Vivienne Kit is an Ophthalmology Researcher at UCL Institute of Ophthalmology. In addition to her clinical duties, she is pursuing a postgraduate research degree in aniridia under the supervision of Professor Mariya Moosajee.

In 2021, Vivienne and her team published the largest PAX6 genotype-phenotype study on aniridia patients in the UK. She shared the results at our 2023 conference.

In amongst their findings, they discovered that a small proportion of those patients had developed retinal detachments. And having since conducted a case review of those affected, they’ve observed a surprisingly high incidence of exudative retinal detachments, which are typically considered uncommon.

Vivienne joined us again at our online conference on 27 July 2024 to tell us more about this discovery and their aim to investigate further. You can see the video and transcript of her presentation below.

Transcript

[Tierney] So we will be hearing next from Vivienne Kit, who is an ophthalmology researcher from UCL, and she’s going to give us a little insight into what she’s been working on.

So I will hand over to Vivienne and I look forward to hearing from her.

[Vivienne] Ok, hi. So first and foremost hi to everyone. I think I might have met some of you before, I recognise some of the names in the group.

But I’m Vivienne, I’m an ophthalmology registrar from North London and I’m currently doing some research on aniridia.

So one of the things that I’m going to talk about today is aniridia and retinal detachment, not something that often is associated with aniridia.

But something that we found when we did a search through our database, I thought would be interesting to talk about today. So that’s what we’re going to talk about today.

So first off, so a bit of background information.

So aniridia is a panocular condition and if you were at the meeting last year you might have heard me talk about this before But we’re going to go through it again, in case there’s anyone new here today.

So aniridia is truly a panocular condition, meaning it affects all aspects of the eye from the front to the back.

So the cornea, which is the front see-through window of the eye, that’s involved in a condition called aniridia-related keratopathy, where you get a limbal stem cell deficiency and generally causing a gradual sort of clouding, a progressive clouding of the cornea, which can reduce your vision over time.

Iris, so in aniridia you can have variable degrees of iris hypoplasia, which is defects of the iris per se.

So in some patients, patients may have a presumably normal-looking iris but may still have PAX6 aniridia. But more classically, patients may present with partial or complete absence of the iris.

Now, moving even further back, the lens.

So again, the lens is important, a bit like the cornea, it helps focus light onto the back part of the eye, called the retina, which helps us see.

So the lens can become cloudy over time and it seems to happen a bit earlier in patients with aniridia.

But also another thing that’s structurally affected is we sometimes see lens dislocation or displacement in patients with aniridia.

Now, nystagmus and foveal hypoplasia is another thing we see very commonly in patients with aniridia. There’s glaucoma and optic nerve hypoplasia.

And the things I’ve mentioned here are things that we generally see in a lot of patients with aniridia.

Now, aniridia is caused by mutation in the PAX6 gene.

And PAX6 is important because it’s involved in development of the eye from when you’re an embryo, so when you’re in the womb, but it’s also continued to be expressed after you’re out of the womb and well into adulthood.

And so there’s a role of PAX6, not only in the development of the eye, but also maintaining its health and function.

Okay, but now here’s the interesting thing.

So aniridia means without an iris, but not everyone born with iris deformities have aniridia related to PAX6. Actually iris deformities from birth are also noted in some other congenital conditions involving genes such as the FOXC1, PITX2, etc.

Now, the other thing is some people may present to a clinic later on as an adult and they might have parts of the iris missing, but they weren’t born with it. It might have been something that was picked up because of injury, so either trauma or because of some surgical incident.

So when you see a patient with an iris defect, it isn’t always PAX6 aniridia.

And so that made us do some research. What we wanted to do was, actually, we wanted to learn more about aniridia in patients with the PAX6 mutation.

So we developed a database. We searched through the electronic and paper records at Moorfields Eye Hospital.

And having attended the genetics clinic and going through these notes, I managed to find 86 patients with PAX6 mutations. And we did an analysis.

We basically looked at every single patient from their first visit to our hospital right to the end, to the most recent, and we looked at what happened to them.

What was their vision at the beginning? What was their vision at the end? How many developed glaucoma, cataracts, aniridia-related keratopathy? All the very typical things that are associated with aniridia.

And in 2021, we published the UK’s largest PAX6 aniridia genotype phenotype study, which I presented last year. And last year when we presented it, we talked about the glaucoma, the cataract, and the aniridia-related keratopathy.

Now, one thing that we didn’t talk about last year, but actually I found very interesting as an ophthalmologist was that, in our database, out of 172 eyes of these 86 patients, 9 had developed a retinal detachment.

Now, a retinal detachment isn’t too surprising, because retinal detachments are more likely to happen in patients who’ve had intraocular surgery.

So if we are looking at a cohort of patients who have had cataracts and had cataract surgery, has glaucoma and has glaucoma surgery, noticing some retinal detachment is not too surprising.

But what was interesting was that over half of these patients with the 9 eyes had something called an exudative retinal detachment. And exudative retinal detachments are considered very rare. It’s not a commonly seen type of retinal detachment.

And it was something that struck me, because why are we seeing more of this type of exudative retinal detachment in our cohort of patients?

Okay, so first, going back a little bit, what is a retinal detachment?

So like I said, aniridia is a panocular condition. It affects the front of the eye right to the back.

And I suppose you can consider the retina the very back bit of it, because the purpose of the cornea and the lens is to focus light onto the photoreceptor layer of the retina, which is right at the back of it.

And the retina has a function in turning this image into signals, which goes to our brain and helps us form an image for us to see. And this retina has a very good blood supply because it’s very active.

Now, what happens in a retinal detachment is this layer of this retina, it starts separating from its underlying retinal pigment epithelium, which we’ll call the RPE, and the choroid, which is highly vascular.

And so, as you can imagine, as it separates, and if you leave it untreated, this retina will become ischemic, or lose its blood supply, and they’ll start damaging these photoreceptors, which is important for helping us to see.

So if you were to leave a retinal detachment, you can get loss of vision.

So retinal detachments, you can divide them into different types.

Rhegmatogenous is probably the most common one we see. And rhegma means tear, and what happens in a rhegmatogenous detachment is you get a tear in the retina. And fluid in the vitreous goes behind that tear and pushes the retina off. That’s a rhegmatogenous retinal detachment.

Tractional. So a tractional retinal detachment occurs when you have a tractional force on the retina. So these are more commonly seen in, say, patients with diabetes, for example, and you develop new vessels which fibrose and pull on the retina and cause it to separate from its underlying layers. So that’s a tractional one.

And then what’s least seen is probably an exudative retinal detachment.

So what happens in an exudative retinal detachment is for some reason you get accumulation of fluid in the subretinal space in between the retina and the RPE and the choroid, and that fluid builds up and causes the retina to detach. And it happens in the absence of a retinal tear or tractional forces, and that just separates it from the other two.

And in the literature, and actually from what we see in clinic, there’s lots of causes for exudative retinal detachment. The list is, I wouldn’t say endless, but it’s a very long list and includes causes like inflammatory conditions, infectious diseases, vascular conditions affecting the eye, even certain medications can cause it and tumours, etc. But aniridia isn’t one, when I looked in the literature, that’s normally associated with it.

And so when we looked at our patients, I wanted to find out, actually, is this something that’s interesting? Is this something that hasn’t really been talked about and is something for us to find out a bit more about?

So we looked a bit more closely at these 9 eyes from 6 individuals with PAX6, who had retinal detachments in our cohort of 86.

So these patients had nonsense, C-terminal extensions, intronic mutations and large deletions. So they had PAX6 mutations.

And 3 patients had bilateral retinal detachments, meaning in 3 of our 6 patients, both of their eyes developed retinal detachments. And in 3 other individuals, they had retinal attachments, but only affecting one eye.

And of note, because I mentioned right at the beginning that having retinal detachment in a patient with aniridia wouldn’t be completely something that I would not consider, simply because if you had intraocular surgery, you’re probably more at risk of developing a retinal attachment.

But actually, in our group, 6 eyes had prior surgery. So of our 9, more than half had had previous surgery.

But 3 eyes were surgically naive. So what that means is in 3 of these 9 eyes, a third of our eyes, these aniridic eyes had no previous surgery, and they still developed a retinal detachment.

And so that makes us wonder actually, is there something else that’s a risk for it?

Now, just of note, I mentioned, yes, previous surgery. All the eyes that had had previous surgery all had had cataract surgery, plus or minus a lens insertion.

Right, so the interesting bit.

So of our cohort of 9 eyes, 5, so just over half, had this rare type of retinal detachment. And 2 individuals actually had it in both of their eyes.

And it makes me wonder, is this actually because of their mutation? Because there is clearly something that’s happening in both of their eyes at the same time.

But at the same time, what was interesting was there was one individual who had a PAX6 mutation, but they had extensive unilateral exudative retinal attachment, meaning they had exudative retinal attachment in one eye, but the other eye, the retina was completely pristine. There was no tear, no traction, no detachment, nothing.

So it’s interesting how in 2 patients, they had extensive exudative retinal detachment. And in another, they had 2 very different looking retinas, despite having the same mutation going on.

And of note, just to completely document what we had, there was 2 other eyes who had retinal attachments, and 2 eyes where we know they had a retinal detachment type, but we weren’t really able to determine what type they had.

Now, when I looked into the literature to find out a bit more about exudative retinal detachment and aniridia, it’s actually very sparsely reported.

There’s been cases of exudation in patients with aniridia, but actually there was no PAX6 confirmation. So like I mentioned earlier, you can be born with a congenital iris deformity that’s not related to PAX6.

And so when I look specifically for patients with a PAX6 mutation and exudative retinal detachment on PubMed, there was only actually ever one case that I could find through my search.

And this was actually a study that looked at coats-like vasculopathy. So coats, this is the condition where you get exudative changes and can result in an exudative retinal detachment.

And they looked at patients with inherited retinal diseases. And in this group of 67 patients, they only reported one single patient with PAX6 and an exudative retinal detachment. And that was all I can find in the published literature.

So it was quite interesting that in our cohort, when we actually went through it and looked in detail, we actually found 5 cases that were there.

Now, there is a possible bias as to why we were seeing more of it. And I think that’s very important to consider.

Because exudative retinal detachment is not something that’s very commonly seen as a type of retinal detachment. And to be fair, some of these patients who came into our hospital were actually referred in because of exudative retinal detachment.

And so we might be seeing more cases of exudative retinal detachment because we are a tertiary centre where more complex cases may be sent to our department. Whereas more straightforward retinal detachments, like red rhegmatogenous retinal detachments, which I mentioned earlier, are more commonly seen, and probably more easily treated at a local hospital, local ophthalmology department, for example.

Okay, so I then wanted to find out, so yes, there’s an interesting thing that we found, which is this exudative retinal detachment in this cohort of patients. But why is it happening?

I’m going to be honest, I don’t actually know. Because if you look down into it, it’s more happening at a cellular level. And actually, I did a research on the patient’s notes, and we never really got down to the cellular level.

But I tried to look up what could have caused it. nAnd there are some things that I found, which is, well, as mentioned earlier, PAX6 is important in the early embryogenesis, so the early development of the eye. But also, once you’re out of the womb, postnatally, it’s also expressed in the retina.

So if PAX6 is involved in the maintenance and the function and health of the retina, could this be an area that we should be looking more into?

Another thing is that PAX6 is involved in expression of different cells in different areas of the eye, but it’s also involved in expression of adhesion molecules, which hold these cells together, and whether that in itself has a role in retinal detachment.

So further study on a cellular level will help us further understand this. But at the moment, I don’t know.

But what I do know is that we found something that was quite interesting and quite not previously reported much in the literature.

So what are the clinical implications?

Now that I’ve mentioned this, I don’t want everyone to rush off and actually, when you go to an appointment, to ask to rule out a retinal attachment, because these are quite rare. This was actually nine out of 176 eyes.

But it’s something for us as a clinician to consider. Because when we see a patient with aniridia, and we know they have a background of aniridia-related keratopathy, clouding of the front part of the eye, we know they have cataracts, and we know they have glaucoma.

And if this patient then tells us “our vision is getting a bit worse”, it’s very easy to attribute it to just say “Oh, your glaucoma might be getting a bit worse, your cataracts is a little worse, and your cornea is a little bit more cloudy, and that’s why your vision is poor.”

Because the aniridia-related keratopathy, the clouding of the cornea, and the clouding of the lens, actually makes it very difficult from a clinical perspective for us to actually evaluate and look at your retina.

So unless we use other means, so unless we purposely dilate if we need to dilate, if you’ve got only a partial iris defect, or unless we try to look at the iris, or we do something like an ultrasound scan, of the eye, we can miss retinal detachments unless we’re specifically looking for it.

And so from an aniridia patient and from a clinician’s perspective, if there ever is a mention of a sudden deterioration in vision, patients complaining of noticing lots of new floaters, flashing lights or shadows, I think those are good enough reasons in an individual without aniridia for us to really have a good look at the retina.

So if anyone does have aniridia and has those symptoms of retinal detachment, it’s worth flagging this up urgently to your care provider.

Right, so watch this space. So we’re currently writing this up as a case series, and hopefully we’ll get that published soon.

So we’re going to be the first case series on retinal detachment in molecularly confirmed PAX6 aniridia patients, with an interesting find of the high degree of patients with exudative retinal detachments. It’s an interesting finding, and there’s only been one published case I found in the literature.

My talk last year was on genotype phenotype, and in our study we found a slightly milder phenotype in patients with missense mutation. And in our case here, 9 patients, no patients had missense mutations.

So that was just another interesting thing we found. And whether there’s any correlation, there’s not enough data, but it’s just something that I noted.

Right, so that’s the end of my talk. It was a whistle-stop through aniridia and retinal detachment. And hopefully it’ll just give something for us to think about and for us to consider in the future. And hopefully we’ll get this published soon.

[Tierney] Thank you so much Vivienne, that was really, really interesting.

And I think it’s interesting for everyone as well to see and hear the method by which you guys actually go through the process of discovering new information. It’s quite an intense process and a lot of work goes into it.

So we’ve got a question in the chat here. Will you continue to work on aniridia at all once your study ends?

[Vivienne] Yeah, I aim to.

I mean, at the moment, I’m still writing a lot of papers, I’m hopefully trying to finish my postgraduate studies focusing on aniridia.

I don’t know what the future holds. I’m a trainee, so I’m running into my last year of training next year. And so it’s all the great unknown of where I’ll be, what I’ll be doing. And I don’t know where I’ll be in 2 years time, because my training ends.

But hopefully, my aim is to continue working with aniridia and learning more about it. But I don’t know where I’ll be.

[Tierney] Always the age old question, where will I be?

And so the next question is was the age of the patients a factor? And is this more common with age?

[Vivienne] Okay, that’s a good question actually.

Off the top of my head, I can’t remember, and I’m not going to be able to tell you because I’m presenting on a laptop whereas I normally work on a desktop, so I don’t have it right in front of me at the moment. But certainly, I know you well, so I can look this up and let you know.

But is age a factor? Normally, I would say, from clinical experience, as an ophthalmology trainee perspective, I don’t think so, because I see retinal detachment in all ages. Certainly, previous intraocular surgery is a risk factor for retinal detachment, not so much for exudative.

Is this more common with age in our cohort? I don’t know. But I can look this up and let you know.

[Tierney] Great, thank you. Are there any other questions from the group?

[Vivienne] Hopefully, once we publish this paper, it’ll be readily available for you to read all of it.

But I tried to compress it all into a talk that I hope wasn’t too… because I thought if I just talked about the numbers, it would be quite boring for everyone. I just wanted to talk about the clinical aspects of it.

But certainly, once we publish it, it’ll be readily available. But I don’t remember it off the top of my head, if I’m honest.

[Tierney] No, that’s fine. That’s brilliant work. Thank you so much, it was an enjoyable talk.

[James] That’s great, yeah. I have one question. Again, not related to the talk itself.

But, as you said, you’re a trainee. So I was wondering, what reflections you had on studying a rare disease versus others and how you felt that compared to your peers, maybe? What difference that made to your studies and education?

[Vivienne] It’s been an amazing experience actually. And I’m not just saying that because I’m giving a talk at an aniridia meeting. But genuinely, aniridia is something that I had no experience of.

I’d never met a patient with aniridia until I saw this research project that came about. And actually, that was my first encounter with patients with aniridia. And it was enlightening in the sense that it’s something I’ve only ever read about in our Oxford Handbook of Ophthalmology, and it mentions it on one little sliver of a page.

And actually, to then see patients with aniridia, and through doing the research that we’ve done to actually understand how it’s impacted them, it gives you a different perspective.

Because when you see a patient, some conditions you can just imagine, you can empathise. But actually, because aniridia is a condition that affects so many different… it’s not like going to a glaucoma clinic and seeing a patient with just glaucoma. But it’s actually a patient who has glaucoma, as well as so many other ocular comorbidities.

It makes you appreciate how difficult it can be, from a clinical perspective, to manage these patients, but also from their perspective, the impact of the condition.

So in terms of researching it, it was quite a good personal experience to learn more about the condition itself.

But it’s also quite different in that aniridia is not that common. So it’s not comparable to, say, a study on glaucoma where you have clinics full of patients with glaucoma. It’s few and far between, but I guess at Moorfields we see more of it.

But it’s been a good learning experience, and one that I’m really glad I picked up that email and replied and signed up to and got involved in.

[James] Well, we’re glad too, thank you very much. And yeah, best wishes for the rest of your studies.

[Vivienne] Okay, thank you.

[Tierney] Brilliant, thank you Vivienne, it was lovely to hear your chat.

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Thank you to Glen for the video editing and write-up.