KERATOCONUS
A Closer Look at Keratoconus
Participants from the second Collaborative Conference on Keratoconus discuss the latest keratoconus findings.
By Rob Murphy

Scientists, clinicians and researchers from around the nation met in Los Angeles in January 2002 for the second Collaborative Conference on Keratoconus. The Conference was sponsored by the National Keratoconus Foundation and moderated by Anthony B. Nesburn, MD, Medical Director of the NKCF. Participants discussed the disease's causes, diagnosis and therapeutic options.

Attendees included scientists who study the genetics and molecular mechanisms that cause keratoconus, as well as surgeons and contact lens specialists who treat patients with this condition. In roundtable discussions, these experts presented the latest keratoconus research developments.

Causes of Keratoconus

The symposium began with a discussion about the risk factors and causes of keratoconus. Corneal specialist Steven Wilson, MD, of the University of Washington School of Medicine, suggested that keratoconus somehow disrupts the normal process of keratocyte apoptosis, the programmed death of corneal cells that occurs following injury to the cornea.

Eye rubbing, contact lens wear or ocular allergies can stimulate keratocyte apoptosis, which is the earliest observable stromal response to an epithelial injury. All three factors are associated with keratoconus. And while keratocyte apoptosis is virtually never detectable in the absence of epithelial injury, a high percentage of keratoconus patients show evidence of such cell death, typically in the anterior stroma, according to Dr. Wilson. This cell death is often associated with breaks in Bowman's membrane. Chronic keratocyte apoptosis can cause stromal thinning associated with keratoconus. Says Dr. Wilson, "This could account for the increased stromal enzyme activity and other components identified in keratoconus corneas in previous studies."

"Over the past eight years, we have demonstrated that keratocyte apoptosis is likely mediated by cytokines released from the epithelium in response to injury," he says. "We can think of apoptosis as a 'gentle, involutional' sort of cell death." That is, the cell dies without releasing enzymes that could damage surrounding tissue.

Dr. Wilson reported another study in which researchers used an electron microscope to analyze five keratoconic and five normal corneas. "We found cells within the stroma of keratoconus corneas that had classic findings of chromatin condensation and budding of membrane-bound structures from the surface of the cell, which is how apoptotic bodies form," Dr. Wilson says. "We found a high rate of keratocyte apoptosis associated with keratoconus. This was prominent at sites of keratoconus-specific histopathology, especially in subepithelial areas near breaks in Bowman's layer."

A genetic component may play a role in some, but not all, keratoconus patients, according to Dr. Wilson. Some patients may have a genetic susceptibility to chronic keratocyte apoptosis. It's likely that most patients have some combination of genetic and environmental factors contributing to their disease.

Dr. Wilson calls his theory a "unifying hypothesis" because it ties in risk factors thought to be associated with keratoconus, like chronic eye rubbing and poorly fit contact lenses.

If his hypothesis is true, why did keratocyte apoptosis not occur in every keratoconus cornea that he studied? Dr. Wilson suggests that there could be sampling error. Perhaps some of the keratoconus corneas were transplanted when the disease was relatively inactive. Or the analyzed section may not have come from the area where keratocyte apoptosis was most pronounced. Genetic factors may play a role. "It is possible that not all corneas with the keratoconus phenotype result from the same genetic defect that leads to keratocyte apoptosis," Dr. Wilson says.

Even if Dr. Wilson's hypothesis that keratocyte apoptosis contributes to keratoconus is valid, it doesn't necessarily identify the initial triggering event which kicks off the cascade of mechanisms that results in disease onset. "I am not convinced that any one of us has found step number one," says M. Cristina Kenney, MD, PhD, of the Cedars-Sinai Medical Center in Los Angeles. "It may be genetic, but there are multiple events going on, involving different biochemical pathways. Something must initiate it. It's a control factor, a transcription factor, an inhibitor, a promoter or something like that."

Dr. Kenney had previously combined the current published findings into a unifying "cascade" hypothesis of keratoconus. She, along with Anthony Bron, MD, of the Nuffield Laboratory at the University of Oxford, and Beatrice Yue, PhD, of the University of Illinois at Chicago, believes keratoconic corneas have increased enzyme activities, decreased levels of enzyme inhibitors and increased toxic by-products that produce a "cascade" of events, causing keratoconus to progress.

Whatever that initiating trigger may be, the pathogenesis surely involves some manner of epithelial-stromal interaction, according to Dr. Kenney. "My theory is that there's probably something in the stroma that feeds up to the epithelium, then feeds back down to the stroma, causing apoptosis and cytotoxic byproducts to occur," Dr. Kenney says.

Dr. Bron advanced an alternative hypothesis. He believes that keratoconus might result from an unraveling of the stromal lamellae. This purported unraveling may work in combination with keratocyte apoptosis to produce corneal ectasia.

"Our group suggests that keratoconus could occur without loss of tissue mass through redistribution of the stroma's structural components, so that the stroma is, as it were, spread thin," Dr. Bron says. "This would require that collagen fibrils and lamellae slide over each other, which would unlock lamellae from the limbus and from their insertion into Bowman's layer of the stroma. This could result from enzymatic action or a failure to set up the normal cross-links between stromal collagen and other matrix components, even as early as postnatal life."

This does not rule out loss of tissue mass occurring at the same time, according to Dr. Bron. It is difficult to obtain evidence for loss of tissue mass, however, and studies which attempted to do so yielded equivocal findings. "A critical question is how much of the ectasia in keratoconus is due to loss of tissue and how much to a redistribution of tissue over a wider area," Dr. Bron says. "This can certainly be a fruitful topic for future research."

A vexing aspect of keratoconus is that multiple factors probably contribute to its onset and progression. While researchers have identified many of these environmental and genetic components, they have yet to explain their origin and how they fit together. "We know that there's some apoptosis, but we really don't know what causes it," Dr. Kenney says. "We know there's increased enzyme activity and decreased inhibitors, but we don't know why. It's very likely that there is not just one key, but multiple keys ­ that there will be a number of either gene defects or changes, and in 10 years we'll be classifying different kinds of keratoconus."

Intacs: A Promising New Surgery

Intacs (Addition Technology) are tiny plastic rings implanted into the cornea which typically correct myopia. Recently surgeons, including Yaron S. Rabinowitz, MD, of the Cedars-Sinai Medical Center, have applied this technology to treating keratoconus.

Intacs have yet to obtain FDA approval for treating keratoconus, but French surgeon Joseph Colin, MD, last year reported encouraging results from 10 patients who had at least one year of follow-up. The procedure for implanting Intacs for keratoconus differs from the myopia procedure regarding the location of insertion. Surgeons make the incision temporally, then implant the inserts both superiorly and inferiorly. "It makes the cone a bit smaller and flatter," Dr. Rabinowitz says. Dr. Colin's study showed that the Intacs procedure not only diminished and flattened the cone, it also increased both the uncorrected and best corrected visual acuity.

After reading these results, Dr. Rabinowitz performed the Intacs procedure on select patients who wanted corneal transplants. "I've found that it definitely flattens the cornea, much more than in a normal patient because for some reason the keratoconic eye is a lot more plastic," Dr. Rabinowitz says. "Whereas you achieve only a 3.00D effect in normal patients, with keratoconus you may achieve a 6.00D or 7.00D effect. When you flatten the cornea that much, contact lens fitting is much easier. The procedure also decreases the size of the cone."

Intacs also decrease corneal surface irregularity. "Surface regularity plays a large role in potential vision," Dr. Rabinowitz says. "By decreasing the regular [and irregular] astigmatism, the ultimate quality of vision when patients are fit with contact lenses tends to improve. In the six or seven patients on whom I've performed the procedure, best-corrected contact lens acuity was better after Intacs."

Dr. Rabinowitz cautions that we have little follow-up data to determine how patients do long-term. Time will tell if Intacs live up to its early expectation. "It looks to me like it is a very promising treatment for patients who are contact lens-intolerant and may want to avoid a transplant, and those who want better acuity with their contact lenses," he says.

Laser Surgery for Keratoconus

Clinicians typically rule out LASIK for keratoconus patients because there is heightened risk of scarring and excessive thinning which could cause corneal perforation. However, Dr. Rabinowitz has performed a laser procedure he calls PRK-SM (photorefractive keratectomy with a smoothing technique) for patients over 40 who have early keratoconus and cannot tolerate contact lenses. Keratoconus may remain fairly stable past age 40. Currently, the two options for these patients are corneal transplant or eyeglasses. Dr. Rabinowitz has achieved visual outcomes using PRK-SM that are similar to what patients can obtain through eyeglasses. If it fails, patients can then opt for a corneal transplant.

Dr. Rabinowitz reported a prospective study in which he performed PRK-SM in 13 eyes of contact lens intolerant patients diagnosed with early keratoconus or suspected keratoconus who wanted corneal transplants. The smoothing part of the procedure addresses the irregular astigmatism. The initial refractive treatment is done with the excimer laser, and a second treatment with a broad-beam PTK (phototherapeutic keratectomy) smoothes out the cornea.

In the six keratoconus eyes that received this treatment, uncorrected visual acuity over nine to 36 months of follow-up varied from 20/25 to 20/50, according to Dr. Rabinowitz. (The 20/50 patient desired monovision correction for presbyopia, so it was intentional.) None of the patients needed a corneal transplant. In the seven eyes with suspected keratoconus, the results varied from 20/15 to 20/20 uncorrected over 12 to 54 months of follow-up. After four years of follow-up, there has been no scarring or progression of the disease.

Corneal Transplants

When the discussion turned to corneal transplants, participants discussed the critical question of when to operate. "We let the patient tell us when they're ready for surgery, within limits," Indianapolis surgeon Francis Price, MD, says. "When they begin to have difficulty functioning with contact lenses, difficulty seeing, then we go ahead and do the surgery."

That varies from one person to the next. "Some people are happy with 20/60 vision," Dr. Price says. "I usually encourage them to consider their difficulties driving. When they have too much photophobia, too many problems with irritation or vision, then we do surgery." Some of these surgical cases may exhibit fairly mild cones, with no scarring and very little change on slit lamp examination.

Las Vegas surgeon Kurt Buzard, MD, is inclined to offer surgery as an option early in the course of the disease. "We feel that if best corrected vision without a contact lens falls below 20/40, we should do a transplant," Dr. Buzard says. "We consider keratoconus a surgical disease, not a medical disease."

Dr. Price advocates surgery before the cones become too big, particularly when using lamellar grafts. "We saw with epikeratophakia, and now with the lamellar grafts, that you can do a deep lamellar graft, essentially down to Descemet's membrane, if you perform the surgery before the cones become too big," Dr. Price says. "Descemet's and the endothelium are the innermost layers of the cornea, which are essentially the only cells to worry about for rejection. With newer techniques, we can dissect down to Descemet's membrane, remove the diseased part of the cornea and essentially wipe the endothelial cells from a donor cornea, which you never do in a standard graft because it keeps the cornea clear."

Removing the endothelial cells eliminates most of the antigenic load from the donor cornea. This allows patients to taper off topical steroids quickly. There is little risk of graft rejection, and the eye is stronger in resisting injury. "With a standard transplant, a hard blow to eye, even 20 years after the surgery, can rupture it pretty easily," Dr. Price says. "This should provide a much stronger eye."

The goal is to perform the surgery before a cone gets so big that a lamellar graft is not an option. "If the cone is too big when you perform a lamellar graft, it can be pushed down when you put the graft in, which could wrinkle the remaining tissue in Descemet's and the stroma," Dr. Price says. "Too much of that wrinkling will prevent a lamellar graft from working visually." In advanced cases that involve a large and bulging cone, Dr. Price performs a standard full-thickness penetrating transplant to avoid wrinkling when the new cornea is placed on the eye.

Whichever approach a surgeon uses, ample evidence indicates that corneal graft surgery can permanently improve a keratoconus patient's quality of life. "I have performed corneal transplants on many keratoconus patients age 18 to 21 who return to their normal lives," says Dr. Buzard. "I see them once a year, and don't believe they have the disease anymore. I think that's the goal. If you solve the problem for them, then they feel like they're normal."

Contact Lens Fitting

Charles Edmonds, OD, of Tucson, AZ, believes that new technologies such as wavefront aberrometry and specular microscopy will yield insights into the pathogenesis of keratoconus and help clinicians fit these patients with contact lenses.

Wavefront aberrometry entails passing a light into the eye and measuring the aberration of the light as it returns through the ocular media. Specular microscopy analyzes the endothelial layer. "Wavefront will allow practitioners to identify and correct higher-order aberrations often seen with keratoconus, and specular microscopy will allow us to monitor endothelial cell changes and make changes in contact lens design and material to reduce cell density loss," Dr. Edmonds says.

Dr. Edmonds advocates fitting keratoconus patients with rigid lenses that feature aspheric peripheral curves, which spread the bearing of the contact lens over a large area of peripheral cornea and minimize trauma to the fragile corneal apex. "When we fit keratoconics, we look at the cone apex as the fragile part of the cornea, and it's pretty small," Dr. Edmonds says. "So we try to spare the fragile apex all the trauma and mechanical stress. There's a multitude of available aspheric rigid lenses that do that."

New York optometrist Demetra Hamakiotes, fits some keratoconus patients with small gas permeable (GP) lenses. "There is no way on a steep cornea that a large lens with one curve will result in an acceptable fit," she says. "You will not have acceptable tear exchange, or you will press on the apex more than you'd like. I think the smaller GP lenses allow us to fit the shape of the eye more precisely."

Dr. Hamakiotes cited the Softperm lens (CIBA Vision), which has a rigid optic zone and a soft periphery, as an example of a larger lens design that would be more useful for keratoconus if clinicians could control the optic zone and peripheral curves. "I'd love to be able to specify dimensions for the center and the periphery," Dr. Hamakiotes says. "It's just not there yet. I think the healthiest option is a GP lens in which I can control the parameters."

Many participants advocated ultraviolet (UV) protection for keratoconus patients who wear contact lenses. Wide-brimmed hats and wrap-around sunglasses can provide protection. You could also order GP lenses with a UV blocker. "Since UV can only do harm, I believe every contact lens should have a UV blocker," says Jan P. Bergmanson, OD, PhD, of the University of Houston College of Optometry. "There is no reason why GP lenses for keratoconus patients should not be ordered with a UV blocker."

CLEK Study Update

Since 1995, Karla Zadnik, OD, PhD, and colleagues at The Ohio State University College of Optometry, have tracked 1,209 keratoconus patients via annual exams in the Collaborative Longitudinal Evaluation of Keratoconus (CLEK) study. Funded by the National Eye Institute, the CLEK study is scheduled to continue through 2004. Dr. Zadnik reported some interim findings at the Los Angeles symposium.

She noted that 75 percent of the 1,209 CLEK patients wear GP contact lenses, of which 88 percent fit the cornea flat. The degree to which they are fit flat increases with the severity of the disease.

Dr. Zadnik and her colleagues noted an association between corneal scarring and contact lens wear, even when controlling for disease severity. They also found markedly more scarring in the group fit flat compared to those fit steep. Interestingly, her group has not found increased incidence of connective tissue disease or other systemic conditions thought to be more prevalent in keratoconus patients.

Dr. Zadnik also addressed the issue of ocular pain. "Keratoconus patients' eyes hurt," Dr. Zadnik says. "These patients report ocular pain whether or not they wear contact lenses." She and her colleagues at Ohio State now treat some keratoconus patients on a trial basis with topical nonsteroidal anti-inflammatories (NSAIDs) to relieve pain. "Patients like it," Dr. Zadnik says. "They say it helps them feel better." Pain relief through NSAID treatment may diminish the extent to which keratoconus patients feel compelled to rub their eyes.

The National Keratoconus Foundation sponsored the Second Collaborative Conference on Keratoconus to enable the free exchange of information among experts working to find the cause and best treatments for that condition.

Rob Murphy is a freelance writer based in St. Louis.