While post-refractive surgery ectasia is uncommon, laser in situ keratomileusis (LASIK) is counted among the most frequently performed procedures worldwide. Small-incision lenticule extraction (SMILE) is also being performed in increasing numbers and now boasts studies of 5-year outcomes, including Ağca et al. in this issue (page 421). While SMILE has a relative biomechanical advantage over LASIK in eyes for which normal biomechanical properties can be assumed,1–4 it does not confer absolute protection against ectasia. Ectasia risk assessment therefore continues to be an important focus of every refractive surgery screening exam.
Assessing ectasia risk begins with understanding its causes. This has been approached by identifying clinical features that are more common in ectasia cases and attempting to relate these statistically to risk. The nature of ectasia presents substantial challenges to statistical solutions, however. Dupps and Seven5 outlined some of these challenges in a previous study and they include: 1) a scarcity of cases due to the rarity of the condition and a negative ascertainment bias in obtaining cases for analysis, 2) sparsity of data for documented cases in which missing risk drivers can skew predictive models or lead to poorly conditioned models with low external validity,6 3) a binary rather than continuous approach to risk assessment due to models built on disease presence rather than disease severity or susceptibility, and 4) a phenomenological rather than mechanistic approach to risk assessment in which the resulting statistical relationships are conditioned to fit the data but do not necessarily elucidate the mechanistic relationships. This confounds attempts to make de novo inferences in patients with novel combinations of risk factors or to develop strategies to mitigate particular risk factors. Additional confusion can arise when the methodological differences between assessing risk factor performance and disease-screening performance are obscured. When approached interchangeably, one can inaccurately conclude that poor performance as a lone predictor of ectasia necessarily implies that a variable is not a significant risk driver for the development of ectasia.
Despite these challenges, clinical features such as preoperative topographic irregularity, high myopic correction, young age, relative corneal thickness metrics, and absolute or relative depth of surgical disruption have all been identified as risk factors for post-refractive surgery ectasia through such work.7–12 Each of these factors reflects an intrinsic (patient-specific), extrinsic (treatment-specific), or interactive (representing an interaction between intrinsic and extrinsic properties) variable that promotes structural failure of the load-bearing corneal stroma.13-16 Awareness of these risk factors has greatly informed the approach to ectasia risk assessment, but clinicians still struggle with decision-making because of the ambiguity that arises when these factors are in conflict.
With the goals of addressing the aforementioned challenges and establishing a more comprehensive means to assess structural risk in refractive surgery, a computational mechanics approach has been applied to quantify the biomechanical impact of intrinsic 3-dimensional (3-D) corneal shape and extrinsic surgical factors.5,17 Finite element modeling leverages numerical solutions to thousands of partial differential equations to test the performance of proposed structures in a virtual domain. By assessing deformations and stresses and strains under physical loading, the impact of perturbations on shape and material performance can be better understood. These methods have been applied to many biological systems but have only recently been directed toward the problem of corneal ectasia after refractive surgery.17–19 In the thesis and its predicate paper,17 maximum principle strain—a measure of the maximum tensile deformation of a given location in the cornea under load—was proposed as a candidate structural susceptibility metric. Strain is an important factor in the tensional homeostasis of soft tissues and is a potentially important predictor of the degradative pathways that promote ectasia. We believe it would be helpful to abstract a few of the key findings from this work here and to highlight relationships to known ectasia risk variables.
The study involved a large-scale computational modeling trial with patient-specific finite element models of keratoconic, at-risk, and normal eyes that were subjected to various magnitudes of LASIK and photorefractive keratectomy (PRK) procedures. The premise was to compare the strain behavior in eyes with very low risk of ectasia (eyes that demonstrated stability after LASIK, thus negative controls) and eyes with a certainty of developing ectasia (keratoconic eyes that already manifest ectasia, thus positive controls). These findings have been incorporated into a cloud-based surgical simulation product (SpecifEye, OptoQuest, Inc) that is being developed for prospective surgical planning and ectasia risk assessment based on full 3-D patient-specific tomography data, and studies in known post-LASIK ectasia cases are underway. While many of the resulting generalizations are intuitive, some require additional unpacking.
- Maximum strains were always higher after LASIK than PRK for the same amount of myopic treatment. For a given eye, PRK decreases the relative risk of ectasia over LASIK.
- Strain increased with higher myopic corrections.
- Strains were higher for thicker LASIK flaps.
- Strain is not always higher for LASIK than for PRK when different magnitudes of myopic correction are compared. For example, a 4-D LASIK with a 100-um flap generates less postoperative strain than an 8-D PRK across all risk groups. While this finding will not necessarily influence surgical decision making for an 8-D myope, it makes the important point that the biomechanical effect of a selective central ablation of the stroma is of comparable importance to the effects of a LASIK flap and that the interaction of flap creation and myopic ablation needs to be considered in assessing risk.
- Higher strains were predictive of relative undercorrection of myopia in LASIK and were associated with an increase in central posterior corneal elevation in LASIK. In contrast, PRK actually favored a slight hyperopic overcorrection due to additional biomechanically-mediated flattening.20 This may account in part for the clinical need to reduce the attempted correction slightly in many PRK nomograms.
- Strains were always higher in at-risk and keratoconic geometries than in controls both at baseline and after simulated LASIK or PRK. It is important to note that every model was assumed to have the same normative depth-dependent corneal biomechanical properties (since patient-specific measurement of these properties were not available); 3D corneal geometry—even without patient-specific material properties ascribed—is therefore an important driver of strain and ectasia risk.
- As Mifflin et al. punctuate in their large patient series on page 495, there is some variance in intended and measured values of residual stromal bed (RSB) thickness in refractive surgery. In the modeling study, RSB thickness and percent stromal tissue altered (PSTA) were strongly associated with the absolute strain present after PRK or LASIK (R2 = 86.7% and 71.7%, respectively). PSTA was more strongly correlated with the strain change produced by PRK or LASIK than was RSB (R2 = 95.6% and 79.7%, respectively). PSTA was defined in the study5 as a modification of percent tissue altered, a previously described risk metric that describes the depth of surgical tissue disruption as a percentage of total preoperative corneal thickness calculated at the center of the cornea.11,21–23 This metric was modified to properly account for the negligible structural contribution of the corneal epithelium to allow direct comparison of PRK and LASIK cases, and is expressed as 100% × (flap thickness – epithelial thickness + ablation depth)/(preoperative central corneal thickness – epithelial thickness) for LASIK and 100% × (stromal ablation depth)/(preoperative central corneal thickness – epithelial thickness) for PRK.
- Of note, intrinsic curvature metrics such as maximum tangential curvature (Kmax) and anterior corneal astigmatism were far less strongly correlated to post-procedure strain (R2 = 9% and 4.9%, respectively). However, this does not mean that they are unimportant for predicting ectasia risk in practice; in fact, corneal topographic features are very sensitive clinical indicators of ectasia risk. What do we make of the much higher dependence of strain on thickness factors in these simulations? Recall that the models assumed identical corneal material properties across all eyes. The finding could be explained if clinical curvature abnormalities such as inferior steepening are intrinsically linked in nature to underlying biomechanical weakness. Clinical and experimental evidence increasingly suggests that this is the case.24–27 If weakness is introduced in the models in a scaled manner as a function of focal steepening, strains increase dramatically and the correlations between corneal curvature abnormalities and strain-based risk greatly increase.
These findings suggest that a combination of patient-specific geometric and biomechanical property data as well as case-specific surgical parameters need to be combined to provide the highest fidelity estimates of ectasia risk. A central requirement for this goal is the continued advance of methods for spatially-resolved biomechanical property measurement, which was first demonstrated in a living human eye using Brillouin microscopy by Scarcelli and Yun28 and more recently with optical coherence elastography in a series of human subjects.29 Computational and statistical approaches offer a promising opportunity to aggregate these key data into clinically useful predictive models, and we look forward to continued progress toward this goal.
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2. Sinha Roy A, Dupps WJ Jr, Roberts CJ. Comparison of biomechanical effects of small-incision lenticule extraction and laser in situ keratomileusis: finite-element analysis. J Cataract Refract Surg
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5. Dupps WJ Jr, Seven I. (2016). A large-scale computational analysis of corneal structural response and ectasia risk in myopic laser refractive surgery. Trans Am Ophthalmol Soc, 114
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16. Dupps WJ Jr, Wilson SE. Biomechanics and wound healing in the cornea. Exp Eye Res
17. Vahdati A, Seven I, Mysore N, Randleman JB, Dupps WJ Jr. Computational biomechanical analysis of asymmetric ectasia risk in unilateral post-LASIK ectasia. J Refract Surg
18. Sinha Roy A, Dupps WJ Jr. Effects of altered corneal stiffness on native and postoperative LASIK corneal biomechanical behavior: A whole-eye finite element analysis. J Refract Surg
19. Sánchez P, Moutsouris K, Pandolfi A. Biomechanical and optical behavior of human corneas before and after photorefractive keratectomy. J Cataract Refract Surg
20. Dupps WJ Jr, Roberts C. Effect of acute biomechanical changes on corneal curvature after photokeratectomy. J Refract Surg
21. Santhiago MR, Smadja D, Wilson SE, Krueger RR, Monteiro ML, Randleman JB. Role of percent tissue altered on ectasia after LASIK in eyes with suspicious topography. J Refract Surg
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23. Santhiago MR, Wilson SE, Smadja D, Chamon W, Krueger RE, Randleman JB. Validation of the percent tissue altered as a risk factor for ectasia after LASIK. Ophthalmology 2019 Jan 25. pii: S0161-6420(18)32481-32483.
24. Hong CW, Sinha-Roy A, Schoenfield L, McMahon JT, Dupps WJ Jr. Collagenase-mediated tissue modeling of corneal ectasia and collagen cross-linking treatments. Invest Ophthalmol Vis Sci
25. Roy AS, Dupps WJ Jr. Patient-specific computational modeling of keratoconus progression and differential responses to collagen cross-linking. Invest Ophthalmol Vis Sci
26. Scarcelli G, Besner S, Pineda R, Yun SH. Biomechanical characterization of keratoconus corneas ex vivo with Brillouin microscopy. Invest Ophthalmol Vis Sci
27. Luce DA. Determining in vivo biomechanical properties of the cornea with an ocular response analyzer. J Cataract Refract Surg
28. Scarcelli G, Yun SH. In vivo Brillouin optical microscopy of the human eye. Opt Express
29. De Stefano VS, Ford MR, Seven I, Dupps WJ Jr. Live human assessment of depth-dependent corneal displacements with swept-source optical coherence elastography. PLoS One
Dr. Dupps is listed on related patents held by Cleveland Clinic and licensed to OptoQuest for computational modeling and is also listed on intellectual property related to optical coherence elastography through Cleveland Clinic Innovations. Dr. Santiago is a consultant for and receives speaker/travel fees from Ziemer Ophthalmic Systems, and is a consultant/speaker for Alcon Laboratories, Inc., outside the submitted work.