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

At least 700 carotenoids are found in nature. Around 50 are included in a typical human diet, 15–16 of which make their way to the circulatory system, but remarkably only three are found in the eye, where they are highly concentrated at the macula.

These yellow macular pigments—lutein, zeaxanthin and meso-zeaxanthin—have powerful antioxidant properties and play essential roles in filtering high-energy, short-wavelength blue light and in minimising the oxidative stress that is known to be a significant factor in age-related eye disease.

Prof. John Nolan of the Nutrition Research Centre Ireland has spent 20 years researching the macular pigments—measuring them and monitoring their effects on health. He says that “the general population is highly deficient in these three carotenoids; even the healthiest person you know is deficient. Nobody is eating enough.” A deficiency in macular pigments has a real and tangible impact on day-to-day quality of life in terms of vision and cognitive function.

Everybody who works in eye care is aware that visual acuity does not describe the whole of visual performance, which is multifaceted and also incorporates aspects of processing speed, contrast sensitivity, glare and visual adaptation. Prof. Nolan’s European CREST trials, supported by a European Research Council Starting Grant, demonstrated that each of these individual visual functions is significantly improved by enriching the macular pigments by means of an oral supplement, not only in subjects with early age-related macular degeneration but also in healthy subjects.

Blue light is a problem for visual performance and increasing its filtration—by increasing macular pigment—reduces visual discomfort and glare disability and improves photostress recovery. Another important aspect of vision is the speed of visual processing, which is strongly modifiable by increasing macular pigment.

For every 0.1 increase in macular pigment optical density, roughly 1 millisecond of reaction time can be gained.

 Increased contrast sensitivity can hugely improve a patient’s quality of life and how they feel about their vision. A patient with a medium or high level of macular pigments can of course still develop macular degeneration, but nutrition can counterbalance genetic factors and optimise their individual disease trajectory.

It is important to measure the concentration of macular pigment in the eye itself because retinal levels correlate only weakly with levels measured in the blood; availability of the fat-soluble carotenoids at their target tissue depends on a subject’s body mass index amongst other factors. Until fairly recently, it has been possible to quantify retinal concentrations using psychophysical methods only, which are known to be highly subjective and variable and also have the disadvantage of measuring at only one point in the eye.

Prof. Nolan has worked with Heidelberg Engineering to develop an experimental software add-on to the Spectralis system, which uses a dual-wavelength autofluorescence system to measure the “optical volume” of the macular pigments (see Figure 1).

 They have developed and validated macular pigment optical volume (MPOV) as an arbitrary unit that provides a measure of the concentration of the pigments within every pixel of the image, across the entire macula, thus allowing the distribution of the pigments to be mapped.

It is now possible to examine a patient and compare their MPOV with that of the general population average in terms of low or high levels of pigment. Most people have around 2000–3000 MPOV, but with appropriate supplementation it is possible to increase that value to 7000–10,000 MPOV. 

 The effects of this increase in MPOV primarily manifest as improved contrast sensitivity rather than a change in visual acuity.

Prof. Nolan’s current research interest is dementia and cognitive function. It has become clear that the levels of macular pigment measured in the eye correlate with their levels in the brain; it has been demonstrated further that these levels correlate directly with cognitive function.

The population of people with Alzheimer’s disease is the most deficient Prof. Nolan has encountered and he is currently conducting an interventional study in these patients. This would not have been possible previously, as people with this dementia are not able to cooperate with psychophysical testing. The Spectralis system makes it possible to quickly and simply measure their macular pigment.

A cross-sectional observation study with 4,000 participants in the Republic of Ireland demonstrated that people who had high levels of pigment outperformed everybody else in all measures of cognitive abilities.

 This was followed with interventional trials, which found that memory and cognition in healthy patients improved on supplementation with the three macular pigments.

It is possible in principle to improve one’s levels of macular pigment by eating significant portions of plants such as spinach, kale and corn. Good nutrition is a baseline and the first step Prof. Nolan takes with his trial subjects is to optimise their nutritional profile via diet.

He said, “I came into this exercise very anti-supplement. I did experiments with hens to try to make eggs the solution; I did smoothie trials; I tried to make food the solution.” However, an affordable supplement purified from Mexican marigolds

, which are rich in the carotenoids of interest, is now readily available

“We have had success with things like folic acid that pregnant people or those planning babies take—for me, this is another example of a nutrient we should all be taking,” Prof. Nolan explained. Colostrum is yellow because of these nutrients and mothers become highly deficient in these carotenoids during pregnancy, showing that nature wants us to have these pigments that affect retinal and brain development right from birth.

A cost–benefit analysis that Prof. Nolan published in the

showed clearly that across a 5-year period, in the population of the Republic of Ireland, using these supplements as standard could save over 250 million Euros from the health budget.

In summary, “thanks to Heidelberg Engineering we have an imaging system that empowers ophthalmology and optometry to take measurements that are truly valuable to measures of nutrition that are working throughout our lifetime.”

Prof. Nolan of the Nutrition Research Centre Ireland, School of Health Science, Waterford Institute of Technology, was recently awarded the Heidelberg Engineering Xtreme Research Award 2020 for his research on macular pigment for vision health and as a biomarker for brain nutrition and function. He has no financial interest in the subject of this article.

Akuffo KO, Beatty S, Peto T, et al. The impact of supplemental antioxidants on visual function in nonadvanced age-related macular degeneration: a head-to-head randomized clinical trial. 

Nolan JM, Power R, Stringham J, et al. Enrichment of macular pigment enhances contrast sensitivity in subjects free of retinal disease: central retinal enrichment supplementation trials – report 1. 

Bovier ER, Hammond BR. A randomized placebo-controlled study on the effects of lutein and zeaxanthin on visual processing speed in young healthy subjects. 

Green-Gomez M, Bernstein PS, Curcio CA, et al. Standardizing the assessment of macular pigment using a dual-wavelength autofluorescence technique. 

Feeney J, O’Leary N, Moran R, et al. Plasma lutein and zeaxanthin are associated with better cognitive function across multiple domains in a large population-based sample of older adults: findings from the Irish longitudinal study on aging. 

Dietary macular pigments, which can now be measured directly and accurately, are hugely important in optimising visual function, especially as we age.

Author | Lisa Stewart, PhD

Articles

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

Dietary supplement improves measurable visual outcomes