THE GENESIS OF KERATOCONUS
How does it all start ?
AN INTERESTING KERATOCONUS STORY
Patient right profile
Keratoconus with onset during childhood
Keratoconus with onset during childhood
Identity : Mr H.R
First visit : 11/01/2017
Mstr. H.R is a 10-year-old male child with no previous medical history or any known family history of keratoconus. He complained of itchy eyes for 2 years.
His refraction at the first visit at the Rothschild foundation (on 11/01st/2017) was : Right Eye (RE) 20/20 with +0.75 (-1.25 x 5 °) and Left Eye (LE) 20/20 with +0.5 (-0.50 x 155 °).
Clinical examination with the slit lamp revealed bilateral tarsal papillae and inferior superfical punctate keratitis. There were no clinical signs of keratoconus.
Corneal topography was performed and revealed the presence of a topographic pattern evocative of early subclinical keratoconus in the left eye.
Here are pictures of the patient’s eye profiles and slit lamp pictures of his ocular surface.
We questioned his mother about the possibility of her son rubbing his eyes frequently. She declared that she had not noticed anything special, but she could remember that she had witnessed her son wiping his left eye more often than the right. We asked this young boy if he knew that he was rubbing his eyes. His answer was clear: not only did he acknowledge rubbing his left eye many times a day, he even confessed that he was finding this habit very pleasurable. He was an avid reader, and when his eyes were itchy, he would rub his left eye, while holding the book in his right hand (he is right handed).
He also likes sleeping on the left side, which is his favorite sleeping position.
His left eye rubbing technique was quite impressive, and amazingly noisy.
Patient performing a noisy eye rub (left eye) with the nail of his left index finger
Patient performing a noisy eye rub (left eye) with his left palm
We explained to this child that he should really stop rubbing and performing the vigorous massages on his eye. We prescribed him an eye shield to be worn at night on the left eye, and saline balanced sterile solutions to rinse the eyes when irritated. We referred him to a specialized allergy consultation, and started him on anti-histamine eyedrops.
One month and a half after the first visit, corneal topography revealed the disappearance of the vertical asymmetry on the left eye. The child declared that he had completely stopped rubbing his eyes. He tried to fall asleep on the back, not on the left side anymore. He had noticed that he would loose easily the left eye shield during the night.
With this unique case report in a young child, it is possible to observe elements involved in the genesis of keratoconus. It is very likely that this child would have developed a frank keratoconus in a few years if he had continued to rub his eyes in such a manner. Like in the adult cases that we routinely follow, the coexistence of a particularly vigorous rubbing technique, exerted on one eye only, and located on the same side as the sleeping position is striking. In this case, the corneal deformation was not very pronounced, and clinically silent. Children usually do not spontaneously complain about a unilateral loss of vision, and the progression of the deformation could have remained unknown for many years if chronic persistent surface inflammation had not triggered an ophthalmic consultation.
This case report may be a glimpse of the earliest manifestation of what will eventually evolve to be a classic presentation of unilateral (or asymmetric) keratoconus .
We humbly believe that by identifying and arresting the eye rubbing habit, we have managed to prevent the impending occurrence of keratoconus in the left eye of this young boy. We will continue following him at our clinic, and post the results of future investigations on this page.
KERATOCONUS GENESIS: LOOKING AT IT WITH A FRESH EYE
Genetic susceptibility has been considered a very plausible factor in the occurrence of keratoconus. The consensus is that keratoconus is an inherited disease primarily caused by a biochemical abnormality, which could be transmitted genetically or occur sporadically. Ironically, few detectable genetic and molecular abnormalities exist in this condition.
It may therefore be more appropriate to reconsider this pathogenetic mechanism, and replace it with the concept of a primarily mechanical disease induced by chronic and vigorous eye rubbing. The study of the cases that are reported on this website strongly support this conjecture.
BIOMECHANICAL FORCES CREATED BY EYE RUBBING
We have found that every patient presenting with keratoconus has a history of chronic eye rubbing, although some are not conscious of their rubbing habit at the first visit. If these patients were not re-examined and interviewed again at subsequent visits, where they all realize their rubbing habit after being sensitized to the possibility, they would be labelled as « non rubbers ». The lack of appropriate interrogation and investigation on the possibility of unconscious eye rubbing may have biased prior studies where this habit is not considered universal in the keratoconus population.
Chronic eye rubbing can cause the corneal collagen fibers to lose part of their biomechanical resistance, resulting in macroscopically obvious structural deformation. This biomechanical mechanism could also better explain the frequent disparity in the degree of affliction between the right and left eyes (patients frequently rub one eye more often and more vigorously than the other) and the focal nature of keratoconus, which has been recently evidenced. Depending on the capacity of the cornea to uphold native structural and biomechanical resistance, a mechanical imbalance is reached and corneal deformation results.
In the mechanical hypothesis, keratoconus cannot occur without repeated mechanical injury such as rubbing. Eye rubbing is detrimental to corneal biomechanical stability through two main pathways, which are synergistic as both reduce the resistance of the cornea.
–The first pathway outlines the mechanical impact of rubbing on tissue structures such as collagen fibrils. Rubbing-related buckling and flexure of these fibrils may facilitate cone formation, associated with fibrillar slippage in the cone region.
– The second pathway corresponds to the impact of eye rubbing on cellular structures, which may undergo changes and apoptosis, further compromising corneal structural properties.
The severity of the corneal deformation depends on the duration, intensity and frequency of rubbing which can eventually exceed the corneal capacity of resistance . Once eye rubbing exceeds the capacity of the cornea to uphold native structural and biomechanical resistance, a mechanical imbalance is reached and corneal deformation results and progresses if eye rubbing is not stopped.
EXPLAINING THE ASYMMETRICAL NATURE OF KERATOCONUS PRESENTATION
How rubbing affects the eye depends on the intensity of the ocular friction, the frequency, the age at which eye rubbing first started and the status of the underlying cornea.
If we rub vigorously, repetitively, over prolonged periods, from a young age and if our cornea is thin to start with, the risk of weakening and further thinning of the cornea is very high.
If the same eye rubbing intensity, duration, and frequency is applied to two corneas, one with natively reduced corneal thickness and strength and the other thicker and stronger, the one with less biomechanical strength will likely succumb to deformity more readily and more significantly than the other. The repetitive force of the fingers and knuckles rubbing the eye can cause corneal collagen to stretch and become disorganized.
Each cornea has a different resistance capacity. A cornea with keratoconus has an increased elastic component, which means that its ability to absorb incident energy is less than a normal cornea.
There are machines to estimate the biomechanical properties of the cornea, such as the Ocular Response Analyzer® (ORA). This tonometer measures the corneal hysteresis (CH) and the corneal resistance factor (CRF). The value of CH and CRF are slightly reduced in cases of keratoconus. The presence of a CRF value lower than that of the CH is a sign that reflects a relative biomechanical fragility of the corneal wall. The aspects of the applanation peaks is an important qualitative parameter in the estimation of the corneal biomechanics.
For the same corneal thickness and intraocular pressure, these measurements are often different from one eye to another, reflecting some native biomechanical variability. Natively weaker corneas may be more sensitive to the effects of vigorous eye rubbing.
The technique of rubbing is important.
The different ways in which a person rubs his or her eyes may also account for the large spectrum of presentation of keratoconus, especially in early disease. Here are the different techniques of eye rubbing (see this page).
The sleeping position also plays a role in the genesis of keratoconus and its asymmetric character. The prolonged contact between the eye and eyelids with the pillow or mattress overnight can cause local irritation, dryness, contamination, and itch, all circumstances that could incite eye rubbing and subsequently lead to inflammation of the cornea and ocular surface. This may also explain why keratoconus is often worse in one eye, the one on the side of the head that the person sleeps on.
Genetics and environnemental factors are also importants, and we explain it below.
GENETICS INVOLVED IN KERATOCONUS : A WEAKER, THINNER AND MORE VULNERABLE CORNEA
The exact genetics of keratoconus has not yet been elucidated. The frequency of occurrence of keratoconus in close family members is not clearly defined, but the pattern of inheritance is estimated to be less than 20%. Even if some familial cases and genetic research are still in favor of a genetic dimension to keratoconus, no genetic mutations have yet been identified in any of the keratoconus chromosome loci. Discordance for keratoconus in two pairs of monozygotic twins has been reported which supports a pathogenetic role for environmental influences such as eye rubbing. Concordance for keratoconus has also been reported between monozygotic twins. In essence, it is difficult to explain with genetics the inter-eye variability in the stage of keratoconus and the different ages of onset.
Genetic components could actually be related to the predisposition of conditions that lead to increased eye rubbing and to variations in corneal thickness and resistance such as Down syndrome, Tourette syndrome, atopy, sleep apnea and sleep disorders, and pregnancy.
A cornea that is genetically weaker or constitutionally thinner may be more vulnerable to rubbing trauma as previously discussed. The central corneal thickness is one of the most highly heritable human traits.
It is easier to explain the variation in the age of presentation, laterality, severity and broad spectrum of phenotypic expression by excessive eye rubbing than a corneal degenerescence caused by an unknown genetic disorder or molecular cascade.
For the same eye rubbing intensity, duration and frequency, corneas with natively reduced thickness and biomechanical resistance may deform more readily and significantly than thicker and stronger corneas. This is the reason why all patients who rub their eyes do not develop keratoconus. Some people inherit of stronger and thicker corneas than others, so the time taken to end up with a keratoconus is longer, and this risk decreases with age due to corneal stiffening.
We also know that pediatric keratoconus is more aggressive than adult keratoconus. In addition, the literature overwhelmingly shows higher rates of failure and progression of corneal collagen cross-linking, intracorneal ring segments and penetrating keratoplasties as compared to adults. While this could be explained by structural differences in the cornea between the two populations (more elastic corneas), the reduced compliance and the persistence of irrepressible eye rubbing in children could also account for the aggressiveness of pediatric keratoconus.
Despite intensive research, no specific gene has been discovered and it is highly probable that none will ever be. It could be possible that the structural changes and deformations in the cornea are initiated and aggravated by eye rubbing.
In conclusion we think that genetics has a role in the development of keratoconus not as cause but as a risk factor, by giving less corneal resistance (lesser tissue thickness or resistance), weaker corneas and a lower quality of stromal collagen.
BIOLOGICAL AND CELLULAR CHANGES INDUCED BY EYE RUBBING
Eye rubbing for 60 seconds has been demonstrated to increase the level of pro-inflammatory molecules in the tear film of normal study subjects. Some of these molecules are called « proteases » are they are able to digest some proteins.
The increase in protease release, protease activity and inflammatory mediator formation after eye rubbing may be exacerbated even further during the persistent and forceful eye rubbing seen in people with keratoconus. Sustained elevated levels of inflammatory mediators in the tears due to repeated rubbing episodes may be significant in keratoconus development and progression.
It has been shown both in animal and human models that there exists a rubbing-related mechanical epithelial trauma which triggers the release of inflammatory mediators and a wound healing response in the cells present in the corneal stroma called « keratocytes ». Slight rubbing for 10 seconds using one finger and in a smooth circular movement repeated 30 times over a 30-minute period was shown to significantly reduce the keratocyte density in human corneas, and also lead to a greater concentration of inflammatory mediators in the tears.
Rubbing-related epithelial thinning may include cell flattening, as well as displacement from the rubbed area of some cells, extracellular fluid, mucin, and cytoplasm from any burst cells. After an experimental fifteen seconds of rubbing in a circular pattern with use of light to moderate force and the finger pad of an index finger, the epithelial thickness of normal human corneas was found to be reduced by 18.4%, both centrally and midperipherally. Recovery to baseline thickness took 15 to 30 minutes centrally and 30 to 45 minutes mid-peripherally.
We therefore conclude that ocular friction has a pejorative role on the corneal homeostasis, responsible for the genesis of keratoconus, on the one hand from a biological point of view by inducing a corneal inflammation responsible for enzymatic proteolysis and also from cellular point of view, resulting in a more pronounced keratocyte apoptosis, responsible for a change in corneal architecture and keratoconus.
ENVIRONNEMENTAL FACTORS ARE ALL REASONS TO RUB
What has been called environmental factors in keratoconus actually correspond to all the situations leading to rubbing of the eyes.
We have listed all the reasons for eye rubbing on this page (see this page), but here are the commonest:
Allergy is the main factor of eye rubbing and keratoconus, causing itchy, red and watery eyes.
Exposing populations with thinner corneas to high levels of pollution, dry air, irritating or allergenic agents and bad and/or intensive working conditions may account for the prevalence of keratoconus in some socio-economic groups.
The recent increase in computer usage has been linked to various ocular symptoms gathered together to be called « Computer Vision Syndrome », and this includes eye fatigue, which elicits eye rubbing, which may in turn account for the increase in keratoconus prevalence.
Sleep apnea has also been associated with an increased incidence of keratoconus. The deprivation of good quality sleep causes chronic fatigue, and fatigue can induce patients to rub their eyes more frequently.
Dry eye and ocular irritation are frequent, especially during pregnancy: the occurrence of keratectasia after pregnancy may be explained again by increased eye rubbing.
Unhealthy sleeping postures are often seen in patients with keratoconus. We have noticed that the patients (like many on this website) are more susceptible to sleeping on their stomach or on their side. Because of the constrained lateral head position, they typically exert an extended pressure against one or both orbits while they sleep. Some patients favor the right or the left side when they fall asleep. The strong correlation between the side which is more compressed in the pillow/arm/hand at night and the side of the more advanced keratoconus suggests that the sleeping habit may play a significant role in the genesis of keratoconus.
To learn more about all the reasons for eye rubbing, visit this page
AGE OF KERATOCONUS ONSET