Changes in the refractive index of the human corneal stroma during laser in situ keratomileusis

ARTICLE

Changes in the refractive index of the human corneal stroma during laser in situ keratomileusis Effects of exposure time and method used to create the flap Sudi Patel, PhD, Jorge L. Alio´, MD, Alberto Artola, MD

PURPOSE: To compare the refractive index and calculated stromal bed hydration lifting the flap before and after photoablation during uneventful laser in situ keratomileusis (LASIK) using a microkeratome (M2, Moria) or a femtosecond laser (IntraLase, IntraLase Corp.) to create the flap. SETTING: Vissum-Instituto de Oftalmolo´gico de Alicante, Alicante, Spain. METHODS: Uneventful LASIK was performed in 76 eyes of 49 patients. Flaps were created using a microkeratome (57 eyes) or a femtosecond laser (19 eyes). On lifting the flap, the refractive index of the stroma was measured using a customized manual Abbe´ refractometer. The measurement was repeated immediately after photoablation. Treatment time was noted. Hydration was calculated using the Fatt-Harris equation. RESULTS: Before LASIK, the mean refractive index was 1.366 G 0.0049 (SD) in the microkeratome group and 1.374 G 0.0047 in the femtosecond group. After LASIK, it was 1.382 G 0.0066 and 1.391 G 0.0102, respectively. The increase after ablation was statistically significant in both groups (P<.001). The increase in the refractive index linearly correlated with treatment time (microkeratome: r Z 0.355, P Z .007; femtosecond, r Z 0.506, P Z .027). Before photoablation, the refractive index was significantly lower in the microkeratome group than in the femtosecond group (P<.001). There was no significant difference in age between the 2 groups. CONCLUSIONS: Photoablation increased the refractive index of the stroma, and the increase was influenced by treatment time. Hydration of the stroma was 1.8 mgm/mgm greater in the microkeratome group than in the femtosecond laser group. J Cataract Refract Surg 2008; 34:1077–1082 Q 2008 ASCRS and ESCRS

Refractive surgical procedures involving the cornea have the potential to affect corneal hydration. During laser in situ keratomileusis (LASIK), the corneal stroma is exposed to the atmosphere and then photoablated using an excimer laser. Water can be lost by passive evaporation, which is possibly accelerated by the photoablative process, leading to a decrease in corneal hydration.1–7 The hydration of the corneal stroma has an inverse relationship to the refractive index.8–14 To our knowledge, this was first proposed by Maurice,8 who used the Gladstone-Dale law15 to show that corneal refractive index depends on the cornea’s water content. Fatt and Harris,9 based on the work of Maurice, derived an algebraic expression equating stromal hydration with the refractive index of the human cornea. Q 2008 ASCRS and ESCRS Published by Elsevier Inc.

These earlier studies provide a clear indication that stromal hydration can be estimated by measuring the refractive index. Our group has shown that measured in vivo, the refractive index at the surface of the stromal bed increases after LASIK. In that previous study,13 the average increase in refractive index implied a fall in hydration induced by ablation of 1.4 mgm/mgm, equivalent to a fall in percentage water content of 7%. The photoablative process may have a temporal effect on stromal hydration and the refractive index. Longer exposure to the excimer laser may lead to more dehydration and further increase of refractive index. The LASIK surgeon can create the flap using a mechanical microkeratome or a femtosecond laser, and the outcomes of surgery are affected by the technology 0886-3350/08/$dsee front matter doi:10.1016/j.jcrs.2008.03.022

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used to create the flap.16–21 The aim of this study was to measure the refractive index of the stromal bed before and immediately after excimer laser photoablation and to determine whether the duration of excimer laser treatment influences a change in the refractive index of the stromal bed and whether the refractive index of the stromal bed is affected by the method used to create the flap. PATIENTS AND METHODS Study Design This prospective consecutive nonrandomized observational study was approved by the Ethical Board Committee and followed the tenets of the Declaration of Helsinki. Signed consent was obtained from every patient after the purpose and procedures of the study had been fully explained. Seventy-six eyes were included in the study. The eyes were divided into groups based on the method of flap creation. A mechanical microkeratome was used in the microkeratome group and a femtosecond laser in the femtosecond group.

Refractive Index Measurement The refractive index of the stromal corneal bed was measured using a handheld Abbe´ refractometer (pocket refractometer, Bellingham & Stanley Ltd.). The refractometer was modified, calibrated, and tested for reliability as described elsewhere.13 The precision of the refractometer was 0.0018 units of refractive index. Contact surfaces were cleaned and sterilized with surgical-grade alcohol before and after the measurement were taken.

Calculation of Hydration from Index of Refraction The hydration values were calculated using the FattHarris9 expression. In numerical terms, this algebraic expression for the human corneal stroma reduces to HZð1:0439  0:67 RIÞ=ðRI  1:3431Þ

ð1Þ

where H is hydration (mass of water present in tissue/mass of dry material in tissue) and RI is the refractive index of corneal stroma. The hydration values were calculated using equation 1.

Accepted for publication March 30, 2008. From the Research, Development and Innovation Department, Vissum-Instituto de Oftalmolo´gico de Alicante, and the School of Medicine, University Miguel Herna´ndez, Alicante, Spain. No author has a financial or proprietary interest in any material or method mentioned. Supported in part by a grant from the Spanish Ministry of Health, Instituto de Salud Carlos III, Red Tema´tica de Investigacio´n en Oftalmologı´a, Subproyecto de Cirugı´a Refractiva y Calidad Visual (Ref. CO3/13). Corresponding author: Dr. S. Patel, PhD, Practitioner Services, CSA, NHS Scotland, 1 South Gyle Cres, Edinburgh EH12 9EB, United Kingdom. E-mail: [email protected].

Surgical Technique and Measurements Preoperative preparation of the patients consisted of 1 drop of tetracaine 0.1% 10 minutes before surgery and 1 more drop at the beginning of the procedure. The eyelids were scrubbed with povidone–iodine 50% (Betadine) diluted in physiologic serum. One drop of the solution was also placed in the lower conjunctival sac. In all eyes, an eyelid speculum was used to begin flap creation. Then, an M2 mechanical microkeratome (Moria) or a 30 kHz IntraLase femtosecond laser (IntraLase, Inc.) was used to complete the flap. The tentative flap thickness with the M2 microkeratome was 110 mm and with the IntraLase laser, 100 mm. According to previous studies,22,23 the tentative thickness should result in a real flap thickness of approximately 100 mm for the M2 microkeratome and 105 mm for the IntraLase laser. The energy levels with the femtosecond laser microkeratome were 1.2 mJ raster, with a side-cut energy level of 2.2 mJ. With both microkeratomes, the flap hinges were located at 12 o’clock and the tentative flap diameter was 9.5 mm. Once the laser flap was created, photoablation was performed with an Esiris platform (Schwind) at 200 Hz in all cases. All ablations were myopic. Myopia ranged from 3.0 to 6.0 diopters (D) spherical equivalent. Once the photoablation was performed, the flap was repositioned and the interface was rinsed with a balanced salt solution for approximately 30 seconds. Then, the flap was left to dry for approximately 50 seconds, assisted by a cannula that dried the epithelial surface with air coming from the pipeline of the operating room. After the flap was lifted, the surgeon examined the stromal bed for irregularities. When the bed was clear of irregularities or complications, the refractometer test block was gently lowered onto the stromal bed. A small portable light source was placed close to the eye to aid observation of the dark and light fields. The refractive index was read off, the refractometer was gently lifted from the stromal bed, photoablation was commenced, a stopwatch was switched on, and the refractometer contact surface was cleaned with alcohol. When the ablation was complete, the stopwatch was switched off, the surgeon checked the stromal bed, and the refractive index measurement was repeated. The stromal surface was not irrigated between refractive index measurements.

Statistical Analysis All data were stored on a computer using a standard spreadsheet (Excel, Microsoft Corp.) and checked for normality (1-sample Kolmogorov-Smirnov test). Subsequently, for each group, the data were analyzed to determine whether (1) the refractive index was altered by photoablation (paired t test); (2) there was a correlation between any change in refractive index and time of exposure to the excimer laser (Pearson correlation coefficient [r]); (3) there was a correlation between any change in refractive index and the refractive index on lifting the flap (r); (4) there was a significant difference in age between patients in the 2 groups (unpaired t test); (5) there was a significant difference in the refractive index between the 2 groups on lifting the flap and immediately after photoablation (unpaired t test).

RESULTS The mean age of the 16 women (27 eyes) and 21 men (30 eyes) in the microkeratome group was 33.5 years

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Figure 1. Mean refractive index before and after photoablation.

(range 20 to 59 years). The mean age of the 5 women (7 eyes) and 7 men (12 eyes) in the femtosecond group was 34.3 years (range 22 to 70 years). The difference in age between groups was not significant (P Z .86, unpaired t test). No patient had complications that could adversely affect the outcomes of LASIK or the corneal refractive index. Within-Group Comparison In the microkeratome group, the mean refractive index of the stromal bed after ablation was significantly higher than before ablation (P!.001, paired t text) (Figure 1). Table 1 shows the mean hydration values calculated using equation 1 and the refractive index values. A significant correlation was revealed when the individual changes in refractive index were compared with the time of exposure to the excimer laser beam (r Z 0.355, P Z .007) (Figure 2). A significant correlation was revealed when the individual changes in refractive index were compared with the refractive index of the tissue before exposure to the excimer laser beam (r Z 0.458, P!.001) (Figure 3). In the femtosecond group, the mean refractive index of the stromal bed after ablation was significantly higher than before ablation (P!.001, paired t test) (Figure 1). A significant correlation was revealed when the individual changes in refractive index were compared with the time of exposure to the excimer laser beam (r Z 0.506, P Z .027) (Figure 2). However, a significant correlation was not revealed when the individual changes in refractive index were compared with the refractive index of the tissue before exposure to the excimer laser beam (r Z 0.385, P Z .103) (Figure 3). Between-Group Comparison The mean refractive index of the stromal bed was significantly lower in the microkeratome group than in the femtosecond group immediately before photoablation and immediately after photoablation (P!.001 and P Z .0016, respectively; unpaired t test).

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DISCUSSION In this study, we found that the mean refractive index of the stromal surface after planar resection of the cornea using the femtosecond laser was 1.374. In contrast, the mean refractive index of the stromal surface after planar resection of the cornea using the mechanical microkeratome was 1.366. The similarity in age between the patients in the 2 groups eliminates age as a causative factor. In both groups, the refractive index values were taken from the mid-stroma. In this study, we did not record the flap thickness in each individual case; however, the difference in thickness between the flaps created using the microkeratome and those created with a femtosecond laser is expected to be 5 mm. Nevertheless, it is possible that the difference in the mean refractive index between the 2 groups was related to differences in the stromal depths. A difference of 0.007 in refractive index exists between the anterior and posterior stromal surfaces of the cornea.24 The difference of 0.007 occurs along a thickness of approximately 500 mm, not 5 mm. Therefore, a small difference in thickness of approximately 5 mm was not likely a dominant factor in the 0.008 difference in the mean refractive index between the 2 groups. Other factors, therefore, must account for the differences we observed. According to the Fatt-Harris relationship,9 hydration of the mid-stroma was 4.0 when the stroma was dissected using the femtosecond laser and 5.6 when dissected using a microkeratome. Many surgeons generously irrigate the corneal surface and keratome grooves when the flap is created mechanically. Although using the microkeratome can be viewed as a relatively ‘‘wet’’ procedure, during this study care was taken to ensure that the stromal bed was not rewetted during flap production and before and immediately after photoablation. All practical factors that have the potential to increase hydration during flap production were controlled as well as possible during the study. The femtosecond laser creates a flap by breaking down and vaporizing local tissue at a preset plane. The gas bubbles formed during this process, coupled with any accelerated evaporation, will dehydrate the stroma, suggesting that the femtosecond flap creation is a relatively ‘‘dry’’ procedure. The suction ring used to stabilize the eye when the flap is created with a microkeratome raises intraocular pressure (IOP), leading to more water flowing into the stroma from the aqueous chamber if the IOP is not elevated above the swelling pressure within the stroma.2,25 The time lapse between placing the ring on the globe, initiating the suction, attaching the microkeratome, creating the flap, and removing the assembly may be sufficient to raise stromal hydration. However, a pressure-inducing suction ring is also used when the flap is

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Table 1. Mean refractive index and hydration immediately before and after photoablation. Mean G SD Refractive Index

Hydration

Flap Creation Method

Before Ablation

After Ablation

Before Ablation

After Ablation

Mean Age (Y) (Range)

Microkeratome* (nZ57) Femtosecond* (nZ19)

1.366 G 0.0049 1.374 G 0.0047

1.382 G 0.0066 1.391 G 0.0102

5.6 G 1.91 4.0 G 0.78

2.6 G 0.73 1.9 G 0.73

33.5 (20–59) 34.3 (22–70)

*

P!.001

created with the femtosecond laser. The refractive index in the femtosecond group compares favorably with the published values for human corneas.24,26–28 This adds weight to the argument that the stroma in the microkeratome group became hydrated above normal values. Although the pressure-inducing suction ring may have raised the stromal hydration in both groups, the femtosecond laser treatment may have counteracted this by accelerating evaporation. In both groups, photoablation led to an increase in mean refractive index. The increases were similar to those our group reported in an earlier study.13 Furthermore, the increase in refractive index was time dependent in both groups. The r2 values suggest that up to 21% of the increase in refractive index was associated with the time of exposure to the excimer laser. If the increase in refractive index is predominately related

to water loss, we would expect the thickness of the stromal bed immediately after ablation to be less than anticipated. According to the thickness–hydration relationship, corneal dehydration leads to thinning.29–31 During LASIK for myopia correction, the central thickness of the stroma immediately after ablation is less than that expected using standard nomograms.32–34 Furthermore, when online optical coherence pachymetry was used to monitor central corneal thickness during hyperopic LASIK, the central corneal thickness reduced at a rate of 0.27 mm/sec.7 This change in thickness was observed in a region precluded from photoablation and as such represents the rate of stromal dehydration that is expected during LASIK. By coupling the Fatt and Harris equation with the thickness–hydration relationships for the human cornea and incorporating this rate of change in stromal thickness as 0.27 mm/sec, one could predict an increase in the stromal refractive index of 0.003 after 120 seconds of exposure. This is the expected increase in the refractive index of the stromal bed by passive evaporation during LASIK over a period of 2 minutes. However,

Figure 2. Change in refractive index compared with time of excimer laser exposure in individual cases. The dotted line represents the least-squares regression line for the microkeratome group and the solid line, for the femtosecond group. Characteristics of the leastsquares lines are as follows: microkeratome, y Z 0.0104 C (0.89  104)t, r Z 0.355, n Z 57, P Z .007; femtosecond y Z 0.0054 C (1.6  104)t, r Z 0.506, n Z 19, P Z .027, where y is the individual change in the refractive index and t is the time of exposure (seconds).

Figure 3. Change in refractive index compared with refractive index immediately before photoablation in individual cases. The solid line represents the least-squares regression line for the microkeratome group. Characteristics of the least-squares lines are as follows: microkeratome, y Z 1.3714  0.3169 RI, r Z 0.458, n Z 57, P!.0001, where y is the individual change in the refractive index and RI is the initial refractive index.

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according to the least-squares regression lines in Figure 2, the actual change expected after 2 minutes of photoablation was 0.021 in the microkeratome group and 0.025 in the femtosecond group. Clearly, these values far exceed those expected from passive evaporation, indicating that accelerated water loss from the stroma accounts for the greater-than-expected increase in the refractive index and the additional thinning of the residual stromal bed reported by others.32–34 It has been claimed that the excimer laser will obliterate collagen–glycosaminoglycans, sparing water molecules.35,36 If water were spared, local hydration should increase and the natural flow of water from the posterior to the anterior stroma should further contribute to an increase in local hydration. Mishima and Hedbys37 report a stromal water flow rate of 0.8  103 mm3/hour per mm2 of surface area, for a pressure differential of 1 mm Hg. For the area of contact during our refractive index measurements (approximately 5 mm diameter circle), stromal surface exposure of 120 seconds, and an IOP of 20 mm Hg, an estimated 0.106 gm of water would have flowed into the anterior stroma, further soaking the region. Without accelerated loss of water from the stromal surface during photoablation, hydration of the surface should have increased with increasing exposure time, leading to a decrease in the refractive index. We observed the opposite; therefore, it is reasonable to accept that photoablation leads to an increase in the refractive index resulting from a decrease in hydration. The magnitude of stromal hydration is a key factor affecting the clinical results of LASIK procedures. When the cornea is dried before photoablation, there is a tendency toward overcorrection; conversely, when the tissue is hydrated, there is a tendency toward undercorrection.3,38 In the microkeratome group, we found a significant relationship between the pre-ablation refractive index and the observed change in the refractive index in individual cases. The lower the pre-ablation refractive index, the greater the change in the refractive index. This suggests that during photoablation, the more hydrated stroma is prone to a greater mass of water loss per unit time compared with the mass of water lost per unit time in the relatively less hydrated stroma. However, we did not find a comparable relationship in the femtosecond group. This may be a statistical anomaly due to a lack of sufficient numbers to reach significance in this group. The difference between the gradients of the 2 least-squares lines in Figure 2 suggests that the change in the refractive index per unit time of exposure to the excimer laser was greater in the femtosecond group. Using the appropriate least-squares line, it can be shown that for a 120-second exposure, the refractive index of the average cornea in the femtosecond

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group would increase from 1.374 to 1.399. In contrast, for the average cornea treated with the microkeratome, the refractive index would increase from 1.366 to 1.387. According to the Fatt-Harris relationship,9 hydration of the typical femtosecond-treated stroma should reduce by 2.1, from 4.0 to 1.9. Similarly, for the typical microkeratome-treated stroma, hydration should reduce by 3.0 units, from 5.6 to 2.6. Thus, if we were to target full myopic correction, a greater proportion of water would be lost compared with ground tissue in the microkeratome group than in the femtosecond group. As such, we would expect myopic undercorrection after the corneal stroma reverts to its equilibrium hydration level. This explains the findings in several studies: Kim and Jo,38 who report a tendency towards undercorrection after LASIK in eyes with relatively wet corneas; Durrie and Kezirian,19 who report that 3 months after LASIK to correct myopia, the mean spherical correction was 0.34 D in eyes in which the microkeratome was used but only 0.19 D in femtosecond laser cases; Kezirian and Stonecipher,18 who report that 73% of eyes treated with a microkeratome and 91% of eyes treated with a femtosecond laser achieved a postoperative refraction within G0.50 D. In conclusion, using femtosecond laser technology to create a corneal flap in LASIK induced changes in corneal hydration that were significantly different from those caused by mechanical microkeratomes. This information may be useful to better understand scientifically the changes in outcomes observed in LASIK when performed using femtosecond laser technology. REFERENCES 1. Maurice DM, Giardini AA. Swelling of the cornea in vivo after destruction of its limiting layers. Br J Ophthalmol 1951; 35:791–797 2. Mishima S. Corneal thickness. Surv Ophthalmol 1968; 13:57–96 3. Dougherty PJ, Wellish KL, Maloney RK. Excimer laser ablation rate and corneal hydration. Am J Ophthalmol 1994; 118: 169–176 4. Terry MA, Ousley PJ, Zjhra ML. Hydration changes in cadaver eyes prepared for practice and experimental surgery. Arch Ophthalmol 1994; 112:538–543 5. Ousley PJ, Terry MA. Hydration effects on corneal topography. Arch Ophthalmol 1996; 114:181–185 6. Aurich H, Wirbelauer C, Jaroszewski J, Hartmann C, Pham DT. Continuous measurement of corneal dehydration with online optical coherence pachymetry. Cornea 2006; 25:182–184 7. Wirbelauer C, Aurich H, Pham DT. Online optical coherence pachymetry to evaluate intraoperative ablation parameters in LASIK. Graefes Arch Clin Exp Ophthalmol 2007; 245:775–781 8. Maurice DM. The structure and transparency of the cornea. J Physiol (Lond) 1957; 136:263–286 9. Fatt I, Harris MG. Refractive index of the cornea as a function of its thickness. Am J Optom Physiol Opt 1973; 50:383–386 10. Laing RA, Sandstrum MM, Berrospi AR, Leibowitz MM. Changes in the corneal endothelium as a function of age. Exp Eye Res 1976; 22:587–594

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First author: Sudi Patel, PhD NHS Scotland, Edinburgh, United Kingdom