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Across the Pond | Nov/Dec 2014

Hypotheses in Keratoconus Diagnosis and Treatment

One surgeon's thoughts, questions, and hopes for keratoconus management.

My team has been pioneering keratoconus screening and corneal collagen crosslinking (CXL) interventions for more than 10 years.1-6 Because many available keratoconus diagnosis, staging, and progression criteria have limited value, we are continually in search of early sensitive and specific criteria for the diagnosis and progression of this disease.

Some of the common established criteria for keratoconus progression that have been used in decision-tree and classification schemes are listed in Established Criteria for Keratoconus Progression.7-9 Even with these guidelines, clinicians often encounter eyes that do not fit fully into the keratoconus or normal cornea groups.


A gold-standard model for keratoconus progression is still needed. When such a model has been established, clinicians will be better able to decide the indications for CXL application in specific patients. In the meantime, I propose that we rely on modern corneal imaging devices to provide more specific and sensitive indicators for keratoconus assessment.

We have noted a higher degree of familial correlation of keratoconus than has been previously reported. Among children who have been diagnosed with keratoconus, topographic and tomographic imaging of their parents shows signs of keratoconus at least 80% of the time in one of the parents (personal data). Admittedly, however, southern Europe (specifically the eastern Mediterranean region) has a high incidence of keratoconus.

We have attempted to correlate the existing diagnostic criteria for keratoconus (as outlined in Established Criteria for Keratoconus Progression) with newer, more sensitive criteria such as overall epithelial thickness and asymmetry of epithelial thickness indices. As an alternative to anteriorsegment optical coherence tomography (AS-OCT), multicolor LED point-reflection topography (Cassini; i-Optics) can provide more sensitive identification of corneal asymmetry. We recently became interested in how the Cassini compares with standard Scheimpflug and Placido discderived asymmetry indices (eg, index of surface variance [ISV] and index of height decentration [IHD]) and with visual acuity and contrast sensitivity data and corneal biomechanical responses in keratoconus patients.

Thus far, our investigation suggests that a better approach may be to examine quantitative indicators that reflect anterior surface variance across the cornea. These anterior shapebased indices provide positive correlation with topographic keratoconus classification (TKC), based on traditional Krumeich-Amsler criteria,10 and may provide quantitative tools for keratoconus classification and progression assessment. Specifically, the average coefficient of determination (r2) between ISV and the determined TKC keratoconus severity grade was 0.793; between IHD and TKC, it was 0.716. In other words, there is significant correlation between the two anterior-surface irregularity indices and keratoconus classification.11-13


Other modern diagnostic devices can also offer a large variety of novel keratoconus-specific indicators that have not yet been studied in a large patient population.

Keratograph 5 (Oculus). This device not only performs standard keratometry but it can also noninvasively examine tear film breakup time and tear meniscus height and evaluate the lipid layer. It also offers seven specific anterior-surface irregularity indices that describe corneal irregularity, including ISV and IHD.

Pentacam HR (Oculus). Specific to keratoconus investigation, the Pentacam HR incorporates the Belin/Ambrosio Enhanced Ectasia Display and can also evaluate anterior and posterior keratometry, simulated keratometry, anterior and posterior elevation, and seven specific anterior-surface irregularity indices that describe corneal irregularity.

Cassini. In addition to standard topometric maps, the Cassini measures anterior surface aberrations and posterior curvature and elevation measurements—a unique feature among topographers. It also includes several keratoconus-specific data, such as the Klyce indices of surface asymmetry index and surface regularity index.

RTVue 100 (Optovue). Unique among Fourier-domain AS-OCT devices, the RTVue offers epithelial thickness maps across a 6-mm wide corneal area. Screenings with this device offer specific distinguishing corneal pachymetric features, namely corneal asymmetry and focal thinning manifested inferotemporally; quantification of this characteristic pattern may be useful in keratoconus diagnosis and ectasia risk assessment.

AS-OCT pachymetry. Four quantitative parameters calculated by AS-OCT pachymetry have also been proposed for keratoconus diagnosis:14 the average thickness of the superior octant minus the average thickness of the inferior (S-I); the average superior-nasal octant thickness minus the average of the inferior-temporal thickness (SN-IT); focal thinning, defined as the minimum minus the median corneal thickness (min-med); and the thickness range, or global thinning, defined as the minimum minus the maximum corneal thickness (min-max). Furthermore, regarding epithelial thickness imaging, the examination reports offer several keratoconus-specific indices, including overall epithelial thickness, epithelial thickness variability, and epithelial thickness range (min-max).


One challenge in CXL treatment is measuring an intervention’s clinical efficacy. Although data confirm a halt in ectatic progression as documented by Kmax reduction,15 refraction stabilization, and improvement in distance BCVA,16,17 several variations have been proposed since the original Dresden protocol (3 mW/cm2 for 30 minutes) was introduced.17 Many of these variations aim to deliver the same amount of energy (5.4 J/cm2) and the same stiffening effect as the Dresden protocol by applying higher fluence (eg, 6, 10, 18, or 30 mW/cm2) and correspondingly shorter ultraviolet (UV)-A exposure times. To the best of our knowledge, however, there has been no direct comparison of these CXL protocols. The method of riboflavin administration as a result of epithelium (epi)-on or epi-off treatment can also affect efficacy. Now several technologies are available to assess the effects of CXL interventions.

Corvis ST (Oculus). This functional in vivo corneal biomechanics analyzer uses a noncontact tonometer to record corneal reactions to air impulses. It enables assessment of corneal properties (corneal hysteresis and corneal resistance factor) for various applications in keratoconus screening and crosslinking assessment.

BioTester 5000 (Cell Scale). This device is a biomaterials biaxial strength analyzer used to measure ex-vivo corneal rigidity (Young’s modulus) within a temperature-controlled media bath. The system captures and graphically displays live time, force, and synchronized video images for analysis and verification of results. Two high-performance actuators (two per axis) provide micron-positional resolution for accurate test motion, with inline overload-protected load cell on each axis and a high-resolution digital internal camera to collect time-synchronized images for post-test analysis.

Two other areas of interest in CXL assessments are analysis of demarcation lines on OCT and enzymatic digestion.


We believe that incorporating the technologies described above can help to ease the challenges associated with understanding keratoconus progression and measuring the effects of our treatment efforts. Analyses should include not only topographic asymmetry and thickness asymmetry indices but also more sensitive anterior segment topographic asymmetry and epithelial thickness indices and the differences in biomechanical response of normal, suspect, and keratoconic corneas. We offer two hypotheses, which are shared below.

A. John Kanellopoulos, MD, is the Director of the LaserVision.gr Eye Institute in Athens, Greece, and is a Clinical Professor of Ophthalmology at New York University School of Medicine. He is an Associate Chief Medical Editor of CRST Europe. Dr. Kanellopoulos states that he is a consultant to Alcon, Avedro, i-Optics, and Oculus. He may be reached at tel: +30 21 07 47 27 77; e-mail:ajkmd@mac.com.

  1. Kanellopoulos AJ, Binder PS. Collagen cross-linking (CCL) with sequential topography-guided PRK: A temporizing alternative for keratoconus to penetrating keratoplasty. Cornea. 2007;26(7):891-895.
  2. Krueger RR, Ramos-Esteban JC, Kanellopoulos AJ. Staged intrastromal delivery of riboflavin with UVA cross-linking in advanced bullous keratopathy: Laboratory investigation and first clinical case. J Refract Surg. 2008;24(7):S730-S736.
  3. Kanellopoulos AJ. Collagen cross-linking in early keratoconus with riboflavin in a femtosecond laser-created pocket: initial clinical results. J Refract Surg. 2009;25(11):1034-1037.
  4. Kanellopoulos AJ. Comparison of sequential vs same-day simultaneous collagen cross-linking and topographyguided PRK for treatment of keratoconus. J Refract Surg. 2009;25(9):S812-S818.
  5. Krueger RR, Kanellopoulos AJ. Stability of simultaneous topography-guided photorefractive keratectomy and riboflavin/UVA cross-linking for progressive keratoconus: Case reports. J Refract Surg. 2010;26(10):S827-S832.
  6. Kanellopoulos AJ, Binder PS. Management of corneal ectasia after LASIK with combined, same-day, topographyguided partial transepithelial PRK and collagen cross-linking: the Athens Protocol. J Refract Surg. 2011;27(5):323-331.
  7. O’Brart DPS, Chan E, Samaras K, et al. A randomised, prospective study to investigate the efficacy of riboflavin/ultraviolet A (370 nm) corneal collagen crosslinkage to halt the progression of keratoconus. Br J Ophthalmol. 2011;95(11):1519-1524.
  8. Hersh PS, Greenstein SA, Fry KL. Corneal collagen crosslinking for keratoconus and corneal ectasia: one-year results. J Cataract Refract Surg. 2011;37(1):149-160.
  9. Wittig-Silva C, Whiting M, Lamoureux E, et al. A randomized controlled trial of corneal collagen cross-linking in progressive keratoconus: preliminary results. J Refract Surg. 2008;24(7):S720–S725.
  10. Lopes BT, Ramos IC, Faria-Correia F, et al. Correlation of topometric and tomographic indices with visual acuity in patients with keratoconus. Int J Kerat Ect Cor Dis. 2012;1(3):167-172.
  11. Kanellopoulos AJ, Asimellis G. Revisiting keratoconus diagnosis and progression classification based on evaluation of corneal asymmetry indices, derived from Scheimpflug imaging in keratoconic and suspect cases. Clin Ophthalmol. 2013;7:1539-1548.
  12. Kanellopoulos AJ, Asimellis G. Corneal refractive power and symmetry changes following normalization of ectasias treated with partial topography-guided PTK combined with higher-fluence CXL (the Athens Protocol). J Refract Surg. 2014;30(5):342-346.
  13. Kanellopoulos AJ, Asimellis G. Forme fruste keratoconus imaging and validation via novel multi-spot reflection topography. Case Rep Ophthalmol. 2013;4(3):199-209.
  14. Wollensak G, Spoerl E, Seiler T. Riboflavin/ultraviolet-A-induced collagen crosslinking for the treatment of keratoconus. Am J Ophthalmol. 2003;135(5):620-627.
  15. Vinciguerra P, Albé E, Frueh BE, et al. Two-year corneal cross-linking results in patients younger than 18 years with documented progressive keratoconus. Am J Ophthalmol. 2012;154(3):520-526.
  16. Caporossi A, Mazzotta C, Baiocchi S, Caporossi T. Long term results of riboflavin ultraviolet a corneal collagen cross-linking for keratoconus in Italy: The Siena eye cross study. Am J Ophthalmol. 2010;149(4):585-593.
  17. Koller T, Mrochen M, Seiler T. Complication and failure rates after corneal crosslinking. J Cataract Refract Surg. 2009;35(8):1358-1362.