Keratoconus care benefits from new diagnosis, treatment strategies

The origin of keratoconus is still hotly debated. Genetic and environmental factors have been widely investigated, as has an inflammatory component.

Some studies have suggested that keratoconus has great clinical variability and may be linked to multiple chromosomal regions, consistent with polygenic mode of inheritance. Candidate genes, such as VSX1, DOCK9 and TGFB1, were identified as potentially involved in the pathogenesis of the disease, but no validation has been achieved in large numbers.

“This suggests that there is a large genetic heterogeneity in keratoconus,” Damien Gatinel, MD, PhD, said in an interview with Primary Care Optometry News sister publication, Ocular Surgery News. “I personally do not believe that one specific gene mutation will ever be discovered. Familial forms of the disease only occur in less than 20% of cases, and common environmental factors may be better incriminated to account for familial penetrance. In addition, some studies have also reported discrepancies in twins.”

Gatinel focuses his practice and research at the Rothschild Foundation and Institut Laser Vision Noemi de Rothschild, Paris, on cataract and refractive surgery and the management of keratoconus.

Jeffrey Sonsino, OD, FAAO, who practices at Optique Eyecare in Nashville, told PCON that a number of researchers are mapping the genomes of patients with known genetic component diseases.

“If I had to guess, I’d say that within 10 years, as the cost of high throughput genetic analysis in ocular genetics research comes down, we will have a better handle on the genetic component of keratoconus,” he said.

Keratoconus may recur in families, but shared environmental factors and heritable traits, such as orbital, eyeball and corneal morphology, are likely to play a greater role than gene mutation, according to David Touboul, MD, PhD, a professor of ophthalmology at the University of Bordeaux in France.

“Corneal topography shows that there are genetically inherited patterns,” Touboul told OSN. “Corneal shape, orbital volume, eyelid positions and muscle insertion, which are part of face morphology, are passed on across generations. All of these components affect the biomechanics of the eye, which is correlated with the stress and strain around the cornea. Muscle tension, the position of the eyeball in the orbit and the stress of eye movements may play a role in what we call the genetics of keratoconus.”

Influence of allergies

Allergies, atopy and myopia, which have been found in several studies to be correlated with keratoconus, have both a genetic and an environmental component, Touboul said.

“The influence of ocular and systemic allergies and atopy is a classic ‘chicken and egg’ argument in keratoconus,” Karla Zadnik, OD, PhD, FAAO, dean of The Ohio State University College of Optometry and chair of the Collaborative Longitudinal Evaluation of Keratoconus (CLEK) Study, said in an interview with PCON.

Eyes may itch from systemic allergies, and when the patient rubs his or her eyes, the trauma from the rubbing may result in keratoconus, she said. “Or, does the patient with keratoconus have a predetermined susceptibility to allergy, so their eyes itch, and the rubbing has no direct effect on the development of keratoconus? There are case reports of atypical, markedly asymmetric keratoconus in one eye that can be correlated with ocular trauma, but those cases are not the norm in terms of etiology.”

Researcher declares war on eye rubbing

According to Gatinel, a spurious variable explains the correlation of allergy and keratoconus, and this variable is excessive eye rubbing.

“The role of eye rubbing in the pathogenesis of the disease has been underestimated. I believe that it is, in fact, the most important and indispensable ingredient in the keratoconus recipe, the root cause of keratoconus,” Gatinel told OSN.

Gatinel’s recent prospective work conducted within the Rothschild Foundation led to the discovery that, in keratoconus, collagen is not actually lost but simply redistributed within the cornea by slippage between the lamellae and possibly via external forces of rubbing.

“Although we agree that some mechanical instability may be the initiating event of the corneal deformation, colleagues and I have accumulated clinical observational and logical evidence that strongly suggest that keratoconus is not a disease that can appear and progress as the direct result of a putative genetic and proteomics affection, but the consequence of a behavioral and mechanical process cause by excessive eye rubbing,” Gatinel said in a separate interview with PCON.

He has revealed that the corneal dome in keratoconus eyes is not truly ectatic nor protruded, but warped and deformed isometrically, with no tissue distension. “This kind of deformation should not be described as ‘ectatic,’ as there is no distension nor protrusion, nor local ballooning at the level of the cornea,” he told PCON.

He also found that the eye in which keratoconus is more advanced is always the one that is rubbed more often, and that a striking correlation exists with the side on which patients preferentially sleep. Typically, patients with keratoconus tend to sleep in the prone position or on one side, giving rise to prolonged nocturnal ocular compression. This may cause local inflammation via heating and contamination from dust mites in the bed linen, which triggers rubbing to calm the itch of that eye, according to OSN.

Gatinel agrees that educating patients not to rub their eyes might prevent keratoconus in some cases and, at least in the early and moderate forms, arrest disease progression.

“Instead of stiffening the cornea, which may never be stiffened enough to resist vigorous eye rubbing, we must declare war on eye rubbing,” Gatinel said.

Any approach that can address the cause of the eye rubbing should be taken, he continued.

“For us, it includes nonsteroidal anti-inflammatory drugs, antihistamines, local lubricants and, in some cases, eye shields to be worn at bedtime for patients who sleep on their stomach or side,” he said.

Clark Chang, OD, MSA, MSc, FAAO, who specializes in corneal cross-linking (CXL) and specialty contact lenses at Wills Eye Hospital, agrees eye rubbing may play a role in the disease. He said there has been a recent surge of researchers and clinicians emphasizing the environmental causes, as it possible to observe and control them.

Sonsino, is skeptical about this correlation, however.

“It was once believed that yellow fingers cause lung cancer in smokers,” Sonsino said. “Just because a factor is associated with a disease does not make for causality.”

Keratoconus and quality of life

Studies have shown that keratoconus has a heavy impact on quality of life. The CLEK study group concluded that the vision-related quality of life of keratoconus patients a mean age of 29 years was similar to that of much older patients with stage 3 and 4 age-related macular degeneration.

“It was a big surprise at the time to see the profound effect of this disease,” Zadnik told OSN. “Many of the patients in the CLEK study were correctable with spectacles or contact lenses to 20/20 or 20/30, so we were shocked to see that they felt as bad about their vision as much older patients with a potentially blinding disease.”

Data were collected at 16 centers across the U.S., including 1,209 patients who were followed annually for 8 years.

“These data should make doctors more empathetic when patients with keratoconus say they have been missing days at work or that, at the end of the day, they can do nothing but go to bed,” Zadnik said.

In addition to decreased quality of life, “these patients report higher degrees of ocular pain, both with and without contact lenses,” she said. “A profile of a profoundly affected patient emerges.”

The Impact study found that the quality-of-life scores for keratoconus patients in France were even below CLEK outcomes, despite the use of new procedures such as CXL.

“We enrolled keratoconus patients with different stages of the disease, including those who had had procedures like CXL, intracorneal ring segments (ICRSs) or corneal transplantation. A total of 550 keratoconus patients were analyzed in 57 participating centers across France,” Valentine Saunier, MD, MSc, told OSN.

About 80% of patients had visual acuity more than 20/40, but there was a significant gap between visual acuity and subjectively reported quality of life.

“Visual acuity is just a number, which does not reflect the way patients see,” she said. “Other factors must be taken into account, like spherical aberration, coma and trefoil, which are significant in keratoconus and have a heavy impact on quality of vision.”

In Saunier’s opinion, these findings point to the need for a new classification of keratoconus that includes parameters such as optical aberration and the psychological state of patients.

Newer screening technologies

Traditionally, keratoconus is detected in patients after they develop visual symptoms, Chang said. New technologies are being incorporated for earlier detection.

A Scheimpflug camera-based tomographer, which is better than topography, Chang told PCON, can account for the additional contributions of the disease from the posterior cornea.

“[The tomographer] images both the front and back corneal layers. And not only does it measure the curvature data points, but it also registers anterior and posterior elevation profiles and pachymetric distributions,” he explained.

With multimetric technologies, Chang said practitioners can recognize disease earlier, as a more complete patient corneal risk profile is explored.

“It’s becoming a standard of care incorporated in a lot of specialty practices in ophthalmology and optometry across the world, leading to a higher detection rate of early keratoconus,” he said.

Additionally, but not yet commonplace, biomechanical testing is another newer technology with promise as a supplementary tool, Chang added. It is being developed and tested more outside the U.S., in clinical settings, he said.

Biomechanical testing can evaluate multiple points and indicate where the cornea is weaker and where to target the treatment, Chang said. It may also be able to gauge the efficacy of certain treatments, such as CXL.

Management with contact lenses

Pending severity of disease and visual symptoms, the standard management of keratoconus usually involves gas-permeable lens designs, such as corneal GPs, hybrid or scleral contact lenses, Chang said.

“Typically, it’s not so much the design but the GP material that’s important because of its ability to reduce or neutralize the negative visual consequences of higher-order aberrations induced by the anterior corneal irregularities,” he said.

“Hybrid contact lenses with a gas-permeable center and soft skirt offer the possibility of great vision and the comfort of a soft contact lens,” Penny A. Asbell, MD, FACS, MBA, told PCON. “New materials and designs make tight fits less likely and provide an ‘off-the-shelf’ contact lens option for keratoconus patients.”

“Given its composition of a GP lens center surrounded by a soft lens skirt, hybrid lenses offer visual improvement similar to a corneal GP lens while still providing a lens handling experience similar to a regular soft lens,” Chang added. “As such, hybrid lenses can be used to deliver good visual rehabilitation results for keratoconus patients – especially those with mild or moderate form of the disease.”

Chang said he is excited about new lens technologies using computer-assisted design and manufacturing because they have more customization capacities, accommodating a more irregular ocular surface.

“Some of the new scleral lens technologies have utilized this design and manufacturing technology and can better fit patients with irregular corneas and even irregular scleral elevations,” he said.

CXL can stabilize the natural progression of keratoconus, making management with contact lenses more effective, Chang said.

Any time progression is identified, no matter how small, CXL should at least be discussed, he said.

He added, “ICRS can have corneal flattening effects that complement the stabilization results of CXL, both of which may help obtain better contact lens fitting outcomes. While still a work in progress, we have worked on better matching ICRS implantation algorithms with various types of keratoconus corneal shapes.”

Chang recommends ICRS be considered to alter the corneal contour to create a new surface for contact lens fitting.

Customized CXL

Customized cross-linking to treat keratoconus holds promise and might soon become the gold standard, according to Theo G. Seiler Jr., MD.

This new approach is based on the findings of several research groups working on theoretical corneal biomechanics and the concept that focal weakening, rather than uniform weakening of the cornea, occurs in keratoconus. Customized CXL creates an individual profile wherein maximum fluence is focused on the weak area and is progressively tapered toward the peripheral, nonectatic region.

“There are several aspects we still have to define,” Seiler told OSN. “Right now, we create the customized profile according to geometric data obtained from Placido-based topography, rotating Scheimpflug imaging or OCT. In the future, Brillouin spectroscopy should allow us also to detect localized biomechanical properties of the cornea and plan the treatment accordingly with micrometric precision.”

In the first preliminary studies, Seiler and his group found that the weakest point of the cornea is highly correlated to the point of maximum posterior float; based on this point, they have designed an irradiation pattern algorithm. Other groups, such as that of Anders Behndig, MD, in Sweden, centered on the maximum keratometry (Kmax).

“This may also be imprecise because the epithelium is thinner above the cone and thicker in the midperiphery,” Seiler said. “However, centration is similar in many cases with the two methods, and the idea of tapering toward the periphery is the same.”

An important advantage of the customized procedure is that a smaller portion of the epithelium is removed, thus reducing healing time and the risk for infection. In the studies published by Seiler and colleagues, epithelial healing time was 2.6 days in the customized CXL group compared with 3.2 days in the standard CXL group, with a débridement area of 9 mm.

In terms of visual gain, flattening of more than 1 D was achieved after 1 year in 40% of eyes in the standard group and 60% of eyes in the customized group, further increasing up to 3 years after treatment. With a higher Kmax decrease, the advantages of the customized procedure were even more apparent. A flattening of 3 D was achieved in double the number of eyes in the customized group compared with the standard group.

A paradigm shift in ICRS use

ICRS use is also undergoing a paradigm shift, according to Touboul. In the past, segments were used in patients with progressive keratoconus to avoid or postpone corneal transplantation but without targeting an accurate refractive correction.

“Now patients are referred earlier because we can offer CXL, and ICRSs have become a minimally invasive, tissue-sparing option to flatten and regularize the surface and improve visual acuity and refraction by reducing coma aberration. Classically, we wait 2 to 3 months after the procedure, see if there are the conditions for contact lens fitting or enhance the results with transepithelial topo-guided phototherapeutic keratectomy,” Touboul said.

“Although in terms of progression we are currently relying to a large extent on CXL as the answer, CXL does not specifically address vision,” Asbell told OSN. “ICRSs stabilize the cornea and change the shape, making it easier to wear glasses and fit a contact lens, even a soft lens, which is generally easier to wear and more comfortable. It is the least invasive procedure, particularly now that we can make the tunnel with the femtosecond laser. I also like it because it is easily reversible.”

The question today is whether, how and in what sequence ICRSs should be combined with CXL. There are several specialists who perform simultaneous CXL and ICRS implantation and some who perform them sequentially in various orders and time intervals.

“We don’t have comparative data, so we really don’t know what the best option is,” Asbell said. “If there is a risk of progression, I would personally do CXL first and then follow up for at least a couple of months, preferably 6 months, to evaluate whether the stromal ring segments might improve corneal shape and visual function. On the other hand, in cases where you cannot document progression or if there is significant keratoconus and you need to do something a little faster, I think ICRSs are the way to go as the first step.”

Comanaging the condition

Sonsino added that there are many aspects to caring for a patient with keratoconus, including monitoring for disease progression, contact lenses, medical treatment such as CXL and surgical correction such as intracorneal segments, corneal transplantation or the Holcomb C3-R procedure.

“Patients must be placed in the center of care and have an optometrist highly skilled in the management of keratoconus and contact lens evaluation and an ophthalmologist highly skilled in corneal surgeries both working together for an optimal outcome,” Sonsino said.

Practitioners need to set aside significant time for consulting with patients with keratoconus, so their questions can be fully answered, Zadnik said.

“The course of keratoconus is unpredictable. The disease progression waxes and wanes and there are a variety of treatments, with no real cure,” she said. “My best advice is to take the time to truly listen to the patient’s frustrations and to use the literature to answer his or her questions, using terminology the patient understands.” – by Michela Cimberle and Abigail Sutton

• References:
• Gatinel D. IJKECD. 2018; doi:10.1016/j.ophtha.2015.10.035.
• Gordon-Shaag A, et al. BioMed Research International. 2015;doi10.1155/2015/795738.
• Kymes SM, et al. Am J Ophthalmol. 2004;doi:10.1016/j.ajo.2004.04.031.
• Saunier V, et al. J Cataract Refract Surg. 2017;doi:10.1016/j.jcrs.2017.08.024.
• Woodward MA, et al. Ophthalmology. 2015;doi:10.1016/j.ophtha.2015.10.035.

• For more information:
• Penny A. Asbell, MD, FACS, MBA, is a professor and director of the Hamilton Eye Institute, University of Tennessee Health Sciences Center. She can be reached at: pasbell@uthsc.edu.
• Clark Chang, OD, MSA, MSc, FAAO, is an attending physician within the cornea subspecialty at Wills Eye Hospital and can be reached at: cchang@willseye.org.
• Damien Gatinel, MD, PhD, is head of ophthalmology at Rothschild Foundation in Paris and can be reached at: gatinel@gmail.com.
• Valentine Saunier, MD, MSc, practices in the Ophthalmology Department at Bordeaux University Hospital. She can be reached at: saunier@gmail.com.
• Theo G. Seiler Jr., MD, teaches general ophthalmology and is a specialist in corneal and refractive therapy, physiologic optics and lasers in ophthalmology. He can be reached at: theo@seiler.tv.
• Jeffrey Sonsino, OD, FAAO, is a diplomate in the American Academy of Optometry’s Cornea and Contact Lens Section.
• David Touboul, MD, PhD, can be reached at: toubould@gmail.com.
• Karla Zadnik, OD, PhD, FAAO, can be reached at: zadnik.4@osu.edu.

Disclosures: Asbell reports no direct financial interest in keratoconus products. She consults for Alcon, MC2, Shire and Santen. Chang reports he is a consultant for Alden, Allergan and Avedro. Sonsino reports consulting relationships with Contamac, Luneau and Synergeyes. Gatinel, Saunier, Seiler, Touboul and Zadnik report no relevant financial disclosures.