1. Statement of Commercial Interest: RDJ: None DRH: honoraria from Reichert for educational lectures on corneal biomechanics Multiple studies have shown ex vivo that keratoconic (KCN) corneas are more elastic and less rigid than normal eyes. Recently, by use of the Ocular Response Analyzer, these properties are able to be measured in vivo. Keratoconus, however, is a disease that often can be easily It is our hypothesis that there is a continuum of impaired biomechanics that is significantly different from normal corneas. It is our hope that through evaluating, understanding, and exploiting these differences, we can more easily diagnose even the earliest forms of forme-fruste keratoconus. By so doing, we hopefully can augment our refractive screening techniques and avoid the disasterous consequences of operating on such a cornea. diagnosed clinically at the slit lamp. It is the more subtle cases of forme-fruste keratoconus that at times can be more difficult to accurately diagnose, which, in a laser refractive center, can have devastating consequences (see picture). It was the goal of this study to evaluate the biomechanical differences between normal and keratoconic corneas through the entire range of disease states: from the earliest stage (‘pre’ forme-fruste keratoconus) all the way through fulminant clinical disease.

2. Retrospective case-review study. 230 eyes of 201 patients were divided into groups according to their keratoconic severity score (KSS) as defined by the Collaborative Longitudinal Evaluation of Keratoconus (CLEK) study group 1 KCN group (KSS=3): 73 eyes of 54 patients (see example figure below). FFKCN group (KSS=1 to 2, or 0 if it is the fellow eye of a KCN): 42 eyes of 32 patients. Controls (KSS=0): 115 healthy eyes of 115 age/sex matched patients Due to its viscoelastic properties, the cornea resists the dynamic air puff differentially on the inward and outward applanation events, resulting in the inward and outward flat phase of the cornea occurring at two different pressure values. Corneal hysteresis (CH) is defined as the difference between these two pressure values. CH is thought to correlate with the amount of viscous dampening inherent to the cornea. The CH measurement also provides the basis for an additional parameter, the corneal resistance factor (CRF). This measure appears to be an indicator of the overall mechanical resistance of the corneal tissue, including both viscous and elastic components, and is derived from specific combinations of the inward and outward applanation values using proprietary algorithms 2. 1.McMahon TT, Szczotka-Flynn L, Barr JT, et al. A new method for grading the severity of keratoconus: the Keratoconus Severity Score (KSS). Cornea 2006;25:794-800 2.Luce DA. Determining in vivo biomechanical properties of the cornea with an ocular response analyzer. J Cataract Refract Surg 2005;31(1):156-62 For each eye Orbscan was used for topographical and pachymetry measurements. The ocular response analyzer (OR) was used to obtain a biomechanical waveform from which the corneal hysteresis (CH) and corneal resistance factor (CRF) are obtained. During the measurement procedure, a rapid air impulse is used to applanate the cornea. Utilizing an electro-optical system, two applanation pressures are recorded (see figure above). The first pressure occurs when the cornea is flattened and moving inward towards concavity and the other as the cornea flattens and is moving outward back to the normal convex shape. This applanation process takes about 20 milliseconds.

3. The table to the right summarizes comparisons between groups. On intergroup analysis, there was a statistically significant difference in mean CH and CRF in the normal group compared to all other groups, including both FFKCN sub-groups (p<0.0001). There was also a statistically significant difference in the mean CH and CRF between the FFKCN and KCN groups (p=0.012 and p=0.001, respectively). However, there was a significant difference in mean CCT between the 3 groups as well (ANOVA p<0.0001).

4. After adjustment for CCT the difference in mean CH and CRF remained statistically significant when comparing normal controls with all other groups, including the 2 FFKCN sub-groups (p<0.0001 in all comparisons). After adjustment for CCT, the difference in mean CH between FFKCN and KCN groups was no longer significant (p=0.13), while the difference in mean CRF remained significant (p=0.015). In further analysis of the FFKCN subgroups, mean CRF between FFKCN-A (fellow eye of the keratoconic) and KCN groups remained significant (p=0.027) but was no longer significant between FFKCN- A and FFKCN-B or FFKCN-B and KCN groups. The table above shows the comparison between each subgroup for both CH and CRF.

5. Correlations between the keratoconic severity score (KSS) and CH, CRF and CCT are shown in the table to the left. There was a strong Spearman correlation coefficient between all three parameters and severity of disease (CH: r=-0.73; CRF: r=- 0.78; CCT=-0.73; ANOVA p<0.001 in all). Student T-test showed a significant difference in all parameters between KSS 2 and 3 (CH: p=0.014; CRF: p=0.003; CCT: p=0.023). Comparison between KSS 1 and 2 showed a significant difference for CCT (p=0.013), but not for CH or CRF (p=0.769 and 0.136, respectively). Linear regression analysis showed a significant correlation between KSS and CH as well as CRF (p<0.001) with the R 2 value strongest in the CRF (R 2 =0.57, figure to left) compared to CH (R 2 =0.48).

6. Our study found that the CH and CRF measurements in eyes with KCN and FFKCN are significantly lower than eyes with normal corneas. This study suggests that the CH and CRF values may be useful additional parameters, in conjunction with topography, to aid the clinician in the difficult task of identifying subtle forms of FFKCN. In particular, when faced with normal topographic findings (KSS<1), the CH and CRF parameters hold significant value in identifying abnormal corneal biomechanics.

7. An important finding in our study is the statistically significant differences in CH and CRF between the topographically normal fellow eyes in patients with manifest KCN in the other eye compared to age and CCT matched normal controls. In our study, there were 10 patients with KSS scores of 0 (n=4) or 1 (n=6) whose fellow eye had manifest keratoconus, (FFKCN-A subgroup). We did not label these eyes as fellow eyes of patients with “unilateral” keratoconus because the authors believe keratoconus to be a bilateral, asymmetric disease. An example Orbscan of an eye with manifest keratoconus (above) and its topographically normal fellow eye (below) is shown.

8. Normal fellow eye (n=10) Controls (n=20) P value Mean CCT (µm)499 ± 34.9500 ±14.80.891 Mean CH (mm Hg)8.6 ±1.410.4 ±1.70.006 Mean CRF (mm Hg)8.7 ±1.410.4 ±1.70.010 Indeed, our findings support this hypothesis: the mean CH and CRF of these eyes (8.6 ±1.4 and 8.7 ±1.4 mm Hg respectively) were statistically significantly different from the mean CH and CRF of eyes from age and CCT matched normal controls (n=20 eyes of 20 patients, 10.4 ±1.7 and 10.4 ± 1.7 mm Hg respectively). Interestingly, there was not a statistically significant difference between the manifest keratoconic eye and the fellow, topographically normal eye with regard to CCT, CH, or CRF. This further supports the hypothesis that the fellow eye is not “normal” but, in fact, has more biomechanical similarity to the pathologic eye.

9. Forme fruste keratoconus can be a subtle ectatic condition often missed by topographic/tomographic analysis. The long term success of refractive surgery, particularly LASIK, depends on our ability to identify corneas at risk for keratectasia. This study suggests that the corneal biomechanical parameters CH and CRF may be useful tools in further refining our ability to identify subtle forme fruste keratoconus. New ORA software will allow detailed assessment of the biomechanical waveform obtained, analysis which may further enhance our diagnostic capabilities. Ultimately, combining ORA metrics with tomographic data should lead us to improved exclusion criteria and, consequently, to a further reduction in the incidence of keratectasia following refractive surgery.