Laser refractive surgery has rapidly become one of the most common elective ophthalmic procedures performed in the United States. Industry estimates suggest that more than 1 million patients have received laser corneal surgery on at least one eye since 1995 (Dave Harmon, Marketscope, personal communication), and projections are that as many as 16 million procedures will have been performed by 2005. Although this corneal surgery has certainly benefited patients wearing glasses or contact lenses, it has severely contaminated the potential donor pool for corneal transplantation. The Eye Bank Association of America does not allow corneas that have undergone surgery, including laser refractive surgery, to be used for penetrating keratoplasty. 1
Laser-assisted in situ keratomileusis (LASIK) and photorefractive keratectomy (PRK) alter the normal anterior corneal architecture through flap creation, tissue ablation, or both. In myopia treatment, the result is a cornea that is flatter centrally and steeper peripherally than a normal cornea and is also generally thinner centrally. Although these changes are beneficial for the living myope, a donor button punched from a post-LASIK cornea poses the risk of irregular astigmatism, induced hyperopia, and possible flap dehiscence in the recipient. The ablation patterns seen in astigmatism and hyperopia correction would create another layer of unpredictability and risk to the recipient's topographic result after penetrating keratoplasty.
Identifying previous refractive surgery presents difficulties for eye banks. Eye banks currently use several methods to screen donor tissue for use in transplantation, including evaluation of the corneas at the slit-lamp biomicroscope, interviews of the donor's family and physicians about the donor's medical and social history, and review of the donor's medical chart. Unfortunately, the slit-lamp examination may not show haze or irregularities indicative of previous refractive surgery. 2,3 Furthermore, medical charts often lack any mention of a donor's ophthalmic history, and the family interview may not reveal laser refractive surgery because the family may not remember that the donor had refractive surgery, may not know of the surgery, or may not think of refractive surgery as surgery. 2,3 Lastly, many eye banks in the United States procure tissue under medical examiner laws in which the medical examiner can release tissue for donation when family members are not known or cannot be located. In these cases, family interviews may not be available to the eye bank. 4,5 An objective and accurate method of screening for previous refractive surgery is an immediate and critical need for the eye bank community.
In our laboratory, we have been investigating the measurement of corneal topography as an additional tool that eye banks may use to screen tissue for refractive surgery. We previously reported our use of the Orbscan slit scanning machine (Orbtek, Inc., Salt Lake City, UT, U.S.A.) to compare the pachymetry patterns of a pair of donor eyes that had undergone PRK with donor eyes that had no history of refractive surgery. 6 Laser refractive surgery for myopia removes stroma near the center of the cornea, so we hypothesized that regional thickness differences measured by the Orbscan could be used to distinguish eyes that had undergone laser refractive surgery from eyes with no history of surgery. Indeed, when we compared the difference in midperipheral and central corneal thickness in the donor with PRK against the normal donor eyes, we found the PRK donor's pachymetry profile differed in color pattern from the normal eyes and was outside two standard deviations of the normal range.
Since publishing our results, we obtained eight more eyes (for a total of 10) from donors that had undergone corneal refractive surgery for myopia. Six of the eyes had undergone laser refractive surgery and two had undergone radial keratotomy (RK). The radial scars in RK are easily recognizable at the slit lamp, but the topography patterns are similar to those seen with PRK and LASIK. RK eyes therefore can provide valuable screening information.
In our current study, we evaluated all 10 donor eyes that had undergone refractive surgery using our pachymetry pattern method. We further evaluated the same 10 eyes with a curvature pattern method and compared the ability of each method to discriminate eyes that had undergone refractive surgery for myopia from normal eyes that had not undergone refractive surgery.
MATERIALS AND METHODS
Measurement of the donor globes with the Orbscan was performed as previously described. 6 Briefly, whole donor globes were mounted horizontally in their eye jars at the Orbscan. To model possible eye bank conditions, the eyes were mounted anatomically, but no attempt was made to modify the intraocular pressure, which was often below detectable levels. Wetting drops were applied, and an Orbscan map was taken of the eye in the eye jar. For the normal eyes, measurements were taken within 12 hours of the donor's death, which is the time interval in which our eye bank usually excises corneas for transplantation. For the refractive surgery eyes, measurements were taken as soon as possible after donor death and tissue receipt by the investigators.
Forty eyes from 22 donors were used for the control group. This is the same data set that we previously reported. 6 None of the control group donors was known to have corneal disease or a history of corneal surgery.
Pachymetry Analysis Method
The Orbscan measures the anterior and posterior surfaces of the cornea and allows maps of pachymetry to be constructed. For this study, the pachymetry maps were set to show five circular zones of thickness: central and then four midperipheral regions located 3 mm from the center (Fig. 1). 6
For each eye, the thickness of the central zone was subtracted from the thinnest midperipheral zone measurement. The differences in corneal thickness between the center and midperiphery in the eyes from the donors who had undergone refractive surgery were then compared with the differences in corneal thickness in the group of normal donor eyes.
Curvature Analysis Method
The Orbscan also produces corneal curvature maps. Tangential, axial, and other maps can be generated from each measurement. The tangential display generates mean curvature calculations at the 3-mm, 5-mm, and 7-mm zones (Fig. 2). For the curvature analysis method, the mean curvature at the 7-mm zone from the tangential display was subtracted from the mean curvature at the 3-mm zone for each eye. The differences in corneal curvature between the 7-mm zone and the 3-mm zone in the eyes from the donors who had undergone refractive surgery for myopia were then compared with the differences in corneal curvature in the normal donor group.
The Student t-test or the nonparametric Mann–Whitney test was used to compare the regional pachymetry and curvature differences in the control group with the pachymetry and curvature differences in the eyes that had undergone refractive surgery for myopia.
Any eye that had undergone refractive surgery, for which the measurement for the pachymetry or curvature method fell outside two standard deviations (SD) of the normal range, was considered to be outside the normal range and thus identified by the analysis method.
The mean age of the 22 donors in the control group was 72 ± 10 years (range, 53–90 years). The refractive surgery group was slightly younger (mean age, 49 years). Characteristics of the refractive surgery group are shown in Table 1.
Pachymetry Analysis Method
The average central pachymetry for the control group was 0.766 mm (Table 2). Corneal thickness over the entire surface was relatively uniform in the control group, with the difference between the center and the thinnest midperipheral reading averaging 0.040 mm. In contrast, the difference in thickness between the center and the thinnest midperipheral measurement in the refractive surgery eyes was greater than 0.040 mm in each of the eyes that had undergone laser refractive surgery. Not surprisingly, the RK eyes behaved more like the control group than like the laser eyes with regard to corneal thickness relationships.
The average difference in thickness between the periphery and the center in the refractive surgery group, including the RK eyes, was 0.086 ± 0.045 mm. This difference was significantly greater than the difference between the periphery and the center in the control group (p = 0.0028). The average difference between the periphery and the center in just the laser eyes was 0.099 ± 0.040 mm (p = 0.0002 as compared with the control group).
The difference in pachymetry measurements between the periphery and center in the control group was −0.012 mm to 0.092 mm (mean ± two SD) (Table 2). The difference between the periphery and center was outside two SD of the control group in four (40%) of 10 eyes that had undergone refractive surgery.
The pachymetry map from one of the LASIK eyes is shown in Figure 1. The thinnest midperipheral reading was 0.740 mm and the average central reading was 0.587 mm, for a difference of 0.153 mm. The cornea is thinnest near the center and gets progressively thicker toward the periphery. In comparison, the color of the pachymetry profile of eyes in the control group was generally purple all over, indicating more uniformly thick corneas. 6
One control eye had a difference in pachymetry measurements between the peripheral and central cornea that was outside two SD of the control range. However, the negative value (−0.029 mm) for the cornea indicates that the periphery was thinner than the center, which is the opposite of all the eyes that had undergone refractive surgery for myopia, which were thicker in the periphery than in the center.
Curvature Analysis Method
The normal control eyes had, on average, a prolate shape, with the cornea steeper in the center and flatter toward the periphery. This is indicated by the negative difference in curvature between the 7-mm zone and the 3-mm zone (Table 3). Conversely, seven of 10 of the eyes that had undergone refractive surgery for myopia had an oblate shape, with the cornea flatter in the center and steeper toward the periphery.
The difference in curvature between the 7-mm zone and the 3-mm zone in the control group was −0.2 ± 1.0 diopters (Table 3). The average difference between the 7-mm zone and the 3-mm zone in the refractive surgery group was 1.6 ± 2.1 diopters (p = 0.02 compared with the control group).
The mean ± two SD difference in curvature between the 7-mm zone and the 3-mm zone in the control group was −2.2 to 1.8 diopters (Table 3). The difference between the 7-mm zone and the 3-mm zone was outside two SD of the control group in four (40%) of 10 of the refractive surgery eyes.
The tangential map from a control eye is shown in Figure 2. The mean curvature at the 7-mm zone was 43.8 diopters and the mean curvature at the 3-mm zone was 44.1 diopters, for a difference of −0.3 diopters. The negative difference in curvatures indicates that the cornea is steeper in the center and flatter in the periphery.
A tangential map from one of the LASIK eyes (LASIK2 right eye) is shown in Figure 3. The difference in curvatures between the 7-mm zone and the 3-mm zone in this eye was 1.9 diopters (Table 3). The cornea has a noticeable blue circle of flattening in the center surrounded by a red ring of peripheral steepness.
Three control eyes had a difference in curvature between the 7-mm zone and the 3-mm zone that was outside two SD of the control range. However, two of the three eyes had negative differences, indicating that their central corneas were steeper compared with the periphery than the rest of the control group. If we consider as false positive only control eyes outside two SD of the normal range in the direction expected of eyes with refractive surgery for myopia (central cornea flatter than periphery), one (2.5%) of 40 control eyes fits the criteria for refractive surgery using this method.
Combination Analysis Method
If the eyes with refractive surgery for myopia are examined for those identified by the pachymetry method or the curvature method (i.e., having results that fall outside two SD of either analysis method), seven (70%) of 10 refractive surgery eyes are identified. Five (63%) of eight of the laser surgery eyes are identified by this method. One (2.5%) of 40 control eyes would be identified as refractive surgery for myopia using the combined technique.
The three eyes not identified by any analysis method used in this study were LASIK1 right eye, LASIK2 left eye, and LASIK3 right eye. LASIK1 right eye and LASIK2 left eye had central flat areas that were off-center in the topography maps (Fig. 4). Tangential maps for both eyes show an obvious circle of blue flattening near the center surrounded by steeper peripheries, but the off-center positioning diminished the magnitude of the difference in curvature between the periphery and the center. As a result, the curvature results for both eyes fall within two SD of the normal range (Table 3).
The third eye not identified by any of the analysis methods (LASIK3 right eye) was from a donor who had less than 2 diopters of correction in both eyes (Table 1). The other eye from the donor (LASIK3 left eye) was identified by our pachymetry method, but neither eye was identified by the curvature method. Visually, the tangential maps of both eyes from the donor only slightly suggest patterns indicative of refractive surgery. This case was identified in the family interview and the corneas were not transplanted.
Eye banks in the United States have a dilemma before them. The eye banks are not allowed to transplant tissue from donors who have had corneal refractive surgery before death, yet the eye banks may not always have the means to identify these donors.
The Lions Eye Bank of Oregon has had five donors in 3 years who were known to have undergone corneal refractive surgery. Of the five donors, three were in the last year, indicating the rate of receipt of such donors is increasing with time. One of the donors had undergone RK, so the scars were readily identifiable with the slit lamp. The other donors had laser refractive surgery for myopia. The PRK donor's cornea was clear and indicated no previous surgery, even when viewed by the eye bank's medical director, who was aware of the surgery. 2 The flaps in the LASIK donors' corneas could usually be seen with the slit lamp, but only by experienced technicians who were alerted to the presence of LASIK by the family interview.
Our laboratory has been investigating the use of corneal topography devices as possible additional tools for eye banks to use to screen for refractive surgery. 2,6 In our previous studies, we used the Orbscan slit scanning machine to produce corneal thickness profiles. We compared the profiles of a donor with bilateral PRK against the thickness profiles of 40 donors who were not known to have undergone refractive surgery. We found normal donor corneas thicken quickly after death, giving pachymetry patterns that are fairly uniform all over. In contrast, the PRK donor's corneas showed a distinct pattern of thinning near the center, presumably the area of ablation. The differences in thickness between the thinnest midperipheral region and the center in both eyes from the PRK donor were outside two SD of the normal range.
Since reporting the results of the pachymetry analysis of the donor with PRK, we received eight more eyes from donors with refractive surgery: two from a donor who had undergone bilateral RK and six from three donors who had undergone bilateral LASIK. In this study, we tested our pachymetry analysis technique against all eyes received and were able to identify four (40%) of 10 of the eyes with refractive surgery. Because RK does not appreciably affect corneal thickness, it was not surprising that those eyes were not identified using our pachymetry method. When we consider just the eyes that had undergone laser refractive surgery, the method identified four (50%) of eight eyes.
Normal corneas are generally prolate, with the cornea steepest in the central region and flattening from the center to the periphery. 7,8 Corneas after refractive surgery for myopia are oblate, with the cornea flattest in the central region and steepening from the center to the periphery. 9,10 These patterns are often readily identifiable. In fact, many refractive surgeons use anterior corneal topography maps as screening tools to rule out patients who are not candidates for refractive surgery because of corneal thinning, keratoconus, or other ectasias. 11,12
Because our pachymetry method identified just 40% of all the refractive surgery eyes and 50% of the laser refractive surgery eyes, we investigated whether the prolate–oblate dichotomy between normal corneas and corneas that have undergone refractive surgery for myopia could be used to differentiate the two groups. This method, surprisingly, gave no better overall differentiation than the pachymetry method, with 40% of the refractive surgery eyes falling outside two SD of the normal range. If just the laser refractive surgery group is analyzed with the curvature method, the differentiation is worse than with the pachymetry method, identifying two (25%) of eight of the laser eyes.
Combining the two analysis techniques allows 70% (seven of 10) of the refractive surgery eyes and 63% (five of eight) of the laser surgery eyes to be identified, an improvement over each separate technique. Combining pachymetry analysis with curvature analysis may have additional benefits not examined in this study, as it might allow corneal ectasias, such as pellucid marginal degeneration and inferiorly displaced keratoconus, to be identified in donor tissue.
Three eyes were not identified by any of the methods described in this study. LASIK3 right eye was from a donor with less than 2 diopters of correction in each eye, the lowest amount of correction in any donor in our study. The mate eye was identified by our pachymetry method, but neither eye had curvature maps that were subjectively or objectively suggestive of refractive surgery. These results may indicate the lower limits of sensitivity of these analysis methods.
To the trained eye, the patterns of flattening and steepening on the tangential maps in LASIK1 right eye and LASIK2 left eye (Fig. 4) clearly suggest refractive surgery for myopia, although the corneas were not identified by the mathematics. In fact, a trained observer would likely identify eight of the 10 curvature maps from the refractive surgery group as indicative of refractive surgery for myopia. It may be reasonable, therefore, for such pattern recognition to be taught to eye bank technicians as a means of increasing the sensitivity of the screening, although subjective identification should not be relied on exclusively for such screening.
The average age of the control group was greater than the average age of the refractive surgery donors. This difference was unavoidable because we did not want to risk contaminating whole eyes that had transplantable corneas by measuring them with the Orbscan. Older donors are less likely to have corneas that are transplantable, so the control group was generally older. Further work is required to determine whether the age differences between the two groups affected the results.
We considered any donor eye with refractive surgery that fell outside two SD of the normal range as identified by the method under discussion. We chose plus or minus two SD as a conventional and reasonable preliminary criterion for evaluation of a method for which no gold standard is available. This criterion reflects our intent to avoid false negatives. The rationale is that it is preferable to suspect a normal cornea has had refractive surgery and thus have to investigate further, by taking a closer look at the cornea with the slit lamp, interviewing the donor's eye doctor, and asking further questions of the donor's family, than to inadvertently transplant a cornea that has had refractive surgery.
During our study, we did not obtain any corneas that had undergone laser refractive surgery for hyperopia. Laser surgery for hyperopia removes tissue in the periphery while sparing the central cornea. 13 It is possible that corneas that have undergone laser surgery for hyperopia would fall outside two SD of the normal range in one or both of our techniques on the opposite end of the normal range from corneas having undergone laser surgery for myopia, similar to what we observed in corneas from a donor with keratoconus in a previous study. 6 However, we cannot establish this relationship until we have such corneas to measure.
We also did not have available to us corneas that had contact lens warpage. Contact lens warpage alters the topography of the cornea and sometimes makes the cornea appear to have keratoconus or other ectasias. 14 Objective screening methods such as those we propose may identify these corneas as abnormal. Although we tend to think of corneas with contact lens warpage as normal corneas that have undergone a temporary change in topography, a recent article by Liu et al. 15 indicates that contact lens warpage can cause corneas to be thinner, steeper, and more irregular than normal. One must consider whether these corneas really are normal and of transplantable quality. In any event, further investigation with the donor family and physicians would be warranted for any cornea identified as potentially abnormal by an objective screening test.
The effect of refractive surgery on donated eyes has not been extensively reported in the literature. In 1997, Schelonka and Ogawa 16 measured the topography of eyes from a donor who had undergone bilateral RK. The donor family did not mention the eye surgery during the consent process, but the eye bank technician identified radial slits during the slit-lamp examination. Tangential curvature maps with the EyeSys placido system (EyeSys Technologies, Houston, TX, U.S.A.) showed central flattening and midperipheral steepening similar to our results.
Mannis et al. 3 described a 56-year-old donor who, the family said, had undergone bilateral RK. No corneal scars were seen with a penlight, so the tissue was excised and prepared for transplantation. Under the slit lamp, however, the corneas showed central subepithelial haze. Further investigation with the donor's ophthalmologist confirmed that the donor had undergone bilateral PRK.
Mannis et al. acknowledge that corneal haze may not be as apparent with the slit lamp in other PRK donor eyes as in the pair they evaluated. They further suggest that LASIK eyes may be even harder to identify, because LASIK is known for its relative lack of haze as compared with PRK. 17
Costs associated with eye banking have increased dramatically in the last few years as a result of increased regulations and required testing and screening. Any additional screening device must be cost-effective and easy to use. Tissue asepsis must also not be put at risk by the use of the device. As currently arranged, the Orbscan cannot fulfill these goals. It is expensive (approximately $40,000 for a new unit) and its horizontally mounted videokeratoscope head is not suitable for aseptic tissue handling and measurement. The software, however, is relatively easy to use. If the cost of the instrument could be at an amount more manageable by eye banks (perhaps $10,000 per instrument) and the instrumentation made vertical, it could be a viable adjunct to the eye bank laboratory for the measurement of the corneal topography in whole globes.
Measurement of corneal topography by eye banks is complicated because more than half of all corneas procured in the United States are procured as corneoscleral rims at the donor, not as whole eyes (also known as in situ excisions). 18 The Orbscan and other similar instruments cannot measure the topography of corneoscleral rims. For excisions performed in situ, portable topography units may provide a method for measuring the topography at the donor site before the enucleation. The authors are currently investigating the usefulness and feasibility of one such device.
More sophisticated algorithms for comparing one portion of the cornea to another must be identified to increase the sensitivity and specificity of this screening method. For this study, we used the numbers that were automatically generated by the Orbscan, with the idea that it should then be easy to have the Orbscan perform the subtractions and flag any outliers. There are certainly more sophisticated mathematics that could be developed, analogous to the algorithms used for screening for keratoconus. 12,19
Few screening methods are meant to be used in isolation. It is unlikely any eye bank would or should rule out corneas for use in transplantation based solely on automated testing. However, pachymetry and topography analysis may provide an additional tool for eye banks to use to identify eyes that warrant further investigation.
The authors thank the Lions Eye Bank of Oregon for the cadaver eyes used in this study.
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