT for this.

Here’s a subject with lots of pigmentary spicules peripherally the macula doesn’t look too bad, at least it’s grossly.  On ___ there’s quite a bit of edema here.  OCT shows the cystoid edema very, very nicely, this is a stratus but even so you can very easily see and the thicknesses substantially greater than the unaffected other eye from CME.  The eye has RP and therefore has a little bit thinner retina.  So the point here as Dr. Gallagher and Dr. Eller pointed this out originally, that if  you look just at the thickness of the retina to determine which patients with RP have cystoid macular edema, you might be fooled because they’re already started, starting off at a thinner retina in most  cases.

This is another example.  So we like to examine all of our RP patients for cystoid macular edema.  At least once a year perhaps.  And using high resolution OCT it actually is very simple to do.   Now here’s another subject, this was an unusual case, this  patient also has thickening of the retina cystoid macular edema.  Now there are a few ways to treat cystoid with our RP, the most common way is to use Diamox orally, has side effects whatever but this patient has risks.  So what do you do here?  Do  you – well maybe we should try him on Diamox.  But wait.  You want to look at these  patients very carefully in the periphery as  well.

And so the cause of the edema I don’t think is well worked out in most RP patients.  But it’s not always from their RP.  And here’s – I’m sorry for the photograph here but this is a wide angle image, there’s something going on here in the corner and this is a wide angle angiogram showing that this patient has sort of angiomatous changes that some RP patients can get and these angiomatous changes need to be treated with laser because Diamox isn’t going to do anything for this patient.

Here’s another RP patient, this one has most of the involvement peripherally, the posterior pole looks pretty good, OCT shows a pretty decent thickness and contour.  Here’s another subject, this one doesn’t have a retinal dystrophy but here’s a patient comes to you with lots of exudate in the posterior pole.  I’m sorry about the fluorescein but this patient has an angioma peripherally.  And the OCT shows that really has a lots of edema here in this eye, tremendous amount. And this patient was treated with laser to make this angioma go away and  this was the picture a few years later and the exudate is completely gone.   I’d rather treat these patients with peripheral angiomas with  laser than cryo because cryo can really  make chronic retinal detachments and so forth so I really avoid cryo but you have to be patient.  It took 2 years to get her improvement of vision.

So  let’s talk a little bit about some of the macular dystrophies, there’s vitelliform which is Best’s which is a relatively rare disease but we do see it.  It’s called vitelliform because it’s supposed to look like an egg yolk, that doesn’t there in that picture but this one does.  So you have this vitelliform or egg-like image or  picture and patients with Best’s have normal peripheral visual field, normal ERGs, normal ____ adaptations but they have abnormal EOGs and when is the last time you used an EOG, probably a long time.

But these subjects or patients actually have good visual acuity typically even later to adulthood and typically one of their eyes is still quite functional.  Best’s has an early age of onset and this egg yolk sort of goes through several stages which are called vitelli retiform changes, I’ll show you a few of those.

Best as well as lots of dystrophies now being characterized genetically, Best is a VMD gene of the vitelliform macro dystrophy gene and if you  have a patient that has any family history of this, this gene is present in virtually all those subjects but just for sporadic cases it’s present about 30 to 70 percent.

The EOG is typically reduced even in the carrier state, excuse me, in affected patients in the carrier - and the RP  is the primary tissue that is affected by that.  Vitelliform stage is usually in early adulthood or infancy, then you get this pseudohypopyon and then you get a scrambled egg, I’m going to show you a couple – sorry, they’re a little bit dark.  This patient has sort of this hypopyon phase, this is a round lesion, it got stuff sort of precipitating out inferiorly, we OCT through that, shows this to be underneath the RPE and it’s sort of a cavity here.  This one’s taken a little bit more through the fovea and you have more fluid here, RPE is here and this is below the RPE.

Here’s a auto fluorescence image, shows that this stuff does fluoresce pretty nicely and then later on it becomes more scrambled if you will and more pigmented. And then some of theses subjects can develop core revascularization and scar tissue and this was – not the same patient but one that has ____ issues, it only happens if it’s going to happen in one eye rather than both.

And you can also have multifocal vitelliform lesions, they’ve been described and a fairly recent article by Boone showing that you can have lesions posteriorly with the ____ phase here shown in OCT but you can also have – there’s a very faint lesion here,  you can’t see it very well,  you can see it better on the fluorescent, looks like a subretinal fluid there actually.

And then there’s another form of this disease which occurs in adults, the inheritance is not well known, but this disease can often be confused with AMD, in fact it’s sometimes very hard to tell.

And patients with adult form of vitelliform can have abnormal ERGs in about a third of them. The inheritance is not well known but it can be dominant and severe visual loss from adult vitelliform is not very common.  Bailey found ____ images, three subjects with adult vitelliform, it looks pretty much like Best’s but – younger patients but you see a lot  more sort of drusen-like kind of changes in pigments so it really is easy to – like these two would be easy to confuse with  AMD and therefore you know these are patients you have to follow over a long period of time because if they just came to you at this stage you might not be able to do so at all.

Then we’ll talk about Stargardt’s and Fundus Flavimaculatus, they can be considered by some as the same disease, some study, usually some people ______ , that disease would occur a little bit later and they’re both caused by ABCA4 gene mutations and are autosomal recessive.

Stargardt’s was first described by Karl Bruno Stargardt, he’s a German and talked about this dystrophy which begins usually at age 6 to 12.  Fundus Flavi starts a little bit later and the flecks that we’re going to talk about are a little bit more prominent in patients that you might classify as fundus flavi.  And where these flecks are located is the subject now of a lot of OCT research, may be to tell us why the disease occurs but they’re not just necessarily under the RP, they can be actually through the use of the retina sometimes.

Stargardt’s, those of you that have patients with Stargardt’s will see on that slide, youngsters who, you know that they really do quite well, they adapt very well as long as they have some accommodations   during their schooling, they really turn out to be quite successful students often and they usually are gainfully employed.

One of the other characteristics of Stargardt’s is this dark choroid and this beaten metal appearance to the fundus picture, show you some examples.  This patient has Stargardt’s, just a little bit of changes in the macula but on fluorescein you see the choroid is completely dark and that’s why the  vessels look so prominent here.  So that’s a prominent feature of patients with Stargardt’s.   Later changes of  Stargardt’s, you get this sort of beaten metal appearance and this is a – this is following the same patients over a few years.  You can see that the atrophy or  pigment change goes right up to the – that vessel there. Then over time they become more distinct, more pigment and the lesion becomes larger.  Now imaging with OCT on Stargardt’s, typically the finding is that the retina is thinning of the macula primarily the three you’re going to find in the same patient, getting a little worse over time, more apparent pigmentation.  And this was in the days we had stratus only on 45 micron thickness of the retina.  She came back actually last week, her ___ now show that this is a much larger lesion, she’s still very functional, same with the other eye and now we have serous OCT to show us the contour a little bit better.  But, again, the retina is very thin in the ____.  And this is just another cut in the other eye.  Very consistent.

Here’s another patient with Stargardt’s, again, these are sort of dark but they have these  little – the look like drusenoid changes, she has some pitting in her posterior pole which became relatively dramatic. And fundus flavi, is there any way to make it click up this, maybe it’s too hard to ask but I’m surprised that your, your device could ___ these images but that’s the way, I guess, we’ll just have to deal with it.

So these little yellow things that look like drusen are called pisciform, thank you, that are fish-like.  They look like little fish if you’re looking into a pond with little minnows.  So that’s one of the hallmarks of fundus flavi as well as pigmentary changes in the posterior  pole.

Here’s the autofluorescence, showing these little deposits a little bit more nicely.  This is the fluorescein, this is macular edema it shows RPE ___ defects so the RPE is pretty well affected so that’s why it looks that way.

Here’s the OCT fluorescence, these are, these tiny little ______  are the Stargardt deposits if you will.  And this is just the other eye in the same patient.

So these, we can image these patients, we can learn about the disease, I think that’s what the key is now, where OCT is applied with such individuals.  I think we’ll stop there.  Thank you very much.

The retinal dystrophies are defined as a group of disorders involving the degeneration of the sensory retinal layers of the retina. But of course it can also involve RPE, Bruch’s membrane, a choroid or a combination of these.  So it’s not very descriptive really.

We’re most familiar with retinitis pigmentosa which is a disease that’s inherited, it’s worldwide incidence of about 1 out of 5000.  Initially effects the photoreceptors but ultimately leads  more to the retinal layers and peripheral pigmentary changes in nerve ____ manifestations.  Now there are different in patterns about RP, I’m not going to go into them really, but there’s autosomal dominance and it serves up the next link.

With respect to patients that come to you with RP, really what can we do for them?  We know they have poor night vision, we know they’re losing their visual field, some of them are on Vitamin A. But then some of them come with central visual loss.  Now that might be due to full receptive RPE loss but there are also a couple of other things that it could be due to.  One would be cystoid macular edema, epiretinal membrane formation or maybe even cataracts.   So you want to make sure that those subjects or patients don’t have those because you can treat some of them.

So here’s a patient with lots of pigment, some RP.  You see a – this big black thing here is a floater that is on the slide field image.  The OCT in patients with RP typically shows a much thinner retina than normal.  And this, it’s a little bit confining because of the floater but the retinal thickness is – it’s not dramatically different in this subject but it can be very thin.

And cystoid macular edema occurs relatively frequently with these  patients with RP. So CME is not rare in RP patients, it  might be 10 to 20 percent of them.  And you can obviously detect CME on      fluorescent angiography but you can also use OCT for this.

Here’s a subject with lots of pigmentary spicules peripherally the macula doesn’t look too bad, at least it’s grossly.  On ___ there’s quite a bit of edema here.  OCT shows the cystoid edema very, very nicely, this is a stratus but even so you can very easily see and the thicknesses substantially greater than the unaffected other eye from CME.  The eye has RP and therefore has a little bit thinner retina.  So the point here as Dr. Gallagher and Dr. Eller pointed this out originally, that if  you look just at the thickness of the retina to determine which patients with RP have cystoid macular edema, you might be fooled because they’re already started, starting off at a thinner retina in most  cases.

This is another example.  So we like to examine all of our RP patients for cystoid macular edema.  At least once a year perhaps.  And using high resolution OCT it actually is very simple to do.   Now here’s another subject, this was an unusual case, this  patient also has thickening of the retina cystoid macular edema.  Now there are a few ways to treat cystoid with our RP, the most common way is to use Diamox orally, has side effects whatever but this patient has risks.  So what do you do here?  Do  you – well maybe we should try him on Diamox.  But wait.  You want to look at these  patients very carefully in the periphery as  well.

And so the cause of the edema I don’t think is well worked out in most RP patients.  But it’s not always from their RP.  And here’s – I’m sorry for the photograph here but this is a wide angle image, there’s something going on here in the corner and this is a wide angle angiogram showing that this patient has sort of angiomatous changes that some RP patients can get and these angiomatous changes need to be treated with laser because Diamox isn’t going to do anything for this patient.

Here’s another RP patient, this one has most of the involvement peripherally, the posterior pole looks pretty good, OCT shows a pretty decent thickness and contour.  Here’s another subject, this one doesn’t have a retinal dystrophy but here’s a patient comes to you with lots of exudate in the posterior pole.  I’m sorry about the fluorescein but this patient has an angioma peripherally.  And the OCT shows that really has a lots of edema here in this eye, tremendous amount. And this patient was treated with laser to make this angioma go away and  this was the picture a few years later and the exudate is completely gone.   I’d rather treat these patients with peripheral angiomas with  laser than cryo because cryo can really  make chronic retinal detachments and so forth so I really avoid cryo but you have to be patient.  It took 2 years to get her improvement of vision.

So  let’s talk a little bit about some of the macular dystrophies, there’s vitelliform which is Best’s which is a relatively rare disease but we do see it.  It’s called vitelliform because it’s supposed to look like an egg yolk, that doesn’t there in that picture but this one does.  So you have this vitelliform or egg-like image or  picture and patients with Best’s have normal peripheral visual field, normal ERGs, normal ____ adaptations but they have abnormal EOGs and when is the last time you used an EOG, probably a long time.

But these subjects or patients actually have good visual acuity typically even later to adulthood and typically one of their eyes is still quite functional.  Best’s has an early age of onset and this egg yolk sort of goes through several stages which are called vitelli retiform changes, I’ll show you a few of those.

Best as well as lots of dystrophies now being characterized genetically, Best is a VMD gene of the vitelliform macro dystrophy gene and if you  have a patient that has any family history of this, this gene is present in virtually all those subjects but just for sporadic cases it’s present about 30 to 70 percent.

The EOG is typically reduced even in the carrier state, excuse me, in affected patients in the carrier - and the RP  is the primary tissue that is affected by that.  Vitelliform stage is usually in early adulthood or infancy, then you get this pseudohypopyon and then you get a scrambled egg, I’m going to show you a couple – sorry, they’re a little bit dark.  This patient has sort of this hypopyon phase, this is a round lesion, it got stuff sort of precipitating out inferiorly, we OCT through that, shows this to be underneath the RPE and it’s sort of a cavity here.  This one’s taken a little bit more through the fovea and you have more fluid here, RPE is here and this is below the RPE.

Here’s a auto fluorescence image, shows that this stuff does fluoresce pretty nicely and then later on it becomes more scrambled if you will and more pigmented. And then some of theses subjects can develop core revascularization and scar tissue and this was – not the same patient but one that has ____ issues, it only happens if it’s going to happen in one eye rather than both.

And you can also have multifocal vitelliform lesions, they’ve been described and a fairly recent article by Boone showing that you can have lesions posteriorly with the ____ phase here shown in OCT but you can also have – there’s a very faint lesion here,  you can’t see it very well,  you can see it better on the fluorescent, looks like a subretinal fluid there actually.

And then there’s another form of this disease which occurs in adults, the inheritance is not well known, but this disease can often be confused with AMD, in fact it’s sometimes very hard to tell.

And patients with adult form of vitelliform can have abnormal ERGs in about a third of them. The inheritance is not well known but it can be dominant and severe visual loss from adult vitelliform is not very common.  Bailey found ____ images, three subjects with adult vitelliform, it looks pretty much like Best’s but – younger patients but you see a lot  more sort of drusen-like kind of changes in pigments so it really is easy to – like these two would be easy to confuse with  AMD and therefore you know these are patients you have to follow over a long period of time because if they just came to you at this stage you might not be able to do so at all.

Then we’ll talk about Stargardt’s and Fundus Flavimaculatus, they can be considered by some as the same disease, some study, usually some people ______ , that disease would occur a little bit later and they’re both caused by ABCA4 gene mutations and are autosomal recessive.

Stargardt’s was first described by Karl Bruno Stargardt, he’s a German and talked about this dystrophy which begins usually at age 6 to 12.  Fundus Flavi starts a little bit later and the flecks that we’re going to talk about are a little bit more prominent in patients that you might classify as fundus flavi.  And where these flecks are located is the subject now of a lot of OCT research, may be to tell us why the disease occurs but they’re not just necessarily under the RP, they can be actually through the use of the retina sometimes.

Stargardt’s, those of you that have patients with Stargardt’s will see on that slide, youngsters who, you know that they really do quite well, they adapt very well as long as they have some accommodations   during their schooling, they really turn out to be quite successful students often and they usually are gainfully employed.

One of the other characteristics of Stargardt’s is this dark choroid and this beaten metal appearance to the fundus picture, show you some examples.  This patient has Stargardt’s, just a little bit of changes in the macula but on fluorescein you see the choroid is completely dark and that’s why the  vessels look so prominent here.  So that’s a prominent feature of patients with Stargardt’s.   Later changes of  Stargardt’s, you get this sort of beaten metal appearance and this is a – this is following the same patients over a few years.  You can see that the atrophy or  pigment change goes right up to the – that vessel there. Then over time they become more distinct, more pigment and the lesion becomes larger.  Now imaging with OCT on Stargardt’s, typically the finding is that the retina is thinning of the macula primarily the three you’re going to find in the same patient, getting a little worse over time, more apparent pigmentation.  And this was in the days we had stratus only on 45 micron thickness of the retina.  She came back actually last week, her ___ now show that this is a much larger lesion, she’s still very functional, same with the other eye and now we have serous OCT to show us the contour a little bit better.  But, again, the retina is very thin in the ____.  And this is just another cut in the other eye.  Very consistent.

Here’s another patient with Stargardt’s, again, these are sort of dark but they have these  little – the look like drusenoid changes, she has some pitting in her posterior pole which became relatively dramatic. And fundus flavi, is there any way to make it click up this, maybe it’s too hard to ask but I’m surprised that your, your device could ___ these images but that’s the way, I guess, we’ll just have to deal with it.

So these little yellow things that look like drusen are called pisciform, thank you, that are fish-like.  They look like little fish if you’re looking into a pond with little minnows.  So that’s one of the hallmarks of fundus flavi as well as pigmentary changes in the posterior  pole.

Here’s the autofluorescence, showing these little deposits a little bit more nicely.  This is the fluorescein, this is macular edema it shows RPE ___ defects so the RPE is pretty well affected so that’s why it looks that way.

Here’s the OCT fluorescence, these are, these tiny little ______  are the Stargardt deposits if you will.  And this is just the other eye in the same patient.

So these, we can image these patients, we can learn about the disease, I think that’s what the key is now, where OCT is applied with such individuals.  I think we’ll stop there.  Thank you very much.