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Etiology, Diagnosis, and Management of Keratoconus: New Thoughts and New Understandings

Patrick Caroline, COT, FAAO

Mark Andre, FAAO

Beth Kinoshita, OD

Jennifer Choo, OD

College of Optometry, Pacific University
2043 College Way
Forest Grove, OR 97116





Keratoconus is a condition of obscure etiology that is characterized by a non-inflammatory thinning and steepening of the central and/or para-central cornea. The condition usually occurs in the second or third decade of life resulting in a moderate to marked decrease in visual acuity secondary to irregular astigmatism and corneal scarring. (Figure 1.)


Figure 1. Corneal ectasia in keratoconus.


Keratoconus most often occurs bilaterally, however there is often asymmetry with one eye affected more than the other and generally the first eye to develop the condition has a more marked progression. (Figure 2.)


Figure 2. Bilateral keratoconus with one eye (right eye) affected more than the other.


This differential rate of progression may be an important consideration when counseling patients on the progression of the condition. Cases of unilateral keratoconus are rare but can occasionally be seen in clinical practice.

The clinical management of keratoconus varies depending on the severity of the condition and can range from non-surgical options such as glasses and contact lenses to surgical interventions including intra-stromal inlays and penetrating keratoplasty.

Early reference to keratoconus was made by Mauchart in 1748 and by Taylor in 1766, but the condition was first adequately described and distinguished from other corneal ectasias by Nottingham in 1854. At that time, the treatment of keratoconus consisted of cauterizing the conical area with silver nitrate and the instillation of miotics accompanied by a pressure dressing.

In the early months of 1888, a French ophthalmologist, Eugene Kalt, began work on a crude glass shell designed to “compress the steep conical apex thereby correcting the condition.” This was the first known application of a contact lens for the correction of keratoconus. (Figure 3.)


Figure 3. Eugene Kalt, MD, first to propose the use of a contact lens for keratoconus.


Prevalence of Keratoconus in the Population

Keratoconus occurs with approximately equal gender distribution in every region and every ethnicity throughout the world. Many studies have been conducted to estimate the incidence and prevalence of the condition, and, although the incidence varies somewhat from to country to country, a 1986 population-based study in the US indicated that approximately 5 in 10,000 people have keratoconus.


Etiology of Keratoconus

There has always been speculation as to the cause of keratoconus, but during the past 10 years our scientific knowledge of the condition has steadily increased. Although we now have a much better understanding of the cellular and molecular changes that occur in this condition, keratoconus remains a condition of unknown etiology.

Recent research conducted by Steven Wilson, MD, at the University of Washington, suggests that keratoconus somehow accelerates the process of keratocyte apoptosis, which is the programmed death of corneal cells that occurs following injury. Minor external traumas, such as eye rubbing, poorly fitted contact lenses, and ocular allergies can release cytokines from the epithelium that stimulate keratocyte apoptosis (the earliest observable stromal response to an epithelial injury).

Although keratocyte apoptosis is virtually never detectable in the absence of epithelial injury in normal patients, a high percentage of keratoconus patients show evidence of such cell death. This typically takes place first in the anterior stroma and is manifested by breaks in Bowman’s layer (Figure 4) and later as stromal thinning (Figure 5). Wilson has also suggested that genetics may play a role in the etiology of keratoconus, in that some patients may have a genetic predisposition to chronic keratocyte apoptosis.


Figure 4. Breaks in Bowman’s layer.


Figure 5. Central versus mid-peripheral thickness changes in advanced keratoconus.


Cristina Kenney, MD, PhD, of Cedars-Sinai Medical Center in Los Angeles, has suggested that keratoconus corneas may have increased enzyme activities and decreased levels of enzyme inhibitors. This combination results in the production of toxic by-products that bring about a cascade of events throughout the cornea, resulting in corneal thinning and scarring.


Genetics in Keratoconus

One of the strongest arguments for a genetic component in keratoconus etiology is that the condition can run in families. Although most patients diagnosed with keratoconus report no positive family history, the likelihood that keratoconus will be found in one or more member of the immediate family is 3.4%, which is 15 to 70 times higher than the general population rate. In addition, keratoconus has been reported in identical twins and in two or more generations of many families.

The advent of computerized corneal mapping techniques has made earlier detection of sub-clinical, and/or slowly progressive forms of the condition more precise. Therefore, it is suspected that familial prevalence rates will most likely increase. Using corneal topographical findings, in 1990 Rabinowitz, et al, showed that 50% of randomly selected family members of keratoconus patients displayed subtle topographical abnormalities somewhat suspect of keratoconus.

Studies to identify the association of keratoconus with various chromosomes have been performed. Reports on a small number of families with keratoconus show a connection between keratoconus and defects on chromosomes 21, 17, and 13. However, at this time it is unknown exactly what specific parts of these chromosomes are defective or how the defects might cause keratoconus.

Future investigations will most likely conclude that more than one gene is associated with the diverse clinical presentations seen in keratoconus. This is based on the fact that there is considerable variation among individuals with keratoconus and so multiple genes are most likely involved. For example, keratoconus manifests in many forms and degrees of severity:


The Environment and Keratoconus

Although it is generally believed that keratoconus has a genetic component, there are increasing data that suggest the environment might also play a role in the development of the condition.

Cristina Kenney’s research team has discovered that corneas with keratoconus have been exposed to a number of factors that can produce reactive oxygen species (i.e., free radicals). These include ultraviolet light, atopy, mechanical eye rubbing, and poorly fitted contact lenses. They propose that susceptible corneas exhibit an inability to process reactive oxygen species because they lack the necessary protective enzymes (e.g., ALDH3 and superoxide dismutase). The reactive oxygen species result in an accumulation of toxic by-products such as MDA and peroxynitrites that can damage corneal proteins and trigger a cascade of events that disrupt the cornea’s cellular structure and function. This can result in corneal thinning, scarring, and apoptosis. (Figure 6.)


Figure 6. Reactive oxygen species within the keratoconus cornea result in an accumulation of toxic by-products that can trigger cornea thinning, scarring, and apoptosis.


If this theory is valid, it might be prudent for keratoconus patients to minimize the factors that can cause reactive oxygen species to be formed. It might be helpful for patients to do the following:

Although the environmental damage theory is interesting, at this time there is no conclusive evidence to support the fact that changes in diet, environment, or emotional state can influence the eventual course of the disease. This is supported by the fact that keratoconus occurs throughout the world in a wide range of geographic, social, and dietary conditions.