Lecture: Management of Inherited Ocular Disorders: Emerging Concepts in the Post Genome Era

Learning objectives of this lecture are:
• To familiarize optometrists with the current research on treatment of inherited ocular disease
• To explore the role of genetic testing
• To develop the knowledge base to appropriately counsel patients and make appropriate referrals
• To become comfortable determining which patients are appropriate candidates  for implantable technology/ “bionic vision”
• Review appropriate visual assistive equipment recommendations

Lecture location: on-board the Orbis Flying Eye Hospital in Chittagong, Bangladesh

Lecturer: Dr. Alexis Malkin


(To translate please select your language to the right of this page)

Well, I want to welcome everyone to the Orbis Flying Eye Hospital. It’s a great first week here in Chittagong. I also want to welcome the Cybersight audience. We’re very lucky today. We’re doing something for the first time, like I said earlier. We’re having our first pediatric low vision conference here on the plane. We’re very, very lucky, from Boston, to have Dr. Alexis Malkin. She’ll be talking about inherited disorders and how you manage those with low vision. So give her a big round of applause, and we’ll start the lecture. So thank you very much.

DR MALKIN: All right. Good morning. So as Hunter said, I’m going to be talking about inherited ocular disorders, both from the retinal management, as well as from the low vision management. So just making sure that you’re looking at both aspects of every case. And we’ll go through a brief introduction, and then I have a number of cases that we’ll walk through, that elucidate some of these points. So I’m hoping that you will be familiarized with the current research on treatment, and that we can have a conversation about what that means for managing our patients with inherited diseases. We’ll talk a bit about genetic testing and what role that has right now. And also what role that will have in the future. We’ll talk about the knowledge base for counseling patients, when they ask you questions about having children in the future, and what it means to have an inherited eye disease. And then we’ll look at some of the technology, the implantable technology, the concept of bionic vision, which I know that my low vision trainees already have had some exposure to this week. And we’ll talk about visual assistive equipment or low vision devices, and what types of things are helpful for these pediatric cases of different ages and different eye disorders. So first let’s talk a little bit about genetic eye disease in general. We know that about 1% of all newborns suffer from a unifactorial genetic disease. And in about a quarter of those cases, the eye is affected. So it’s a small number, but when we think about the number of years that these people are a part of the low vision community, they’re members of the low vision community for the most number of years, because they’re diagnosed at birth. And so 60% of cases of blindness among infants are caused by inherited eye diseases. And making sure that we’re getting these infants diagnosed, managed, and then dealing with the genetic testing for when treatments are available, is a really important part of management. And like I said, this segment of the population are those with the longest years with low vision. So it’s not somebody getting diagnosed much later in life, who only has a few years where they need this additional visual assistance. So when we’re thinking about what we can do once we have this information, and once we start to understand these genetic disorders, one of the most important things is giving patients an accurate diagnosis, and also an accurate prognosis. So different variants within different conditions have different prognoses. So if we can get that specific gene or determine exactly which genotype is affected, we may be able to better educate our patients. Because we have better ability to track these patients over time, we can also have a much better tracking of the prognosis. We can predict a little bit better how their vision is going to change throughout their lives. And we know that genetic testing is becoming faster and more affordable. It’s still very expensive for certain conditions, but it’s becoming much more readily available for the more common conditions. So when we talk about altering the prognosis, there’s two aspects. One is the part that the low vision group is most focused on, which is: How rapidly will the condition progress? And how do we intervene for the visual function? The other question is from the medical side, which is: Do we have a treatment being developed that we can then implement early on in the disease, if we know the specific genetic type? So there are some gene replacement therapies that are being studied. There’s gene silencing studies. There’s the suicide gene therapy or antiapoptosis therapy. And there’s antigrowth factor therapies. And these are all in — some in very early clinical research phases and some in a little bit later. But without knowing the specific genetic type, we don’t know which treatment may be applicable to our patient. So when we look at what is currently going on in terms of ocular gene trials, we’ve got a handful of clinical trials that are available. So Lebers congenital amaurosis — we already know what gene is affected, and there are active clinical trials going on. The same is true for some forms of retinitis pigmentosa. The MERTK gene, as well as the Usher gene — those have active trials. The Stargardt trials have been under development for many years. Choroideremia. Some early trials with macular degeneration. When they can find the specific gene that’s involved. Some of the corneal opacifications. And Lebers hereditary optic neuropathy. So we already have made huge advances, even in the last 5 to 10 years, of what conditions have been identified and where there are active trials. But when you’re thinking about testing your patient, what are the considerations? And what is the risk/benefit of getting that testing? So we know that a blood test is relatively low risk. But it can often be very costly. And is it worth spending money with your patient to find that information, if there’s not an active trial? Or if the positive yield on that test is very low? So going through the testing, but not being sure you’re going to even get a positive gene response. So that cost/benefit ratio is really an important consideration, when you’re looking at whether or not you want to genetically test your patient. There’s ethical considerations. If you find out that someone is gene positive for a condition, but they don’t have any signs or symptoms, what does that mean for them, long-term? And does that perhaps change their attitude towards having children in the future, knowing they’re gene positive, even if they’re not expressing the gene? So there are ethical considerations, when you look at genetic testing. And genetic counselors play a very important role in educating patients about whether or not genetic testing is appropriate. There are also questions as to how useful the information is, when there aren’t current treatments. And one of the big questions people are asking, especially with macular degeneration, is: Can we personalize the treatment better if we know the specific genotype? So we know there’s many genes that affect conditions like retinitis pigmentosa or macular degeneration. And so is that something where knowing the genotype may change our treatment, as they advance through the disease? It doesn’t yet. But it is a consideration. And what’s the sensitivity and specificity of the test? This goes back to that cost/benefit ratio, that risk. Are you going to get a false positive or a false negative with the testing? And then what do you do with that information? And how do you work with your patient to understand what that means? And many hospitals still don’t have really active genetic counseling programs. Particularly genetic counselors that are trained in ophthalmologic conditions. They are starting to be more and more comfortable hiring genetic counselors who can specialize, but it’s a pretty new field, in terms of giving people that kind of counseling, when they’re dealing with these diagnoses. So if you’re thinking that you have a patient, they’re asking you: You know, should I get my genetic testing ordered? Is this something that exists? And what information can I get, if I get that test? There is the Online Mendelian Inheritance in Man Database. So you can actually type in clinical features, phenotypes, or a specific diagnosis, and it will give you information as to whether or not that genetic test exists, as well as how sensitive and specific it is. In the US, a few years ago, they completed the eyeGENE project. And this was a project developed by the National Institutes of Health, National Eye Institute, where they wanted to start to categorize patients with different phenotypes, and then see if they could match up the genotype. So the understanding was that there were so many patients across the US and across the world that had specific conditions, but there was no searchable database to find all of the ones with a specific genetic variant. So the NIH offered free genetic testing, so that they could look at what gene was affected and match that up with the phenotypes. There were many, many, many samples collected, but not very many positive results. And they also felt like… People were spread out across centers. So this was a little bit more difficult to track. And when we look at the different types of cases that presented as a part of the eyeGENE project, we can see actually the most important thing, I think, is that honeycomb dystrophy was one of the most common diagnoses that presented for the free genetic testing, but it’s a relatively rare condition, and we’ll see in a moment how many positive hits there were with that. But there was a huge range of conditions. Stickler’s syndrome, microphthalmia, achromatopsia, aniridia, Lebers optic neuropathy, who entered their DNA into the eyeGENE project. When we look at the positive hits, that’s in the darker brown bar. And the lighter brown bar is the other cases. So if we look for a moment at the Doyne’s honeycomb dystrophy, which had so many people who participated, there were only a few positive hits. Less than 10% that matched up to a specific gene. And this 90% who didn’t match up to the known honeycomb dystrophy gene. So we can also see with Usher’s syndrome, much higher positive rates. And I think it’s much more understood which gene causes Usher’s syndrome. But you can see it was variable rates across the different conditions with whether or not the patients had positive hits in the genetic testing. So when we start to think about how to approach the patient, and how to figure out if that patient may benefit from this kind of testing, these are the questions that I tend to ask: You know, what are the characteristics of that patient? Is it a condition that was congenital? We know that the inherited eye diseases are sometimes present at birth. But sometimes they’re things like Lebers hereditary optic neuropathy, where the presentation is a little bit later in life. We want to know: So what is that expected age of onset? Is this a child who should have already presented with symptoms? Or is it a child that may still have a few more years before they actually have symptoms that present? And is there a gender predilection? So is it more in males or more in females? And does our patient fit that particular characteristic? And then, before you start recommending genetic testing, do you feel like you have enough information to provide adequate counseling? So do you feel comfortable saying to a patient: Here is what the positive result means for you? Or: Here is what a negative result may mean for you, even though you already have visual impairment? And I think right now the answer for many people is: We don’t really have enough information. I’m hoping by the end of the two hours today you’ll feel like you do have a little bit more adequate information to provide appropriate counseling. And then, from the low vision side of things, how do we provide the appropriate support? And how do we work with that patient to make sure that they continue to be functional with their diagnosis? So let’s start here, with the first case. How many people have seen aniridia cases? Almost all of my low vision trainees, for sure, and then some of the ophthalmologists as well. So this is a patient — it’s a little bit older. Not quite pediatric. But still young adult. This is a 25-year-old who presented to our mobile clinic. It’s not quite as mobile as the airplane, but we did have a mobile van that we drove out to different parts of Massachusetts. And he was there for low vision evaluation. Diagnosed with legal blindness, according to the US Social Security definition. Secondary to his congenital aniridia, microcornea, and congenital cataracts. He had already had cataract surgery, so he was pseudophakic at presentation. He also had a family history of aniridia. Both his father and his brother. So we’ve already got three affected males in one family. But no glaucoma history in their family. So when he presented, he was 20/160 in each eye. And he had congenital horizontal nystagmus. But otherwise his extraocular motilities were full. He had full finger counting fields. And refraction improved his acuity one line in the right eye, two lines in the left eye. So some improvement with trial frame refraction. And you can see that his refraction was a compound myopic astigmatism. So when we think about aniridia, it is mostly autosomal dominant. And in the US, it’s about 1 in 90,000. So relatively rare. And the typical clinical characteristics are bilateral iris hypoplasia at birth, but there’s usually some iris tissue, if you do gonioscopy, or may be noticeable as well on slit lamp exam. It’s not usually total aniridia, but it’s near total aniridia. That residual iris may appear normal, or it may have absence of stroma or pigment, depending on the particular patient. There’s no specific racial predisposition for aniridia cases. And if we look at the pictures here, you can see that there actually is some residual iris. And here in retroillumination, you can see the IOL. As well as bits of iris surrounding. When we think about the specific genetic makeup of aniridia patients in this autosomal dominant form, it’s a mutation of the PAX6 gene. This is one where we actually know the gene that is affected. PAX6 has a central role in embryogenesis, and so it’s important in differentiating the lens, the cornea, the ciliary body, and the retina. So pretty important throughout eye development, with the PAX6 gene. If it’s deleted as a part of a larger chromosomal deletion and not just the PAX6 gene on its own, it becomes known as WAGR syndrome. WAGR. And that involves Wilms’ tumor, or a nephroblastoma, aniridia, genital abnormalities, as well as retardation or intellectual disability. So if you have a patient who presents with aniridia, you want to make sure that they’ve seen a nephrologist, that they’ve had kidney testing. Because they may not know the greater association of the syndrome. And particularly important is if you do see intellectual disability, then you should be thinking about the syndromic version of aniridia. That should be jumping to the top of your differential. So for those who are seeing infants and very young children, it’s absolutely essential to get that consult with nephrology when you’re diagnosing someone with aniridia. When we look at the other associations for the eye — so there’s some albinism, which makes sense, because there’s no iris, and it is involved in differentiation of many ocular structures — often ectopia lentis and lens dislocation, arcus can be present even in the very young patients, keratoconus, cataract in anywhere from 50% to 80% of aniridia patients, depending on the study. Glaucoma in up to half. Nystagmus, strabismus, and optic nerve hypoplasia, in about 75%. So it’s not just as simple as removing the cataract and correcting for the lack of iris. If there’s also optic nerve hypoplasia, you’re dealing with a more complex and challenging visual condition. And then we talked about the systemic associations as well. So let’s go back to our patient. So this was the 25-year-old with two affected family members. Who had moderately to severely impaired visual acuity, as well as nystagmus. So he did have prior experience with visual assistive equipment. He used a hand magnifier, and he used the Pebble digital portable electronic magnifier. So for those of you not familiar with low vision aids, the Pebble is a portable CCTV. So it’s a digital magnifier. His had a 4-inch screen on it, allowing for enhanced contrast and portability. It weighs under a pound. He can carry that with him. His reading threshold using the MNREAD was 0.4/2M. So he was able to read large print reasonably fluently. That gave us a predicted add of 5 diopters to read 1M print, which in the US is basically standard newspaper print. That’s 1M for us. His contrast sensitivity in the right eye was moderately reduced. In the left eye, it was mildly to moderately reduced. So he’s got a number of factors affecting his overall visual function. His goals at that visit were glare control — was number one. That’s to be expected, when we’re dealing with aniridia. Almost every patient has a glare complaint. He was interested in distance magnification. And he wanted improved reading posture and comfort. He didn’t really like the way that he was managing his reading with his devices or with his glasses. So for this particular patient, there were a number of things we looked at on this first low vision visit in our clinic. The first was grey polarized filters to help with the glare. He wasn’t as interested in having contrast enhancement through his filters. He just wanted light blocking and neutral density. So he opted for the grey filters, and that was most comfortable for him, indoors and outdoors. We also looked at using a monocular telescope for initial distance spotting, so that he could get used to using distance magnification and become comfortable with the telescope. But we knew that there were some more complex considerations for this patient. One being that he didn’t really want to have to put on filters all the time, and he didn’t feel like they corrected enough of the glare to make him fully satisfied. So we actually looked at using a specialty tinted prosthetic iris contact lens, which you can see here. And we looked at using a bioptic telescope, so that if he’s using his telescope for extended periods of time, he won’t develop the fatigue holding that telescope. So the bioptic would give him a lot of options, in terms of continuous distance viewing. And this particular bioptic design is very lightweight. And he really liked the concept of a lightweight, easy to use bioptic design. So let’s talk about that tinted contact lens. And what we did with him. So you can see the image here. He’s got excellent coverage with the contact lens. Relatively stable. Rotates about 5 degrees to the right. But that’s not too bad. Left eye had no rotation, and also good centration. They both had enough movement. They weren’t particularly loose or tight, but good enough movement to provide a safe contact lens fit. So ultimately, this is what we ordered. It was a Proclear toric with an 11.5-millimeter iris diameter in the right eye in black, to give that glare control, and a 10.5 diameter in the left eye. And he was very happy with that potential option. And you can actually see them in the image here, hand painting on that prosthetic iris. Any questions about that first case with aniridia?

>> You can tell that the person is pseudophakic. You can prescribe contact lens, but cornea…

DR MALKIN: So it’s a very good question. The question is that he’s pseudophakic, so we prescribed a distance contact lens for him, but now he doesn’t have that myopic prescription to be able to take his glasses off and read at near. So he was using the hand magnifier for most of his near work, and so he was comfortable still using that through the contacts. He is someone we should be looking at reading glasses, if he’s going to do spot reading without the hand magnifier, or even to make his digital magnifier clearer and work better for him. A reading add would be appropriate for him. That’s a very good question. Because, as we know, with his glasses, he could just take them off and get reasonably good reading. But if you put him in a contact, he loses that ability. So here’s a second case of aniridia. For some reason, my colleague, who contributed some of these cases for us, she sees a lot of patients with aniridia. So give a special thanks to Dr. Ross for her work on these cases. So this patient is a 30-year-old female. So a little bit different presentation here. She’s African-American. And she was an established patient in our clinic. She came in for a low vision assessment with a chief complaint of having blurry vision in both eyes, for distance and near, without correction. She lost her glasses about 6 months ago, and hadn’t come back in for follow-up, and she felt like her vision loss was gradual even over that 6 months, so without the glasses, it was still changing. And she felt like she had a little bit of a foreign body sensation and some fluctuations in her vision throughout the day. She denied other ocular symptoms, so she wasn’t having flashes or floaters. She was not having diplopia. No significant headaches. Her last eye exam was about 6 months ago, so she lost her glasses kind of right after that last exam, and her last medical exam was about a month ago. So her history is congenital aniridia, bilateral. And it’s confirmed with a PAX6 mutation from the NIH eyeGENE project. She had submitted for that genetic testing when it first became available. She’s registered with the Massachusetts Commission for the Blind. In Massachusetts, we’re one of a few states in the US where people who are legally blind have mandatory registration with our State Commission. So optometrists and ophthalmologists are required to have their patients in the system within the state, to ensure that they receive appropriate services. Patients are okay to deny services once they’re registered, but it is a legal obligation to make sure that they are contacted by the Commission and that they have resources available to them, if they need them. In terms of her family medical history, she has a mother and a sibling with aniridia. So we know this PAX6 gene is present in her family. And her mother has diabetes. Our patient is also diabetic. She’s only 30, but she’s a type II diabetic. She has never had retinopathy. And her last A1C was 7.9, about a month ago. So reasonably good diabetic control. She’s using albuterol, naproxen, and metformin. So a little bit of asthma, some pain control, and her diabetic management. Her best corrected vision when we saw her was 20/160 in each eye. And this is a picture of the anterior segment of her right eye. So tell me what you see. If anyone wants to volunteer what they notice.

>> Iris coloboma.

DR MALKIN: Anything else that people notice about that picture? It’s actually not a cataract, but you don’t have depth, so you don’t know what layer it’s on there. So if you focus on the superior cornea, there’s quite a bit of corneal haze.

>> I think there is some corneal involvement in the superior corneal area. Because this area — there is something wrong.

DR MALKIN: And obviously this is a slit lamp photo. You’re not in a dynamic situation. You can’t see the layers. But we were most concerned about the way that the superior cornea looked. Because we already had established the aniridia and the iris issues. That part was known to us. Her left eye — I think it’s a little bit more prominent. She does actually have more iris, but you can see atrophy. And then she’s got this superior corneal haze again. Does anyone have any ideas what that might be caused by? She’s not a contact lens wearer at this point in time, as far as I know. Nothing beneath the upper eyelid. Flipped her lids. Underneath the lids looks good. So let me give you a little bit more detail. And we will get to the answer. So she does have a little bit of a narrow palpebral fissure from photophobia. She’s got some very mild blepharitis, mild meibomian gland dysfunction, but nothing out of the ordinary. Her lacrimal system looks good. We did a pretty thorough anterior segment exam, because of that foreign body complaint. She has some diffuse hyperemia. She doesn’t have any preauricular nodes. No swollen lymph nodes. That was checked that day. She does have inferior-superior stromal pannus. Some neovascularization, which you can’t get a good photo of, and stromal haze, with a mix of fluorescein staining. Some areas of positive staining and some areas of negative staining. And both corneas looked fairly similar. And in the right eye, as you describe, she’s just got that temporal iris root. And in the left eye, she’s got more of a keyhole shape to her pupil. But aniridia in both eyes. And then there’s those pictures again. So this is actually a case of aniridia-associated keratopathy. So it’s relatively common in patients with aniridia. Anywhere from 20% to 90%, depending on the study. There aren’t enough people with aniridia to have a lot of numbers, to get that data. Typically it happens in the first decade of life. But it can happen later. And the etiology is thought to be a combination of limbal stem cell deficiency plus the abnormally differentiated epithelium from the PAX6 gene mutation. So you get this thickening and vascularization of the peripheral cornea, and ultimately, that corneal haze and irregular epithelium. The increased risks and why we’re concerned, besides just ocular comfort, is that she is at risk of recurrent corneal erosion, ulceration, and subepithelial fibrosis. So aniridic keratopathy is something to be looking for, and to ensure that you’re managing it relatively aggressively. And they’ve done some studies on the PAX6 gene mutation in mouse models to look at why this might be happening. And they also have learned that PAX6 is involved in MMP9. So that is really important in collagen and normal cell remodeling and wound healing. I think we all remember that from our corneal anatomy. But if PAX6 is affected, now this patient is going to have less cornea healing, and they’re going to have more potential corneal problems. So when we have MMP9 deficiencies, we get fibrin accumulation, disruption of the collagen arrangements, infiltration of inflammatory cells, and then the stromal cell apoptosis, which is what’s causing that stromal haze. And in the mouse model, they saw pretty quick loss of corneal transparency in the PAX6 mutation. So we often think about aniridia only in terms of the iris. The cataract and glaucoma — because we know of the anterior chamber abnormalities — but aniridic keratopathy is a very real consideration as well. So when we look at what the evidence-based practice says for keratopathy in aniridia, we can look at this particular study, which was a record review. Meta-analysis and retrospective review of about 155 eyes, 80 patients. Ages 4 to 82. So a very wide range of patients with aniridia. And they wanted to look at what the incidence of that aniridic keratopathy was, and did it lead to further vision loss, separate from just the aniridia on its own. So in that study, 78% of the patients had documented aniridic keratopathy. So really high numbers. The median age was 33 years for the presentation, and aniridic keratopathy increases with age. So we can see that it was only about 50% in the 0 to 10-year-olds, and going up to close to 100% in the older patients. They also found that 56% of the patients in their study had cataracts, and the average age of cataract surgery was at 33. So much younger onset cataracts, as compared to normals in that population. And we also see that there’s visual decline, as the patients get older. So we can see here, on the Y axis, this is the percent of patients with eyes that have worse visual acuity than 20/200, and then on the X axis is their age. And they removed glaucoma patients from this data, because we know that the glaucoma is also affecting the visual prognosis. So if you can see that… Excuse me. This is eyes with better vision than 20/200, the percent. And then worsening to only 40% have better than 20/200 vision in that 51+ age group. So when we think about the symptoms of our patients with aniridic keratopathy, very similar to any other anterior segment symptom you might have. So dryness, redness, increased photophobia, compared to their normal kind of baseline photophobia that they have from aniridia. Epiphora. They may have some associated meibomian gland dysfunction, abnormal tear film, and reduced tear meniscus. So severe dry eye types of symptoms. And this is just here for your reference. But they have a way to classify the amount of aniridic keratopathy that is seen. So phase I, which is the slight limbal insufficiency, into phase III, which is the much more severe. And when you get to phase III, this is where the central cornea is involved, and where you start to have much more significant visual consequences. So when we talk about managing the aniridic keratopathy, we have to look at both managing the visual function, as well as the visual comfort. So first, preservative-free artificial tears. And darker tinted glasses, again, to manage the photophobia. And as it goes on to more advanced, they’re using autologous serum drops and amniotic membranes to help prevent significant worsening of the keratopathy. In the very severe stages, they are looking at doing limbal stem cell transplants, but they’re not doing penetrating keratoplasties, because it’s already a condition with a known limbal stem cell deficiency. So the goal in these patients is to recognize it early, to be very aggressive with the lubrication, and to hopefully avoid central vision loss from aniridic keratopathy. So there are some alternatives for patients with aniridic keratopathy. There are iris prosthetic implants. These are not FDA approved in the US. They have been shown to have a lot of risky complications. I expect that that technology will get better, but right now, we’re not recommending the prosthetic iris. But the Boston keratoprosthesis, the KPro, is a good design for somebody who can’t have a penetrating keratoplasty. So that is FDA approved. And it’s a button that’s implanted into the central cornea. So it’s not live tissue. And you can see that here. So that tends to preserve good central vision, although it is a very invasive procedure. So this is saved for the late stages of aniridic keratopathy.

>> When we heard that for iris prosthesis implantation, sometimes glaucoma happen. Is it true?

DR MALKIN: So there is a risk of glaucoma with an iris prosthesis. So I think that is why it has not been FDA approved in the US, is those complication risks are too high right now. So I don’t think that the technique is developed enough for the US to approve it. Exactly. It can close the angle if you’re trying to implant a prosthesis. Yeah.

>> This (inaudible) has a poor vision. If you have prescribed the dark glass, he cannot enjoy vision. How many alternate solution?

DR MALKIN: So the dark glasses actually help them have better vision. So even though they have reduced vision, and you have concerns about reducing the amount of light entering the eye, much of why their vision is so reduced is because of the glare. And so giving them the darker glasses is a good balance between maintaining vision and blocking glare. And then they can use some of the technology like contrast enhancement to make sure that they can still function visually, even with that reduced light coming into their eye. But they do tend to do better with less light coming into the eye, unlike many other ocular conditions. All right. So let’s go on to the third case. We’re gonna shift gears a little bit to move away from aniridia. And to go to a bit of a younger patient. So this is a case of Stickler syndrome. This is a 5-year-old who presented to our clinic at Perkins School for the Blind in Boston. And when he came into the room, he was carrying his tablet at about 10 centimeters, and that was all he was visually engaged with. He wasn’t looking where he was walking. He wasn’t engaged with the number of interns surrounding him. He was looking at his tablet, held at 10 centimeters, and walking into the room. So the primary concerns, as presented by his parents, were that he has trouble navigating new environments, even when he’s not carrying his tablet. He’s still having trouble navigating. He falls and he’s bumping into furniture, and that’s been getting worse over the past six months or so. They also wanted to know what recommendations would be appropriate as he starts school. So they asked for what types of accommodations and what visual assistive equipment may benefit their 5-year-old while he goes into kindergarten and advances in his education. So his relevant history is, as we expect with Stickler syndrome, he has a history of high myopia. More than 6 diopters. He has a history of strabismus and alternating esotropia. He has congenital nystagmus, and the parent said that he had reduced vision and they thought possibly reduced visual fields had been diagnosed in the past. He has no systemic conditions that are known at that time, and he’s not on any oral medications. He is currently wearing a flat top bifocal that was prescribed for him to try to help his reading ability, particularly with that close working distance. So when we look at the testing of this young man, little boy, his best corrected vision in the right eye was 20/1300. That’s converted from the Feinbloom chart. And the left eye was 20/300. He does have full and extensive eye movements, but he has congenital horizontal nystagmus. His finger counting fields — he was actually able to participate fairly well in that test. Moderately restricted right eye worse than left eye. And he was not able to do contrast sensitivity with his right eye, due to the level of acuity loss. But his left eye was moderately to severely reduced at 1.05 log units. His color vision was normal. 9/9 on the color vision made easy test. And he did have a 10 to 12 prism diopter alternating esotropia, but a strong left eye preference. His refractive error at this point is +14.75 with a little bit of astigmatism in the right eye, 0.8 in the left eye, and he’s in a +4.50 add. So he is no longer a high myope. He now is hyperopic. I think we can all figure out why that change happened in his refractive status. So if we think about what that contrast sensitivity measure means, for those of you who don’t measure contrast sensitivity on a regular basis, he was at 1.05, which is right at the level of true visual disability. So 1.80… Sorry… Is normal for children. So that’s down here. And he’s at 1.05. So he’s right at about this level. So pretty significantly reduced, compared to normals of his age. And he actually was able to participate in a Goldman visual field. He’s a pretty focused five-year-old. Not that common, to do that. And you can see that he does have constriction, particularly to the size 3 targets. A little bit smaller target in the right eye. Quite a bit of nasal constriction. To the size 5, he’s reasonably full, but a little bit constricted. His left eye was a bit better, but still constricted compared to normal. He’s only got about 90 degrees of field. And for a five-year-old, you would expect a bit better for that, especially to the size five target. So looking at his general eye health, he is aphakic. I think everyone probably guessed that, given the history of high myopia, and now the high hyperopic refractive error. Other than that, reasonably normal anterior segment findings. So the mom presented us with some additional ocular history. So his right eye had a history of retinal detachment, proliferative vitreoretinopathy, and subretinal fibrosis at 11 months of age. So not that surprising, that that eye has the much worse acuity, and that he doesn’t have a right eye fixation preference with his strabismus. He has had a pars plana vitrectomy, lensectomy, scleral buckle, epiretinal membrane peel, endolaser, and silicone oil in 2012, so at a very young age. And they did remove the silicone oil a couple of months later in that right eye. His left eye has a history of hypotony, as well as retinal detachment and choroidal detachment and ciliary body detachment. So, again, a very complex history for this five-year-old. He had a cataract and posterior synechiae. That was all diagnosed at about age 4. So the left eye was much more functional until very recently. He did have complex surgery there, in 2016, with silicone oil, and then they did remove the silicone oil a few months later. So he’s now had lensectomies in both eyes, because of that very complex retinal surgery that he was undergoing. So what causes retinal detachments in pediatric patients? You know, this is obviously not common, for a five-year-old to have that kind of extensive retinal surgery. So degenerative myopia is one cause. Trauma, the leading cause, about 40% of cases. And then congenital anomalies make up much of the rest. So things like colobomas, some incidence with optic nerve hypoplasia, juvenile retinoschisis, Marfan syndrome, and Stickler syndrome. And Stickler syndrome is the leading cause of inherited retinal detachments in children. There are also some congenital anomalies that cause pediatric non-rhegmatogenous retinal detachments, including ROP, which is tractional, and Coats’ disease or retinoblastoma, which can cause exudative retinal detachments. But Stickler syndrome is a very common cause of retinal detachment in the pediatric population. So a little bit about Stickler syndrome. Just a refresher on it. It’s a hereditary connective tissue disorder, associated with congenital megalophthalmos, retinal detachment, deafness, cleft palate, joint hypermobility, and premature arthritis. So it is a syndrome. There’s multiple body systems affected. They often have giant retinal tears and then subsequent detachments. So 65% of Stickler patients have retinal detachments. They have associated high myopia, strabismus, premature cataract, and glaucoma. All of which you would expect with that kind of presentation. So if we look at the subgroups and the genes that have been studied in Stickler syndrome, we can see that there is a variety of different genetic anomalies, including one that is ocular-only. So that’s not really the full Stickler syndrome. But they have different associations, depending on which variant of the gene that they have. And when we think about Stickler only versus Wagner syndrome, because they are similar, the ocular-only variant of Stickler syndrome and Wagner syndrome were initially thought to be the same disease entity. Because neither presents with systemic manifestations, but they have very similar ocular findings. Both have that abnormal vitreous, and both have high myopia, vision loss, and decreased vision. Wagner syndrome is actually a mutation in a different gene. It’s in the CSPG2. And it’s autosomal dominant, with very rare retinal detachments. They do have all those other associations, but not the retinal detachments. Whereas Stickler syndrome, when it’s the ocular-only variant, that’s the other gene that’s listed there, the COAL2A1. And it is autosomal dominant, but there are some that occur through de novo mutations, which means that there is no family history. Most are autosomal dominant. And they have much more common retinal detachments than Wagner syndrome. So differentiating in some cases doesn’t really matter. You’re going to treat the patient for how they present. But when we go back to those initial topics of: Can we intervene? Is there a role for genetic intervention? We need to know which gene is affected. So Wagner syndrome versus ocular-only Stickler — it does matter to have that differentiation of the gene, in case there is a treatment down the road. So what do we do for these patients? If we know that 65% of Stickler syndrome patients can have retinal detachment, do you prophylactically treat them? There was a study in 2014 that was retrospective, and they suggest that prophylactic cryotherapy does reduce the risk of retinal detachments both in patients who have had a detachment in the other eye and those who have not. So this study, for Stickler syndrome, did recommend that. This again goes back to: Maybe I do genetic testing to differentiate if it’s ocular-only Stickler, and perhaps I’m recommending cryotherapy. Whereas if it’s Wagner, with very similar presentation, you’re probably not going to recommend cryotherapy. There’s no benefit to that, when the risk of retinal detachment is so low. And we know that treating prophylactically would help avoid those really complicated issues that this patient faced, like proliferative vitreoretinopathy. And this is the Cambridge Prophylactic Cryotherapy Protocol. You can see the region of the retina that they do that in. So back to our patient. So unfortunately, he was born kind of at the time that that study was ongoing, so he did not have prophylactic treatment. He had retinal detachments in both eyes, and presents with this complex history and having more functional problems over the last six months or so. So right now, he is using an iPad. He loves it. It’s his favorite thing to use. But he also uses a laptop. He likes to be on the computer. And he’s using ZoomCaps, which are just the large print stickers put on the keys of the laptop. And his parents have noted that he does very well with increased lighting. And so whenever he’s doing near tasks, they give him extra light. After our assessment, we recommended that he use the dome magnifier, so that he could spot read smaller print. It’s pretty easy for him to use in the classroom, especially in kindergarten, for those rare instances where the print is very small. He actually did quite well with a telescope. And he was already getting orientation and mobility training. And so they were going to integrate the use of the telescope in that training for things like safe street crossing and for identifying his parents when they’re picking him up. Things like that. We highly recommended eye protection during all sports and physical education. And ensuring that he’s wearing more than just polycarbonate glasses, because of that risk of RD in the future. And we thought that a CCTV may be useful for him down the road. Right now, at age 5, he doesn’t really need it. He can do what he needs to do with learning to read with his iPad, and with the large print of those types of books. So when we think about the genetic testing, I know I touched on this a little bit already. But we know that it can be done to positively diagnose all the variants of Stickler syndrome. And there are mutations identified for all of the different genes. In this case, we did request genetic testing, and he had the ocular-only mutation. That matched what we were seeing. He wasn’t deaf. He didn’t have a cleft palate. No associated arthritis. No systemic abnormalities. So it was good to confirm that and to educate the parents that he doesn’t expect to have those other systemic associations down the road. There is a 50% risk of a patient passing on the condition, because it is autosomal dominant. So this is where genetic counseling is something that should be considered, and the patient needs to be thinking about those questions as they get older. And I would never advise a patient yes or no about whether or not you should consider having children with an autosomal dominant condition. But it is important for them to understand that it is dominant. So it is a one in two chance. So let’s go on to case four. They’re going to cut us off shortly. But we’ll go to case four, and then I think we’ll be stopping for surgery. So this is a patient with oculocutaneous albinism. Some people joke that these are the easiest patients within low vision to handle. I think that this case will show you that this is not always true. So this was a five-year-old who came in to Perkins School for the Blind, again, and she was accompanied both by her mother, as well as by her teacher of the visually impaired. She had an incoming diagnosis of oculocutaneous albinism. Fairly easy to make that diagnosis. And she was born in China, but had been adopted by a US family a couple of years ago. So at age 3. There were some questions about some severe developmental delay, as she hadn’t met any of her developmental milestones. So as of that visit in 2015, at age 4, she was pretty much non-verbal. She had a lot of difficulty visually engaging. And she had significant behavioral delays. So the parents at this follow-up evaluation with the teacher of the visually impaired — they had concerns about visual assistive equipment, because they felt like she was becoming more verbal, her behavior was improving, and she was engaging more with her peers. And they wanted to figure out: Is there a new level of visual functioning, compared to last assessment’s, when she was not really able to engage in the exam? So when we look at this particular case, so she actually did well with Lea Matching. She was 20/150 in the right eye, 20/250 in the left eye. She, like all of the patients so far, had congenital nystagmus, but good ocular motilities otherwise. She did have a head tilt. So a chin-down posture. Likely getting her into her null point. Finger counting fields were full. And she actually, with the Double Happy Contrast Test, got to 1.80, so to normal contrast sensitivity. That’s pretty typical of albinism, that they have normal contrast sensitivity. With the Lea Playing Cards — which all of my trainees have worked with this week, and there’s a picture here — she was able to get to 1M at 0.09 meters, or 9 centimeters. So she could get to small print at a close working distance, but not unreasonably close for a child, age 5. And she actually had intact color naming and matching. So we used the caterpillar here for her to match the colors and name the colors. On her cover test during the exam, she had a constant right esotropia that was worse at near, but it was reduced with an additional +2 at near. So a definite accommodative component there. And her dry retinoscopy. We did this by fogging one eye to reduce the nystagmus, without causing any problems. Pretty high hyperopic prescription, with some astigmatism. And on cycloplegia, a little bit more symmetric, but still a high hyperopic refractive error. Yes?

>> Here we see the retinoscopy is high hyperopia. Shows the high hyperopia. But the near vision is almost normal. How is it possible?

DR MALKIN: So she’s 5, so she still has a lot of accommodation. We didn’t measure her sustained reading on that test. It was just that she could force herself to accommodate for that short period of time to identify the small symbol. But I don’t think she would have any kind of sustained reading ability with that much hyperopia. But she can actually accommodate, you know, the 17 diopters she needed to, to read at that distance. Yeah. It’s not gonna be comfortable. Yeah. Very strong accommodation at age 5. She’s got a little bit of astigmatism that helps a bit, but… Not something I would recommend for sustained reading. But a very good question. Because that’s a lot of hyperopia to be accommodating through, to get good near vision. So the parents had some concerns, particularly because she was adopted, so they didn’t have a family history. And she had all of those developmental delays. So they wanted to know if something more was going on with this particular patient. So she actually had genetic testing, which confirmed OCA type 1 and the mutation on the TYR gene. This was important, because it ruled out Hermansky-Pudlak syndrome, which is associated with a different gene, and when we’re worrying about Hermansky-Pudlak syndrome, that’s because it has associated systemic bleeding, as well as lung and kidney defects. So it was important for the parents to ensure that she didn’t have this additional systemic association. Although it’s quite rare. It also ruled out Chediak-Higashi syndrome, which is a mutation on the CHS1 gene, and again, these are associated with fever, bleeding, infections, and organ failure. So the parents were being very proactive in ensuring that it was truly just oculocutaneous albinism, and they were trying to figure out if there was something else causing the developmental delays. So, again, this is a chart for your reference of the different types of oculocutaneous albinism. And what their phenotypic presentation will be. So she had OCA type 1. So very light skin, very light hair. There was no melanin made. And it was the worst visual prognosis. It’s very uncommon in Africans, but otherwise pretty evenly distributed. So here’s her anterior segment exam. Pretty much a classic presentation of oculocutaneous albinism, with profound iris transillumination. And much like we would expect, very typical albino-appearing fundus. Her optic nerve is actually normal. Small, but consistent with her hyperopia, not optic nerve hypoplasia. She does have foveal hypoplasia. And her retina was intact. So for this particular child, we wanted to look to see what her response would be. We’d already tried some visual assistive equipment in the past, but she just wasn’t engaged in the exam. So in this case, we gave her a monocular telescope, and this mostly non-verbal child said, “This helps your eyes!” So we felt like that was a pretty big success. And she also said, “The letters are bigger!” So we know she was using it, and we know that it was actually allowing her to visually engage. And it even got her to as good vision as 20/70 to 20/80 letters. So that’s a huge improvement, compared to where she was, entering. And also that she’s perceiving the impact of it. We are now starting to think that maybe she will be able to engage in more visual activities. She does like to use an iPad, so we recommended a slant board, so that she can get it closer, without having to bend her neck and have posture issues. And you can see a picture of a pediatric-friendly slant board up there. We recommended the dome magnifier. She was spot reading at about 3 inches, which is very, very close, and she could get to 1M. And we actually recommended the VisioBook in the classroom. So that’s a type of CCTV that has both distance and near focusing. So that will let her be a little bit more engaged in the classroom. She was very interested in using this device. And you can see a picture of someone using it here. We also thought that that would help her with her motor tasks like tracing and coloring, because that close working distance was really hard for her to sustain. So if we can get her with magnification, perhaps she can have more sustainable visual activities. So our plan at that visit was to give her the full cycloplegic prescription. That was one of the most important things that she needed. And we wanted to recommend transition lenses, because she was more comfortable with the transitions than she was with just the yellow tint indoors. She needed more glare control. And especially in school, she’s going inside and outside quite a bit. So the transitions were a good solution. She wears a visor most of the time to shield her eyes from the glare. And she does have polarized sunglasses. Her parents don’t send those to school with her, but when she’s traveling with her family, they’ll help her switch into her polarized sunglasses. We also recommended that she continue with that dome magnifier and the slant board. And we thought that she should actually start working with the telescope. A little bit lower power than she probably will ultimately need. But a good telescope to get her familiarized with it. Perkins School for the Blind was providing orientation and mobility training, and they provide a lot of reinforcement for telescope use. So we were able to do that piece for her. We talked to the parents about the exam findings, and also the anomalous head position. Basically letting the parents know that it’s okay for her to have that chin-down position, because it does seem to be getting into her null point, and allowing her to have the most useful, most stable vision. And we wanted her to come back in just a couple of weeks, because we were prescribing a higher cycloplegic prescription, and we wanted to make sure that she was actually going to be comfortable wearing it, and that her vision would improve a little bit, even in a few weeks. And when we think about what we’re going to do for this child for the future, one of the things that came to the top of our list was considering a bifocal, because she does have that accommodative esotropia, and I think the bifocal will help her with sustaining her near vision. We didn’t jump to that on that first visit, because we wanted to see how she did with that full cycloplegic prescription first. That may reduce her near strain enough, and it may actually reduce the amplitude of her esotropia. We did want her to continue with the low vision devices. There are a lot of studies suggesting that the use of low vision devices before the age of 8 allows for the most likely continued use as children get older. So before the age of 8, there’s a lot less self-awareness and a lot less focus on being different than their peers. So if it becomes a part of who they are before age 8, they’re more likely to keep using it as they get older. We do also have to be concerned about amblyopia. So you don’t want to forget about the basics with these low vision patients. So we know that she has a certain maximum visual potential, because of the albinism. But she also has a bilateral high refractive error, and there is a risk of amblyopia in addition to the albinism. So keeping that in mind and monitoring very closely, as well as the fact that with her esotropia, she has a strong left eye preference. So making sure that we’re watching that right eye, to see if we can maximize visual development. One of the things that comes up a lot for our patients in the US is whether or not they’ll be able to drive and will they have career limitations because of their vision. So things like amblyopia management, that may impact that one, two, or three lines of acuity, that could open up some options for your patient. So this goes back to kind of the original question of the case, and what the parents were concerned about. Is albinism associated with global developmental delay? Do you feel like yes, it is? Is it not? Have you seen kids with albinism that have the associated developmental delay? And how common is that presentation? Not common. Yeah, yeah. You’ve seen one.

>> (inaudible) albinism patient. He was a -3. Both eyes -3. Cylinder bar. But can I (inaudible) the cylinder bar, albinism and nystagmus. With nystagmus, -3. Cylinder bar. Can I give (inaudible) -3? (inaudible). Nystagmus, no problem.

DR MALKIN: I would make sure that you’ve cyclopleged the patient to ensure that there’s not a difference in the astigmatism and hyperopia after cycloplegia. Because often they will present with more astigmatism because of the accommodation. But actually, Dr. Marmor’s lecture later today will talk about that. So… Yeah. Dr. Marmor is gonna get into that exact question.

>> Patient has esotropia, but he has myopia. Can I give the prescribe? Full correction?

DR MALKIN: So when you’re dealing with a myopic patient who is also esotropic, you would really want to look at the effect of the near power. And if it’s an amblyogenic refractive error, you want to correct for the amblyogenic factor. But you would want to do a careful near assessment to look to see if there’s an accommodative component. It’s a bit less common with myopia. They shouldn’t have an accommodative esotropia. It’s typically hyperopia. But I would ensure that you’ve cyclopleged and that you’re not getting a false level of myopia, and making sure you give the absolute maximum plus power for the best vision to relax the esotropia. But I’m… Yeah. Yeah. You want to kind of push the maximum amount of plus power for that myopic patient, if they have an overlying esotropia. But you want to correct anything that’s amblyogenic. You want to make sure — and we will get into that later today, too. So I think all of you already were aware that global developmental delay and albinism are not typically associated. So it’s possible that a patient has albinism and global delay, but we don’t expect that. This was a very atypical presentation. So typically it is normal neurodevelopment. There are some possible comorbidities, like attention deficit disorder, and there’s mixed research on that. Perhaps it’s because they often have high hyperopic prescriptions, which are also associated with attention deficit disorder. But you do want to make sure that you’ve evaluated that component. In very rare cases, there is a syndrome called Prader-Willi-Angelman syndrome, which is a specific genetic deletion, and in that case, they have microcephaly, severe speech impairments, seizures, ataxia, and hypotonia. But that is not common. That’s a very rare association with albinism, and not what our patient had. I’m not sure the… I would have to look up the statistic. It’s very, very small. So for our patient, the thought about her developmental delay was actually related to the fact that she had been adopted, and they weren’t sure of the condition of where she was raised in China. So was she getting appropriate neurostimulation as an infant? And we could see that with the appropriate counseling and guidance of her parents, she was starting to develop speech. They were getting her into physical therapy, occupational therapy, and speech therapy, to help maximize her development. So let’s go back to our cases. So we have been talking about aniridia. We’ve talked a bit about albinism. Let’s talk about another relatively common condition in the pediatric population, or in our young adult, working adult population. And that is Stargardt maculopathy. So this particular case is about a 22-year-old, who, again, came to our mobile clinic for an assessment. And he had the incoming diagnosis of Stargardt maculopathy. He was diagnosed at age 10, and reported significant decline in his vision into his teens and into his 20s. He’s 22 now. So at this assessment, he had had a previous low vision assessment, but he wanted to know the extent of his visual impairment. This is one of the most common questions we get asked, is: You know, what is my vision? How impaired am I? He would also like to explore options for doing pottery. That was a particular interest of his. And he really needed devices for hands-free near work. So both for pottery and for other activities. Right now, he brought his magnifier in, and it’s wrapped with duct tape, so it’s not working so well. He thinks he needs a new device, because it’s a little bit worn out. So when he comes in for his exam, the findings were very similar between the two eyes, so there’s only differences if they’re noted. But he is 20/320 vision, best corrected, in each eye. So pretty severely impaired. Good extraocular motilities. His peripheral vision is good, but very dense central scotomas. Just as you would expect with Stargardt disease. And his contrast sensitivity is moderate to severely reduced, at 1.00 log units. He has a myopic prescription that was pretty similar to what we were finding. So in terms of the visual assistive equipment for this particular patient, although he wants a hands-free option, he is also very interested in updating or replacing his magnifier. And we looked at the 28-diopter LED hand magnifier for spot reading. And he was able to resolve 0.5M. So that was allowing him to do the spot reading of very small print, like the back of a food package or a medication label. In addition, we looked at using an 8x telescope to get him the distance clarity he wanted. So he can use an monocular for distance spotting. But we also looked at a spectacle-mounted system for near. And that was something that he thought may be very useful as a hands-free system. We looked at using it as a monocular style, so that he can alternate between the magnified view and the non-magnified view. So he can use one eye through the telescope and one eye with his regular vision, to keep the context of what he’s looking at with detail. We also wanted to look at bioptic systems. So he came in for an evaluation with me at the Carroll School for the Blind. It’s another non-profit organization in the Boston area. And we looked at the Iris Vision, which is a head-mounted virtual reality display. So this is something that’s basically a virtual bioptic. And it allows for that hands-free magnification, both of distance and of near. So here you can see this is in the full screen mode. You can magnify the entire image you’re looking at, but you can also magnify just a portion. So using this bubble-style magnification, you can see the ceramic detail much better. But still have some awareness of where he is on that shelf of books. And this is what the IrisVision looks like. It uses a standard Samsung Galaxy phone in a VR headset, with additional software added onto it. So this is something that he thought may be very useful when he’s looking at hands-free magnification. So when we look at his posterior segment findings, we have pictures from 2000. These are with Optos, which is why the images have that kind of greenish hue to them. And you can see here in 2000, when he was early in his diagnosis, pretty typical-looking Stargardt presentation. When you look at his pictures now, 2016, it’s a pretty different appearance to it. I apologize for the flipped images. But very different appearance. There’s a lot more pigment. The retina looks much more atrophied. And if this were to walk into my clinic, I’m not sure that Stargardt would be the top of my differential diagnosis. So in this particular patient, he did get genetic testing done, and he has the ABCA4 gene mutation. So that’s the dysfunctional A2E. So an autosomal recessive Stargardt disease. What we know about this particular gene is that when your A2E protein becomes dysfunctional, you get accumulation within the outer segment cell membranes and accumulation throughout the retina. The RPE kind of goes into overdrive, attempting to phagocytose this accumulation, and you get the cellular toxicity, RPE death, and retinal atrophy. He didn’t have any indication of the autosomal dominant form, because of the lack of family history, and he didn’t test positive for the STG3 gene. So when we look at different phenotypic types of Stargardt disease, we tend to think of the more common, but there are also rarer phenotypes. So the median age of onset for group 1 was 23 years. Group 2 was 18. And group 3 was 9. And if you remember, our patient presented with diagnosis at about age 10. So he fits that group 3 characteristic a little bit more. The median duration of the disease for those in group 3 is 19 years, as opposed to a shorter duration in group 1 and group 2. We also know that with that longer duration of disease, the visual acuity outcome is worse. So 80% of patients had 20/200 or worse acuity. And particularly noteworthy is, in addition to the central macular atrophy, they do get flecks extending throughout the midperiphery, with 90% to the equator. So that’s a little bit different than other presentations of Stargardts. And if you do a fluorescein angiography, they have slightly variable findings amongst the three groups. So the limitations of looking at a phenotypic study, where they’re breaking it down by that presentation and not by which gene is affected, is that they didn’t have equal patients in each subgroup. So it’s hard to make general classifications from that. And the percentages may not actually represent the true population with Stargardt disease. In addition, this was relying on the patients and on the records for age of onset and duration of the disease. So were they recognized at that appropriate age of onset? When do we say that the duration of the disease has ended? It wasn’t formalized in terms of the retinal testing that gave the end of the duration of disease. But it does look like using fluorescein angiography may be useful in these patients, because of the differences that you could see. So here in group 1, all patients had macular atrophy. In group 2, some did. And there were patches of decreased fluorescein in the midperiphery, in the third group. So there were definite differences in these different phenotypes. There are also confirmed distinguishing features between the groups. And when you’re trying to educate and advise your patient about possible duration of the disease, you’re thinking about… Perhaps we look at this retrospective study and we look at what those phenotypic variations were. So for that particular case, we already knew his confirmed genetic variant. And he was already in his 20s. So he was already progressing fairly far through his disease. And at 20/320 vision, we’re not expecting a lot more progression of the disease. Instead, we were focused on the visual rehabilitation. And on making sure he can keep achieving his goals. And it looked like either the near telescope mounted onto glasses or a virtual reality headset will allow him to achieve those specific goals. Any questions about that Stargardt case?

>> I have a question about the near vision management of the Stargardt cases. You have shown that the child is responding good with +28-diopter handheld magnifier. But in our clinic, we (inaudible) seen that, that children (inaudible) spectacle prism magnifier — (inaudible) spectacle prism magnifier rather than the handheld magnifiers. Is there any problem with that prism spectacles? My question is that.

DR MALKIN: So usually when I’m getting up to a 28-diopter type of power, I would be looking at an aspheric spectacle, rather than a prism spectacle, because they can’t really be binocular at 28 diopters. But a spectacle device is very appropriate. In this case, the reason we were looking at the hand magnifier is he wanted it just for quick (inaudible). So he wanted to carry it in his pocket. He’s in his early 20s, so at the grocery store, to double check a price or a label. But if he were doing any kind of continuous task, then a spectacle device would make a lot of sense. And the reason we looked at a telescope for near, again, rather than a spectacle, was the better working distance with that telescope, because he wants to do pottery. So he needs to be kind of closer to arm’s length, and the working distance of a high powered spectacle would be too close to actually do the pottery work that he’s doing. But there’s definitely no problem with using a spectacle device. Especially in children and for the sustained reading. We tend towards the handheld devices for the spot reading, and some sort of spectacle mounted or bioptic type of device, or the virtual reality systems for the continuous reading. Any other questions about the Stargardt case, before we… So another case about a more common condition is a case of a patient with retinitis pigmentosa. So this is a 17-year-old Hispanic patient who presented, and he did have (inaudible) diagnosis. That was confirmed in retina. He doesn’t have a known family history, because he is adopted. So they don’t know if any other family members have it. And the primary concerns, both for the patient and for his father, were school accommodations. And also understanding the diagnosis and prognosis. Unlike family histories of RP, they didn’t have anyone they could look to, to try to understand what this patient should expect, as he gets older. He also had some mobility concerns. And at 17, he’s becoming more and more independent, and he had concerns with his ability to navigate safely. So the exam findings, much like you would expect with retinitis pigmentosa, especially early on, he actually had very good acuity. 20/25 and 20/30. So his central acuity was excellent. He had no problems with extraocular motilities. But on confrontation visual fields. It was clear very early that he had severe constriction. He had reasonably good contrast in the right eye. 1.68. Very mildly reduced from normal. And a little bit more reduced in the left eye. He had a myopic, astigmatic prescription, although not a very large version. And that was what got him to that acuity level. And his reading — he actually was the same with and without correction. We measured both ways. His critical print was 0.4/1.25M. So a little bit worse than I would expect, given how good the acuities are, and the myopic refractive error. But he really could not read fluently past 1.25M. So our hospital had done Humphrey visual fields on him. And found that he had about 18 degrees of central field remaining in the right eye. With a mean deviation of -24.82. And reasonably reliable field testing. The left eye, he only had about 6 degrees of central field remaining. And a mean deviation of -28.85. So this confirms what we picked up in our testing. Was that he had very severely constricted fields. I would have preferred a Goldman visual field as my first measure, because from a functional standpoint, that will tell me if there’s a temporal island of sparing somewhere. But this was the testing that was done on that particular day. So we work with what we have. And here are his Optos photos. So you can see really, really significant bone spicules. I’m not sure in this photo you can appreciate the arteriole attenuation as much, but it’s definitely present. His macula still looks pretty good, for the most part. And the same picture here. We also have fundus autofluorescence, which confirms exactly what we were seeing on the Optos, as well as on the visual field. All of the pieces match up quite well. That the area of usable vision is spared, but his midperiphery to his periphery is significantly affected. So at that point, that was his first exposure to low vision rehabilitation. He came in not really sure what all of this meant, and not understanding how much his peripheral vision was affecting him now, and what might happen in the future. So at that visit, we were actually able to register him with the Commission for the Blind. Because he has less than 20 degrees in the better-seeing eye. In addition, his mean deviation on Humphrey was reduced enough, and so we were able to qualify him by either method for the US definition of legal blindness. That was a really important step for this young man. Because he’s looking at going to university, and he will need additional assistance as he goes to a new environment. In addition, where we live in Boston, there’s a lot of access to public transportation, but it’s not cheap. And if someone’s going to use it as their primary mode, they can actually qualify for reduced fare public transportation, if they have a disability causing legal blindness. For this teenager, that was something that was really important to him. That he would be able to go out and get into the city, independently, and that he wouldn’t have to spend the full fare, because it is very, very expensive. We did recommend a functional vision assessment with the teacher of the visually impaired in the classroom. We know his acuity is good. But he does have contrast loss. He has that severe field loss. And his reading fluency isn’t quite as good as we really would expect it to be. We recommended some glare control options. He’s in a high school, where they can control the lighting, and he felt that his teachers would be very supportive, making adjustments to what blinds were pulled down and what overhead lights were used. That’s not always true. We don’t always find teachers that are so accommodating. But he felt pretty confident that they would help him with the adjustments to the lighting. And that he could wear a hat in classroom. If we wrote a letter, allowing that. We did also want him to have an orientation and mobility assessment. So no one has ever assessed his walking, and no one has ever assessed whether or not a white cane would be beneficial. When I see a field with that level of reduction, I would assume that he should be using a white cane. We did also encourage extended time for tests, and particularly for Scan-Tron tests. So those are the ones where you have to bubble in the answers. And he was having trouble with his visual field actually tracking where he was on that answer sheet from his test. So going back and forth from a test document to an answer sheet and having to fill in the bubbles — he was making errors. So giving him a little bit more time to double check himself and to use a line guide or to use isolation may be very helpful. We looked at using the monocular telescope, but just for minification. He didn’t need any distance magnification, but he could reverse it. And he appreciated the minification effects that he got. We were thinking about actually getting a bioptic-mounted minifier, if he starts to use that monocular telescope more. We also talked about using the enlarged cursor on the computer. And you could see it was happening when I was doing it here. He uses a Mac. And when you shake the cursor, it gets bigger. So he could enlarge it, but we also taught him this feature, so that when he loses track of the cursor, if it false into an area of missing field, it becomes easier for him to find the cursor. He thought that was a really cool trick that he hadn’t turned on, on his system. So when we think about retinitis pigmentosa, there’s a huge range of genotypes and phenotypes. So there are over 40 different genotypic variations, and the inheritance pattern varies. So it can be autosomal dominant. It can be autosomal recessive, which is most genotypes, including Usher’s syndrome. It can be X-linked recessive. And there are some Y-linked inheritance patterns noted with RP. But there’s no easy way to talk to a patient with retinitis pigmentosa about what their potential is for passing on that gene, unless you know the family history, and then you can start to make some guesses. But in a 17-year-old with no known family history, because he was adopted, we don’t know which form he has. So when we think about what’s available, in terms of genetic testing, there is a lab in the US, Carver Labs, that can do the testing, and gives you a sense of the cost. So this is not an inexpensive test. So if you’re looking at the autosomal dominant, they test for these specific genes. It’s $320US, and it takes 8 to 10 weeks. Now, if someone is autosomal dominant, there’s a question as to how useful is it to get that information. Until we have a treatment that’s aimed at a specific gene. Because if you already know that they’re autosomal dominant, then I’m not sure that the genetic testing is giving you additional information or helping with the prognosis. With someone who is autosomal recessive, they can test for fewer genes. This is what comes up in the panel. And you’ll see it’s also the ABCA4 gene that’s associated with Stargardt. That’s a much more expensive test. We’re at $833US. And it takes a little bit more time. And then the X-linked. There’s only two genes that they test in that panel. Same price range. And same time frame. So you need to really have a good conversation with your patient, and probably with a genetic counselor, about how useful this testing is right now, with where your patient is in their disease process. So this is gonna be a repeat for some of the trainees here in the room, but hopefully new for some of you on Cybersight. But when we talk about what the treatments are for retinitis pigmentosa, one of the biggest things that people talk about is the bionic vision. So this is not a gene-mediated treatment, but it is a surgical implant to help people who are losing their vision from RP. So this is a patient who lives in Boston, and he’s showing off his Argus system. And you can see that he has the glasses, and those are a set pair of glasses that Argus gives you. There’s a video camera here in the center. There’s an external coil. Which is connected to the video processing unit. And when you’re using your Argus system, you have all of those pieces on at once. Inside the eye, you have a titanium tack holding this microelectrode array onto the retina. They use an OCT to find the area of retina that has the most usable retinal cells, and that’s where they try to place the microelectrode array. And this is just a schematic of the casing of the piece that they implanted on the outside of the eye. Scleral buckle. So here you can see this is our patient. A patient’s glasses. You’ve got the titanium tack with the electrode array. It’s connected to this implant, which is then connected to the unit. It is a very complex surgery. And it does involve putting in a scleral buckle. So a lot of people are concerned about the invasiveness of that kind of surgery. But if you think about what the patients are coming in with, they have to have no better than light perception vision in order to qualify for the procedure. So although it is a very invasive procedure, you’re taking someone with light perception vision. So the risk is lower that they’ll lose what they have. Because that’s not very usable vision. And here’s an example of somebody using the Argus system in a lab, and you can see that she’s accurately tracing that X on the screen. And let me just walk you through these box plots. So here you can see what the stimulus was at the top. So the highest contrast here, the solid shapes, and then the non-solid shapes, the outline shapes, here. Sorry. This is jumping. And here you can see when the Argus system was turned on what percent correct identification they had. And here is when the Argus system is off. So the p significance here is 0.002. So it is statistically significantly better for the group when the Argus system was turned on, as compared to off, for the identification of the outlined shaped. In the second box plot, we can see that the p-value here is less than 0.001. So again, statistically significant difference in how well they were able to identify the outlined shapes. So when we talk about how much useful vision can you get back, these are the types of information I like to give to my patients. Explain that it is very good for the high contrast targets, but that they have to keep in mind that it may not allow them to do a lot of the other things they’re hoping to do. And they moved to more complex shapes, as patients were better able to use their Argus systems. And so here we have three different categories. We’ve got, again, the solid objects and the outlined objects, but more complex now. More like daily living objects. In this first column — this is with the system turned on — in the second column, it’s when the signal is scrambled. So it’s random signal, to create a placebo type of control. And here is when the system is off. So between on and scrambled, it was a p of 0.193. And between on and off, it was a more significant p-value. And here, with the outlined shapes, which actually theoretically are harder, the p-value there between on and scrambled was 0.002. And for the overall was 0.006. So they were able to perform significantly better with their device on. So in terms of what this means for the Argus and where we are in the US, North America, with the Argus, it is FDA approved, but it’s a humanitarian use device. This is very good from a research standpoint, because it means that the patients are committing to a research study when they get the device implanted. So they have gone through an IRB protocol and review at the institutions, and they can actually bring the patients in for these different measurements. What happens for the patients is they see these patterns of photopsias, and those are individually programmed, so that the patient can differentiate silhouettes. In many cases, this is an occupational therapist or an orientation and mobility specialist, working with a technician, to calibrate the device to better pick up the silhouette. But the patients are in controlled environments initially, and they work with this technician to get the device programmed appropriately for how they perceive things. But as we talked about before, and as you can see just from how they identify objects, the patterns of light are not supposed to approximate normal vision. The patients need extensive vision rehabilitation to make use of the device, and it’s a part of — where we are all working together in a team approach to maximize how they’re doing.

To wrap up with all these different cases we talked about, reason that we care about all of this genetic testing and that we want to become more familiar with what’s available is, as we said in the beginning, to give patients an accurate prognosis and diagnosis, and also to look at interventions beyond what we’re doing with low vision rehabilitation. But even with what we’re doing. So having that confirmation of achromatopsia may have changed the way that you look at the tinting for that particular patient. You want to be able to connect your patients to these types of worldwide resources. So that if they qualify for a clinical trial, that they may be able to get involved in that type of process. Any questions?

>> Yeah. You can explain… (inaudible) in our country, you know, most of the persons come to us and they are very poor. Genetic investigation and genetic replacement is always very costly. So how we can (inaudible)?

DR MALKIN: So when there are significant cost limitations, you could actually contact some of the labs that offer the testing, or if there is a clinical trial, they will often pay for the testing, to find out if someone is gene positive for the testing that they’re looking at. They’re not going to test everybody, but with certain phenotype characteristics, the researcher may be able to help cover some of the costs of finding out what that genetic variant is. We also know that the more the genetic tests are being used and perfected, they’re becoming lower and lower cost and much more readily available. So right now, you may not feel that it’s worthwhile to do the genetic testing on every patient. But it is something to be aware of and to watch for when they do become more accessible and much less expensive. But it is worth looking at with the clinical trials, to see: Are they offering genetic testing as a component? Or in the US, the eyeGENE project was totally free. So that was something where the samples were collected for free, and the patients were given their results for free. And that was funded through the National Institute of Health.

>> I want to know: What is the suicide genetic trap? Suicide genetic trap?

DR MALKIN: The suicide apoptosis? It’s a specific type of gene therapy. I’m not gonna get into all the different types, but basically it’s going in and causing the defective cells to go through apoptosis, so that they’re no longer causing the defect. But that’s just one of the many techniques that geneticists are using in the research. So it’s actually not looking at that suicide gene, using that technique to have apoptosis of the defective gene. So it’s a particular way that they do the genetic treatment to activate a certain type of apoptosis to stop the particular defective gene. Well, I am not a geneticist, so I don’t want to go into too much detail on the genetic techniques. We can save that for another Cybersight lecture on all the different genetic splicing and variations.

>> In case of… Use a Peli prism, Peli prism… How much is useful in case of (inaudible) patients?

DR MALKIN: So the question is about Peli prism for hemianopic patients. So I use Peli prism a lot, both for the more congenital or early onset brain injuries, as well as for acquired. For stroke patients, exactly. And for other patients with hemianopia. I like to wait at least three months after the stroke, because you want the patients to start to stabilize. And I often will wait up to a year before we apply the prism. And with those patients, it’s a question of what the goals are. So I find the Peli is most effective for mobility. So for patients who are having difficulty navigating and walking, and it’s not so useful for reading, for reading, I think that scanning training and occupational therapy training are the most effective. But I will show all of my hemianopic patients Peli prism to see if they have a response. And I do have a number of patients who use them, especially when they’re walking in crowded environments. Yes? Basically the Peli prism induces diplopia. And they get kind of a shadow of a second image in their peripheral vision. It’s not a clear, sharp image. It’s an image to alert them that there may be something in their peripheral vision and to remind them to either turn their head and look or to step to the side before they pump into something. So it is definitely worth considering. We use almost always the Press-On. Because our patients don’t want to spend the money for the ground-in prism. Obviously the ground in is much more stable. You can be more precise with your measurement. And you don’t have to worry about it peeling off. Patients — they’re usually using the Peli prism early after the stroke, in that first few years. And over time, they get better and better at scanning and peripheral awareness, and they may use it less as time goes on.

November 27, 2017

Last Updated: October 31, 2022

1 thought on “Lecture: Management of Inherited Ocular Disorders: Emerging Concepts in the Post Genome Era”

Leave a Comment