KERATOCONUS PROGRESSION

Although identification of progression is central to the diagnosis and management of keratoconus, the question of how progression should be measured is a matter of debate. As research in this area continues, fuelled in part by the availability of new diagnostic technologies, the consensus of attendees at the Expert Meeting on the Surgical Management of Keratoconus in Amsterdam was that five parameters should be considered.

They include keratometry, the full corneal pachymetric map, posterior corneal elevation and two topometric-derived indices of cornea curvature irregularity generated by the Pentacam (Oculus) – index of surface variance (ISV) and index of height decentration (IHD).

The group also noted that progression should not be diagnosed based on any single parameter, but rather should be supported by multiple variables, and ultimately, a regression model may be developed using a combination of variables that would offer a sensitive and specific tool.

The consensus opinion was derived taking into account the attendees’ expert opinions and evidence presented by Michael Belin MD and A John Kanellopoulos MD.

Dr Belin suggested that posterior surface corneal elevation and the full pachymetric map are the best parameters for determining progression.

“The full pachymetric map is more sensitive than just a single central thickness reading, which can vary significantly with examination. Unlike central pachymetry, CDVA and anterior surface curvature, posterior elevation is affected minimally if at all by surface treatments such as rigid gas permeable contact lens wear that is common among patients being looked at for progression,” said Dr Belin, professor of ophthalmology and vision science, University of Arizona, Tucson.

He also noted that use of anterior surface curvature for documenting progression is confounded by the fact that it changes with the measurement axis, while CDVA can vary day to day and depending on lighting and pupil size.

The use of ISV and IHD was proposed by Dr Kanellopoulos based on research he conducted with George Asimellis PhD, evaluating correlations between multiple parameters and keratoconus severity. After publishing an initial report based on data from 212 eyes with keratoconus [Clin Ophthalmol. 2013;7:1539-48], Drs Kanellopoulos and Asimellis expanded their investigations to a cohort of 1200 keratoconus and suspect eyes.

KeratOconus Stage

They analysed CDVA, keratometry, central pachymetry and seven anterior surface keratometric and topometric indices generated by the Pentacam, including ISV and IHD. When the eyes were categorised using Amsler-Krumeich criteria, only ISV and IHD were predictive of keratoconus diagnosis and stage.

“Our findings should clear the myth that CDVA and corneal thickness are useful to identify progression since we found there was significant overlap in their values between groups,” said Dr Kanellopoulos, medical director, Eye Institute, Athens, Greece, and clinical professor of ophthalmology, NYU Medical School, New York, NY.

"These parameters may further complement the evaluation of the full pachymetric map mentioned already. The Scheimpflug imaging may be biased by imperfections in cornea clarity and epithelial irregularities, resulting in falsely positive findings on the posterior corneal surface and possibly on the pachymetric mapping," he said.

Future directions

Moderating the discussion, Sheraz Daya MD, consultant and medical director, Centre for Sight, London, UK, observed that the purpose of obtaining a consensus on parameters for measuring progression was to provide a current foundation for guiding clinical practice and research. However, the proposed methodology is subject to change as more information and new techniques emerge.

Looking ahead, there was some interest in epithelial thickness. Dr Belin noted this measurement is currently not applicable as a screening tool in clinical practice and that while there is evidence that epithelial irregularity may be a marker of keratoconus, there are no data showing this parameter has utility for detecting progression.

Dr Kanellopoulos observed that new anterior segment OCT technology used by his team in Europe over the last two years may enable studies on epithelial thickness as it facilitates the mapping compared to very high frequency ultrasound biomicroscopy. In routine epithelial mapping of all cones in his practice, his research group was able to identify and report on the normal epithelial distribution, dry eye and keratoconus. Especially when evaluating contact lens wearers and/or dry eye patients, the epithelial maps may prove pivotal in establishing the correct diagnosis (or not) of early keratoconus and or progression.

new Device

He also suggested research should be conducted using a new corneal topography device that uses multi collared LED illumination spots to register reflection topography (Cassini, i-Optics). Potential advantages of this technology that his team has evaluated over the last year appear to be more accurate data in the corneal centre in comparison to traditional Placido topography, and no bias from cornea clarity issues in comparison to Scheimpflug tomography. His team has already reported in several papers the potential advantages in selected cases. He nevertheless pointed out that keratoconus screening and progression assessment may require correlation of all of the technologies mentioned above along with newer modalities such as the developing Brillouin phonon spectrometry of the cornea that may offer objective biomechanical data and status.

As a completely different approach for the future, Jesús Merayo-LLoves MD, PhD, presented research suggesting the possibility of using biomarkers to detect keratoconus progression. He explained that even though keratoconus is typically considered a non-inflammatory disease, several researchers have reported finding increased levels of inflammatory molecules in the tears and corneal tissue of eyes with keratoconus.

To further investigate this area, Dr Merayo-LLoves and colleagues undertook a study in which they used x-omics array analysis to determine levels of more than 600 proteins in tear samples from 18 patients. The study subjects included individuals with different grades of keratoconus as well as unaffected controls, and the analyses showed that certain proteins were specific for keratoconus and could be used to discriminate between different disease severity levels.

“Based on available data from clinical and laboratory research, we believe keratoconus is a neuroinflammatory disease with rubbing as a major risk factor. Our findings on protein changes in the tears suggest the possibility of having biomarkers to diagnose keratoconus and its progression,” said Dr Merayo-Lloves, associate professor of ophthalmology, University of Oviedo, and director of research of the Foundation of the Instituto Oftalmológico Fernández-Vega, Oviedo, Spain.

“In addition, protein interaction network analysis of data on protein profiles associated with keratoconus may lead us to new understanding on the pathogenesis of this disease.”

Michael Belin: mwbelin@aol.com

A John Kanellopoulos: ajkmd.lv@gmail.com

Sheraz Daya: sdaya@centreforsight.com
Jesús Merayo-Lloves: merayo@fia.as