Dr. Rosenfeld: It was extraordinary this morning at Retina Subspecialty Day. We had a session on dry macular degeneration. I think my colleagues would agree, if that session had been held five years ago, you could have heard a pin drop. The attendance would have been minimal, and the place was packed, and that’s because everyone’s coming to the realization--as we said in a meeting we once held at a Bascom Angiogenesis meeting--the title of the meeting was “Dry is the New Wet,” and if dry could be sexy, OCT has made dry sexy, because for the first time, we can really follow our patients with dry macular degeneration

I’m sort of going to use this to segue into how we’re using OCT for wet macular degeneration, but there are a lot of people that need to be acknowledged, and Carmen put together a terrific research group at Bascom Palmer

And, the person that came up with a lot of the algorithms that I’m going to discuss today, Giovanni Gregori--and we’ve had a slew of fellows and residents who have worked on this over the years, and it’s very--it is one of the most satisfying moments to see all this work kind of come to fruition and have these algorithms that we can actually use in clinical trials

So, I showed this slide this morning, and, you know, when we think of macular degeneration, we think of this normal disease progression. The dry macular degeneration--the drusen, the pigmentary changes can go to wet macular degeneration or dry, and we’ve been very fortunate over the last few years--we have anti-VEGF therapy

And, what I tell my patients, we’re taking the wet and we’re going to convert it back to dry and hopefully they see better, and everyone says, “Yeah, that’s a success.” And, unfortunately, now that I’ve been following these patients since 2001/2002, I have patients that look like this

This is a patient from the PrONTO study who was ecstatic, went from 20/50 to 20/25, five injections a year for two years, and then we followed this patient. No more injections, and this is what happens to the patient over the next four-plus years. The geographic atrophy progresses, eats through the foveal center, and this patient is very unhappy now, having thought she dodged the bullet and she could see better after the initial treatment

So, we wouldn’t consider this a success now, would we? But by following her over the years, at least I could tell her what was going on. And, it’s been very useful, because this OCT imaging really allowed me to follow her entire course of her disease. So, now the dry has gone on to geographic atrophy and it’s not very successful

So, the only way we’re going to define success in treating this disease is to stop dry macular degeneration, and it’s very encouraging to talk to the younger participants here at the meeting and they get it. They understand that coming up with dry is really the secret

We published a paper this past year in which we looked at patients who lost vision in the MARINA and the ANCHOR, the Lucentis trials, and they lost vision because the underlying dry macular degeneration progressed

Now, that’s how we usually follow patients with dry macular degeneration--color fundus photography. We see these drusen, and we go, yep, macular degeneration. But there’s a secret life to drusen that we now appreciate by using OCT. For clinical studies, this isn’t a very satisfying way of following the disease. It’s very hard to reproducibly draw these drusen, and you’re only looking at two dimensions. What about the third dimension

Well, we use the same scan pattern for all our patients, this 200-by-200 pattern, and what’s really neat is you can scan them now and you can analyze them with this new software that’s coming out, scans that you did years ago, so you can compare actually how their disease has progressed

So, we do the 200-by-200 as well as other scan patterns, but we like it because we get a 30-micron separation between the A scans and the B scans, and it’s very quick, okay? And, when we do that, we perform the raster pattern. We get the usual B scans and the algorithms that were originally developed. We get the internal limiting membrane, and you’ve seen this. We get the RPE segmentation, and you can see the beautiful contour of the drusen. Now, these are drusen that elevate the retinal pigment epithelium

But, what Giovanni Gregori developed is this RPE elevation map. It follows the deformations of the RPE, and what he does is essentially subtracts mathematically a normal RPE floor from the perturbed RPE floor, from the elevation. What he gets is a difference map, and from this difference map we can calculate area and volume

And, I love this. I don’t know if you can see it. Maybe we can turn the lights down a little bit to really see this beautiful distribution of drusen here. And, you can do the raster pattern, you can see the RPE segmentation, and there’s the difference map. You get an area and volume measurement, and it superimposes very nicely right on the drusen there. Okay

So Giovanni Gregori performed this study on 103 eyes. It’s highly reproducible. We can do the same scan over and over and get exactly the same measurements. Okay

So, we started following patients, and this was a patient we followed early on because now we have two-plus years' follow-up on this patient. And, clearly--I don’t know if you can see it. Maybe we can get the lights down even more. You can see the soft drusen here. And, this is what the patient looked like at baseline, and three months later, you get a blow up of the drusen. You can see, looks about the same after three months

But then you start looking at this drusen profile, and what we started learning is the drusen undulate over time. They go up, they go down, they go up, they go down. And then sometimes--we followed the patient. It says, “Baseline in three months” on top there, and then it gets to six months and the drusen just went away

Now, this has been reported in literature before, but this is the first time using this approach we ever saw such a dramatic change, and we asked ourselves is this going to stay the same? And, it has stayed the same, and it has stayed the same

So, then we asked the question what’s going on in the patient’s other eye? So, this is the patient’s other eye, and, well, you have trouble seeing it up there, but I’m going to blow it up for you. So, that’s that patient’s eye at baseline. The other eye three months later, it’s undulating, it’s getting bigger, and then three months later, it looks the same. It’s changed a little bit, and then it went away again. This is the other eye of the patient

But, if you look at the color fundus photo, it really hasn’t changed all that much. So, this is the secret life of drusen that we never appreciated before. We’re looking in the eye and it looks like it hasn’t changed, but there’s been a dramatic change here. All right

So, we thought, “A-ha, wouldn’t this be a neat way to test new treatments for dry macular degeneration to see if they can have an effect on the drusen volume without any bad outcomes--no geographic atrophy, no choroidal neovascularization?” So, we did this natural history study that’s online in ophthalmology, and we looked at 143 eyes and we followed them for up to two years, and we found, not surprisingly, that some are stable, some increase, some decrease. All right

But, we were really interested in that population that decreased. So, this is what the drusen--example of the drusen that looks like when they’re stable, and nothing much changes over the course of the year. It’s 40 percent of the patients

But, this is what the new printout is going to look like, all right? You’re going to get this printout in the new software, which isn’t available yet--but soon--and you’re going to get the drusen map and you’re going to hear about the sub-RPE illumination that looks at geographic atrophy, but that’s that middle portion here, and here’s that difference map and all the quantitative values are down here. But, you can see there’s no geographic atrophy here, okay

Here’s a patient that increased drusen volume. You can see the increase in the drusen here and the increase in the map and the measurements increase, and this is what the readout looks here. Here are the maps superimposed on the SLO image--no geographic atrophy. And, this is the increase in the drusen, and the numbers are all here

And, drusen can also decrease, and they can decrease by forming geographic atrophy, they can for choroidal neovascularization, or they can go away without any significant anatomic abnormality. So, this is an example of a patient in which the drusen--this drusenoid PED collapses into geographic atrophy. You can see it here on the autofluorescence. You can see it here on the B scan, the increased illumination into the choroid. You can see the drusen going away here on the segmentation map

And, here you can see the geographic atrophy and the absence of the drusen volume, and this is what it’ll look like on the printout. You’ve got the drusen going away, you’ve got the geographic atrophy appearing, and you get the quantitative values down here. All right

And, now the drusen can go away, and here’s a little secret. Have you noticed that when a patient comes in with choroidal neovascularization, they don’t seem to have many drusen in the back of the eye? That’s because the drusen go away and then they develop choroidal neovascularization. It’s interesting. We’ve seen this over and over again. Something’s going on there, and I’d love to hear from somebody if they know the secret of why drusen go away before choroidal neovascularization appears

And, this is what the printout will look like here. You can see the drusen going away. They stay away, and the choroidal neovascularization appears

And, here, this is what we’re looking for, that 4 percent in which the drusen go away and there are no sequelae. That’s what we want to try to reproduce. And, now that we know that it happens 4 percent a year, we can design clinical trials to create that end point knowing that it occurs at a frequency of 4 percent. Okay? And, that’s what the printout looks like. Not surprisingly, the drusen go away and stay away

So, we think this is a really interesting novel strategy for following patients with dry macular degeneration. For those of us that are clinical trialists and want to develop treatments for dry macular degeneration, I think this is a really convenient way to have a short-term clinical trial to see if we’re having a treatment effect in a disease that otherwise we’d have to run trials for years to see if we’re having a treatment effect

But, you know what else is a elevation of the retinal pigment epithelial? Something we see all the time, and that’s a retinal pigment epithelial detachment. So, here we have drusen, and here we have a retinal pigment epithelial detachment

So, now I’m going to show you how the same algorithm is useful for following patients with wet macular degeneration, all right? There’s the PED, so we do the same sort of subtraction. We subtract the segmentation from the RPE floor, and we get a difference map. Now we have area and volume measurements of PEDs

And even though this was developed for dry macular degeneration, we’ve been using this to follow patients with wet macular degeneration. This paper’s impressed looking at the reproducibility of this

And let me show you how, in two examples, it shows the need for using this modality if you want to try treat and extend or PRN dosing with anti-VEGF therapy

This is a patient that was in one of our clinical trials. The right eye had hemorrhagic pigment epithelial detachment. Unfortunately, it’s cut off here, but this is the pigment epithelial detachment. You can see the sub-retinal fluid here on the retinal thickness map. You can see the ring of fluid, the PED, and there’s the difference volume measurement and the volume here. Okay

So, this patient’s treated--given the second treatment of an anti-VEGF agent. The PED diminishes. The sub-retinal fluid is gone. You can see from the map it’s gone. The volume of the PED has diminished. So, we’re following this patient every two weeks in another clinical trial for the other eye, so we decided to watch this patient

So, we watch this patient, and the PED doesn’t change much on appearance--this is two weeks later--but you can see the volume is starting to creep up, 2.6 millimeters cubed, 3.2 millimeters cubed. The next visit, the patient comes in two weeks later. There, the fluid has returned and the volume has increased even more, and we treat and the volume goes down

So, for those of you that like to watch pigment epithelial detachments, this is a really nice way of following those eyes. And, if you start seeing it increase, the volume increase, you better treat. Otherwise, that patient may develop an RPE tear. They’ll certainly come back with RPE, with sub-retinal fluid

This is another case that we were following. This patient had received nine anti-VEGF treatments. We give her a tenth. She asks, “Is that enough?” “Well, let’s follow you,” I said. And, so here is her pigment epithelial detachment four weeks following her tenth injection. The pigment epithelial detachment is stable, 0.83 millimeters cubed, 0.82 millimeters cubed. We watch

The patient comes in two weeks later. It’s increasing. Not only is the volume increasing, but you can see that the two-dimensional contour of the PED is increasing. Since there’s no fluid, we watch. The patient comes back in. We now detect fluid on the OCT, we detect fluid on the retinal thickness map, and the volume and area of the PED has now increased. We treat, and it goes away

So, it’s really nice, because using this algorithm, we can see where the contour of the RPE changes as well as the volume of the RPE detachment changes. So, this is going to be a very useful algorithm if you want to study dry macular degeneration, if you want to study vascularized pigment epithelial detachments, and clinical trials are under way looking at this approach

So, the reason why I like the Cirrus spectral-domain high-definition OCT is that it’s one-stop shopping. I can use it on my patients with wet macular degeneration to make the diagnosis, to follow them with anti-VEGF treatment, to look at drusen, and to look at geographic atrophy, so you can follow patients for the entire lifecycle of the disease

Thank you very much