In the next three issues of Cataract & Refractive Surgery Today, "Peer Review" will highlight current articles relating to corneal ectasia. This first installment brings to light the lessons learned over the past 15 years of LASIK surgery worldwide. Next, we will entertain the use of intracorneal rings for the treatment of keratoconus and ectasia. The final installment will address the latest arrival to our armamentarium: corneal cross-linking.

As LASIK surgeons, we are all familiar with the potential risks for the development of corneal ectasia after LASIK. In the early years of performing this procedure, we used anecdotal information to define our criteria for exclusion. This practice unfortunately led to several ectactic surprises despite following what we thought were safe guidelines. A recent review of medical claims associated with keratorefractive surgery showed that 12% were related to ectasia following uncomplicated LASIK.¹

Over the past decade, we have developed tools to reduce the risk of ectasia. Our mechanical prowess has led to the creation of flaps with femtosecond lasers (Femto LDV [Ziemer Group AG, Port, Switzerland], VisuMax [Carl Zeiss Meditec, Inc., Dublin, CA], IntraLase FS [Abbott Medical Optics Inc., Santa Ana, CA], and Femtec [20/10 Perfect Vision AG, Heidelberg, Germany]). Mechanical keratomes have also improved the accuracy of keratectomy. The advent of zero-compression head technology (available on the Zyoptix XP [Bausch & Lomb, Inc., Rochester, NY] and the ML7 [Med-Logics, Inc., Laguna Hills, CA]), in addition to the development of calibrated LASIK blades (Med-Logics, Inc.), allow us to create flaps with tolerances that rival those of femtosecond lasers (±12 µm).

The articles summarized in this edition of "Peer Review" were selected from over 100 articles published over the past decade. We hope you enjoy this installment, and we encourage you to go back and review the articles in their entirety at your convenience.

—Mitchell C. Shultz, MD, Section Editor

DEFINING ECTASIA
Corneal ectasia is a serious postoperative complication of LASIK that is characterized by a progressive increase in corneal curvature. To develop a consistent clinical definition of this condition and to better understand its underlying pathogenesis, Twa et al retrospectively reviewed 21 peer-reviewed studies containing the keywords LASIK and ectasia. Upon comparing the clinical characteristics of patients with ectasia (86 eyes of 59 patients) and those who underwent uncomplicated LASIK (103 eyes of 63 patients), the investigators identified "nine postoperative clinical variables that were significantly associated with corneal ectasia after LASIK."² Postoperatively, the ectatic eyes had a significantly higher degree of residual myopia (-3.69 D vs -0.38 D for the control group), thinner residual stromal beds (259 µm vs 334 µm for the control group), and a higher degree of toricity (2.87 D vs 0.57 D for the control group). The study's authors determined that the presence of two or more of these findings had high sensitivity and specificity for the diagnosis of ectasia.²

INDIVIDUAL RISK FACTORS
Several studies have investigated how individual pre- and intraoperative clinical variables contribute to ectasia.

Corneal Topography
Surgeons currently use two devices to screen patients for topographic abnormalities associated with the development of postoperative ectasia. In a retrospective review of eight patients, Wolf et al found that Scheimpflug imaging (Pentacam Comprehensive Eye Scanner; Oculus, Inc., Lynnewood, WA) detected the characteristic signs of forme fruste keratoconus (ie, symmetric inferior corneal steepening, asymmetric bowtie patterns, central corneal irregularities with peripheral corneal steepening) more effectively than placido-based topography. According to the investigators, the Pentacam detects more subtle indicators of forme fruste keratoconus because it generates "a complete topical map of the anterior corneal surface and the posterior curvature."³ In contrast, the study's authors wrote, placido-based topography provides information only on anterior corneal curvature.³

Residual Stromal Thickness
As a general rule, surgeons strive to perform LASIK on patients whose central corneas measure a minimum of 500 µm preoperatively and to leave the eyes with a stromal bed of at least 250 µm. In 2007, Salz and Binder observed that this "magic number" of 250 µm was not derived from a peer-reviewed double-blind prospective trial.⁴ Instead, they said, this widely-accepted cut-off value was extrapolated from theoretical calculations⁵ and retrospective reviews of ectatic eyes.⁶

A long-term study of 107 highly myopic eyes (range, -10.00 to -35.00 D) found that only one of 15 eyes that had a residual stromal bed measuring less than 250 µm after LASIK developed ectasia. Nevertheless, the investigators strongly recommended that surgeons perform "careful preoperative screening and … surgical planning to avoid residual thin stromal beds, [and also perform] intraoperative pachymetry … to identify unexpected[ly] thick flaps."⁷

Biomechanical Factors
The Ocular Response Analyzer (ORA; Reichert Ophthalmic Instruments, Depew, NY) may provide information on how ectasia affects the biomechanical properties of the cornea. Measurements obtained from the contralateral eyes of the same patient showed that corneal hysteresis (6.6 ±0.62 mm Hg vs 6.8 ±1.27 mm Hg) and the corneal resistance factor (6.2 ±0.48 mm Hg vs 6.9 ±0.87 mm Hg) were only slightly diminished in his ectatic versus nonectatic eye. When the investigators reviewed the output patterns produced by the ORA, however, they noted a significant difference in the height of the signal peaks (representing applanation events) between the ectatic and nonectatic eyes (P<.01). According to the investigators, "the difference in the signal morphology led to the conclusion that the [ectatic and nonectatic] corneas are biomechanically distinct."⁸

Dawson et al used light and electron microscopy to examine the histologic structure of corneal tissue recovered from ectatic eyes undergoing penetrating keratoplasty. Compared with the nonectatic corneas of patients who underwent uncomplicated LASIK, the ectatic tissue showed "focal areas of central epithelial hypoplasia or hyperplasia, one to several small Bowman's layer breaks, and thinning of the corneal stroma in the residual stromal bed."9 Overall, the ectatic corneas had a residual stromal bed that was 47% thinner than that of healthy corneas.⁹

The investigators also noted changes in the ultrastructure of the ectatic corneas that included thinner corneal stromal lamellae relative to nonectatic areas of the same cornea (0.88 ±0.16 µm vs 1.30 ±0.07 µm) and larger-than-normal distances between collagen fibers (50.3 ±3.4 nm vs 45.2 ±2.1 nm). Based on these findings, the investigators concluded that ectasia is probably not caused by the direct failure of collagen fibrils but instead "can best be explained by interlamellar biomechanical slippage (ie, interlamellar fracture) followed by subsequent interfibrillar biomechanical slippage (ie, interfibrillar fracture.)"⁹

IDIOPATHIC ECTASIA
Patients may develop ectasia even in the absence of documented risk factors. Klein et al described the characteristics of eight eyes of eight patients that became ectatic after uneventful LASIK. Preoperative evaluation with the Orbscan II (Bausch & Lomb, Inc.) showed that five of the eight eyes had normal topographies. Of the remaining three, two had with-the-rule astigmatism, and one had subtle inferotemporal steepening and a fairly low elevation of the posterior cornea. In addition, all of the eyes had residual stromal beds measuring 250 µm or more (mean = 300 µm).¹⁰

Randleman et al described idiopathic ectasia in two patients who underwent hyperopic LASIK. In the first case, a 47-year-old whose preoperative topography showed inferior steepening in the far corneal periphery of his right eye developed ectasia 6 months after hyperopic LASIK. Despite retaining a 290-µm thick residual stromal bed, the eye had advanced corneal steepening that required treatment with a rigid gas permeable contact lens. The second patient also developed postoperative ectasia despite his normal preoperative topography. Forty months after undergoing hyperopic LASIK, the second patient complained of blurred vision that was attributed to mild inferior steepening with a skewed radial axis on topography.¹¹

PREDICTING RISK
Investigators have used the generally accepted risk factors for ectasia to develop quantitative models for identifying patients at risk of developing this condition after LASIK.

Randleman et al compared the clinical characteristics of ectatic eyes (158 cases from the peer-reviewed literature and 13 unpublished cases) with the same criteria in eyes (n = 186) that underwent uncomplicated LASIK at the Emory Eye Center in Atlanta. Next, the investigators identified specific risk factors for ectasia and performed statistical analyses to "elucidate the relative importance of each identified risk factor in eyes commonly considered for LASIK."¹² Finally, they used the results of their analyses to compile the Ectasia Risk Factor Score System. This system calculates patients' risk of ectasia by assigning points for aspects of patients' preoperative topography, thickness of the residual stromal bed, age, preoperative corneal thickness, and preoperative refraction (Tables 1 and 2). When the investigators applied this system to their ectatic and control populations, they found that it correctly identified 91% of the ectatic eyes (91% specificity) and only 3.8% of the controls (96% sensitivity) as having a high risk of developing ectasia.¹²

In a follow-up study, Randleman et al applied their Ectasia Risk Factor Score System to a new series of ectatic (n = 50) and healthy (n = 50) eyes. They found that the model correctly classified 46 (92%) of the ectatic eyes as having a high risk of developing the condition after LASIK. Because the model incorrectly identified only three (6%) of the control eyes as high risk, the investigators determined that the "sensitivity and specificity of the Ectasia Risk Score in this study were essentially the same as they were in the previous study."¹³

Hypothesizing that the surgeon's choices of microkeratome, laser, and pachymeter introduce variation into the thickness of the corneal flap and the residual stromal bed, Reinstein et al created a statistical model that calculates the probability that a specific set of instruments will produce an excessively deep keratectomy during LASIK. To calculate an individual's risk of developing ectasia, the surgeon enters a series of parameters for a specific treatment protocol into the treatment, accuracy, and precision sections of the model. These parameters include the patient's preoperative corneal thickness; his targeted correction; the intended size of the treatment zone; the type of laser to be used; the mean thickness of the flap; the standard deviations of the flap's thickness, corneal thickness, and depth of ablation; and a cut-off value for residual stromal thickness. The model then calculates the probability that a specific clinical protocol will leave a residual stromal bed that is thinner than the selected cut-off value.¹⁴

In a second article, Reinstein et al described how they used their predictive model to (1) estimate the residual stromal thickness at which ectasia is likely to occur in a population and (2) calculate the minimum residual stromal thickness that surgeons should target if they want to reduce the risk of ectasia to a specific level. When the investigators applied their model to a series of 5,212 eyes that underwent LASIK at a high-volume refractive surgery practice in Canada, they found that ectasia was most likely to occur in eyes that had a residual stromal bed measuring less than 191 µm. To reduce the rate of ectasia in this population to one in 1 million procedures, the surgeon would have to leave a minimum residual stromal thickness of 329 µm. An alternate calculation for the same population is shown in Figure 1.¹⁵

STRATEGIES FOR STABILIZING AND CORRECTING ECTASIA
A retrospective review of patients with post-LASIK ectasia treated at the Emory Eye Center in Atlanta provides an overview of the available corrective options. Postoperatively, most of the ectatic eyes evaluated by the investigators achieved a final BCVA of 20/40 with rigid gas permeable contact lenses (57 eyes), spectacles (seven eyes), penetrating keratoplasty (six eyes), or collagen cross-linking (two eyes). Two eyes did not receive additional intervention to manage their ectasia.¹⁶

According to Chan and Boxer Wachler, the first step in managing ectasia is stabilizing its progression. They recommend starting patients on timolol or a prostaglandin analogue within 6 months of the onset of ectasia to lower the IOP and minimize corneal bulging. If the ectasia appears to be stable on repeat topographic testing, the surgeon can then consider performing cross-linking to strengthen the cornea. To ensure that the cornea is stable, the patient should continue to use the topical hypotensive agent for at least 3 months after corneal cross-linking.¹⁷

Section editor Mitchell C. Shultz, MD, is in private practice and is an assistant clinical professor at the Jules Stein Eye Institute, University of California, Los Angeles. He acknowledged no financial interest in the products or companies mentioned herein. Dr. Shultz may be reached at (818) 349-8300; izapeyes@gmail.com.

1. Bailey CS, Bailey JA. Claims of alleged medical negligence in refractive surgery: causes and avoidance. Cont Lens Anterior Eye. 2007;30:144-147.
2. Twa MD, Nichols JJ, Joslin CE, et al. Characteristics of corneal ectasia after LASIK for myopia. Cornea. 2004;23:447-457.
3. Wolf A, Abdalla W, Kollias A, et al. Mild topographic abnormalities that become more suspicious on Scheimpflug imaging. Eur J Ophthalmol. 2009;19(1):10-17.
4. Salz JJ, Binder PS. Is there a "magic number" to reduce the risk of ectasia after laser in situ keratomileusis and photorefractive keratectomy? Am J Ophthalmol. 2007;144(2):284-285.
5. Probst L, Machat J. Mathematics of laser in situ keratomileusis for high myopia. J Cataract Refract Surg. 1998;24(2):13-29.
6. Randleman JB, Russell B, Ward MA, et al. Risk factors and prognosis for corneal ectasia after LASIK. Ophthalmology. 2003;110:267-275.
7. Condon PI, O'Keefe M, Binder PS. Long-term results of laser in situ keratomileusis for high myopia: risk for ectasia. J Cataract Refract Surg. 2007;33:583-590.
8. Kerautret J, Colin J, Touboul D, Roberts C. Biomechanical characteristics of the ectatic cornea. J Cataract Refract Surg. 2008;34:510-513.
9. Dawson DG, Randleman JB, Grossniklaus HE, et al. Corneal ectasia after excimer laser keratorefractive surgery: histopathology, ultrastructure, and pathophysiology. Ophthalmology. 2008;115:2181-2191.
10. Klein SR, Epstein RJ, Randleman JB, Stulting RD. Corneal ectasia after laser in situ keratomileusis in patients without apparent preoperative risk factors. Cornea. 2006;25(4):388-403.
11. Randleman JB, Banning CS, Stulting RD, et al. Corneal ectasia after hyperopic LASIK. J Refract Surg. 2007;23:98-102.
12. Randleman JB, Woodward MD, Lynn MJ, Stulting RD. Risk assessment for ectasia after corneal refractive surgery. Ophthalmology. 2008;115:37-50.
13. Randleman JB, Trattler WB, Stulting RD. Validation of the Ectasia Risk Score System for preoperative laser in situ keratomileusis screening. Am J Ophthalmol. 2008;145:813-818.
14. Reinstein DZ, Srivannoboon S, Archer T, et al. Probability model of the inaccuracy of residual stromal thickness prediction to reduce the risk of ectasia after LASIK part I: quantifying individual risk. J Refract Surg. 2006;22:851-860.
15. Reinstein DZ, Srivannoboon S, Archer T, et al. Probability model of the inaccuracy of residual stromal thickness prediction to reduce the risk of ectasia after LASIK part II: quantifying population risk. J Refract Surg. 2006;22:861-870.
16. Woodward MA, Randleman JB, Russell B, et al. Visual rehabilitation and outcomes for ectasia after corneal refractive surgery. J Cataract Refract Surg. 2008;34:383-388.
17. Chan CCK, Boxer Wachler BS. Corneal ectasia and refractive surgery. Int Ophthalmol Clin. 2006;46(3):13-25.