Lisa Stewart, PhD

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This four-part series of articles summarises an afternoon of presentations, plus a debate, on the topic of corneal ectasia that was held as part of the 29th Cologne Adventsymposium, an annual meeting organised by Laserforum e.V., in Cologne, Germany, on 4 December 2021. Chaired by Drs Omid Kermani and Georg Gerten, the presentations each considered the condition from a different perspective and are available 

In Part 1, we look at the role of eye rubbing in keratoconus. This is based upon a presentation that ophthalmologist Prof. Damien Gatinel gave during the one-day event.

The contribution of exogenous traumatic factors to keratoconus was first pointed out by the late John Nottingham in 1854;

 since then, all studies published on the risk factors for keratoconus have mentioned high friction. The thesis that Prof. Gatinel supports is that eye rubbing is not a trivial risk factor but rather a causal factor without which the disease would not occur.

According to Prof. Gatinel, the stake of this debate is not only academic: if this conjecture, which is summarised as “no rub, no cone,” is true then there is tremendous hope that we can not only halt the progression of this disease but prevent it as well. “It remains a mystery to me how the ophthalmological community remains largely reluctant to accept this theory that obeys the laws of physics and is corroborated by clinical evidence,” Prof. Gatinel said.

Keratoconus occurs when the energy delivered by friction exceeds the natural resistance capacities of the cornea, which vary from subject to subject, resulting in permanent deformation. There must, of course, be a favourable genetic environment; however, Prof. Gatinel believes that keratoconus is not primarily a genetic disease but also a behavioural one. Excessive rubbing is 

 but its action may be triggered and/or potentiated by certain genetic cofactors.

A recent article concluded that mechanical causes were necessary for keratoconus to develop in genetically susceptible individuals.

 Another recent study found that eye rubbing with the knuckles was the most important predictive factor for keratoconus, whereas the presence of a family history was not significant.

Many elements plead against an entirely genetic origin for keratoconus, Prof. Gatinel pointed out. Firstly, if keratoconus were purely genetic, it should always be bilateral; truly unilateral forms are debated but Prof. Gatinel is convinced that they do exist 

. And secondly, there is a large predominance of sporadic cases (85% vs 15% with a family history). Despite intensive research, a specific gene for keratoconus has not yet been found.

The right cornea is affected by keratoconus. The left cornea remains negative for all topographical and biomechanical indices of detection.

“In my opinion, the genetic dimension to keratoconus is indirect and concerns the degree of corneal resistance (for example corneal thickness or the quality of the stromal collagen) and the susceptibility to allergies and other factors that encourage patients to rub their eyes. The discordance between monozygotic twins suffices to discard the genetic root cause hypothesis,” Prof. Gatinel said 

Four genetically identical eyes, raised in the same environment but only one of which has been excessively rubbed. A single such discrepancy is sufficient to demonstrate the need for external factors.

Contrary to what is sometimes suggested, Prof. Gatinel was very clear that the cause of keratoconus is not inflammation. The inflammatory dimension of keratoconus arises from the causes of eye rubbing (allergy or dryness) and the consequences of the rubbing (e.g., excretion in tears of inflammatory mediators), he believes. Chronic inflammatory pathologies of the cornea result in focal thinning associated with focal flattening and not steepening (as evidenced by the sequelae of interstitial, microbial or interface keratitis after LASIK, which commonly causes a hyperopic shift).

In addition, Prof. Gatinel pointed out that it is wrong to consider that keratoconus corresponds to an ectasia with a stretching of the corneal tissue. Indeed, his group recently showed that the corneal surface area does not differ significantly between healthy eyes and keratoconic eyes.

Prof. Gatinel believes that the term “corneal ectasia” should be reserved to describe the morphological changes that the cornea undergoes in Marfan syndrome, in which the corneas are typically softer and thinner but flatter. The cornea in keratoconus is thin but steep and this thinning and steepening are focal.

He added that molecular mechanisms and signalling pathways that would select a specific part of the cornea to deform spontaneously under the sole influence of the forces of intraocular pressure have not been described; rather, the influence of an external mechanical force better accounts for the characteristics seen.

Repeated rubbing eventually causes a focal thinning and a subsequent biomechanical weakening of corneal integrity. In the early stages, this causes a vertical sag and this explains the frequent early induction of against-the-rule or oblique astigmatism.

In 1965, the English statistician Sir Austin Bradford Hill proposed a set of nine criteria to provide epidemiological evidence of a causal relationship between a presumed cause and an observed effect 

 Prof. Gatinel demonstrated that the hypothesis “no rub no cone” satisfies these criteria, as follows.

Regarding the first three criteria (strength, consistency, specificity), the literature abounds with articles showing that eye rubbing is always associated with keratoconus. It has been discovered that in unilateral or very asymmetric forms, the most affected eye is always the most rubbed and highly correlates with a side or stomach sleeping position with prolonged compression of the orbit 

The fourth criterion (temporality) is particularly important. In all cases, rubbing precedes the appearance of keratoconus by months or years. These actions are sometimes unnoticed—a small proportion of patients say they do not rub but, in Prof. Gatinel’s experience, once awareness of rubbing has been raised it is acknowledged by nearly 100% of patients during the second visit.

 A very asymmetrical or even unilateral keratoconus. The picture of the sleeping position was taken by the mother of this patient whom, on the whole, only rubbed his right eye.

Speaking about the fifth criterion (dose-response relationship), Prof. Gatinel explained that when difficulty arises in separating corneas affected by keratoconus from those with forme fruste, it is because there is a continuum between healthy corneas and very deformed corneas. In early forms of keratoconus, rubbing is typically recent or much less vigorous and frequent.

Prof. Gatinel recently published a study that shows that rubbing with the knuckles is worse than rubbing with the softer pulp of the fingers;

 this correlation between severity of rubbing and severity of deformation vehemently pleads for an external cause. The extreme variability of the topographic presentation modes of corneal deformation is matched only by the extreme variability of rubbing in duration intensity and frequency.

He went on to describe how the next three criteria relate to plausibility and coherence, occasionally confirmed by experimental evidence. Corneal resistance can be reduced by eye rubbing itself and this is a mechanical route to keratoconus,however, in addition to the mechanical stress induced by the action of shear and compression forces, the action of rubbing the eyes triggers the local secretion of cytokines, proteases and metalloproteinases.

 These molecules weaken the stromal tissue and make it more vulnerable to the action of friction.

Prof. Gatinel is not surprised that cases of eye subluxation, hyphaema, glaucoma and retinal detachment have been attributed to excessive eye rubbing. A ptosis is sometimes observed on the most-rubbed side of the eye; this is also not surprising, because the eyelid also suffers repeated trauma.

Regarding the ninth criteria (analogy), the IntraCor technique for presbyopia correction (intrastromal femtosecond laser surgical compensation of presbyopia with six concentric intrastromal ring cut) is an analogous model which shows that the selective severe incisional biomechanical weakening of the central stroma induces its immediate deformation.

Another analogy that is useful to distinguish direct causal responsibility from optional risk factor, according to Prof. Gatinel, is that of sunburn, which is more common in patients with a clear phototype—pale skin—but which absolutely requires exposure to ultraviolet light. As some phototypes are more UV-sensitive, some keratotypes may be more sensitive to eye rubbing.

Prof. Gatinel summarised by explaining that the “no rub no cone” conjecture meets the Bradford-Hill criteria. There is ample evidence that keratoconus requires interaction with environmental factors for a genetically determined predisposition to manifest as a phenotypically apparent disease, he stated: among these factors, excessive eye rubbing is a must 

“Beyond the academic debate, refusing to admit the causal and essential role of excessive rubbing deprives us of the possibility of halting the progression of the disease or even eradicating it by educating patients at risk,” Prof. Gatinel concluded.

 Proposed route for keratoconus physiopathology. 

(All images courtesy of Prof. Damien Gatinel)

The content of Prof. Gatinel’s presentation was debated with the other presenters—Prof. Renato Ambrósio Jr. (Brazil), Prof. Dan Reinstein (UK), Dr Tim Archer (UK) and Prof. Farhad Hafezi (Switzerland)—and with members of the online audience.

 It is widely believed that there is no unilateral keratoconus. How does this fit with the predominant cause of keratoconus being chronic trauma from eye rubbing?

 There are published cases of strictly unilateral keratoconus. There is no consistent model for keratoconus that explains the focal stiffening and weakening without an external force working on the cornea. Therefore, if you rub only one eye then you will have unilateral keratoconus; if you rub both eyes you will have bilateral keratoconus; and if you rub one eye more than the other you will have more pronounced keratoconus on that eye. This seems elementary to me.

In keratoconus, the cornea is not initially soft. When you have a soft cornea for other reasons, such as Marfan syndrome, the evolution is completely different from keratoconus. This simple observation should make us step back from what we believe and consider keratoconus as a cornea that has been made softer, or in which softness has increased focally, because of rubbing trauma, which creates focal mechanical stress whose action is amplified by the biomolecular consequences of rubbing.

 We have found easy consensus that keratoconus is a bilateral disease that can be very asymmetric in many cases. The point is that even though keratoconus is bilateral we can have a traumatic, biomechanically-induced ectasia, in only one eye or sometimes in both eyes, which is really hard to distinguish from keratoconus.

As in any disease, susceptibility and environmental factors work together. Avoiding eye rubbing or sleeping on the eye will help prevent ectasia from developing or keratoconus progressing.

 I have patients who rub their eyes but do not have keratoconus. Can you explain why not everybody who rubs their eyes gets keratoconus?

 This is why I like the sunburn analogy. When you go to the beach, not everyone will get sunburnt but if there is no UV light then nobody burns. Many people rub their eyes and a proportion of them develop keratoconus.

Nobody will ever delineate ‘keratoconus and not keratoconus’. It is just a relation between how much you rub and how much your cornea resists it. Some people rub infrequently and their cornea is elastic enough to dissipate the trauma, but after some time then the cornea starts to sag.

In patients of 12 or 13 years of age, a slight vertical against-the-rule or oblique astigmatism is the first sign of keratoconus. You will discover that these patients rub their eyes and if they stop rubbing, they will not progress further.

We have clinical evidence to show that when the cornea is not rubbed it does not develop keratoconus. The argument that everyone rubs and but not everyone has keratoconus does not invalidate this. Taking the sunburn analogy again: no UV, no sunburn; no rub, no cone.

There are people who are more genetically predisposed to sunburning than others, so are there corneas that are more genetically predisposed to developing keratoconus from eye rubbing?

 What is strongly hereditary is the initial corneal thickness. A thin cornea is more prone to keratoconus. By analogy, there may be keratotypes. It would be very nice to research them, but if you are pragmatic and think that the priority is to eradicate keratoconus, the first thing is to educate people not to rub.

I think genetics are more important in terms of allergies, and that behaviour and psychological conditions are important as you are more prone to rub when you have stress. People who work at night are more exposed to keratoconus because they are tired and rub their eyes, which is an environmental factor.

 Eye rubbing certainly is something you should avoid, but I have my difficulties withthis simplification. We have all seen probably thousands of keratoconus patients in our careers and I have many patients that tell me, even upon repeated questioning, that they have never excessively rubbed their eyes.

I would like to see studies that go beyond this very nicely constructed hypothesis, which to me still lacks scientific validation. I have an issue with simplifying a complex disease to those 11 letters “no rub, no cone.” It is human nature to simplify complex things but it carries a lot of danger. I think keratoconus remains a multifactorial disease.

In our laboratory, we have assessed the force of knuckle rubbing, which is probably the most severe. We constructed a device to rub 

 porcine corneas, through an eyelid, 10,500 times.9 Biomechanically, nothing happened to these corneas. The stress-strain measurement after 10,500 severe rubs was just as good as that in an eye that had not been rubbed at all.

What I like about this study is that it dissociates pure mechanical force from the secondary effects that happen in a living organism. I do believe that eye rubbing causes inflammation, which may increase the susceptibility to or cause keratoconus.

 There is a very nice video from Dr Arthur Cummings that explains how to rub the eye by just pressing against the caruncle.10 There is no disagreement on the fact that eye rubbing is very bad, but I also see a lot of patients who are adamant they do not rub their eyes at all but in whom ectasia progresses.

But how is that possible? The force from the eyelids is so low; how can you have tissue deforming? There is this fuzzy consensus that the cornea self-deforms but I showed that inflammation and Marfan syndrome make the cornea flatter, so we need to stop thinking that inflammation and a soft cornea explains keratoconus. There is no theory, apart from eye rubbing, that accounts for the deformation.

1. Nottingham J. Practical observations on conical cornea and on the short sight and other defects of vision connected with it. London: John Churchill; Liverpool: Deighton & Laughton, 1854.

2. Rabinowitz YS, Galvis V, Tello A, et al. Genetics vs chronic corneal mechanical trauma in the etiology of keratoconus. 

3. Moran S, Gomez L, Zuber K, Gatinel D. A case-control study of keratoconus risk factors. 

4. Crahay FX, Debellemanière G, Tobalem S, et al. Quantitative comparison of corneal surface areas in keratoconus and normal eyes. 

5. Hill AB. The environment and disease: association or causation? 

6. Mazharian A, Panthier C, Courtin R, et al. Incorrect sleeping position and eye rubbing in patients with unilateral or highly asymmetric keratoconus: a case-control study.

7. Zhang J, Yang S, Tan Y, Wang Y. Effects of mechanical compression on cell morphology and function in human corneal fibroblasts. 

8. Balasubramanian SA, Pye DC, Willcox MD. Effects of eye rubbing on the levels of protease, protease activity and cytokines in tears: relevance in keratoconus. 

9. Abdshahzadeh H, Abrishamchi R, Torres-Netto EA, et al. The impact of repetitive and prolonged eye rubbing on corneal biomechanics. Poster presentation at the 38th congress of the ECSRS, 2–4 October 2020.

10. Cummings A. How to stop eye rubbing. Available at https://www.youtube.com/shorts/Dh4IZE1icco.

Articles

Eye rubbing is an essential factor in the development of keratoconus. “No rub, no cone” is the rule: a genetic predisposition for the disease will come to nothing without excessive eye rubbing.

The pathophysiology and pathomorphology of corneal ectasia: Keratoconus will not develop without eye rubbing

This is the fourth 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 Ophthalmology Times Europe®, 

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

. Part 3, published in the September 2022 issue, covered 

. In this final instalment of the series, we look at recent developments in corneal cross-linking. This is based on the presentation that Prof. Farhad Hafezi gave during the event.

Reviewed by Dr Omid Kermani and Prof. Farhad Hafezi.

 Comparison of corneal stiffening achieved with different epi-off CXL irradiation protocols: blue is the Dresden protocol (30 minutes at 3 mW/cm2); red is 10 minutes at 9 mW/cm

; green is 5 minutes at 18 mW/cm2; purple is control with no cross-linking.

 (Image courtesy of Prof. Hafezi, adapted from Hammer et al. 2014

Prof. Hafezi began his presentation by explaining that there are three essential components for every corneal cross-linking (CXL) procedure: UV light, riboflavin and oxygen. When CXL was first developed in the early 2000s, it involved corneal epithelial cell debridement (making it an “epi-off” procedure) to enable riboflavin to be applied to the cornea and saturate the stroma.

This was followed by the delivery of UV, total dose (fluence) 5.4 J/cm

-intensity light for 30 minutes. This is known as the Dresden protocol.

One of the basic laws of photochemistry is the Bunsen–Roscoe law of reciprocity. If all reagents are in excess, then the amount of reaction that occurs depends solely on fluence—not the speed at which the light energy is delivered. Under these conditions, doubling light intensity and halving the irradiation time should have the same effect.

But would this principle hold true in CXL? Prof. Hafezi’s group tested the biomechanics of several different accelerated CXL protocols (

) and found a 10-minute protocol that, although it induces significantly less corneal stiffening than the Dresden protocol, is enough to stabilise a keratoconus in most cases.

Comparison of stiffening results from different epi-off cross-linking protocols. 

(Image adapted from Abrishamchi et al. 2021

Prof. Hafezi explained that “the reason that increasing acceleration of the cross-linking reaction results in decreasing stiffening effects is that the speed of oxygen diffusion into the stroma is the rate-limiting factor in cross-linking. If the cross-linking reaction is too fast, the oxygen cannot diffuse in fast enough and efficacy is lost, unless intensity is increased to compensate.” If there is no oxygen in the cornea, no stiffening occurs at all.

Until recently, Prof. Hafezi always reverted to the 30-minute Dresden protocol for particularly aggressive forms of keratoconus, such as in a young child or an ectasia after LASIK. However, he has now developed and published an accelerated epi-off protocol that compensates for the acceleration-related loss of stiffness by increasing fluence (

). This new protocol achieves the same stiffness as the Dresden protocol while saving the surgeon 20 minutes of time.

“The holy grail for cross-linking would be a truly effective epi-on procedure,” Prof. Hafezi said. Leaving the epithelium intact would mean faster healing, less haze and an even lower infection risk. “The quest for good, efficient epi-on has been going on for more than a decade. What do we need to make it work?”

If the epithelium remains in place, then the UV irradiation needs to be increased because the epithelium blocks around 15 to 20% of the light. This is relatively easy: increase the fluence from 5.4 to 7.2 J/cm

The next element is riboflavin. Riboflavin is a relatively large molecule, so transporting it through the tight junctions of the epithelium is not easy. One method is iontophoresis, which uses an electrical current to encourage transport.

The third factor is oxygen diffusion. The presence of the epithelium forms yet another barrier to oxygen diffusion into the cornea. It has been proposed that pulsing the light on and off might be effective: the idea is that oxygen is consumed when the light is on, so the oxygen can re-diffuse during the light’s off period.

The next question was: what happens with a slow procedure? Irradiating for 1 hour, instead of 30 minutes, with half the intensity, produces very efficient epi-on cross-linking.

 Prof. Hafezi said, “This was a proof of principle, and as a scientist I am happy—but as a clinician I don’t want to spend an hour in the operating room.”

One approach to increasing the amount of oxygen in the cornea during CXL, goggles that are fed a continuous stream of 100% oxygen, was proposed 2–3 years ago. However, Prof. Hafezi was not keen: “This makes sense. It should work. I don’t like it. Why? Because it is additional technology and I want to simplify the procedure, not make it more complicated and more expensive.”

“It is not necessary to have 100% oxygen surrounding the eye; what is needed is enough oxygen in the stroma for the cross-linking reaction to proceed effectively. What was needed was an intelligent combination of everything we have learned so far.”

There is now a published epi-on protocol that consists of normal air (no oxygen boost), iontophoresis to push riboflavin into the cornea, pulsed light, gentle acceleration, high fluence, and there are 3-year follow-up clinical data showing that it is effective.

The next question was, could epi-on CXL be undertaken without iontophoresis? Prof. Hafezi’s group has been assessing the ability of penetration enhancers to get riboflavin to pass through the epithelial cell tight junctions, spending almost a year at the Swiss Federal Institute of Technology using multiphoton microscopy to assess the extent of riboflavin penetration, in order to find a penetration enhancer combination that achieves a stromal riboflavin concentration that is similar to that achieved with epi-off CXL.

This means there is now a gently accelerated high-fluence epi-on protocol, which takes approximately 30 minutes in total (including 15 minutes of irradiation), that can be performed at the slit lamp. This protocol is currently undergoing clinical evaluation.

Prof. Hafezi reminded the audience that the original Dresden protocol required a minimum stromal thickness of 400 µm in order to protect the corneal endothelium from being exposed to potentially damaging levels of UV irradiation. Historically, surgeons have artificially increased the corneal thickness prior to treatment, either by swelling the cornea with hypo-osmolaric riboflavin

 or through the use of a riboflavin-soaked contact lens.

However, these methods have disadvantages. The amount of swelling achieved by the hypoosmolar riboflavin is unpredictable, and, because contact lenses form an additional barrier to oxygen diffusion, their use reduces the stiffening efficacy by around 30%.

What Prof. Hafezi proposes now is what he describes as individualised cross-linking. Previously, surgeons adapted the cornea to the CXL protocol; now the technique can be adapted to each patient’s cornea. His research group modelled the interaction of oxygen, UV light, riboflavin and the stroma, and made an algorithm to predict the extent of cross-linking based on these parameters.

Using this, they developed the “sub400” protocol, which uses measurements of the thinnest point of the cornea to calculate the optimal duration of a 3 mW/cm

 intensity irradiation (via a simple look-up table) in an otherwise standard epi-off CXL protocol that leaves the same un-cross-linked stromal safety margin as the Dresden protocol to avoid harming the endothelium.

Clinical results have been very encouraging, with around 80% of corneas having successful prevention of ectasia progression after 1 year, even in corneas as thin as ~200 µm that would otherwise have gone on to require keratoplasty.

This opens up a possibility for a new indication for CXL, keratoglobus. Prof. Hafezi has published a case report of sub400 CXL being used to successfully halt disease progression.

 The C-eye portable cross-linking device in use. 

Describing his aims, Prof. Hafezi said, “We developed the sub400 protocol and epi-on for one reason: we want to democratise access to cross-linking, moving away from an expensive infrastructure toward equipment we all share, which is the slit lamp, and this is why we developed the C-eye device” (EMAGine AG, Zug, Switzerland; 

According to Prof. Hafezi, the device is “small but high-tech. It can treat at the slit lamp with more than 11 different protocols—for keratoconus, for refractive, for keratitis—so if you ask me how often I go back to the laying position, I do, but only for special cases such as patients that are not compliant or who require general anaesthesia.” 

 Surgeon’s view of the cornea through C-eye during slit lamp cross-linking. 

What about riboflavin distribution when treating at the slit lamp: is it affected by gravity? Prof. Hafezi said, “The short answer is yes but it takes an hour before the first changes become apparent, which is more than enough time to perform cross-linking”.

With regards to fixation, it is much better with an upright patient who is comfortable and has a fixation light on the other eye so they know where to look. However, is the Dresden protocol, which takes half an hour, achievable?

“We don’t need to [perform this],” explained Prof. Hafezi. “Most cross-linking procedures take around 10–12 minutes; PACK [photo-activated chromophore for keratitis] cross-linking for keratitis takes around 6 minutes, and that’s easily feasible, especially if you give the patient the surgeon’s chair so they are really comfortable and spend 30 seconds at the beginning to make sure that the height is well adjusted.”

He added: “The last question is the most important: can we leave the operating room for the procedure room or even the examination room? Yes, we can. With epi-on there is no question at all: the epithelium is on. With epi-off, you do not only stiffen the cornea but also sterilise it, so the answer is yes.”

The trend of the past 4 or 5 years has been for office-based procedures. Intravitreal injections

 have been shown to be safe performed in the procedure room, or even the examination room, with no increased risk for endophthalmitis, so cross-linking in the procedure room should be possible.

Prof. Hafezi concluded his presentation by reiterating that cross-linking at the slit lamp broadens access to the procedure.

 It is suitable for all indications—epi-on, epi-off, keratoconus, PACK cross-linking—and is available to patients with a variety of special needs.

Following Prof. Hafezi’s presentation, its content was debated with the chairs and other presenters—Dr Omid Kermani (Germany), Dr Georg Gerten (Germany), Prof. Damien Gatinel (France), Prof. Renato Ambrósio Jr. (Brazil), Prof. Dan Reinstein (UK) and Dr Tim Archer (UK)—and with members of the online audience.

: It seems that we are coming to a time when cross-linking can be performed in the practice room. I am sure our audience wants to learn a little bit more about this technology. How do you soak the cornea when the patient is sitting upright? And how do you make sure that, due to the position of the patient, the lower cornea is not soaked with more riboflavin than the upper cornea?

My second question is just to clarify epi-on or epi-off: do you do epi-on cross-linking with the C-eye device? How do you avoid the necessity of doing iontophoresis?

 This procedure is like any type of surgery and comprises multiple steps that come one after the other. We looked at each step and tried to predict potential obstacles.

We instil riboflavin when the patient is in a simple reclining chair at an angle of around 20°. The patient then comes to the slit lamp and is positioned vertically: we showed about 4 years ago

 that we have 60 minutes from the moment when the cornea becomes vertical until you see the first gradient between upper and lower cornea. You are right that a gradient develops and more riboflavin accumulates in the lower cornea but the difference after 1 hour is 2%, so you have plenty of time.

The third thing is that we should not change too many paradigms at the same time, so the C-eye device is created to make the procedures simple and efficient and to democratise access; any type of epi-off procedure can be performed.

We thought about how to remove the epithelium at the slit lamp for a long time because, even if a surgeon has been doing this with the hockey knife for years with the patient horizontal, the movement of the hand needed to do it when the patient is upright is very different due to the curvature of the cornea. It can be quite hard to remove the epithelium without cutting into Bowman’s layer.

We eventually developed a process in which we tap the cornea with freshly prepared 40% ethanol on the tip of a cotton pad. After 70 seconds there is a beautiful erosion of 8 mm, with no harm to the cornea, and this can be done by any beginner in the field.

The way we avoid iontophoresis in epi-on was to go back to earlier studies

 on mixing penetration enhancers and modify the osmolarity of the solution to increase the paracellular transport within the epithelium, so the riboflavin can pass through the epithelial cell tight junctions directly into the stroma.

 Regarding the therapy of keratoconic patients: when they walk into our office they do not say, “Doctor, please cross-link my cornea.” They say, “Doctor, how can I see better?”

You showed us these sub400 protocol patients and I fully agree that it makes a lot of sense to cross-link these keratoglobus or almost pellucid marginal degeneration cases you showed us. After that, these patients often have huge astigmatisms. Would it be possible, after cross-linking, to use intra-corneal rings and so combine cross-linking and other procedures?

You are absolutely right; cross-linking might make sense to stabilise the tissue but then we have to improve on vision. Especially in thin corneas, this is a question we get a lot: what is the use of cross-linking a cornea if the patient cannot see afterwards?

We are in the lucky situation in Switzerland to have three manufacturers of scleral lenses within 50 kilometres and I have seen cases that came from transplantation waiting lists with a cornea of 200 µm of residual stroma, huge epithelial compensation, K readings of 160 D. After cross-linking, they obtain a visual acuity of 0.7 with a scleral lens. So even extreme cases can now profit, and the best cornea is your own: the longer you can preserve your own cornea the better.

For the other aspects, I have been performing wavefront-guided PRKs on much less extreme cases for a number of years now, to regularise the corneas to improve corrected distance visual acuity, and epithelial mapping makes my Trans-PRK much more precise.

 I think for optical restoration there is nothing better than a contact lens. So, when I have a patient with keratoconus, I fight on two fronts: the cessation of eye rubbing—I give them a patch at night, send them to the allergy specialist, ask them to make sure that they do not rub any more, etc.—and for visual rehabilitation, I am disappointed sometimes with surgical procedures. They may be satisfying for the surgeon, but the patient is eventually dissatisfied because he does not really see the improvement.

I would go for a hard contact lens. I do not really use cross-linking because, again, when patients stop rubbing, they do not progress.

That is the time to do PRK on those who have just a minor astigmatism to correct. As long as I am sure that they do not rub any more I am happy to do PRK or fit contact lenses. I am very conservative in terms of surgery with those keratoconus patients.

 I agree that eye rubbing is very bad for anyone. For rehabilitation of vision we have to go through the sequence of glasses and contact lenses. Imaging can help tremendously with the scleral lens, but some cases need surgery, which means rings, and patients are disappointed because they have very high expectations.

The first thing in treating keratoconus is patient education, which includes not rubbing the eye but goes very far beyond that. You have to tell them about the disease, what they may expect and the possible need for transplant. I agree that even with a very thin cornea, if you cross-link it a transplant has a higher chance to be more stable in the future.

This has not been proven by a scientific study, but we see a lot of post-op patients late after transplants even though they may have some residual ectasia in the periphery. I think cross-linking is a very good thing even for a pre-transplant case. A lot of people would debate this, because it may make the cornea harder, but I think ectasia should be treated as a specialty and we have to respect the disease and not to oversimplify.

Even though eye rubbing is bad for everybody I think many patients still progress; I cannot explain how but no explanation does not mean it does not happen. I have seen many patients progress who promise they do not sleep on the eye and do not rub the eye. These cases have to be prognostically detected early because they need cross-linking very early; as soon as possible in many cases.

The pathophysiology and pathomorphology of corneal ectasia:

Prof. Hafezi is a refractive and cataract surgeon based at the ELZA Institute in Zurich, Switzerland. He is the chief scientific officer of EMAGine AG, producer of C-eye, and holds a patent on a UV light source (PCT/CH 2012/000090).

Dr Kermani specialises 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. Hammer A, Richoz O, Arba Mosquera S, et al. Corneal biomechanical properties at different corneal cross-linking (CXL) irradiances.

2. Richoz O, Hammer A, Tabibian D, et al. The biomechanical effect of corneal collagen cross-linking (CXL) with riboflavin and UV-A is oxygen dependent. 

3. Abrishamchi R, Abdshahzadeh H, Hillen M, et al. High-fluence accelerated epithelium-off corneal cross-linking protocol provides dresden protocol-like corneal strengthening. 

4. Torres-Netto EA, Kling S, Hafezi N, et al. Oxygen diffusion may limit the biomechanical effectiveness of iontophoresis-assisted transepithelial corneal cross-linking.

5. Mazzotta C, Bagaglia SA, Sgheri A, et al. Iontophoresis corneal cross-linking with enhanced fluence and pulsed UV-A light: 3-year clinical results.

6. Hafezi F, Mrochen M, Iseli HP, Seiler T. Collagen cross-linking with ultraviolet-A and hypoosmolar riboflavin solution in thin corneas.

7. Jacob S, Kumar DA, Agarwal A, et al. Contact lens-assisted collagen cross-linking (CACXL): A new technique for cross-linking thin corneas. 

8. Kling S, Hafezi F. An algorithm to predict the biomechanical stiffening effect in corneal cross-linking. 

9. Hafezi F, Kling S, Gilardoni F, et al. Individualized corneal cross-linking with riboflavin and UV-A in ultrathin corneas: the sub400 protocol. 

10. Hafezi F, Torres-Netto EA, Randleman JB, et al. Corneal cross-linking for keratoglobus using individualized fluence. 

11. Salmon B, Richoz O, Tabibian D, et al. CXL at the slit lamp: no clinically relevant changes in corneal riboflavin distribution during upright UV irradiation. 

12. Tabandeh H, Boscia F, Sborgia A, et al. Endophthalmitis associated with intravitreal injections: office-based setting and operating room setting.

13. Ianchulev T, Litoff D, Ellinger D, et al. Office-based cataract surgery: population health outcomes study of more than 21 000 cases in the United States. 

14. Hafezi F, Richoz O, Torres-Netto EA, et al. Corneal cross-linking at the slit lamp. 

15. Salmon B, Richoz O, Tabibian D, et al. CXL at the slit lamp: no clinically relevant changes in corneal riboflavin distribution during upright UV irradiation. 

16. Gatzioufas Z, Raiskup F, O’Brart D, et al. Transepithelial corneal cross-linking using an enhanced riboflavin solution.

Corneal cross-linking (CXL) is improving all the time, although all protocols retain the basic requirements for oxygen, riboflavin and UV light. Recent developments mean that CXL at the slit lamp is feasible, which will improve access to the procedure.

The pathophysiology and pathomorphology of corneal ectasia: Part 4

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 

. 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.

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.

Author | Lisa Stewart, PhD

Articles

The pathophysiology and pathomorphology of corneal ectasia: Part 4

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

The pathophysiology and pathomorphology of corneal ectasia: Multimodal imaging techniques yield vital screening and diagnostics data

The pathophysiology and pathomorphology of corneal ectasia: Keratoconus will not develop without eye rubbing