Managing Progression in Keratoconus

This guide reviews comprehensive protocols for managing the progression of keratoconus (KC), incorporating aspects of testing, diagnosis, monitoring, and treatments.

Keratoconus (KC) is an ectatic corneal disorder characterized by progressive corneal thinning and conical protrusion, leading to irregular astigmatism, myopia, and significant visual impairment. Early detection is important for optimal patient outcomes.

Initial diagnosis: signs and symptoms of keratoconus

Progression is often challenging to detect and difficult to define.

Clinicians should be on the lookout for:

• Progressive myopia and irregular astigmatism uncorrectable with spectacles and frequent changes in refractive correction
• Shifting magnitude and/or meridian of refractive or keratometric astigmatism
• Visual blurring (slight to severe) and distortions such as ghosting or halos
• Suspicious topography
• Anterior segment signs include corneal scarring, Vogt's striae, Fleischer ring, Munson’s sign, and Rizzutti’s sign.

Table 1: Signs and symptoms based on KC severity

Stage	Signs	Symptoms
1 - Subclinical	Suspicious topography or tomography; normal slit-lamp findings; and 20/20 best-corrected visual acuity (BCVA) achievable with spectacle correction	None or slight blurring of vision
2 - Early	“Scissor reflex”: Mild, localized corneal steepening and thinning; increasing keratometric differences between inferior and superior cornea; increases in corneal aberrations (particularly coma-like aberrations); mild changes in refractive error; and reduction of spectacle BCVA	Mild blurring or slightly distorted vision
3 - Moderate	Those of stage 2 (normally of greater severity) plus: significant corneal thinning; Vogt’s striae; Fleischer’s ring; < 20/20 spectacle BCVA, but 20/20 spectacle BCVA with contact lenses; increased refractive changes; increased visibility of corneal nerves; corneal scarring and opacities normally absent	Moderate blurring and distorted vision
4 - Severe	Those of stage 3 (normally of greater severity) plus severe corneal thinning and steepening (>55D); corneal scarring; < 20/30 BCVA with contact lens correction; Rizzuti’s sign; Munson’s sign; corneal opacities; and corneal hydrops	Severe blurring, distorted vision, and monocular polyopia (typically reported as “ghost” images)

Table 1: Modified from Santodomingo-Rubido et al.

Prevalence of progressive Keratoconus

The global prevalence of KC is estimated at 138 per 100,000; however, it is variable and affects up to 5% of the population of the world, especially in Middle Eastern and Asian ethnicities. Men and women are affected, with the most significant incidence occurring in young adulthood (age 20 to 30) and progression occurring up to 40.

The prevalence is higher among first-degree relatives of patients with KC. Incidence rates of KC have been estimated to be between 1.5 and 25 per 100,000 persons/year.

Predictors in adult patients

In adults, KC progression is often more gradual but can still result in significant visual loss. Predictors for progression are similar to those discussed above in pediatric patients. A steeper Kmax and younger age have been cited as the most important predictors for progression.

Corneal steepening on tomography is a critical factor for clinicians to monitor. For example, every 1D of steepening above a baseline Kmax has been associated with a 7% and 3% greater chance of worsening BCVA and thinnest corneal thickness (TCT), respectively.11 Other predictors for progression that have all been shown to affect the time worsening of KC requiring corneal transplant are rapidly declining BCVA, rapid fluctuations of refractive cylinder, and ethnicity.

Hormonal imbalances have been linked to keratoconus, both clinically and experimentally, with both genders affected. Previous studies have categorized the human cornea as an extragonadal tissue, showing modulation of the gonadotropins, specifically luteinizing hormone (LH) and follicle-stimulating hormone (FSH).

Multiple studies have shown data (both in vitro and in vivo) to further delineate the role of hormones/gonadotropins in the KC pathobiology. Several authors have discussed the role of the hypothalamic-pituitary-adrenal-corneal (HPAC) axis playing a major role in KC progression; this may also explain why the disease rapidly worsens between puberty and middle age before stabilizing.

Historical detection of Keratoconus progression

Accurate detection and monitoring of keratoconus progression is challenging yet essential for timely intervention. We will discuss the historical techniques followed by the more current/modern methods widely used in clinical settings today.

Slit lamp examination

Despite the implementation of more advanced technologies, a detailed slit lamp examination is not to be forgotten and can reveal characteristic signs of keratoconus, including:

• Vogt's striae: Vertical (rarely horizontal) fine, whitish parallel stress lines in the deep/posterior stroma of Descemet’s membrane of the cornea caused by the tension of corneal stretching (Figure 1).
• Fleischer rings: A yellow/brown ring encircling the base of the cone caused by the deposition of hemosiderin is best viewed using a cobalt blue light filter.
• Corneal scarring: This results from advanced disease or mechanical trauma, such as eye rubbing, and occurs particularly where the cone is most prominent.
• Munson's sign: When the patient looks downward, a V-shaped protrusion of the lower eyelid is observed, indicative of advanced keratoconus. This is a later sign.
• Rizzuti sign: A cone-shaped illumination is seen on the nasal sclera when the light is directed to the cornea from the temporal side.
• Corneal hydrops: Severe KC can cause corneal edema due to a break in the posterior limiting lamina, allowing aqueous to enter corneal stroma/epithelium.

Figure 1: Slit lamp photograph demonstrating Vogt’s striae.

Figure 2: Slit lamp photograph demonstrating corneal hydrops; the left image shows acute hydrops presentation, while the right image shows the same eye after resolution. Note the significant stromal scarring that remains after resolution of corneal edema.

Figure 3: Anterior segment ocular coherence tomography (OCT) of corneal hydrops; the top image shows severe disease, the middle image is during resolution, and the bottom image shows final scarring after resolution.

Retinoscopy

Retinoscopy can reveal a characteristic “scissoring” reflex, a key sign of irregular astigmatism associated with KC. Although less commonly used now due to advanced imaging techniques, this method can still be valuable in initial clinical assessments. Unfortunately, retinoscopy is unreliable for measuring KC progression, especially when multiple clinicians examine the KC patient.

Keratometry

Manual or automated keratometry measures the curvature of the anterior corneal surface. These values are obtained by topography/tomography devices.

KC progression can be followed by observing:

• Increasing keratometric values: Indicating significant corneal steepening over time.
• Irregular astigmatism: Detected by inconsistent readings in different meridians and/or irregularity in Placido rings/mires.

Corneal pachymetry

Corneal pachymetry measures corneal thickness and should be obtained both optically and ultrasonically. The Belin-Ambrósio Enhanced Ectasia Display (BAD) uses information from the Pentacam (Oculus) and has gained popularity as a comprehensive map showing front and back elevation and corneal thickness in a single view. It has been proven to be valuable in the early diagnosis of KC and can be used to detect KC progression.

The BAD provides:

• Thinnest point measurement: Crucial for identifying focal thinning.
• Anterior and posterior elevation maps: Helping to identify subtle ectatic changes.

Utilizing the Belin-Ambrósio Display

The Belin-Ambrósio Display, as seen in Figure 4, can help detect subtle signs of corneal ectasia that may be nebulous or missed on the standard 4 Maps Refractive (4MR) map. A patient presented for refractive surgery evaluation in November 2019. The 4MR (Panel) map looks overall unremarkable, some questionable changes on the back surface elevation map (Panel A).

However, the BAD map better highlights the posterior changes on the best-fit sphere display. Based on these suspicious features seen on the BAD, the patient was told to return in 6 months for repeat imaging. The patient returned for repeat imaging 1 year later (November 2020). The 4MR map at this time shows unequivocal posterior changes (Panel C), which are again highlighted in the BAD map (Panel D). The patient was advised not to have laser vision correction and was followed as a keratoconus suspect.

Figure 4: The Belin-Ambrósio Display compared to the 4 Maps Refractive map, highlighting subtle changes in the back surface elevation map not shown in the 4MR map.

Refraction changes/Visual acuity

Monitoring changes in refraction and visual acuity is essential for detecting keratoconus progression.

Key points include:

• Visual acuity testing: A significant or subtle drop in BCVA may indicate progression and warrant close observation.
• Manifest refraction: Noting any significant changes in sphere, cylinder, and axis. An increase in irregular astigmatism is a common indicator of KC progression.

Vision distortions

Patients with KC often experience various visual distortions that can signal disease progression.

Monitoring these symptoms involves:

• Patient history: Detailed history to capture and monitor subjective changes in vision, such as increased ghosting, halos, or double vision.
• Functional vision assessments: Evaluating how visual distortions affect daily activities can provide insight into disease impact beyond standard VA tests.
• Objective measurements: Utilizing wavefront aberrometry to quantify higher-order aberrations, which often increase with KC progression.Current detection of keratoconus progression.

Corneal topography

Corneal topography provides a detailed two-dimensional map of anterior corneal curvature and can identify corneal astigmatism and other irregularities. Due to their lower cost and accessibility, topography devices (e.g., Atlas [Carl Zeiss Meditec], Cassini [i-Optics], etc.) tend to be more common.

Corneal tomography

Using Scheimpflug technology, such as with the Pentacam (Oculus), corneal tomography allows for three-dimensional analysis, including posterior corneal surface evaluation. Tomography also gives detailed data about corneal thickness. These two metrics are crucial for monitoring progression in all KC patients and may be used together to gain a full picture.

Recently, Galilei G6 (Ziemer) has gained popularity as a device that combines dual Scheimpflug capabilities with Placido disc-based corneal topography. Other devices include the Orbscan (Bausch and Lomb) and MS-39 (CSO).

Key indicators on topography/tomography include:

• Asymmetric bow-tie pattern: Often seen in early disease and almost universal in patients with KC.
• Increased keratometry values: Indicating steepening of the cornea.
• Thinning patterns: Paracentral, and particularly inferiorly, seen in tomography scans in KC.

Figure 5: Corneal topography showing the left eye of a patient with classic keratoconus changes, including inferior steepening, displacement of the thinnest point of the cornea infero-temporally, increased K-max, anterior elevation, and posterior elevation.

Epithelial thickness mapping

Epithelial thickness mapping (ETM) is an emerging tool that is gaining popularity for early screening in KC. In normal eyes, the corneal epithelium demonstrates a distinct and non-homogenous thickness profile, being thicker inferiorly versus superiorly and thicker nasally versus temporally. This pattern is explained by the mechanics of the eyelid and blinking on the epithelium.

In eyes with KC, the pattern is notably different from normal, with the thinnest area of epithelium overlying the cone as the cornea attempts to mask conical protrusion and maintain a smoother anterior surface. Surrounding the thin area of the cone is a ring of thickened epithelium, referred to as the “epithelial doughnut pattern,” often seen in keratoconic corneas.

ETM can help highlight these changes even before apparent changes in tomography and topography. The thinnest and thickest epithelium regions in KC eyes are outside the range seen in the normal population.

As for monitoring progression using this method, the degree of epithelial compensation is correlated with the severity of keratoconus. Monitoring patients for subtle changes in epithelial thickness, particularly in the area overlying the cone, is a modern method for detecting early progression in KC and is continuing to be studied.

Following up with keratoconus patients

Consistent follow-up is key for effective monitoring and management of KC. A recommended follow-up schedule of visits every 3 to 6 months for patients with progressive KC, or more frequently if rapid changes are noted/intervention is undertaken. As part of follow-up, patient education should be directed at informing patients about the importance of promptly reporting new symptoms and avoiding eye rubbing.

Keeping detailed records of all clinical findings, refraction changes, patient-reported symptoms, and topographic/tomographic measurements will help monitor progression accurately and adjust treatment plans over time. Clinicians should also advise patients to encourage their first-degree family members (e.g., siblings) to be evaluated for KC and other vision changes.

Managing progression and treating keratoconus

KC management and treatment vary based on the progression and severity of the disease. Figure 6 demonstrates a flowchart developed by a panel of ophthalmology experts worldwide. Generally, mild cases are treated with glasses, moderate cases with contact lenses, and severe cases that cannot be managed with scleral contact lenses may require various types of corneal surgery. Progression in all cases is prevented with early intervention, including corneal cross-linking.

Figure 6: Flowchart that details keratoconus management.

Figure 6: Modified from Santodomingo-Rubido et al.

Corneal collagen cross-linking (CXL)

CXL is a primary treatment for halting the keratoconus progression by increasing the cornea's biomechanical stability and rigidity.2 This is done through the formation of covalent bonds between collagen fibrils and corneal stroma and apoptosis of keratocytes in the anterior stroma caused by ultraviolet-A (UVA) radiation activating riboflavin. CXL was introduced in the late 1990s and has since become widely accepted and adopted worldwide.

There are two main techniques in use, epithelium-on and epithelium-off, as well as an accelerated option:

• Epithelium-on (transepithelial) technique: This method preserves the epithelial layer, reducing the risk of infection and speeding up recovery time. However, it may be less effective due to limited riboflavin penetration, though recent studies have shown nearly equivalent efficacy.
  • Alternate techniques to avoid full epithelial removal involve disrupting the epithelium in some way, either mechanically or chemically.
• Epithelium-off (standard) technique (Dresden protocol): This technique involves removing the epithelial layer, including the basement membrane, to allow better penetration of riboflavin into the corneal stroma. It is generally more effective but comes with increased risks of infection, haze, post-operative pain, closer follow-up, and longer recovery.
• Accelerated CXL: This is a faster option that uses higher fluence UVA and reduced exposure time to maintain almost constant total irradiance. Accelerated CXL can be performed using epi-on or epi-off techniques.

Additional CXL modifications and techniques have been reported and continue to be studied, including contact-lens-assisted CXL, corneal lenticule-assisted CXL, slit-lamp CXL, and scleral device-assisted CXL.20

Monitoring patients after CXL and adjuvant treatments:

• Follow-up appointments: Recommended follow-ups are required, per surgeons’ practice patterns, to monitor corneal healing and assess corneal stability. If progression continues, a small number of patients may require repeat CXL.
• Adjuvant treatments: Topical antibiotics, anti-inflammatory medications, and lubricating eye drops are typically used post-treatment to promote healing and prevent infection. Pain management is also an important factor in the immediate post-operative period, particularly with the epi-off technique.

Spectacle or contact lens correction

• Spectacles: These are suitable for the early stages of KC when astigmatism and myopia are milder and vision can still be adequately corrected.
• Soft contact lenses: While more comfortable than rigid contact lens options, soft lenses conform to corneal shape. With the irregularity of the keratoconic cornea, vision is usually not corrected satisfactorily.
  • Some newer options are becoming available to account for this and show some promise in clinical performance. Soft toric contact lenses may also be an option for mild KC cases.
• Rigid gas permeable (RGP) lenses: Provide a smooth refractive surface, improving vision by masking corneal irregularities. This has been historically preferred and remains an economical method for KC patients.
• Scleral lenses: These are larger lenses that vault over the cornea and rest on the sclera, providing stable vision. They are particularly beneficial for advanced KC, where other lenses fail to achieve an acceptable fit. Cost considerations may limit its use for all patients. Additionally, the availability of a skilled contact lens fitter and multiple visits for optimal fitting may limit its applicability in some cases.

Intrastromal corneal ring segments (ICRS)

ICRS involves the implantation of ring segments into the corneal stroma to flatten the cornea and reduce refractive errors, particularly irregular astigmatism. Historically, ICRS involved surgeons placing one or two semi-circular polymethacrylate (PMMA) rings into the corneal stroma to achieve corneal flattening. Several PMMA ring types are available, including INTACS (CorneaGen, USA), Ferrara Rings (Ferrara Ophthalmics), and Kerarings (Mediphakos Inc., Belo Horizonte, Brazil)

ICRS can be particularly useful in KC eyes where contact lenses are no longer effective. It may delay the need for corneal transplantation and facilitate contact lens use. Despite these benefits, in younger patients with more aggressive KC, ICRS implants do not stabilize disease progression. Previously, ICRS fell out of favour among some cornea specialists due to their inability to prevent KC progression.

However, now in the current era of CXL, ICRS combined with CXL (either before, during, or after) can be extremely effective to achieve corneal flattening and KC stability. Regular follow-ups to assess the position and effect of the ICRS segments on corneal curvature/vision are required, and careful monitoring for signs of KC progression post-treatment is recommended.

Figure 7: Slit lamp photograph showing post-operative day 1 appearance of two INTACS ring segments implanted in the corneal stroma.

Biological ICRS

In recent years, biological ICRS using human corneal tissue have gained popularity, primarily corneal allogenic intrastromal ring segments (CAIRS) and corneal tissue addition keratoplasty (CTAK).

Corneal allogenic intrastromal ring segments

CAIRS use surgeon-cut donor cornea tissue for intrastromal implantation. These rings/segments can be of any type/length and can be fresh, processed, unprocessed, or preserved. The safety profile and visual results have shown these implants are a viable alternative treatment for KC.

In addition, personalized customization has emerged and has been shown to achieve differential flattening across the cone, leading to an improvement of at least 2 lines of uncorrected distance visual acuity in many patients.

Compared to synthetic ring segments, CAIRS shows advantages in customizability, efficacy, an absent need for large inventories, and the allogenic nature is less likely to lead to complications such as anterior or posterior stromal necrosis, migration, melt, extrusion, and intrusion.

Corneal tissue addition keratoplasty

Another ICRS procedure known as CTAK uses preserved donor corneal tissue as lamellar inlays shaped by femtosecond laser.31 Specifically, CTAK uses an arc-shaped, sterilized, allogenic stromal tissue that is pupil-sparing and customized to each individual’s KC profile.31

Biocompatibility of the allogenic tissue has been encouraging thus far with clear lenticules, a minimally observed tissue interface, and a lack of inflammation seen after implantation. The resulting visual acuity and topography have so far shown meaningful improvement, and are comparable to traditional penetrating keratoplasty and deep anterior lamellar keratoplasty (DALK).

There are some notable advantages with CTAK compared to traditional keratoplasty procedures, such as no need for sutures, no interface haze over the visual axis, limited rejection of the preserved corneal tissue, and the ability to remove the CTAK tissue if needed. This procedure is suitable in patients with moderate to severe KC.

CAIRS and CTAK are active research and innovation areas that will likely continue to improve the options for KC treatment.

Photorefractive keratectomy (PRK)

PRK can be combined with CXL, either as a staged or combined procedure, for selected patients to improve refractive outcomes. In particular, customized topography/wavefront-guided procedures can significantly improve corneal regularity and visual outcomes in KC when combined with CXL. Post-operative care and follow-up are similar to an epi-off CXL procedure.

Intraocular lens (IOL) options

Phakic IOLs (monofocal and toric) can be used in patients as a lens-based refractive surgery that avoids corneal tissue manipulation that may worsen corneal pathology. Phakic IOLs are a valid refractive approach capable of correcting moderate to high degrees of myopia and astigmatism, especially anisometropia, which is associated with good BCVA. Phakic IOLs can be combined with CXL before or after to combine refractive and preventative goals.

KC patients can develop cataracts, which may make IOL calculations difficult in severe cases with atypical or extreme keratometries. In mild-moderate KC patients, however, visually significant cataracts present an opportunity to perform lens-based surgery to improve patients’ vision.

Monofocal IOLs are a safer and more effective choice in patients with extreme corneal powers, severely irregular corneas, or contact lens dependence (especially rigid or scleral contact lenses) for correction of irregular astigmatism. Toric IOLs may be used in select KC patients with regular astigmatism in the central aspect of the cornea who are not contact lens dependent.

Corneal transplantation

For advanced KC with severe corneal thinning, post-hydrops scarring, contact lens intolerance, or when other treatments fail, corneal transplantation may be indicated. KC has been reported as the reason for 18% of penetrating keratoplasty (PK) procedures and 40% of DALK surgeries.

Several corneal transplantation techniques are described below:

• Penetrating keratoplasty (PK): As the quintessential corneal transplant surgery, full-thickness corneal transplantation involves removing and replacing the entire corneal tissue with a donor cornea. PK is suitable for cases with significant scarring that contact lenses cannot manage otherwise. Approximately 10 to 20% of patients with KC will go on to have PK at some point in the course of their disease.
• DALK: DALK is a modification of PK in which the partial-thickness donor graft allows retention of the patient’s endothelium, reducing the risk of allograft reactions and graft failure. DALK is technically more challenging than PK, given the higher risk of Descemet’s perforation when attempting separation of the overlying stroma.
• Bowman Layer Transplantation: A newer treatment option for advanced KC to flatten the recipient cornea and halt progression of ectasia and delay or potentially eliminate the need for PK/DALK. The procedure is less invasive than the other transplant options and involves the implantation of an isolated specimen of the donor Bowman layer into a stromal pocket of the recipient.
  • This transplant has been shown to yield a long-lasting, optically improved, flattened anterior curvature with a good safety profile and high success rate.

Key takeaways for managing keratoconus

• The management of KC progression starts with early detection, followed by accurate monitoring and tailored treatments based on disease course.
• Diagnosis requires recognizing specific signs and symptoms, with consideration of the unique predictors of progression in both pediatric and adult populations.
• Regular monitoring using visual acuity, refraction, slit lamp exams, and corneal topography and tomography are critical for detecting progression.
• Treatment options vary from conservative measures, such as glasses and contact lenses, to surgical interventions, such as CXL, ICRS, and corneal transplant procedures, depending on the severity of the disease.
• Comprehensive patient follow-up and education are essential to mitigate KC progression and optimize visual outcomes.

Early KC progression detection remains a challenge, but with advancing technology and research, the quality of vision and life for patients living with KC continues to improve.