KERATOCONUS AND ECTASIA

New Protocols for Managing Keratoconus and Corneal Ectasia

Learn how treatment advances are changing your role.

Dr. Thakrar has a specialty contact lens practice in Vaughan, Ontario that focuses primarily on keratoconus and dry eye disease. She is also a consultant for Vistakon and a clinical optometrist at TLC Laser Eye Center. You can reach her at thakrarv@gmail.com.

By Vishakha Thakrar, OD, FAAO

Advancements in treatments for keratoconus and corneal ectasia have transformed the management protocols and long-term prognoses of these conditions. The spectrum of care extends beyond vision correction, as new techniques may delay or halt the progression of keratoconus and other corneal thinning disorders (Vinciguerra et al, 2013). In this article, I discuss corneal collagen cross-linking (CXL), alone and in combination with other therapies, as well as implantation of intrastromal corneal ring segments (ICRSs) and the role of contact lens practitioners in caring for patients receiving these treatments.

Keratoconus Pathogenesis

Keratoconus is a noninflammatory, progressive thinning disorder that is usually bilateral but typically affects one eye more than the other (Krachmer et al, 1984). The frequency of keratoconus ranges from 1 in 320 to 1 in 2,000, with approximately 10 percent to 25 percent of patients progressing to corneal transplantation (Rabinowitz, 1998). Keratoconus typically presents during adolescence and slows when patients reach their 30s. Data strongly support genetic contributions to the disease (Steele et al, 2008; Tuft et al, 2012); however, environmental factors appear to have an important role in its expression (Sugar and Macsai, 2012).

The pathogenesis of keratoconus remains unclear, but it appears to involve alterations in the organization and structure of the collagen fibrils and changes to the extracellular matrix of the corneal stroma (Vinciguerra et al, 2013; Greenstein et al, 2012; Chai et al, 2011). Structural weakness in the cornea results in corneal protrusion, irregular astigmatism, corneal scarring, and loss of best-corrected visual acuity (BCVA).

Eyecare practitioners traditionally prescribe eyeglasses as well as soft and GP contact lenses to manage the visual symptoms of keratoconus. Although these devices may improve vision, they do not stop or slow the progression of the disease. New therapeutic and surgical techniques are having a profound effect on the prognoses for patients who have keratoconus and corneal ectasia.

Corneal Collagen Cross-Linking

CXL is a breakthrough procedure used primarily to treat keratoconus and corneal ectasia. It may offer new hope to patients who have been plagued with corneal thinning disorders. The technique was introduced in the 1990s (Spoerl et al, 1998; Spoerl and Seiler, 1999) and first performed on humans in 2003 (Wollensak et al, 2003; Wollensak et al, 2004). The concept arose from the low frequency of keratoconus in people who have diabetes and the lack of disease progression in patients older than 40 years.

CXL uses riboflavin (vitamin B2) and ultraviolet-A (UV-A) radiation to increase the biomechanical and biochemical stability of the stromal collagen fibers. Riboflavin has a dual purpose: 1) to initiate covalent bonds between collagen fibers when irradiated; and 2) to protect the endothelium and other posterior structures by preventing UV-A from penetrating the anterior 300μm of the corneal stroma (Vinciguerra et al, 2013; Greenstein et al, 2012; Chai et al, 2011; Goldich et al, 2012, and others). Keratocyte apoptosis occurs in the treated area at the time of surgery. Repopulation of the keratocytes begins one month post-treatment and can return to pretreatment levels in six months, resulting in morphological changes to the cornea (Greenstein et al, 2012; Wollensak et al, 2004).

Some studies have demonstrated that CXL is a safe and effective technique for delaying and even halting the progression of keratoconus; however, complications such as stromal melting and corneal haze have been reported (Vinciguerra et al, 2013; Greenstein et al, 2012; Chai et al, 2011; Goldich et al, 2012, and others) and more information is needed.

Researchers have shown that CXL can produce significant flattening of corneal topography as well as improvements in BCVA, uncorrected visual acuity (UCVA), and refractive and aberrometric results (Greenstein et al, 2012; Chai et al, 2011; Goldich et al, 2012; Vinciguerra et al, 2009, and others). Average keratometry values can vary postoperatively with each patient and can continue to flatten over time. In a retrospective case series, Raiskup-Wolf et al (2008) showed maximum keratometry (Kmax) flattening of 2.57D at 3 years. In a prospective, nonrandomized study of 28 eyes, Vinciguerra et al (2009) demonstrated a Kmax decrease of 6.16D over 12 months. In a retrospective case series, Hoyer et al (2009) showed a Kmax decrease of 4.34D at 3 years. Topographical improvements have shown no correlation to improvements in visual acuity.

CXL is currently performed in 450 centers worldwide. In September 2011, the U.S. Food and Drug Administration (FDA) granted orphan drug status to a 0.1% riboflavin ophthalmic solution (VibeX, Avedro) combined with a UV-A irradiation system (KXL, Avedro) to perform CXL to treat keratoconus.

Patient Selection

Candidacy for CXL includes patients between the ages of 10 and 35 years who have progressive keratoconus, corneal thicknesses of at least 400μm, and minimal corneal scarring (Bochner Eye Institute, Toronto, Canada). However, with careful screening, many patients who do not meet these criteria can be treated successfully.

A recent study demonstrated improvements in refractive, topographic, and aberrometric characteristics in patients older than 40 years of age who were treated, but the improvements were more modest than those observed in younger patients (Vinciguerra et al, 2013). These data suggest that even patients who have stable keratoconus may achieve improved vision and corneal flattening after their corneas have stabilized. Whether improved vision is a sufficient reason to cross-link older patients is debatable, particularly if they are seeing well with contact lenses or eyeglasses. Further study is necessary to assess potential complications of treating older patients.

CXL should be considered in patients under the age of 18 years, as keratoconus progresses more rapidly in young people than in any other group. Vinciguerra et al (2012) demonstrated improved BCVA, UCVA, sphere and cylinder, topography, aberrometry, and tomography with no endothelial cell loss in patients 9 years to 18 years old. Further safety and efficacy studies should be performed in children and adolescents; however, this should not deter surgeons from proceeding with CXL in carefully selected patients.

Contraindications to CXL may include dense central corneal scarring, autoimmune disease, severe dry eye, history of herpes keratitis, pregnancy, and very thin corneas (Bochner Eye Institute, Toronto, Canada). Patients who have advanced keratoconus have a higher risk of developing sight-threatening haze (Raiskup et al, 2009). Careful observation post-operatively is necessary.

CXL Procedure

Traditional CXL involves removing the central epithelium to a diameter of 7mm to 9mm and applying riboflavin (0.1%) drops every minute for 30 minutes (Figure 1). The eye is then exposed to UV-A with a wavelength of 370nm and a surface irradiance of 3mW/cm2 for 30 minutes (Figure 2). With this level of radiation, keratocyte death does not extend beyond 300μm. A bandage lens is applied to the cornea for pain management and to facilitate re-epithelialization.

For safety, the surgeon must maintain a minimum corneal thickness of 400μm after epithelium removal, because significant endothelial cell loss can occur when corneas less than 400μm are treated (Hafezi et al, 2009; Wollensak et al, 2003; Gokhale, 2011). If a cornea is thinner than 400μm, hypotonic solution may be used to artificially swell the cornea to 400μm (Hafezi et al, 2009). Generally, the cornea must be at least 320μm to 330μm thick to be artificially swelled for treatment, but this minimum requirement may vary depending on the surgeon’s preference. If the cornea cannot swell to 400μm, the procedure may not be performed. Corneal thickness is measured throughout the procedure to ensure that the minimum thickness is maintained.

Phase 3 studies of the KXL System for Accelerated Cross-linking (Avedro) are currently underway in the United States. The system uses an irradiance of 30mW/cm² for three minutes, thereby maintaining the same energy level as the traditional procedure and enabling surgeons to perform CXL in a significantly shorter time.

Topography-Guided PRK Combined With CXL Topography-guided photorefractive keratectomy (PRK) in combination with CXL was first performed by Kanellopoulos and Binder (2007) with the intention of further visual rehabilitation. The combination procedure has yielded promising results, with improvements in visual acuity and refraction, topography, and aberrometry (Figure 3).

Figure 1. Application of riboflavin (0.1%) eye drops. Courtesy of Raymond Stein, MD, FRCSC.

Maximum suggested ablation depth is 50μm, with treatment of cylinder followed by sphere (Kanellopoulos and Binder, 2007; Alessio et al, 2013; Jankov et al, 2010; Kymionis et al, 2009). Performing both procedures on the same day — PRK followed by CXL — is believed to yield better results compared to performing PRK after the cornea has been cross-linked (Kanellopoulos, 2009).

Post-CXL Care and Potential Side Effects

Patients who have undergone CXL receive fourth-generation fluoroquinolones, topical steroids, and artificial tears postoperatively. There is some debate over administering nonsteroidal anti-inflammatory drugs (NSAIDs) to patients after CXL, owing to a potential risk of complications including corneal melt (Bujak, 2013). Once the cornea has re-epithelialized (approximately five days postoperatively), the bandage contact lens is removed.

Figure 2. Application of UV-A irradiation. Courtesy of Raymond Stein, MD, FRCSC.

Mild-to-moderate corneal haze is a common side effect of CXL, but it has minimal visual consequences in most cases. Patients who have thinner corneas are at a higher risk of sight-threatening haze. Disruption of the ocular surface and damage to the epithelial and sub-basal nerves may affect the arc reflex involved in tear production and cause dry eye. Dry eye that develops after CXL usually resolves, similar to refractive surgery postoperative findings, but it may persist for longer periods. Other potential complications include keratitis, corneal melt, scarring, endothelial cell loss, and reactivation of herpes keratitis (Wollensak et al, 2003; Spoerl et al, 2007; Kymionis et al, 2012; Gokhale, 2011).

Figure 3. Topography-guided PRK combined with CXL, (left) preoperatively; (center) postoperatively; and (right) difference map. Courtesy of Raymond Stein, MD, FRCSC.

Figure 4. Pentacam images of a patient, (left) before CXL; (center) one month after CXL; and (right) 12 months after CXL.

CXL has been performed on humans for approximately 10 years, so we do not have data on the effect of aging on a cross-linked cornea. Further observations will provide a better understanding of the long-term safety and efficacy of the procedure.

Post-CXL Vision Correction

Depending on the severity of keratoconus, post-CXL management options typically include spectacles, soft contact lenses, or, more commonly, corneal and scleral GP lenses. CXL does not eliminate the need for contact lenses in many patients, particularly those who have moderate-to-severe keratoconus. Patients who have mild disease may be able to wear spectacles or soft contact lenses successfully after surgery.

The protocols for post-CXL contact lens fitting vary for new and established lens wearers. Vinciguerra et al (2013) have shown that corneal flattening may occur up to 48 months postoperatively. Initially, corneal thinning and steepening occurs after surgery, followed by relative flattening and thickening of the cornea (Figure 4). Because of these changes and their effects on vision, patients should be informed before the procedure of the strong possibility that they will need to change their current contact lenses.

Established lens wearers usually can return to their habitual lenses two weeks postoperatively, as long as the lens is not compromising the corneal surface. If the fit and vision are acceptable, you may choose to delay refitting until relative corneal stability is observed. In my experience, patients who wear corneal GP lenses may require base curve radius and peripheral curve changes to optimize the fit. Figure 5 shows a piggyback fit after CXL. Scleral lenses can be more forgiving because they vault the cornea, allowing for changes to the corneal shape with little modification to the design (Figure 6). Interestingly, despite the corneal curvature change or lack thereof, optical quality typically improves (Vinciguerra et al, 2013; Vinciguerra et al, 2012; Caporossi et al, 2010; Kanellopoulos and Binder, 2007).

If a patient has never worn contact lenses, I try to delay fitting for two to four months after the procedure to avoid multiple refits because of corneal fluctuations. Nevertheless, corneal flattening will likely continue after four months, and the patient should be informed that refits may be required.

Figure 5. Piggyback contact lens fit after CXL.

Figure 6. Scleral lens fit after CXL.

Figure 7. Corneo-scleral lens fit after ICRS implantation. Courtesy of Stephen P. Byrnes, OD, FAAO.

Intrastromal Corneal Ring Segments

ICRS implantation is a safe method for flattening the cornea while maintaining central clarity in patients who have keratoconus. During this procedure, polymethylmethacrylate segments are implanted into intrastromal channels that are made mechanically or with a femtosecond laser. The advantages of using a femtosecond laser instead of a mechanical spreader include better centration and faster, more precise channel creation (Carrasquillo et al, 2007).

Once implanted, the ICRSs shorten the central arc length and flatten the anterior cornea, leading to forward displacement of the peripheral cornea. This flattening effect can minimize topographic abnormalities and improve BCVA, UCVA, and spherical equivalent. These outcomes are further enhanced when a femtosecond laser is used for channel creation.

ICRS implants have been modified and improved in recent years. Surgeons can now choose the diameter, size, thickness, and position of the implant as well as the number of segments needed to achieve optimal flattening. Traditionally, ICRS implants have been reserved for patients who have mild-to-moderate keratoconus. With new modifications, however, surgeons may be able to treat severe keratoconus.

Among the various types of ICRSs, Intacs (Addition Technology), which is available in the United States, is probably the best known. Implants available outside of the United States include Ferrara (Mediphacos, Belo Horizonte, Brazil); MyoRing (Dioptex, Linz, Austria); and Bisantis (Optikon 2000 spA and Soleko spA, Rome, Italy). Recently, Addition Technology released Intacs SK, which incorporates a smaller optic zone for severe keratoconus.

Potential complications with ICRS implantation include corneal perforation, infection, corneal infiltrates, corneal neovascularization, epithelial breakdown, ring migration and extrusion, and corneal thinning (Health Quality Ontario, 2009; Carrasquillo et al, 2007; Daxer, 2010; Shetty et al, 2008, and others).

Combined CXL and ICRS Implantation Chan et al (2007) found that ICRS implantation combined with CXL improved refractive cylinder and topography compared with ICRS alone. The thought is that the ICRS helps to regularize the cornea by flattening the cone as the cross-linking procedure halts further corneal thinning. Researchers have suggested that, although both CXL and ICRS have a flattening effect on the cornea, for optimal results, CXL should be performed after ICRS implantation, preferably on the same day (Kılıç et al, 2012). This is a relatively new procedure, and further research is required to determine the best protocol and long-term stability.

Contact Lens Fitting Post-ICRS

Traditionally, surgeons have reserved ICRS implantation for lens-intolerant patients who have mild-to-moderate keratoconus and no corneal scarring. Essentially, the goal is to enable patients to wear eyeglasses or to be fit more easily with contact lenses. Clinically, however, lens fitting after ICRS implantation may present more challenges. Corneal GPs are often difficult to fit over the pronounced elevation created by the ICRS implants. In these situations, we need to consider alternatives such as soft and hybrid designs and corneal GP designs specifically made for post-ICRS patients. I have found scleral and corneo-scleral lenses most effective for fitting these postoperative irregularities (Figure 7) because they can vault the elevated area without relying on corneal topography as other lens types do. Nevertheless, be sure to appropriately manage patients’ expectations with respect to postoperative outcomes and methods of visual rehabilitation.

Improved Prognoses

CXL and ICRS implantation have enabled successful treatment of many patients throughout the world. Recent modifications to these procedures have the potential to provide superior vision correction. Further studies are necessary to determine the long-term stability and safety of the combined procedures. Nevertheless, it is an exciting time, not only for practitioners who treat and manage keratoconus, but most importantly for patients who are living with the consequences of corneal thinning diseases. These surgical advancements will likely reduce the need for corneal transplantation and improve the prognoses for affected patients. CLS

The author would like to thank Matthew C. Bujak, MD, PT, FRCSC; Nick Nianaris, MD, FRCSC; Allan Slomovic, MA, MD, FRCSC; and Raymond Stein, MD, FRCSC, for their help with this article.

For references, please visit www.clspectrum.com/references.asp and click on document #209.