From Trials to Treatment: Real-World Applications in Medical and Surgical Retina Part 2 of 3

CASE 1: DIABETES AND FLOATERS

Dr. Wykoff: The first patient is a 54-year-old female with floaters. Dr. Khurana, this is your case — would you please summarize?

Dr. Khurana: This patient has a history of diabetes for 8 or 9 years, seeing floaters, is 20/30 in both eyes (Figure 1). There are large areas of non-perfusion in the periphery noted on FA. There are areas of neovascularization. The left eye shows pre-retinal hemorrhage, and she had had a vitreous hemorrhage in both eyes. Her A1c was reasonable at 7.8. Her diabetes was under control on oral agents.

Figure 1. A 54-year-old woman presents with floaters.

Dr. Wykoff: Who would use PRP as the first line on this patient?

Dr. Steinle: It depends on how compliant I think the patient is going to be. PRP will offer a lifetime of protection at the cost of losing some peripheral functionality. Anti-VEGF injections will preserve some peripheral vision and reduce any macular edema at the risk of the patient disappearing due to non-compliance or re-emerging months or years later with advanced pathology, such as a tractional detachment or neovascular glaucoma.

Dr. Prenner: Based on this history, I would treat her with PRP.

Dr. Boyer: I would treat her with anti-VEGF first, and then I would do PRP. You may be surprised that the right eye improves a lot. The left eye looks so ischemic that you are definitely going to need PRP.

Dr. Olmos: If it were my eye, I would want some PRP on board.

Dr. Prenner: I would not. If it was my eye, I would treat myself with anti-VEGF. But, here is the issue: how do you develop proliferative diabetic retinopathy (PDR)? By not taking care of yourself; once you have PDR, you have most likely defined yourself as an unreliable patient. I just do not trust this population to follow-up enough to be managed with anti-VEGF monotherapy at this point.

Dr. Olmos: Diabetes is a different disease depending on the genetic and ethnic makeup.34 In Los Angeles, California, we have seen people of Native American and Hispanic heritage who go blind but have the same A1c as their upper-crust Caucasian neighbors. They may not have the resources to take care of themselves either. We must take all that into consideration when treating a particular patient.

Dr. Boyer: You bring up some good points — it is not only blood sugar control, but also blood pressure control. Some of my patients come in with good blood sugar numbers, but they have sleep apnea. There is something else that has precipitated the progression. But, if they say they have not seen their primary care physician for 6 or 9 months, that patient is getting a PRP. They are not compliant, they are not seeing their doctor, and long term, I am concerned they will stop coming to see me as well.

Dr. Steinle: The right eye appears to have borderline macular edema on the FA. So, I would start anti-VEGF injections in the right eye, but PRP in the left. I use the presence of macular edema as a tiebreaker — if a patient has peripheral ischemia with NVE, but also has a degree of macular edema, anti-VEGF nicely treats both the peripheral NVE and the central edema.

Dr. Wykoff: I prefer combination therapy. I would put in an anteriorly-oriented PRP towards the ischemic zones in both eyes after treating her with anti-VEGF injections to stabilize the eyes. Patient compliance is a real issue, and I agree that doing our best to gauge likely patient compliance is important to guide management.

Dr. Khurana: We all have those diabetic patients who do not show up and have compliance issues. That is concerning. But writing them off as being potentially non-compliant with us is perhaps doing a disservice. We know the anti-VEGF load can work. We all know the downsides of PRP and that anti-VEGF is equally effective from Protocol S.³⁵By immediately categorizing these patients as non-compliant, are we doing them disservice by not even offering anti- VEGF and jumping right to PRP?

Dr. Wykoff: What if we opt not to do any PRP in these two eyes, and use anti-VEGF montherapy? Then after 6 months, we see the patient is completely compliant and comes in every month. Now the eyes are largely normalized, with resolution of all neovascular fronds by examination and reduction in all intraretinal hemorrhages. What would be your management plan?

Dr. Boyer: You have to follow them.

Dr. Khurana: The disease has been modified, but you still need to closely monitor them. We only have 2 year follow-up from Protocol S (with the 5-year results pending).

Dr. Wykoff: Be more specific. Treat and extend? PRN? Continue monthly forever?

Dr. Khurana: I would perform widefield angiography, quarterly.

Dr. Olmos: I would perform PRN treatment.

Dr. Prenner: I tell patients that their disease has regressed and we will now watch them closely. If there is recurrence, we will reinstitute therapy. I do not employ a prophylactic injection or a maintenance injection at this point.

Dr. Wykoff: Anyone use quarterly dosing in attempt to maintain stability and avoid progression? In eyes like this, I often do.

Dr. Khurana: No. If there was a study showing that a shot every 3 or 4 months was beneficial or decreased the rates of progression, that would be great. In Protocol S, though, the recurrence rate was almost 55%.³⁵ So PRP is not a ‘one and done’ idea. The CLARITY study looked at aflibercept in PDR only, no DME, 65% needed follow-up PRP.^36,37

Dr. Boyer: Aside from the compliance issues with anti-VEGF, we do not know what the endpoint is. Is disc neovascularization your big endpoint? You can follow that pretty easily. You can follow the macular edema. In this other eye, there is a considerable amount of leakage. I would feel much more comfortable putting a PRP to the non-perfused areas and watching them carefully at that point.

Figure 2. PDR with fibrovascular proliferation and retinal traction nasal to the optic nerve head with associated sub-hyaloid hemorrhage and non-center involving DME.

Dr. Wykoff: Would the eye in Figure 2 change things? An eye with more advanced PDR with visible and substantial fibrovascular tissue associated with a moderately-sized preretinal hemorrhage. How would you manage this differently than the less advanced PDR case in Figure 1?

Dr. Prenner: I would be very careful about the sub-hyaloid component as those are the cases that need early surgical intervention. Otherwise, my management would not change.

Dr. Boyer: We have all seen crunch after giving an anti-VEGF. That is a risk when there is any form of traction. I might be inclined to avoid the crunch and do PRP.

CASE 2: DME WITH MINIMAL RESPONSE ON OCT TO MULTIPLE TREATMENTS

Dr. Steinle: Figure 3 shows the case of a 65-year-old male with significant DME in the left eye. There was no response to bevacizumab, aflibercept, or triamcinolone. There is a large amount of central DME, and nothing seems to work. The FA reveals several central microaneurysms (MAs) within the foveal avascular zone (FAZ). Based on the poor response to anti-VEGF and steroid therapies and considering the vision is 20/25, would you just stop and monitor this patient — or what tips can you share regarding the treatment of refractory DME?

Figure 3. Significant DME shown on FA (A). Minimal response shown on OCT following multiple injections (B).

Dr. Olmos: What does the patient think about the situation? Is he symptomatic with his 20/25? How is the fellow eye?

Dr. Steinle: The patient has 20/25 vision in both eyes with minimal complaints.

Dr. Khurana: Where did the patient start with vision?

Dr. Steinle: He started with 20/30. But, the OCT reveals significant macular edema with no response to therapy. My concern is while the patient is 20/25 today, what will his vision be in a year? In 2 years?

Dr. Prenner: The location of the pathology is a bit less concerning as there is an inner retinal cyst, but relatively well preserved outer retina. I think that this kind of fluid is much better tolerated as the photoreceptors are less involved. The patient is not responding to anti-VEGF therapy, nor to the initial steroid. You might consider changing the regional depot steroid with dexamethasone or adding laser.

Dr. Khurana: What about focal laser? There is that extrafoveal macular atrophy present that is leaking.

Dr. Steinle: Do you feel comfortable venturing inside the FAZ with your focal laser treatments?

Dr. Prenner: Generally not, but if that is required, I will use Micropulse laser first.

Dr. Olmos: Does it work in your hands?

Dr. Prenner: I do think Micropulse laser works in some cases, but know that I have some observer bias as I want the treatment to work for my patients. However, in the absence of prospective, randomized trial data, the jury is certainly still out.

Dr. Boyer: In this eye, just because triamcinolone did not work does not mean dexamethasone would not work. For me to say a patient is not responding means I want to see him in 2 weeks. That may show some sort of anti-VEGF response. I would try dexamethasone. The problem is you cannot use a steroid frequently in a phakic patient. But, I do think it is worth trying to see if there is any response.

Dr. Steinle: If you see an OCT improvement with dexamethasone without significant intraocular pressure elevation, you could consider a long-term implant such as the fluocinolone implant for continuous low dose therapy.

Dr. Olmos: We use very little focal laser nowadays. But recently, I did have a pregnant patient, a type 1 diabetic, with macula threatening edema, who was planning on breast-feeding. I did not want to give her anti-VEGF, so I discussed the risk of the macular edema affecting the central vision and whether she wanted laser as a preventive method, which she opted to have. That was probably the most recent time I have used focal laser.

Dr. Khurana: I use focal laser, but I will manage DME following the Diabetic Retinopathy Clinical Research Network (DRCR.net) Protocol I. I start an anti-VEGF. For those who persist, I will add laser 6 months after initiation of anti-VEGF therapy.³⁸ I have tried micropulse and a variety of low threshold lasers, and they have not been impressive. There is a tendency to want everything flat immediately, but these patients can do very well over long periods to time even when there is fluid present.

CASE 3: DR ASSOCIATED ISCHEMIA WITHOUT DME

Dr. Wykoff: Figure 4 shows an eye similar to the previous case, but it is now symptomatic, with 20/50 vision. The FAZ is extensively enlarged, with no significant DME. The patient is unhappy. What are you going to do? The other eye is normal.

Dr. Boyer: You might be surprised that using anti-VEGF alone can cause an improvement of vision even if the edema does not improve. In this case, I think the patient would improve, and you would even treat that small tuft of neovascularization.

Figure 4. Symptomatic patient with 20/50 vision with no clinically relevant DME and an enlarged FAZ. Approximate size of normal FAZ outlined with red circle. NVE is also visible inferior to the arcade vasculature.

Dr. Steinle: And Protocol S showed us regarding the area under the curve, vision improved with anti-VEGF.³⁵ This is a patient in which I would actually consider it.

Dr. Khurana: That has been truly fascinating. Patients who did not have DME in Protocol S actually had vision improvement with anti-VEGF, and I do not know if anyone has a real anatomic reason.

Dr. Prenner: I agree with the approach, but I suspect that there will be little clinical improvement as the source of this visual compromise is largely macular ischemia. Patients will want something done often times, even when the treatment rationale may be limited.

Dr. Khurana: Dr. Prenner makes a good point that we often treat to manage patient expectations. They sometimes expect treatment, but it can be more important, at times, to manage their expectations.

Dr. Boyer: If you explain it just like that — we do not know if these injections will help, but we have nothing else to offer. So we are going to treat you three times in a row, and then re-evaluate the situation. You would be surprised how many improve.

Dr. Wykoff: To Dr. Boyer’s point, even without an improvement in Snellen visual acuity, many of these patients subjectively feel like they are seeing better and have improved visual function globally with anti-VEGF therapy. This may be related to the reduction in leakage and other vascular parameters seen with angiography after treatment.

Dr. Steinle: With PDR, even with mild NVE, patients can experience micro-hemorrhages from the neovascular fronds. These ‘subclinical’ vitreous hemorrhages can significantly impair vision. Sometimes, anti-VEGF injections can clear the vitreous by involuting the leaky NVE and halting these subtle vitreous hemorrhages. After a course of anti-VEGF treatments in PDR patients, it is not only impressive to see significant regression of DR severity on FA, but it is also impressive to see how much clearer the media is on repeat FA.

CASE 4: FLOATERS

Dr. Khurana: A 64-year-old man complains of floaters that did not go away after they had with previous intravitreous injections. He presented 5 days after a bevacizumab injection. Figure 5 shows a very noticeable spot in the field in the vitreous on the retinal surface.

Figure 5. Noticeable spot in the field in the vitreous on the retinal surface.

Dr. Wykoff: Does anyone tell patients before using bevacizumab that this is a possibility? Has anyone altered their source of bevacizumab or the type of syringes they are using since we have become more aware of the possibility of silicone oil droplets after the use of repackaged bevacizumab?

Dr. Prenner: We changed our consent to reflect recent recommendations from OMIC.

Dr. Khurana: Syringes were changed that do not use silicone oil lubricant.

Dr. Boyer: I have only had this happen once, but my partners have had it multiple times.

Dr. Steinle: We recently published that more than 20 cases showed silicone oil bubbles after bevacizumab injections in our practice, compared to one case in the prior decade.39 We have experienced a significant uptick in occurrences recently.

Dr. Khurana: We just published on this.⁴⁰ We had a 57-fold increase in silicone oil droplets after bevacizumab from May to November 2017 compared to the previous 7-month period. Like Dr. Prenner, we have changed our consent form and believe our incidents were attributed to the insulin syringes. Now, we use non-insulin syringes (Norm-Ject syringes do not use silicone oil), which may minimize the incidence of floaters.

My hypothesis is that there was a change in the manufacturing of the insulin syringes, resulting in increased amounts of silicone. The amount of silicone is within the normal limits for delivering insulin. However, these insulin syringes are being used my multiple compounding pharmacies across the country to prepare bevacizumab and would explain the increased incidence we witnessed last year.

Dr. Prenner: We have heard from the ASRS Therapeutic Surveillance Committee that the incidence of this, fortunately, has dropped in the last 6 months.

CASE 5: HOW TO TREAT DME AFTER PARS PLANA VITRECTOMY

Dr. Steinle: Figure 6 is a 55-year-old man who has a history of vitrectomy for tractional retinal detachment and now presents with diffuse ‘spongy’ DME. How do you treat vitrectomized eyes that have significant DME?

Figure 6. A 55-year-old man with diffuse DME. This patient had a vitrectomy in this eye in the distant past for a tractional detachment.

Dr. Prenner: Fluocinolone acetonide is a nice option for these cases as well. Unlike with Ozurdex, if the implant migrates into the anterior chamber, it will not cause corneal decompensation.

Dr. Khurana: I would urge caution when using the dexamethasone implant in vitrectomized eyes with loss of lens capsule, as anterior chamber migration can occur resulting in permanent corneal decompensation.⁴⁰

Dr. Steinle: There are anecdotal reports that the small fluocinolone implant can be left in the anterior chamber for greater than 6 months without any acute corneal problems. The fluocinolone implant might be a safer option in vitrectomized eyes at risk for anterior implant migration.

Dr. Olmos: In this scenario, I would first give an anti-VEGF.

Dr. Steinle: Do you change your protocol for which anti-VEGF you select and how often you retreat based on the fact that this patient had a previous vitrectomy?

Dr. Wykoff: In a small, post-hoc secondary analysis involving 25 eyes from Protocol I, the DRCR.net has reported that eyes having undergone prior vitrectomy received a similar number of anti-VEGF injections through 3 years compared to eyes not having undergone vitrectomy.^41,42 Is that your experience?

Dr. Prenner: Although initial studies suggested that vitrectomized eyes limit the durability of anti-VEGF therapies, the evolving science seems to suggest there is no difference, as compared to non-vitrectomized eyes.

Dr. Olmos: In my practice, there does seem to be a little difference, where anti-VEGFs are shorter-acting. I like to leave a little vitreous skirt after PPV for the anti-VEGF.

Dr. Boyer: That is my experience, too. Patients may go 4 weeks, but not 5 weeks.

CASE 6: ASYMPTOMATIC SEVERE TRACTIONAL RETINAL DETACHMENT IN TYPE 1 DIABETES

Dr. Steinle: This is a tough case — a new 29-year-old woman is referred with no complaints, 20/20 vision (Figure 7). She is completely asymptomatic and has been told to see us for her first exam. She has had type 1 diabetes for 22 years. How do you approach this patient?

Figure 7. A 29-year-old female with type 1 diabetes presents with a severe TRD and 20/20 vision.

Dr. Olmos: I would approach her with a lot of words, a lot of hand holding, and a lot of explanation.

Dr. Prenner: I would spend my initial time trying to educate her and have her develop an understanding of her disease. Hopefully, we can engage family members and have them buy into the process as well. Quickly after, I would treat her with PRP.

Dr. Khurana: I do not jump to treatment immediately because they need a lot of buy-in on a lot of levels — the family, the doctor, etc. I would do laser, actually do a little lighter and a few sessions. With all that neovascular activity, all the traction, I would be very worried about a crunch thing and whether they need surgery or not. I would love to get PRP in before we ultimately have to do surgery.

Dr. Prenner: Dr. Boyer, what are your thoughts about waiting to let these kinds of eyes mature a little bit after laser versus going in early? How do you decide your window timeframe to operate?

Dr. Boyer: I use traction to the fovea. Right now, this is a 20/20 eye. Even in the best of hands, postop may not be 20/20. We all have seen patients where you can peel that off. If I really document that the traction is increasing to the fovea, I may show the progression to the patients and go in at that point to try to save central vision.

Dr. Prenner: This is also a very good time to bring the endocrinologist and internist heavily on board. Hariprasad et al. had a paper this year that looked at the death rate in people after tractional retinal detachment surgery, and found nearly 50% mortality at 10 years.⁴³

CASE 7: AMD

Dr. Olmos: Figure 8 shows a 78-year-old man presenting with 20/20 but complaining of a “gray spot” in his central vision. He has never seen an eye doctor before, as he never had any trouble with his vision. What would you do, and what is the end point of therapy?

Figure 8. A 78-year-old man presenting with 20/20 but complaining of a “gray spot” in his central vision.

Dr. Boyer: With a hemorrhage like this one, it will be difficult to visualize what it is. It may be a macroaneurysm, but, if it is not, it is likely a CNVM. OCTA may be able to image it, but I do not believe that would alter your management strategy. You could also use indocyanine green (ICG). If it is polypoidal choroidal vasculopathy, I would start with aflibercept as that has been successfully used in these cases.^44,45 I would not do a pneumatic displacement as it would result in a poor outcome with that superior hemorrhage. I would not rush to treat. Some of these patients clear; I would explain that it is probably going to get worse before it gets better.

Dr. Olmos: I treated this patient with aflibercept. I gave two monthly injections, after which the OCT was markedly improved, and in fact, dry. Then I gave a treatment holiday.

Dr. Prenner: What was the thought process concerning halting intervention?

Dr. Olmos: He has a CNV that is not subfoveal. It is extra-macular, and that is fortunate for him because, if he does bleed, it will not be subfoveal. What would everyone else have done?

Dr. Prenner: I would treat and extend.

Dr. Boyer: I would treat and extend.

Dr. Steinle: I would treat and extend too. I would try to extend out to where we treat quarterly. I do not want him to be extended too far beyond quarterly and risk bleeding again — as he has demonstrated a propensity for bleeding in the past.

Dr. Boyer: Some of these patients are so extrafoveal that you can use photodynamic therapy (PDT) on them. These CNV really do go away in that case.

Dr. Wykoff: Would you use full fluence PDT for that location?

Dr. Boyer: Yes, and when they are that far away, full fluence is not a problem. Look at the choroid, which is very thick. That patient is not going to have visual loss. I am surprised that the patient developed CNV.

Dr. Khurana: Would you do PDT over a thermal laser?

Dr. Boyer: I would. I am always wary towards the fovea, and they always recur toward the fovea. I am more likely to cover the whole thing with PDT, and I feel a little bit safer. I can always laser.

CASE 8: AMD WITH A TWIST

Dr. Olmos: Figure 9 shows a 63-year-old East Asian male who has had distortion for about a year in the right eye. He was initially diagnosed with dry AMD and was asked to begin AREDS2 antioxidant multivitamins. Five days prior to these images, he developed acute vision loss in the left eye. The presenting vision is 20/50 OD and 20/100 OS.

Figure 9. Distortion for 1 year OD and acute vision loss OS, presenting with 20/50 and 20/100, respectively.

Dr. Wykoff: Looks like more than dry AMD at this point.

Dr. Olmos: I thought so, and OCTA showed vascular network in the outer retina choroid complex layer. This patient is a practicing dentist and is distraught because he is now unable to practice. I treated with bilateral bevacizumab, and, although OS responded beautifully, neither his fluid nor his OCTA findings budged after three doses in the OD. What now?

Dr. Khurana: On OCT, the right eye looks like there is a cyst.

Dr. Prenner: This is like pachychoroid, with pachy drusen and central serous chorioretinopathy variant with secondary CNV in the other eye, maybe?

Dr. Olmos: The patient remains symptomatic OD, but he does not want any more treatment in that eye.

Dr. Prenner: Was he less symptomatic after bevacizumab? What happened in the left eye?

Dr. Olmos: The left eye returned to 20/20, so he is happily functioning and does not want more therapy in the right eye. He is on a treat and extend regimen in the left eye.

Dr. Khurana: If I observed more cysts in the outer retina, it might be idiopathic parafoveal telangiectasia (IPTs or macular telangiectasias). CNV can develop after that as well. These cysts are so deep; typically, those are more outer retinal cysts with IPTs that you will see, so that may not be the right diagnosis.

CASE 9: WHEN TO STOP TREATMENT

Dr. Boyer: Figure 10 shows an 85-year-old male pediatrician I started seeing in 2007. He was treated with ranibizumab and PDT at that time. In 2010, he was 20/80 with a central subfield thickness (CST) of 447 μm, still receiving monthly injections of ranibizumab. By 2011, he now has 20/100 vision, and his OCT has not budged. Is this the end game? I brought him back in a couple of weeks instead of monthly and realized he had responded.

After more than 20 injections, his vision fluctuated between 20/60 and 20/200 on ranibizumab. I changed treatment to aflibercept in 2012, and, by the fourth injection, the thickness improved and vision was 20/100 (Figure 11).

Now, in 2017, the patient is basically dry (CST is 233 μm), has 20/80 vision, and is happy. I was ready to give up. So, when do you stop? Here is a patient who went 10 years on treatment, and he was functional.

Figure 10. Treatment after 5 years with monthly ranibizumab.

Figure 11. Same eye after changing treatment regimens.

Dr. Steinle: The first 2 years of the 5-year CATT data showed that exudative AMD patients did really well when they were receiving frequent injections,46,47 but then when we reduced that treatment burden in years 3 to 5 in the real world, the vision dropped way down and ended below baseline at year 5.

Dr. Boyer: The SEVEN-UP study showed the same thing.⁴⁸ In their subgroup analysis, those patients who received more frequent injections did better. Do not give up on these patients, even if they look hopeless.

Dr. Prenner: How do you decide when it is time to change biologics? That might be helpful. Does anyone have patients who require bimonthly injections? I have a couple.

Dr. Khurana: Do you switch agents every 2 weeks?

Dr. Prenner: You really need to use bevacizumab at least every other injection, if not for all injections, from a cost perspective.

Dr. Wykoff: Thank you all for your insights and comments regarding these retina cases. The field has seen tremendous progress over the last 10 years, and there is certainly more to come.

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