Corneal sensation is essential to maintaining the integrity of the ocular surface. Neurotrophic keratitis can result from common ocular disorders such as herpes simplex, herpes zoster infections, or from uncommon insults affecting the Vth cranial nerve such as tumor, irradiation, or strokes.1 In its early stages, neurotrophic keratopathy can manifest as an interpalpebral punctate keratitis and visual fluctuation and can progress to loss of epithelial integrity and corneal stromal melting.2
Corneal surgical procedures may disrupt the normal organization of corneal innervation; this includes refractive surgery, which has been shown to cause decreased corneal sensation. This has been documented after epikeratophakia,3 radial keratotomy,4 photorefractive keratectomy,5 and laser in situ keratomileusis (LASIK).6–9
As the popularity of LASIK has grown, the number of patients experiencing dry-eye symptoms has grown as well. According to the 2003 Refractive Surgery Survey,10 dry-eye symptoms are the most common problem encountered after LASIK and occur in 15% to 25% of patients. Several factors may influence these symptoms, but decreased corneal sensation may play a major role. Wilson et al.11,12 have described corneal staining after surgery as LASIK-induced neurotrophic epitheliopathy. Other potential factors include difficulty wetting the ocular surface due to mechanical and shape factors and a loss of neuroregulatory factors derived from the corneal nerves that promote epithelial health.
The subject of corneal innervation has gained importance in recent years because of the observation that corneal nerves are routinely injured following modern refractive surgical procedures. An example is LASIK surgery, in which a microkeratome is used to create a hinged lamellar corneal flap, disrupting the normal organization of corneal innervation. This damage can lead to transient or chronic neurotrophic deficits.11,12 Some authors suggest the corneal nerves predominantly enter the cornea at the 9 and 3 o'clock positions, thus creating a LASIK flap with a hinge that provides a potential conduit for superficial innervation. A vertical flap (superior hinge) would transect both major areas of corneal innervation, whereas a horizontal flap (nasal hinge) would transect only 1 of these areas.13 This suggests that a nasally hinged corneal flap may cause less loss of sensation than a superior hinge.13–16 However, Müller et al.17 report finding that leashes extend across the corneal apex preferentially in the 6 to 12 o'clock direction and other leashes approach the apex in the 5 to 11, 7 to 1, 9 to 3, 2 to 8, and 4 to 10 o'clock directions. Descriptions of the anatomy of mammalian corneal innervation are numerous; nevertheless, many aspects of corneal nerve architecture remain incompletely understood. The true distribution of corneal nerves is controversial and still being elucidated.
The purpose of this study was to determine the effects of hinge position (superior versus nasal) on corneal sensation and dry-eye signs and symptoms after LASIK.
PATIENTS AND METHODS
Included in this prospective randomized masked study were 94 eyes of 47 myopic patients of both sexes with low to moderate myopia up to –8.00 diopters (D) with or without astigmatism up to –3.00 D who had bilateral LASIK treatment. Patients were identified from those accepted and scheduled for LASIK surgery at the Magill Laser Center. Once identified as a LASIK candidate, informed consent to participate in the study; the patient had to provide in accordance with the guidelines of the Medical University of South Carolina Institutional Review Board.
Laser ablation in both eyes was performed using the Visx S3 laser (n = 43) using an optical zone of 6.5 mm or the LADARVision 4000 laser (Alcon Laboratories) (n = 4) with an optical zone of 7.0 mm, under topical anesthesia. The superior hinge flap was created using the Hansatome microkeratome (Bausch & Lomb) with a 180 μm plate depth and the nasal hinge was created using the Amadeus microkeratome (Advance Medical Optics) with a 160 μm plate depth. The Hansatome had a standard hinge that was not adjustable. The Amadeus unit was adjusted based on keratometry values and a nomogram to achieve a 5.0 mm hinge width. The hinge position was randomly assigned to the first eye, and the alternate hinge location was created in the patient's other eye. Hinge location was masked to the patient and technicians collecting the data. An 8.5 mm ring size was used in all cases. The hinge width was measured with calipers at the time of surgery.
Postoperatively, all patients were given prednisolone acetate 1% ophthalmic solution (Pred Forte) and ofloxacin 0.3% ophthalmic solution (Ocuflox) to use 4 times a day for 1 week. Patients were also directed to use nonpreserved artificial tears (Refresh Tears) 4 times a day for 2 weeks and then as needed.
Every patient had preoperative and postoperative (1 week and 1, 3, and 6 months) evaluations. Uncorrected and best corrected visual acuity (CSV-1000ETDRS, Vector Vision), contrast sensitivity (CSV-1000E, Vector Vision), corneal sensation (Cochet-Bonnet Corneal Aesthesiometer, Luneau Ophtalmologie), basic secretion test, tear breakup time (TBUT), ocular surface staining, and a questionnaire containing 12 questions evaluating dry eye under specific conditions (Ocular Surface Disease Index [OSDI])17 were obtained for each patient.
The Cochet-Bonnet corneal aesthesiometer was used to assess corneal sensation, as previously described.18 It consists of a thin 6.0-cm adjustable nylon monofilament touching the cornea. The filament is soft when fully extended and becomes firm when retracted into the handpiece, creating a pressure gradient that ranges from 11 to 200 mg/mm2. To measure corneal sensation, the filament is applanated against the corneal surface perpendicularly until a small bend is noted; subsequently, the filament is retracted until the patient feels it. The length of the filament at this point is the numeric measurement of corneal sensation. The higher the number obtained, the more sensitive the cornea. Corneal sensation was measured centrally, superiorly, inferiorly, nasally, and temporally approximately 3.0 mm from the central point.
Basic Secretion Test
After installing a drop of proparacaine 1% in each eye and drying the fornix, a sterile standardized Schirmer Tear Test Strip (Alcon Laboratories) was placed in both inferior fornices at the junction of the lateral and middle third and then measured at 5 minutes. The strip wetting was measured and recorded in millimeters.
Tear Breakup Time
Sodium fluorescein was instilled into the eye and the time (seconds) from the last blink to the first area of breakup was recorded.
Ocular Surface Staining
The conjunctival and corneal staining measurements were graded from 0 (none) to 4 (severe) based on the amount of staining when compared to the Oxford Scheme of ocular surface staining. The cornea was divided into the central cornea the superior, inferior, nasal, and temporal quadrants, similar to the segments suggested at the National Eye Institute Industry Workshop.19 The conjunctiva in the superior, middle, and inferior third of the exposed conjunctiva was evaluated. Lissamine green and fluorescein were used to stain the ocular surface.
Ocular Surface Disease Index
The Ocular Surface Disease Index (OSDI) was developed by the Outcomes Research Group (Allergan) and consists of a 12-item questionnaire designed to provide a rapid assessment of the symptoms of ocular irritation consistent with dry-eye disease and their impact on vision-related functioning. The 12 questions are subscaled into 3 categories: vision-related function (6 questions), ocular symptoms (3 questions), and environmental triggers (3 questions). The grading of the OSDI is from 0 to 4, where 0 indicates none of the time; 1, some of the time; 2, half of the time; 3, most of the time; and 4, all of the time. The total OSDI score was calculated on the basis of the following formula: OSDI = [(sum of scores for all questions answered) × 100] / [(total number of questions answered) × 4].17 The results are numerical from 0 to 100, where the higher scores represent a greater disability.
Wilcoxon signed rank test and paired t test were used for statistical analysis. A P value less than 0.05 was considered statistically significant. It should be noted that a large number of comparisons have been performed, so actual P values have been reported when results were found to be significant. Assuming the listed standard deviations, this study has 80% power to pick up differences in mean scores of 0.7 mm ± 1.5 for corneal sensation, 0.8 ± 1.8 seconds for TBUT values, 2.3 ± 5.0 mm for Schirmer's scores, and 0.8 ± 0.17 logMar for visual acuity.
Forty-seven patients with a mean age of 38.6 ± 9.9 years (range 22 to 55 years) had bilateral LASIK with 1 eye randomly having a superior-hinge and the other a nasal-hinge flap. All patients had myopia with or without astigmatism, with a mean preoperative spherical equivalent (SE) of –4.2 ± 2.0 D (range –0.5 to –9.75 D).
Table 1 summarizes the preoperative values for visual acuity, average keratometry, pachymetry, central corneal sensitivity, TBUT, basic secretion test (BST), SE, intraoperative hinge width measurements, and ablation depth. No preoperative differences were found between groups.
Bilateral small epithelial slides without frank defects were noticed in 3 patients (6 eyes). A unilateral epithelial slide without frank defect was found in 1 patient (nasal hinge group). In these patients, LASIK was performed cautiously and proper care was taken in the postoperative period. There were no other intraoperative or postoperative complications at the 6-month examination.
The mean preoperative corneal sensation was 5.21 ± 1.17 mm (out of 6.0 mm) in the nasal group, and 5.27 ± 1.12 mm (out of 6.0 mm) in the superior group. At 6 months, there was a return from preoperative levels in the nasal-hinge group to 4.8 ± 1.13 mm and 4.9 ± 1.11 mm in the superior-hinge group. There was no statistical difference between preoperative and 6-month postoperative sensation in either group. There was no difference between groups at both time points.
Baseline mean central corneal sensation was 5.28 ± 1.23 mm in the nasal group and 5.26 ± 1.09 mm in the superior group. Central corneal sensation was significantly (P<.001) depressed at all postoperative visits in both eyes compared to baseline (Figure 1). However, there was no difference in central corneal sensitivity between eyes at any postoperative visit. Sensation was lowest at the first postoperative week (mean 2.86 ± 2.55 mm nasal group; 3.09 ± 2.43 mm superior group) and gradually improved with time but was significantly lower at 6 months (mean 4.24 ± 1.87 mm nasal group; 4.43 ± 1.58 superior group).
Corneal sensation measured postoperatively in the temporal, nasal, and inferior quadrants was generally less than at baseline. At 1 month, there was a significant difference in nasal sensation between the 2 groups. The eyes with the nasal hinge had significantly better nasal sensation (mean 5.1 ± 1.44 mm) than those with the superior hinge (mean 4.46 ± 1.87 mm) (P = .007). This trend was present at all postoperative visits but obtained statistical significance only at 1 month (Figure 2). Corneal sensation in the superior quadrant was significantly depressed in both eyes at 1 week (P<.03) and 1 month (P = .02), and in the superior-hinge group at the 3-month visit (P = .039). It returned to baseline in both groups by the 6-month visit.
Basic Secretion Test
Preoperative mean BST was 15.61 ± 11.9 mm in the nasal group and 15.35 ± 11.6 mm in the superior group. Eyes in the Amadeus and Hansatome groups had a significant (12.1 ± 9.16 mm, P = .038; 11.57 ± 7.94 mm, P = .037, respectively) decrease in tear production at the 1-week visit compared with preoperative levels. In neither group was the BST statistically different from baseline at any other time point. There was no difference between groups at any examination (Figure 3).
Corneal and Conjunctival Staining
Corneal staining was present in all areas in 18 patients (38.3%) preoperatively. Three patients (6.4%) presented staining in the central area. Although the mean scores were less than 1 in all 5 areas at all time points, there was no statistical difference between the preoperative and postoperative staining scores. Additionally, there was no difference between the staining scores between groups at any time point. Preoperative and 6-month postoperative central corneal staining scores are seen in Figure 4.
Results of conjunctival staining were similar to those found in the cornea. At no time point was the average staining for the entire group above 1 in any sector. There was no statistical difference between preoperative and postoperative scores for either microkeratome. Furthermore, there was no difference between groups at any time point.
Tear Breakup Time
At the 1-week and 1- and 3-month visits, TBUT was low compared with baseline. However, statistical significance was found at the 3-month visit when comparing the 2 groups (nasal, 8.14 seconds; superior, 7.70 seconds) to the baseline (10.6 and 9.98 seconds respectively; P = .002 and P = .001, respectively) and at the 1-week visit (P = .026) in the nasal hinge group. At the 6-month visit, TBUT levels returned to normal (Figure 5). Values between groups were never significantly different.
Ocular Surface Disease Index
The mean preoperative OSDI score was 17. The scores were significantly elevated at 1-, 3-, and 6-month postoperative visits compared with preoperative scores (P<.01). Table 2 illustrates the numerical OSDI scores that range from 17 to 42, where the higher scores represent a greater disability. The scores were highest at 1 month and gradually decreased to near baseline at month 6. The questionnaire showed no statistical difference between the hinge positions and the patient's complaints between the 2 groups.
With the exception of the 1-week visit, there was no statistically significant difference in contrast sensitivity between the groups. There was a statistically significant difference (P = .047) at 18 cpd, with a decrease in contrast in the nasal hinge group at the 1-week visit only.
Normal tear function is essential for maintaining corneal function and structure. Dry eye has become an increasingly well documented complication following LASIK. A number of possible etiologies explaining the appearance of this complication have been proposed, including damage of the globlet cells by the pressure generated by the suction ring, alteration of the corneal curvature affecting tear stability, and medications that can induce transient dry-eye symptoms.11 More significant is the transection of a significant number of afferent sensory nerves in the cornea during the formation of the flap, and therefore interruption of the cornea–trigeminal nerve–brain stem–facial nerve–lacrimal gland reflex arc that influences both basal and stimulated tear production.6,12–14,16,20,21
The microkeratome severs most of the nerves that course from the limbus to innervate the stroma and epithelium in the central cornea. This may produce a neurotrophic epitheliopathy that could cause decreased tear production based on an inhibited feedback loop from the cornea to the lacrimal gland. The decrease in basic secretion test at the first-week visit in our patients may be related to this inhibition. Damage to the corneal nerves may also have a direct effect on the health of the epithelium. In diseases in which the trigeminal nerve has been damaged, a nonhealing epithelial defect can occur. This epithelial breakdown may be due to poor blinking, decreased tear production, or loss of direct neurotrophic effects on the epithelium. In some patients with dry eye after LASIK, there are signs of dryness with relatively few symptoms and ample tear production. These patients may be suffering from the loss of the direct effects that the corneal nerves may have in maintaining a healthy epithelium.
This study confirms the alteration in the ocular surface that has been previously reported. Central corneal sensation was significantly depressed in both groups for the entire 6-month duration of the protocol. This is compatible with results from several other studies.14,16,22 Nasarella et al.16 demonstrated a decrease of corneal sensitivity at the central and paracentral areas for as long as 9 months. Furthermore, Battat et al.21 found that corneal and conjunctival sensitivity did not return to preoperative levels, even by 18 months postoperatively. We noted a transient decrease in tear production at 1 week that increased to normal levels at 1 month. The TBUT was also reduced at the 1-week and 1-month visits. These alterations were shown to be subjectively important because patients reported increased dryness using the OSDI 1, 3, and 6 months postoperative visits.
Donnenfeld et al.13 and Lee and Joo,15 among others, have described differences between nasal and superior hinges in corneal sensation and dry eye, based on the observations of studies that showed nerve fibers oriented in a 9 o'clock to 3 o'clock (temporal-to-medial) orientation. Our study demonstrated improved nasal corneal sensation at 1 month in the nasal hinge group but found no difference in dry eye. This agrees with recent studies using in vivo confocal microscopy that show that subbasal nerve fibers run in a 6 o'clock to 12 o'clock (superior-to-inferior) orientation.17 As mentioned earlier, Muller et al.17 reported finding that leashes extend across the corneal apex preferentially in the 6 to 12 o'clock, whereas other leashes approach the apex in the 5 to 11, 7 to 1, 9 to 3, 2 to 8, and 4 to 10 o'clock direction.
The current description is that nerve bundles enter the cornea at the periphery in a radial fashion parallel to the corneal surface. Most stromal nerve fibers are located in the anterior third of the stroma; however, thick stromal nerve trunks move from the periphery toward the center below the anterior third of the stroma due to the organization of the collagen lamellae.17 Eventually, the stromal nerve fibers turn abruptly 90 degrees and proceed toward the corneal surface. The nerves penetrate Bowman's layer throughout the peripheral and central cornea.23 After penetrating Bowman's layer, the large nerve bundles divide into several smaller ones. Each small nerve bundle then turns abruptly once more at 90 degrees and continues parallel to the corneal surface, between Bowman's layer and the basal epithelial cell layer, as an epithelial leash. The exact orientation and the depth of nerve fiber bundles is not known and may vary between patients.17,23–25 There is also a question as to how the nerves regenerate. Will nerve fibers reinnervate the central cornea by growing from underlying stroma or will peripheral nerves grow centrally? The pattern of regrowth could affect the speed of reinnervation as well as our understanding of the potential benefits of certain hinge locations.
Donnenfeld et al.13 demonstrate a significant reduction in corneal sensation that did not return to preoperative levels even by 6 months in eyes with superior hinge flaps, whereas there was full recovery at 6 months in the nasal hinge group. We did not note such a large difference between groups. One difference between the studies was flap diameter. We used an 8.5 mm ring in all cases, whereas they used a 9.5 mm ring. A larger flap could denervate a larger surface area of the cornea and enhance any differences caused by hinge location. Lee et al.15 also compared hinge location and dry-eye signs. They found a significant decrease in TBUT and BST at 2 months in the superior-hinge group compared with the nasal-hinge group. On the other hand, Kumano et al.14 showed that the decrease in corneal sensitivity in patients with a nasal hinge was significantly greater than in those with a superior hinge (P<.01) at 1 and 3 months postoperatively, although there was no significant difference between the groups at 6, 9, and 12 months after surgery.
We found a significant difference in nasal corneal sensitivity only at 1 month, with better sensation in the nasal hinge group. This study demonstrated little difference in dry eye measurements when an 8.5 mm ring was used. We also established that dry eye and decreased corneal sensitivity affect many LASIK patients postoperatively and that even 6 months after surgery, corneal sensitivity was significantly decreased compared to preoperative measurements.
Factors such as flap size, hinge width, and flap depth play an important role in the health of the corneal surface. Flap thickness can be among the key issues because corneal nerves can be severed at various stromal levels. It is well known that there is variability between microkeratome models.26 To control differences in flap thickness due to the variability between the 2 microkeratomes used in this study, head serial numbers for our 2 microkeratome models with the closest mean flap thickness were used. Our data indicated that our Amadeus 160 had a mean flap thickness of 152 ± 25 μm and our Hansatome 180 generated a mean flap thickness of 167 ± 39 μm.26
In conclusion, it is important that surgeons attempt to avoid inducing dry eye after LASIK. Careful preoperative evaluation to identify patients at risk for dry-eye symptoms and preoperative treatment may minimize this common finding postoperatively. Use of a vertically hinged flap improves corneal sensation in the nasal quadrant and may theoretically decrease the chance of dry-eye symptoms, although we could not confirm this. Further elucidation of corneal nerve organization and regrowth patterns may help us understand how to minimize dry eye after LASIK.
1. Martin XD, Safran AB. Corneal hypoesthesia. Surv Ophthalmol 1988; 33:28-40; see notes, 217
2. Lambiase A, Rama P, Aloe L, Bonini S. Management of neurotrophic keratopathy. Curr Opin Ophthalmol 1999; 10:270-276
3. Koenig SB, Berkowitz RA, Beuerman RW, McDonald MB. Corneal sensitivity after epikeratophakia. Ophthalmology 1983; 90:1213-1218
4. Shivitz IA, Arrowsmith PN. Corneal sensitivity after radial keratotomy. Ophthalmology 1988; 95:827-831; discussion by JP Gilbard, 831–832
5. Kanellopoulos AJ, Pallikaris IG, Donnenfeld ED, et al. Comparison of corneal sensation following photorefractive keratectomy and laser in situ keratomileusis. J Cataract Refract Surg 1997; 23:34-38
6. Matsui H, Kumano Y, Zushi I, et al. Corneal sensation after correction of myopia by photorefractive keratectomy and laser in situ keratomileusis. J Cataract Refract Surg 2001; 27:370-373
7. Patel S, Pérez-Santonja JJ, Alió JL, Murphy PJ. Corneal sensitivity and some properties of the tear film after laser in situ keratomileusis. J Refract Surg 2001; 17:17-24
8. Benitez-del-Castillo JM, del Rio T, Iradier T, et al. Decrease in tear secretion and corneal sensitivity after laser in situ keratomileusis. Cornea 2001; 20:30-32
9. Chuck RS, Quiros PA, Perez AC, McDonnell PJ. Corneal sensation after laser in situ keratomileusis. J Cataract Refract Surg 2000; 26:337-339
10. Solomon KD, Fernández de Castro LE, Sandoval HP, et al. Refractive surgery survey 2003. J Cataract Refract Surg 2004; 30:1556-1569
11. Wilson SE, Ambrósio R Jr. Laser in situ keratomileusis-induced neurotrophic epitheliopathy. Am J Ophthalmol 2001; 132:405-406
12. Wilson SE. Laser in situ keratomileusis-induced (presumed) neurotrophic epitheliopathy. Ophthalmology 2001; 108:1082-1087
13. Donnenfeld ED, Solomon K, Perry HD, et al. The effect of hinge position on corneal sensation and dry eye after LASIK. Ophthalmology 2003; 110:1023-1029; discussion by CJ Rapuano 1029–1030
14. Kumano Y, Matsui H, Zushi I, et al. Recovery of corneal sensation after myopic correction by laser in situ keratomileusis with a nasal or superior hinge. J Cataract Refract Surg 2003; 29:757-761
15. Lee K-W, Joo C-K. Clinical results of laser in situ keratomileusis with superior and nasal hinges. J Cataract Refract Surg 2003; 29:457-461
16. Nassaralla BA, McLeod SD, Nassaralla JJ Jr. Effect of myopic LASIK on human corneal sensitivity. Ophthalmology 2003; 110:497-502
17. Müller LJ, Marfurt CF, Kruse F, Tervo TMT. Corneal nerves: structure, contents and function. Exp Eye Res 2003; 76:521-542; errata 2003; 77:253
18. Schiffman RM, Christianson MD, Jacobsen G, et al. Reliability and validity of the Ocular Surface Disease Index. Arch Ophthalmol 2000; 118:615-621
19. Pérez-Santonja JJ, Sakla HF, Cardona C, et al. Corneal sensitivity after photorefractive keratectomy and laser in situ keratomileusis for low myopia. Am J Ophthalmol 1999; 127:497-504
20. Lemp MA. Report of the National Eye Institute/Industry Workshop on Clinical Trials in Dry Eyes. CLAO J 1995; 21:221-232
21. Battat L, Macri A, Dursun D, Pflugfelder SC. Effects of laser in situ keratomileusis on tear production, clearance, and the ocular surface. Ophthalmology 2001; 108:1230-1235
22. Toda I, Asano-Kato N, Komai-Hori Y, Tsubota K. Dry eye after laser in situ keratomileusis. Am J Ophthalmol 2001; 132:1-7
23. Müller LJ, Pels EL, Vrensen GFJM. Ultrastructural organization of human corneal nerves. Invest Ophthalmol Vis Sci 1996; 37:476-488
24. Kim J, Foulks GN. Evaluation of the effect of lissamine green and rose bengal on human corneal epithelial cells. Cornea 1999; 18:328-332
25. Müller LJ, Vrensen GFJM, Pels EL, et al. Architecture of human corneal nerves. Invest Ophthalmol Vis Sci 1997; 38:985-994
26. Solomon KD, Donnenfeld E, Sandoval HP, et al. Flap thickness accuracy: comparison of 6 microkeratome models; Flap Thickness Study Group. J Cataract Refract Surg 2004; 30:964-977