Published in Cornea

Emerging Diagnostics and Therapies for Keratoconus: What Ophthalmology Residents Should Know

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28 min read

The last few decades have seen many exciting advances in the diagnosis and treatment of keratoconus, allowing doctors to help preserve and enhance vision for these patients in ways we never could before!

Emerging Diagnostics and Therapies for Keratoconus: What Ophthalmology Residents Should Know
Keratoconus is a non-inflammatory, progressive corneal ectasia, characterized by bilateral asymmetric degeneration, leading to paracentral thinning and protrusion.1,2 Non-surgical treatment of the reduced vision often seen in keratoconus includes spectacle correction and contact lenses (rigid gas-permeable (RGP), scleral lenses). Surgical treatment modalities that do not require corneal transplantation include photorefractive keratectomy (PRK), intracorneal ring segments and intraocular lens placement.2 These surgical techniques can help correct refractive error, but are not designed to halt disease progression.2 Additionally, although these treatment modalities may correct vision for a period of time, at least 20% of keratoconus patients may still progress to the point of requiring corneal transplant (penetrating keratoplasty (PKP) or deep anterior lamellar keratoplasty (DALK)).2
Recently, there have been many exciting advances in technology surrounding diagnosis and treatment of keratoconus, allowing eye care providers to help preserve and enhance vision for these patients in ways we never could before. This article reviews novel corneal imaging techniques and their role in providing earlier diagnosis and detection of keratoconus. I’ll also elaborate on corneal crosslinking (CXL) as a method to halt keratoconus progression, as well as methods to enhance and improve vision for these patients, from specialty contact lenses to laser vision correction, to intraocular surgery.

Enhanced diagnostics

Prior to availability of advanced imaging modalities for keratoconus (e.g. tomography, topography), most clinicians were dependent upon exam findings such as unstable refractive changes (i.e. increasing myopia and astigmatism), and worsening symptoms (e.g. blurred vision, glare, streaking of images). Corneal pachymetry can provide information about corneal thinning over time, but may miss early cases (“forme fruste”) of keratoconus.3-5 Similarly, slit lamp examination may not show signs of early keratoconus (e.g. Vogt Striae, Munson sign, etc). Manual keratometry can demonstrate abnormal corneal contour (blurred/distorted mires, high astigmatic values); meanwhile, automated keratometry provides information regarding astigmatic values that may be too high for measurement with manual methods.6,7 Computerized imaging—tomography and topography—can map out abnormal corneal shape, change in anterior and posterior astigmatism, and even permit diagnosis of forme fruste keratoconus.8-10 As such, new diagnostic scales (e.g. Belin-Ambrósio enhanced ectasia display) have been developed to help track progression, and document risk factors for visual loss.8-13
Enhancement in imaging diagnostics has brought about research into corneal epithelial mapping of keratoconus patients. It has been shown that epithelial distribution in keratoconus eyes follows a specific pattern, and therefore screening for these patterns in keratoconus patients may help pick up early cases and serve as effective adjuncts to examination of potential refractive patients.14 Although use of epithelial mapping is not as widespread as other tomography/topography methods, as it becomes better understood, its use will likely increase amongst corneal and refractive specialists.14,15

After diagnostics—halting progression and corneal cross-linking

Corneal collagen cross-linking (CXL) for keratoconus has been shown to improve the biomechanics of the cornea.1 It has been demonstrated that in keratoconus, the collagen is disorganized, leading to irregular astigmatism, high myopia, and alteration of refractive function.1-2,16-19 Wollensak et al. demonstrated that application of riboflavin eye drops to eyes with keratoconus, followed by exposure to UVA light at a specific wavelength (370nm, 3mW/cm2) resulted in the halting of keratoconus progression in all subjects studied.2 In addition, 70% of patients had regression, with reduction of the maximal keratometric (K) reading by 2.01 diopters (D) and refractive error by 1.14D.2 In Wollensak’s and others’ CXL studies, corneal and lens clarity, intraocular pressure, and endothelial cell counts remained unchanged after cross-linking, with visual improvement in 65% of patients.1-3,16-19

Epithelium-off cross-linking

First described by Dresden in 1997, epithelium-off (“epi-off”) cross-linking is considered standard of care and is the only FDA-approved method of CXL in the United States.1,2 It involves manual debridement of the corneal epithelium (usually the central 8mm zone), followed by application of 0.146% riboflavin eye drops for at least 30 minutes, and finally application of UVA light (365nm wavelength) for an additional 30 minutes.1,2 A bandage contact lens (BCL) is usually placed at the end of the procedure and the patient is given antibiotic and anti-inflammatory eye drops for at least 1-4 weeks. The BCL is removed once the central epithelial defect has resolved. This treatment technique has demonstrated improvement in maximum corneal curvature as well as best-corrected visual acuity (BCVA).20

Epithelium-on CXL

Epithelium-on (“epi-on”) has evolved as an alternative modality (although not yet FDA approved) for CXL. This technique does not involve epithelial debridement, in an effort to reduce risk associated with creation of an epithelial defect (e.g. corneal ulceration, keratitis and pain, among others).21-25 While this technique is favorable for the aforementioned reasons, it does have a higher failure rate and therefore higher rate of need for retreatment—possibly due to limited riboflavin penetration into the stroma due to corneal tight junctions.21-25 To combat this, alterations in the riboflavin molecule, addition of photo-enhancers, and iontophoresis have been trialed as techniques to help improve success of epi-off CXL.21-25 Recently, Avedro (Waltham, MA), the company that gained US FDA approval for epi-off CXL, has completed enrollment for a US-based epi-on CXL Phase 3 clinical trial. It is important to note that not every patient with keratoconus is a good candidate for CXL— for example, pachymetry less than 400µm and corneal scarring are considered contraindications.20

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What to do after cross-linking?

Following the introduction of CXL internationally in 2003, and the United States FDA approval in 2016, it has gained acceptance worldwide as a method of halting the progression of ectasia in keratoconus, allowing for potential visual improvement and rehabilitation.1-3,16-19 At this time, there are many emerging treatment algorithms for visual enhancement after CXL in keratoconus.

Contact lenses

For many years, rigid gas permeable contact lenses have been used to aid vision in keratoconus patients, as well as patients with other corneal irregularities.26-30 Over time, advances in contact lens (CL) manufacturing has provided more comfortable contact lenses (i.e. scleral, hybrid, and PROSE (Prosthetic Replacement of Ocular Surface Ecosystem) lenses) which has enhanced wear-time as well as visual improvement options for keratoconus patients.26-30 In addition, corneal flattening that occurs post-CXL may permit soft CL wear with excellent comfort and visual results.26-30

Surface ablation (PRK)

Given the irregular contour of the cornea, as well as focal thinning that may persist after cross-linking, conventional excimer laser ablations are usually not indicated. However, to date, multiple studies have demonstrated the efficacy of topography-guided surface ablation/photorefractive keratectomy (PRK) in keratoconus patients who have undergone cross-linking.31-35
Topography-guided custom PRK is a technique using an excimer laser to treat corneas with variable topographic indices (i.e. keratoconus).34-41 Conventional and wavefront-guided laser therapies used for ‘routine’ PRK and LASIK work by reducing the corneal tissue to a lower level, thus removing a larger amount of tissue in order to create a more spherical cornea, based on the flattest part of the cornea.34-44 This can be challenging, (or impossible) in eyes with high refractive error or significant corneal irregularity.34,40,41 Thus, in cases where it is important to correct irregularity without large tissue reserves available (i.e. keratoconus), wavefront laser treatment is not an optimal option—or not an option at all.33-41
Topography-guided ablation offers a unique advantage by removing significantly less tissue than wavefront-guided ablation, frequently saving one-third more tissue.34-41 Utilizing this technique broadens the spectrum of treatable patients, even those with significant surface irregularities.31-43
There have been multiple publications on technique as well as sequence of PRK surrounding CXL for keratoconus patients. The Athens protocol, as described by Dr. Kanellopoulos, is a successful immediate-sequence treatment of CXL and nomogram-adjusted PRK.18,19 In addition, the largest US-based study by our team has demonstrated safe and efficacious techniques of CXL followed by topography-guided PRK once keratometric and refractive stability had been achieved (at least 3 months post-CXL).37 Topography-guided PRK following CXL can provide substantial visual and topographic improvement—in some studies improving vision to 20/40 or better in more than 80% of cases.37
Recently, Dr. Mark Lobanoff has published on a sophisticated algorithmic software (Phorcides) for programming topography-guided laser treatments, which may be extrapolated for keratoconus eyes post-CXL in the near future.44

Anterior segment surgery

Intracorneal ring segments: alone and combined with other procedures

Intracorneal ring segments are polymethyl methacrylate (PMMA) segments originally designed to be surgically inserted into the deep corneal stroma for refractive correction of mild myopia (-1.00 to -3.00D).45 In the early 2000s, use of intracorneal ring segments were expanded to help flatten severe degrees of keratometric astigmatism. Their use has had great degrees of visual and astigmatic success, as well as demonstrated improvement in contact-lens tolerance.45
INTACS (Addition Technology, Inc. Lombard IL) are intracorneal ring segments approved for use in the US. Most published studies suggest that the best indications for INTACS are patients with mild-moderate keratoconus with a clear optical zone and contact lens intolerance.45,46 Guidance regarding safe use of INTACS requires the following:
  • upper limit of the steepest keratometry reading should not exceed 58D
  • no scarring in the visual axis
  • corneal pachymetry at least 450µm thick in the area in which the INTACS are to be placed45,46
Most studies to date show an average of 2-3D of flattening accompanied by 2-3 lines of gain in best-corrected visual acuity.45-48 It is felt that improvement in BCVA is due to the decrease in higher order aberrations (HOA) produced by the INTACS.47-49 Long-term studies of up to 9 years for keratoconus and 6 years for post-LASIK ectasia have demonstrated safety and stability with maintenance of the initial refractive effect, although a small percentage of patients may still progress.47-49 Given this, and the widespread use of CXL to halt progression of keratoconus and ectasia, many surgeons are considering combined use of CXL and INTACS (whether immediate or delayed sequential approach) to help maintain and enhance their patients’ vision.49-51
Additional surgical techniques to help enhance vision in keratoconus patients is through the use of intraocular lenses (IOLs) with INTACS.45-51 The theory for success in this technique is that INTACS can help improve BCVA by reducing higher order aberrations, and an IOL can be used to help address uncorrected myopic refractive error.45-51 In patients with clear crystalline lenses, phakic IOLs may be used (e.g. Visian ICL, STAAR Surgical, Monrovia CA; Verisyse Phakic IOL, Abbott Medical Optics, Santa Ana CA), whereas those patients with cataractous lenses may undergo cataract surgery with intraocular lens placement. Use of toric (astigmatism-correcting) IOLs may be successful in these circumstances.51-55

Cataract surgery

In patients where keratoconus has stabilized (naturally or via CXL), and who have visually significant cataracts, and lack of corneal scarring, cataract surgery may be performed to help provide visual improvement. Options for IOLs used here include traditional monofocal IOLs, as well as toric IOLs to help correct astigmatism.56,57 Multifocal or presbyopia-correcting IOLs are generally not recommended in keratoconus eyes as the irregular corneal shape and increased HOA can induce disturbing and even disabling visual aberrations. Following cataract surgery with monofocal IOL, vision can be further rehabilitated with glasses and/or contact lenses and even PRK in certain circumstances.51-57 Use of a toric IOL can significantly improve uncorrected (UCVA) and best corrected visual acuity (BCVA) in patients with mild-moderate and stable keratoconus.56,57

Corneal transplantation

Corneal transplantation, whether penetrating keratoplasty (PKP) or deep anterior lamellar keratoplasty (DALK) still plays a role in the treatment of advanced cases of keratoconus not amenable to crosslinking, glasses, contact lenses or other procedures.58-62 These patients usually have severely thinned corneas and/or corneal scarring preventing significant visual improvement with other methods. Corneal transplantation is generally associated with good visual results and excellent graft outcome in these patients.58-62 Following corneal transplantation, visual rehabilitation options include glasses, contact lenses, and even surface ablation in some cases.


Our diagnostic and treatment options for keratoconus have experienced a massive evolution over time—we are now able to prevent the need for corneal transplantation in some patients due to earlier detection and treatment. Combination of early diagnostics and a variety of successful management strategies allows for better and more advanced treatment of our keratoconus patients, as well as the ability to preserve and enhance their vision. As more research is done, and more patients are being treated, we are surely on our way to ‘reshaping’ keratoconus.


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Alanna Nattis, DO, FAAO
About Alanna Nattis, DO, FAAO

Dr. Alanna Nattis is a cornea, cataract and refractive surgeon, as well as the Director of Clinical Research at SightMD. She is an Ophthalmology Editor for Eyes On Eyecare, and serves as an associate professor in ophthalmology and surgery at NYIT-College of Osteopathic Medicine. She completed a prestigious Ophthalmology residency at New York Medical College and gained vast experience with ophthalmic pathology in her training at both Westchester County Medical Center and Metropolitan Hospital Center in Manhattan.

Following her residency, she was chosen to be a cornea/refractive surgical fellow by one of the most sought after sub-specialty ophthalmic fellowships in the country, training with world-renowned eye surgeons Dr. Henry Perry and Dr. Eric Donnenfeld. During residency and fellowship, Dr. Nattis published over 15 articles in peer-reviewed journals, wrote 2 book chapters in ophthalmic textbooks, and has co-authored a landmark Ophthalmology textbook describing every type of eye surgical procedure performed, designed to help guide and teach surgical techniques to Ophthalmology residents and fellows. Additionally, she has been chosen to present over 20 research papers and posters at several national Ophthalmology conferences. In addition to her academic accomplishments, she is an expert in femtosecond laser cataract surgery, corneal refractive surgery including LASIK, PRK, laser resurfacing of the cornea, corneal crosslinking for keratoconus, corneal transplantation, and diagnosing and treating unusual corneal pathology. Dr. Nattis believes that communication and the physician-patient relationship are key when treating patients.

Alanna Nattis, DO, FAAO
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