It's great to see you. I know you presented yesterday on quality of life—yesterday afternoon. Could you tell me a bit more about the key takeaway points from your presentation?

 Yeah, so I'm a glaucoma specialist, and a cataract surgeon. And nowadays with advances in glaucoma surgery, there's a new type of glaucoma surgery that most ophthalmologists are familiar with called minimally invasive glaucoma surgery. And this is surgery that can be very easily and fits perfectly well when it's combined with cataract surgery.

 So, at the same time, as a patient having a cataract surgery, we can now do operations to better control or optimize their glaucoma.
I've been doing this for at least the last 10 years now. And what I've noticed—certainly in the last few years, as we're doing higher volumes of these patients—is that when patients come back to their post-op visit, the next day or one week later, you can see a big transformation in the patients. They are seeing better, so they're happy. The eye pressures are better controlled, they're taking less glaucoma medications, and they just feel less anxious about glaucoma.

Glaucoma is the leading cause of irreversible sight loss in the world. And a lot of patients worry about this in between the clinic visits, glaucoma can dominate their lives. And you see that once their pressures are better controlled, and you sort of told them their glaucoma is stable, that really allays a lot of their anxiety.

Then you've got the other patients, big group of patients, majority of patients that hate taking their drops. You know, imagine if you have to put drops twice a day for the rest of your life. That can isolate you, can limit your social interactions with others, and again, creates that insular approach that "I have a stigma of a disease or chronic disease."

 And they sort of dissociate themselves from society. So getting patients off glaucoma drops then frees them from that. So they have that sort of physical independence from not being on the drops. But on the other side, their eyes are a lot more comfortable.

Glaucoma drops are effective, or they can make the eyes red, sore, itchy, watery. So we've looked at a study essentially, as opposed to just seeing patients in the clinic, actually doing a study to look at patient-reported outcome measures, using some well-established patient reported outcome measures such as the glaucoma severity scale, glaucoma quality of life, the ocular surface disease index.

So we looked at all the these both before the surgery, four months after the surgery, and just recently 12 months after surgery. And we see a big improvement from before the surgery to four months. And that improvement has been maintained at 12 months.

 So and then when we examine their eyes, we look at the surface of the eyes, look at how healthy their tear film is, how healthy their eyes are in general. And that also has shown a big improvement.

So you know, it's nice to have post-op patients that are happy. They're—happy patients make happy doctors. And really, of course, glaucoma is about controlling the eye pressure, about preventing further visual field loss and keeping patients from visual disability in their lifetime.

But if patients are happier, more confident, less anxious, and have a better quality of life, then that's a that's a huge—

 A win-win. And it's something that probably as clinicians we underestimate, and hopefully these kinds of studies will help make it more commonplace to sort of start off thinking as there's a patient at the end of that eyeball.

 So one step towards that. Lots of more work to do. But yeah, very happy with the initial results.

What would be the next steps for this research?

So the next step would be to apply it to other glaucoma surgeries and not just the minimally invasive glaucoma surgeries but some of the bigger surgeries that we need to do for patients who are a little bit more advanced or the glaucoma is a bit more aggressive, and maybe potentially looking at at other types of surgery as well.

We know some stuff about cataract surgery, but you know, retinal surgery, and those sorts of things, so not just limited to glaucoma. And then within our own data, we've got 12-month data, but it'd be lovely to see whether this is maintained at two years, three years and five years. They're the next steps, really.

Yes. Oh, that sounds really good. Well, thank you very much for sharing your insights with Ophthalmology Times Europe.

Videos

Mr Gokulan Ratnarajan recaps his 2022 ESCRS presentation: "A Real World Comparison Of iStent Combined With Phacoemulsification And Endocyclophotocoagulation (Ice2) With Preserflo And Xen-45 Implants In The UK; Short- And Long-Term Outcomes."

Should endocyclophotocoagulation be considered part of MIGS? Mr Ratnarajan delves in

Great strides have been made in recognising and treating keratoconus. Recent imaging technologies, such as optical coherence tomography, have identified thinning of corneal tissue over the cone, and wave-front aberrometry shows higher-order aberrations that may facilitate the diagnosis.

Yet the pathway to diagnosing the condition is not always free of roadblocks, according to Dr Sumit Garg, professor of cataract, corneal and refractive surgery at the Gavin Herbert Eye Institute, University of California, Irvine, California, United States. Dr Garg said that keratoconus has two components: genetic and environmental. The latter, he said, includes allergies and eye rubbing (during waking and sleeping hours), which is a huge driver of keratoconus progression. If eye rubbing persists, progression can occur despite cross-linking treatment.

Dr Garg also pointed out that the diagnosis can depend on where a patient lives and their genetic make-up. “The keratoconus prevalence is individualised and [keratoconus] can be prevalent in up to 5% of particular populations as shown in a recent study,” he said.

 With the rapid advancements in this field, the next step is determining the role of genetic testing in this patient population.

Genetic testing in patients at risk of keratoconus is in its infancy. Dr Garg reported that AvaGen75 (Avellino) is a test—the first of its kind— that looks at variants of genes reported to be associated with keratoconus. “The test, which looks at 75 genes and more than 2,000 variants, provides a scale ranging from 0 to 100 that defines the genetic risk of a patient developing keratoconus,” Dr Garg said.

The manufacturer reports that the test provides a risk score from data based on multiple gene clusters that have a high correlation with keratoconus, with the goal of providing an early diagnosis. Dr Garg emphasised that keratoconus is polygenic and not binary (i.e., the presence of genes does not necessarily mean that a patient has clinical evidence of keratoconus). He also cited a study

 that found that when genetic testing is coupled with advanced imaging, the chances of identifying keratoconus early are greater.

In his practice, he is offering genetic testing as an option, especially when there is a suspicion of keratoconus. Those who request a refractive surgery and those with family members who have been diagnosed with keratoconus are also offered testing.

Representative results of genetic testing

Dr Garg reported the case of a woman aged 32 years, who was referred for an ocular evaluation for a possible LASIK procedure. The patient was highly myopic with high cylinder, but her vision had been stable. The best-corrected vision was 20/20 bilaterally; she denied eye rubbing.

The topography maps indicated possible posterior changes, with some steepening in the corneal centre, and changes on the ABCD score. The Kmax values were generally thin overall. The patient had no family history of keratoconus.

Genetic testing showed moderate-to-high risk of keratoconus. The decision was made not to perform the refractive procedure and to perform a follow-up examination in 6 months. If the changes were progressive, corneal cross-linking could be considered. If follow-up showed no progression, an implantable collamer lens could be considered.

A second case was that of a woman aged 31 years, who presented after being evaluated for LASIK in another practice, where a photorefractive keratectomy was recommended. The patient, who was a mild myope with low cylinder, had no recent refractive changes and she denied eye rubbing.

The patient’s best-corrected vision was 20/20. The maps did not show any abnormality and the genetic testing was inconclusive. The patient became pregnant and any refractive considerations were postponed.

A third case was that of a man aged 27 years, who presented for a LASIK evaluation. The patient was a mild myope and previously wore contact lenses. The refraction was stable. His maps showed slight corneal thinning but a good residual stromal bed. His father had a history of keratoconus. Dr Garg said that for this patient, genetic testing is the next step and may help in the treatment plan.

“Genetic testing is new and holds a lot of promise,” Dr Garg concluded. “It helps us to risk-stratify our patients, help with clinical quandaries, and hopefully will facilitate earlier diagnosis and screening for keratoconus. It is important that the disease is not binary but rather a spectrum. Patients must understand that if they undergo genetic testing it will not determine whether they have keratoconus. Genetic testing will provide another data point to help identify keratoconus.”

This article is adapted from Dr Garg’s presentation at the American Society of Cataract and Refractive Surgery’s annual meeting in Washington, D.C. He is a consultant to Avellino and Glaukos.

1. Torres Netto EA, Al-Otaibi WM, Hafezi NL, et al. Prevalence of keratoconus in paediatric patients in Riyadh, Saudi Arabia. 

2. Chen S, Li XY, Jin JJ, et al. Genetic screening revealed latent keratoconus in asymptomatic individuals. 

Articles

According to one study, when genetic testing is coupled with advanced imaging, the chances of identifying keratoconus early are greater.

Genetic testing for keratoconus facilitates earlier recognition of condition

Nicox SA announced that the last patients completed their final (3-month) visit in the Mont Blanc Phase 3 clinical trial of NCX 470 0.1% for the lowering of intraocular pressure (IOP) in patients with open-angle glaucoma or ocular hypertension.

A total of 691 patients were enrolled in the trial. NCX 470, Nicox’s lead clinical product candidate, is a novel, potentially best-in-class, nitric oxide (NO)-donating prostaglandin analogue eye drop.

“We are pleased to have reached this milestone in the Mont Blanc Phase 3 clinical trial, and I would particularly like to thank our clinical sites and the Nicox development team for their incredible efforts in continuing to drive this trial to completion in the face of the COVID-19 pandemic situation.” Doug Hubatsch, EVP, Chief Scientific Officer of Nicox, said in a news release. “NCX 470 has the potential to be a best-in-class glaucoma treatment, and we look forward to sharing the top line results in early November.”

Mont Blanc is a multi-regional, double-masked, 3-month, parallel group trial evaluating the efficacy and safety of NCX 470 ophthalmic solution 0.1% compared to latanoprost ophthalmic solution, 0.005%. Latanoprost is the most widely prescribed first-line therapy for open-angle glaucoma or ocular hypertension. The primary efficacy evaluation in Mont Blanc is based on time-matched IOP at 8 AM and 4 PM at Week 2, Week 6 and Month 3.

The second Phase 3 trial on NCX 470, Denali, is being jointly conducted and equally financed with Nicox SA’s Chinese partner, Ocumension Therapeutics. Top line results are currently expected after 2024.

According to Nicox SA, the patients made their final 3-month visit last week. Top line results of the trial are expected in November.

Mont Blanc: Final visit completed in Phase 3 trial of NCX 470 for the treatment of glaucoma

 This transcript has been lightly edited for clarity.

So thank you for joining me, Professor Dirisamer. I understand you participated in an instructional course on refractive surgery. I'm Caroline, editor of Ophthalmology Times Europe, and I would love to hear more about the key takeaways from that instructional course.

Thanks for the kind invitation to talk to you. Yeah, what we tried to say or to transport in this instructional course, are, where are the limitations and indications for the specific treatment options we have in refractive, in modern refractive surgery, either with laser refractive surgery or lens based surgery like phakic IOLs or refractive lens exchange.

Excellent. And what would you say the main challenges are that people have to pay attention to?

Yeah, since we get more and more precise pre-operative assessments, we get nicer and very precise devices based on different technologies like OCT-based, or like, [audio unclear]-based, and also epithelial mapping, for example. So there are many, many parameters for refractive surgeons have to keep in mind and have to look into their decision whether the patient gets refractive surgery and which kind of refractive surgery. This is very important since this kind of an elective procedure. So there's no medical need for that. You have to be more precise, and rule out the suspicious cases. That sounds easy, but it's tricky.

Exactly, there's not really a certain rule. Now you can really say, Okay, this is safe or it's not safe. There are some, but it remains the decision by the surgeon what we do.

And I suppose with more experience, it becomes easier to...

And it's, of course, an individual decision for each surgeon because someone may feel more comfortable with this technology, the other one with the other techniques. So we try to cover the latest publication and latest scientific works and see what changed.

There are some changes. So we are very happy to have epithelial mapping. So this is a tool that it's getting more precise to rule out suspicious corneas.

Yeah, I think we are getting close to zero complication rates.

No, but close enough. I was going to ask you what you're most excited about in the field, but I would imagine it's epithelial mapping. Or is there anything else?

Well, in terms of diagnostic, I think epithelial mapping is pretty, pretty cool. But there was a biomechanical measurements, which are coming more and more in terms of surgical techniques. I think the SMILE technique, which is a femtosecond laser lenticule extraction, I think this becomes the future of cornea and refractive surgery. Yes. Many, many companies are now providing this technique. So let's developing tool we have in our armamentarium.

Yeah, yeah. How long, how long has that been around now? It's just a few years, isn't it?

More than 10 years. Yeah, we probably see next year or so hyperopic treatments for SMILE and cyclotorsion compensation and so on. So this, yeah I'm looking forward to that.

Professor Dirisamer, that was really interesting. Thank you very much for sharing your insight.

Prof. Martin Dirisamer speaks with Editor Caroline Richards about his ESCRS instructional course, "Mastering laser refractive surgery: Indications and outcomes."

Investigating better indications and outcomes in laser refractive surgery

Faricimab approved for treatment of nAMD, DMO by European Commission

the European Commission (EC) approved faricimab (Vabysmo, Roche), a bispecific antibody for the treatment of wet age-related macular degeneration (AMD) and diabetic macular oedema (DMO). Faricimab is the first and only EC-approved drug to target two distinct pathways, Ang-2 and VEGF-A, that often cause retinal disease that may lead to visual loss.

“Many people with nAMD and DMO struggle to keep up with the monthly eye injections and physician visits, often associated with current standards of care, and unfortunately their vision may suffer as a result of undertreatment,” said Prof. Ramin Tadayoni, head of the ophthalmology department, Lariboisière, Saint-Louis and Rothschild Hospitals, Paris, France, and European Society of Retina Specialists (EURETINA) president elect.

“For people in Europe living with these conditions, today’s approval offers the first new mechanism of action in over a decade; one which could improve and protect their vision with fewer injections over time,” continued Prof. Tadayoni in a press release.

Circumnavigating the bumpy road to vernal keratoconjunctivitis: Time is key

Vernal keratoconjunctivitis (VKC) is a progressive, vision-threatening condition. However, it is rare and may not be in the forefront of clinicians’ minds when evaluating a child with a persistent allergic ocular surface complaint. In fact, 88% of clinicians in one study noted that primary care physicians and paediatricians commonly under-diagnose or misdiagnose the disorder—which then goes untreated or undertreated—largely because the later involvement of the cornea can be misleading.

This finding was reported by Dr Leonard Bielory, a professor of medicine, allergy, immunology, and ophthalmology at Hackensack Meridian School of Medicine in Nutley, New Jersey, United States. The limited awareness of VKC is the focus for Dr Bielory, who emphasised it as a barrier to timely identification and management of this disruptive ocular surface disorder. Frequently, VKC is initially misidentified as an allergy or infection, and referral to a specialist is often delayed until symptoms have become severe.

Fixoflex ring: Prof. Pallikaris describes how to utilise the device during IOL implantation

Prof. Ioannis Pallikaris discusses his 2022 ESCRS presentation: "Peripheral Capsule Reconstruction And IOL Centration With The Fixoflex Ring".

EDOF lens tech is evolving to help more patients with intermediate vision

Assistant Prof. Basak Bostanci discusses her ESCRS presentation, “Extended Range Of Vision In Unusual Cases” and how EDOF lens technology is evolving to include a wider pool of candidates.

Prof. Martin Dirisamer discusses his instructional course on common mistakes when performing DMEK and how to avoid them at ESCRS.

Investigating the effects of canaloplasty on corneal epithelium

Dr David Lubeck talks with Caroline Richards of Ophthalmology Times Europe about his ESCRS presentations, touching on surgical effects on corneal epithelium and the iTrack Global Registry for glaucoma.

An end-of-week review of what happened in ophthalmology from 17 to 23 September 2022.

Weekly review in ophthalmology: 17-23 September

This transcript has been lightly edited for clarity.

 Thank you for joining me today, Dr Lubeck, to discuss your presentation on endothelial cells, which I understand you just gave, in fact. It's lovely to meet you here in sunny Milan. I'm Caroline, editor of Ophthalmology Times Europe. Could you please tell me more about your presentation and what the key takeaway points were?

Caroline, we and surgeons who have done MIGs surgery have been drawn more and more to the possible consequences of damaging corneal epithelium as we do our procedures. There's much still to be learned about how these procedures affect the epithelium over the long term.

Canaloplasty, which is procedure I've been doing for about seven years, there was little to no data on its effect on the endothelial. Two years ago, Robert Noecker and I began a prospective study to determine the effects of canaloplasty on the cornea...

We found very, very strongly that canaloplasty has no negative impact on the corneal epithelium compared to cataract surgery alone. So essentially, it has minimal impact to no impact on the health of the cornea.

 Where do you see this research going in the future?

We hope to extend the current study up to 5 years, but we've also embarked on a much bigger data registry project called the iTrack Glaucoma [Global] Data Registry. It's being housed in the ISGR, the National Glaucoma Surgery Registry. And we hope to enrol up to 1,000 patients in that over a fairly short period of time, and then have a much more comprehensive look at knowing the efficacy, safety profiles and the nuanced elements of the procedure.

 It sounds like it will be really valuable data when that comes through.

It's essential. We don't have for this procedure. We don't have a single, large database, and it's been around for a long time.

 Well is anything else you would like to add, anything you're really excited about at present? Or have we covered everything?

The procedure is attractive in the beginning because it's non-destructive, there's no stents left behind. And from a Bayesian standpoint, or reasoning, it makes sense in terms of what it does for glaucoma, and the treatment. It has tremendous implications for the future.

Once we understand not only the biomechanics, but the bio-physiology of glaucoma, I believe that this technology is going to have a future application to different modalities of treatment.

 Oh really? Oh, that sounds excellent. Well, thank you very much for your insights today, Dr Lubeck.

It's a pleasure. Thank you very much, Caroline.

 So thank you for joining me at this year's ESCRS, Professor Dirisamer. I understand tomorrow you're due to present on DMEK. I would love to hear more about that. Could you tell me the key takeaways from the instructional course?

 Yeah, thank you for the kind invitation. Yeah, we are having a course about DMEK and how to avoid mistakes in converting to DMEK because it was like a kind of transformation from PK and DSAEK. And, you know, obviously, mistakes we made, we try to [make it so] the younger people do not have to do the same mistakes. Well, it's about the indication, how to start and what are the key points where I can avoid complications, and to get together the perfect outcomes.

So it's, I think, very important for a beginner to start with DMEK, to pick up easy cases. So not start with challenging cases. But pick easy cases. And from there, follow certain rules. So if you follow these rules, and these suggestions, I think it could do this transformation pretty easily.

 And so do you think that'll be a good uptake on DMEK in and amongst the younger ophthalmologists?

 Yes, I think it's, at least in German-speaking countries, I think the most popular transportation. And so I think the younger colleagues, they started with us; in my case, it was the same thing. So I think you can kind of overtake the other data procedures that don't have to DSAEK anymore. They can start right away with DMEK.

And, yes, so we tried to give them a kind of stepwise approach to solve problems we have to face in the beginning with DMEK. And, yeah, I think this could work out for most people. Of course, you need some surgical skills, you need some surgical training as well. But you also should be aware of the theory behind.

 Yeah, that's I think that for younger people and younger colleagues, I think this might be a good basis.

 Yeah. And what would you say the main challenges in performing this procedure? What goes wrong most often?

 I would say the most the most challenging part is that it's basically a two-step surgical procedure, so you have to prepare your graft, sometimes on your own. Of course, there's prepared tissue available, but in many parts of the world, there is not. So you have to prepare the tissue both by yourself; this is the first challenge. You have a challenge already, and the surgery part hasn't even started.

 Of course, you have to know how to store this tissue, how to stain it. And so it's a combination of many things. I would say complication number one, if you make a sealed [audio unclear] detachment. But on the other, the other side, it's not a big complication. You can solve it pretty easy. But it's better to avoid it. So we do everything that we can to not get a complication, and there's some tips and tricks, how you can do that.

 All right. Well, it sounds like it would be a great course for ophthalmologists to attend tomorrow. I'm sure they're very much looking forward to learning more.

 Yeah, oh well, I can imagine. It sounds really interesting. Thank you very much for sharing that with me here.

Avoiding errors when converting to DMEK

Dr Mark H. Blecher dives into his AAO 2022 topic: "One-Year Visual Outcomes Following Monocular Implantation with a Small Aperture IOL."

Investigators report positive visual outcomes one year after monocular implantation of small aperture IOL

Dr Ines Lains, PhD, and colleagues from the Massachusetts Eye and Ear, Harvard Medical School, Boston, reported that adjunct treatment with intravitreal antivirals or early pars plana vitrectomy (PPV) did not improve the rates of retinal detachment (RD) in patients with acute retinal necrosis (ARN).

ARN is rare but can have devastating visual consequences, Dr Lains explained. Over time, patients with ARN have a high risk of developing retinal traction and necrotic retinal breaks, which can lead to the development of a RD.

“RD is one of the most common consequences of ARN,” she said. Systemic antivirals are the mainstay treatment for ARN, and even though clinicians may empirically add intravitreal antivirals or early PPV, data on this topic remains controversial.

The investigators conducted a cross-sectional retrospective cohort study using IRIS Registry data to determine the association between the initial treatment regimen for ARN and RD rates at 6 and 12 months.

The researchers identified 533 eyes of 457 patients that met their criteria. Among them, 358 cases (67.2%) received only systemic antivirals, while 155 (29.1%) received adjunctive intravitreal antivirals, and 20 (3.8%) underwent early PPV.

“At 6 months, the rates of RD were comparable among eyes treated with systemic antivirals alone (19.6%), adjunctive intravitreal antivirals (18.7%, 

= 0.51),” they reported. Similar results also were seen at the 12-month evaluation (

The results also showed that, compared to use of systemic antivirals alone, treatment with adjunctive intravitreal injections or early PPV did not affect the time to development of RDs (

Dr Lains commented, “To our knowledge, this is the largest dataset of patients with ARN that has been analysed to date. Our results suggest that adjunctive treatment with intravitreal antivirals or early PPV do not improve rates of RD rates in patients with ARN. These findings are important because they support that, despite the theoretical advantages of these adjunctive strategies, systemic antivirals - the current mainstay of ARN treatment - are appropriate and provide similar outcomes, thus contributing to guide management of this blinding disease.”

The results also showed that, compared to use of systemic antivirals alone, treatment with adjunctive intravitreal injections or early pars plana vitrectomy did not affect the time to development of retinal detachments.

Retinal detachment rates following acute retinal necrosis are unaffected by early treatment with antivirals, vitrectomy

This is the third in a series of articles that summarises an afternoon of presentations, plus a debate, on the topic of corneal ectasia that was held as part of the recent 29th Cologne Adventsymposium, an annual meeting organised by Laserforum e.V., in Cologne, Germany. Chaired by Drs Omid Kermani and Georg Gerten, the presentations each considered the condition from a different perspective and are available 

Part 1, published in the June 2022 issue of 

considered the contribution of eye rubbing to the development of keratoconus

. Part 2, published in the July/August 2022 issue, 

looked at developments in diagnostics and classification methods for ectatic corneal diseases

. This third part of the series covers epithelial imaging and is based on the presentation by Prof. Dan Reinstein and Dr Tim Archer.

Reviewed by Dr Omid Kermani, Prof. Dan Reinstein and Dr Tim Archer.

Prof. Reinstein began his talk by introducing the concept of the epithelial thickness profile, explaining that he had been the first to publish 10-mm epithelial thickness maps of the normal virgin cornea with 1 µm precision.

 As expected, he found the central thickness to be around 50 µm but, going against everything that had been published previously, found that the epithelium does not have an even profile, being an average of 6 µm thinner superiorly than inferiorly and about 1 µm thicker nasally than temporally. Right and left eyes have mirror asymmetry.

His group has now published around 40 papers on the epithelium alone. “OCT is now confirming many of the things that we discovered originally with ultrasound,” he explained. “What we have learned is that the epithelium changes in all situations where you change the stromal surface curvature.”

According to Prof. Reinstein, looking at how the epithelium behaves in different situations allows four basic rules to be written on how the epithelium acts and how it remodels after a stromal surface change, as follows.

The epithelium thickens to fill any relative depressions.

The epithelium thins over relative peaks within the stroma.

The change in the epithelium is proportional to the change in the stroma. Higher myopicablation produces more central epithelial thickening and peripheral thinning;

 higher hyperopic ablation produces more peripheral epithelial thickening and central thinning.

 Epithelial changes are more marked the more severe the keratoconus.

The amount of change is defined by the rate of change of curvature (or curvature gradient). For example, a depression from a corneal ulcer that is 1-mm wide and 200-µm deep will be almost entirely smoothed by the epithelium, but a 4.5-mm zone depression made in the stroma by PRK is compensated for less. This corresponds with the improvement in refractive stability and reduction in regression when using larger optical zones.

The cornea has a front (stromal) surface and a back surface. In keratoconus, the front and back surfaces extrude and the epithelium remodels over the peak to become thinner, but it also becomes thicker around the peak to form a “doughnut” shape. As Prof. Reinstein explained, interestingly, when you have a very mild back surface extrusion yoked to a very mild front surface extrusion, the epithelium is able to fully compensate.

This leads to focal thinning of the epithelium in a doughnut pattern overlying the back surface elevation, which is eccentric. The front and back surface data alone may get lost in the soup of statistical variation and therefore fail to signal keratoconus with enough sensitivity.

Commercially, what has become of interest, and what spawned the OCT epithelial thickness industry, was Prof. Reinstein’s demonstration that you could have inferior steepening that could be confirmed by an epithelial thickness map not to be keratoconic but rather due to a thicker inferior epithelium.

His study of 1,500 eyes demonstrated that mapping the epithelium allowed exclusion of keratoconus in 84% of these highly equivocal back surface elevation abnormalities.

 This then led to an increase in patients eligible for excimer laser surgery.

Having studied the epithelial thickness profile in keratoconus and established that the more advanced the keratoconus, the thinner the epithelium becomes over the cone and the thicker it becomes around the doughnut, Prof. Reinstein then sought to try and parameterise how this difference in epithelial modelling could be exploited in the very mildest keratoconic cases.

In one of the earliest machine-based pattern-recognition studies from topographic maps,

 Prof. Reinstein’s researchers set up around 160 variables in epithelial profiles that they thought might be relevant with respect to keratoconus screening, only six of which turned out to be relevant. This provided an automated algorithm with exceedingly high specificity and sensitivity for keratoconus. It detects a 1- or 2-µm change in epithelial thickness profile, which is much more sensitive than the 1- or 2-µm elevation detected by a topographic or tomographic device with back surface mapping.

Prof. Reinstein explained that the epithelial thickness profile can be used as an adjunctive tool in cases of suspected keratoconus and has applications in cases with seemingly normal topography, cases where both topography and tomography are suspect, and most importantly, those that have normal topography and normal tomography.

 shows a case with normal front surface topography, normal Belin/Ambrósio and BAD-D (Belin/Ambrósio display, D value) and nothing remarkable between the back and front surfaces. The epithelial thickness profile shows quite significant focal thinning in the centre of the cornea and the pattern deviation map also shows inferior thinning in an unexpected location.

The Reinstein-Silverman-Keratoconus (RSK) score in this case implies a definitive keratoconus diagnosis.

Prof. Reinstein said, “The point is that keratoconus can be detected with high sensitivity. This avoids false negatives when screening for keratoconus using only topography by proving that the epithelial thickness profile has the doughnut configuration. [It also avoids] false positives in cases that machine algorithms classify as keratoconic … but use of an epithelial profile shows a thicker epithelium over the zone where there is increased steepening.”

Prof. Reinstein explained that the epithelium is a dynamic layer that changes easily with all kinds of conditions and therefore contact lens warpage, anterior basement membrane dystrophy, tear film abnormalities, meibomian gland dysfunction, dry eye and eyelid forces can lead to epithelial redistribution. 

 illustrates a cornea that (left) has been out of a soft contact lens for 3 days and appears very keratoconic and then (right) looks less keratoconic after 2 weeks; the difference is epithelial remodelling.

 Contact lens warpage resembling keratoconus.

Anterior basement membrane dystrophy (ABMD) produces a very abnormal epithelial profile with duplication of the basement membrane and, therefore, thickening of the epithelium. 

 shows an example of the epithelial profile showing doughnut-shaped thinning, which might well be mistakenly interpreted as being keratoconus but is actually ABMD.

 Anterior basement membrane dystrophy resembling keratoconus.

As a way of indirectly proving that it is the eyelid forces that cause epithelial thickness changes, 

 shows a patient with a Bell’s palsy, who does not blink very much with one of his eyes. The epithelium is thickened significantly in that eye, producing a myopic shift, whereas the epithelial thickness profile is much more even in the eye that blinks normally.

 (All images courtesy of Prof. Dan Reinstein)

Thus, performing refractive surgery without epithelial maps, when there are multiple commercially available devices to provide such a map, seems unwise. Instead of relying entirely on machine learning, it is better to use one’s clinical skills in order to screen for keratoconus.

Following Prof. Reinstein’s presentation, Dr Archer debated its content with the other presenters—Dr Kermani (Germany), Prof. Damien Gatinel (France), Prof. Renato Ambrósio Jr. (Brazil) and Prof. Farhad Hafezi (Switzerland). The responses in italics below were not given at the time, because of time constraints, but have been provided during the review process.

Epithelial mapping seems to be a very important step in diagnosis in both keratoconus and ectasia. Do you use high-speed ultrasound or OCT?

 There are variety of machines on the market to map the epithelium. Most of the maps we showed in this presentation were from the ArcScan Insight 100 very-high-frequency digital ultrasound device but we also showed quite a few maps from the MS-39 OCT device, so yes, we use both systems.

 If you look at epithelial mapping from a clinical perspective, if the epithelium is so delicate, would that be a reason not to do topo-guided LASIK? Or is that a procedure in which the epithelium already masks the effect of whatever we do to the stroma?

Most topography-guided systems derive the ablation algorithm using the front surface topography, which means that it will be less accurate in eyes with an irregular epithelium. Most patients have a reasonably regular epithelium but some do not. In eyes with an irregularity on the epithelium, this will throw off the topography-guided algorithm and you may end up with an outlier.

If you have a global irregularity, like a decentration or a small optical zone, the epithelial remodelling is more global; most of the irregularities show through on the topography and topography-guided treatment works very well.

If you have localised irregularities, there is a lot more epithelial remodelling, which masks the defect, and so topography measurements cannot see the actual shape of the stroma. In this case, topography-guided treatments do not work very well and can actually make things worse.

The link between epithelial thickness and topography is very important. Topography-guided treatments should not be done without first measuring the epithelial thickness and ensuring that it is reasonably regular.

 Damien, what is your opinion on epithelial mapping? Is it so sensitive and helpful in our daily diagnosis that we really need to add it to our multi-modality diagnostics? Do you use it?

 My view is that I have not yet seen a patient for whom the epithelium was altered from what you expect in a normal patient, yet the cornea was not deformed on the anterior or posterior surface. I do not believe that there is a primitive deformation of the epithelium. As eye rubbing is exerted directly on the epithelium, you may expect to see some deformation, but it is not clinically obvious.

Of course, when you have keratoconus you have a specific pattern, which usually shows as a regularisation pattern. What I find fascinating is how the epithelium remodels itself. If I were involved in epithelial research I would hire a real surface scientist or a physicist or mathematician specialised in those things to understand what drives the epithelium to remodel itself. I know we blink 10,000 times a day but still, how does this work?

The epithelium feels the defects but it is fascinating that it remodels, probably in response to both biological and physical elements like surface tension. When you put a drop of water on a surface it takes a shape that depends on the hydrophilicity or hydrophobicity of the surface but also obeys physical laws. The epithelium probably obeys the same laws but I would love to see some research in that direction.

It is good that the epithelium regularises the cornea, but how much and how can we predict it? This is really fascinating to me. In refractive surgery, if you could predict how the epithelium would react to a specific profile of ablation you could maybe anticipate it and correct for it.

 We agree with Prof. Gatinel that there would not be epithelial thickness changes in an eye with keratoconus without a deformation of at least the posterior surface. However, the point that we are making is that the epithelial thickness profile is used as an adjunctive tool to confirm or exclude keratoconus in eyes with equivocal changes on tomography.

In general, keratoconus screening is improved with the addition of further measurement modalities. Epithelial thickness mapping and Corvis biomechanical measurements are two examples of how keratoconus screening can be improved beyond topography and tomography alone.

 Kanellopoulos and Kahn performed hyperopic LASIK in combination with cross-linking and showed that the results are more stable with regard to regression and stability than without cross-linking,

 so your point is valuable and we should look into this.

 We do not agree with this statement. The Kanellopoulos study is interesting; however, the population included only 34 patients so the results have a very low statistical power and have not been replicated to date. As a comparison, our published results for hyperopic LASIK using the MEL 90 demonstrated better stability than the group that included cross-linking in the Kanellopoulos study.

The pathophysiology and pathomorphology of corneal ectasia: 

Dan Reinstein, MD, MA (Cantab), FRCSC, DABO, FRCOphth, FEBO

Timothy Archer, MA (Oxon) DipCompSci (Cantab) PhD

Prof. Reinstein is the medical director of the London Vision Clinic and holds professorships at Ulster University (Coleraine, UK), Columbia University (NY, USA) and the Sorbonne University (Paris, France). Prof. Reinstein is a consultant for Carl Zeiss Meditec (Jena, Germany) and CSO Italia (Florence, Italy) and acknowledges a financial interest in Artemis Insight 100 VHF digital ultrasound (ArcScan Inc.).

Dr Archer has been the research manager at London Vision Clinic since 2003. Dr Archer has no financial interest regarding the topic of the article.

Dr Kermani is specialised in cataract and refractive surgery and has worked in private practice since 1993. He is based at the Augenklinik am Neumarkt in Cologne. He has no financial interest regarding the topic of the article.

1. Reinstein DZ, Archer TJ, Gobbe M, et al. Epithelial thickness in the normal cornea: three-dimensional display with Artemis very high-frequency digital ultrasound. 

2. Reinstein DZ, Archer TJ, Gobbe M. Change in epithelial thickness profile 24 hours and longitudinally for 1 year after myopic LASIK: three-dimensional display with Artemis very high-frequency digital ultrasound.

3. Reinstein DZ, Archer TJ, Gobbe M, et al. Epithelial thickness after hyperopic LASIK: three-dimensional display with Artemis very high-frequency digital ultrasound. 

4. Reinstein DZ, Gobbe M, Archer TJ, et al. Epithelial, stromal, and total corneal thickness in keratoconus: three-dimensional display with Artemis very-high frequency digital ultrasound. 

5. O’Brart DP, Corbett MC, Verma S, et al. Effects of ablation diameter, depth, and edge contour on the outcome of photorefractive keratectomy. 

6. O’Brart DP, Gartry DS, Lohmann CP, et al. Excimer laser photorefractive keratectomy for myopia: comparison of 4.00- and 5.00-millimeter ablation zones.

7. Reinstein DZ, Archer TJ, Gobbe M. Corneal epithelial thickness profile in the diagnosis of keratoconus. 

8. Reinstein DZ, Archer TJ, Gobbe M. Stability of LASIK in topographically suspect keratoconus confirmed non-keratoconic by Artemis VHF digital ultrasound epithelial thickness mapping: 1-year follow-up. 

9. Silverman RH, Urs R, Roychoudhury A, et al. Epithelial remodeling as basis for machine-based identification of keratoconus. 

10. Kanellopoulos AJ, Kahn J. Topography-guided hyperopic LASIK with and without high irradiance collagen cross-linking: initial comparative clinical findings in a contralateral eye study of 34 consecutive patients. 

11. Reinstein DZ, Carp GI, Archer TJ, et al. Outcomes for hyperopic LASIK with the MEL 90® excimer laser. 

The epithelium adapts to compensate for changes in the cornea and these changes can be detected with high sensitivity, reducing both false positives and false negatives in the diagnosis of keratoconus.

Investigators report positive visual outcomes one year after monocular implantation of small aperture IOL

Retinal detachment rates following acute retinal necrosis are unaffected by early treatment with antivirals, vitrectomy

Corneal ectasia part 3: OCT epithelial thickness measurements allow monitoring of corneal changes