Laser in situ keratomileusis (LASIK) is a relatively safe, predictable, and effective method for correcting low to moderately high (up to -15.00 diopters [D]) myopia with many advantages over other existing procedures such as fast and painless recovery of vision, less regression, and less subepithelial haze.1"3 However, patients subjected to LASIK surgery often report dry eye symptoms postoperatively, and tear fluid abnormalities have often been reported.4"7 These symptoms represent the most common adverse effect of LASIK surgery3 and are supposed to be associated with severing of the corneal nerves in LASIK surgery. The lamellar incision made with the microkeratome to create the flap cuts the nerve fiber bundles of the superficial stroma and the subbasal nerve plexus at the flap. Nerve fiber bundles in the corneal bed located in the middle third of the stroma are spared but suffer a variable degree of injury during photoablation.8"13 Accordingly, an early loss of corneal sensitivity to coarse mechanical stimulation has been reported followed by a progressive recovery of sensitivity during the following 6 postoperative months, and by 6 to 12 months sensitivity has recovered to normal levels. 10,12,14"20 On the other hand, confocal microscopy studies have shown that morphological recovery of corneal innervation may take even longer than 12 months or total nerve recovery may never occur after LASIK.9·10·12 These studies also suggest a correlation between regeneration of subbasal nerves after surgery and recuperation of mechanical sensitivity.12
In this study, we evaluated corneal sensitivity and subjective dry eye symptoms and objective findings after high myopic LASIK surgery. The purpose of our study was to determine the relationship between subjective dry eye symptoms and objective findings as well as to clarify the impact of corneal sensitivity in these patients.
PATIENTS AND METHODS
The study evaluated 20 eyes of 20 patients (14 women and 6 men) who had undergone high myopic LASIK 2 to 5 years previously. Mean patient age was 34±7.4 years, and mean follow-up was 44.2±11.3 months (range: 23 to 58 months). A cohort of patients who met the inclusion criteria was selected from the database of our hospital. They were sent an invitation letter in which we offered an additional follow-up examination. The inclusion criteria were high myopic correction (> 10.00 D) with or without astigmatic correction and time interval after the last LASIK surgery of 3=2 years. Exclusion criteria were retreatments and history of any other ophthalmic surgical operations. The first 20 consecutive patients were included in the study. Ten eyes of 10 normal volunteers (6 women and 4 men, mean age 39. 8± 10.4 years) served as a control group. Informed consent was obtained from every participant of the study. The study was approved by the local ethical review board. The tenets of the Declaration of Helsinki were followed.
The corneal flap was created with an automated Hansatome microkeratome (Hansatome, model HT 230; Chiron Vision, Hansa Research & Development Ine, Miami, FIa). The intended thickness of the flap was either 160 or 180 microns with a superiorly located hinge. Subsequent laser ablation was performed using the VISX Star S2 (VISX Co, Sunnyvale, Calif) excimer laser. Patients were prescribed topical ofloxacin 3 mg/mL (Exocin; Allergan Pharmaceuticals Ltd, Westport, Ireland) three times daily for 7 days and fluorometholone 1 mg/mL (Liquifilm-FML, Allergan Pharmaceuticals Ltd) twice daily for 7 days starting on day 2. Nonpreserved artificial tears were to be used four times a day for at least 6 months after the operation. All operations but one were uneventful and were performed by the same surgeon (T.M.T.) between 1999 and 2002. One patient developed diffuse lamellar keratitis (DLK) due to epithelial erosion during the surgery.
All patients were evaluated for uncorrected (UCVA) and best spectacle-corrected (BSCVA) visual acuity, manifest and cycloplegic refractions, tonometry, slitlamp examination, and dilated funduscopic examination. Corneal fluorescein staining was graded from 0 to 15, as recommended by Lemp.21
A Schirmer's test was performed using a Schirmer test strip (Clement Clarke International Ltd, Harlow, United Kingdom). Two drops of oxybuprocaine hydrochloride 4 mg/mL (Oftan Obucain; Santen Oy, Tampere, Finland) were administered to prevent reflex tearing. The strip was positioned at the intersection of the temporal third with the nasal two thirds of the lower eyelid and the patient waited for 5 minutes with his eyes closed until the strips were removed and the length of the moistened area was measured.
TEAR BREAK-UP TIME
To measure tear break-up time (BUT), one drop of oxybuprocaine hydrochloride 3 mg/mL and sodium fluorescein 1.25 mg/mL (Oftan Flurecain, Santen Oy) dye was instilled in the lower conjunctival sac with a micropipette. The tear film was observed under cobalt-blue-filtered light. The interval between the last complete blink and the first appearance of randomly distributed dry spots was measured. The average of three measurements was obtained.
SUBJECTIVE DRY EYE SYMPTOMS
Subjective symptoms were evaluated using the Ocular Surface Disease Index (OSDI) questionnaire, which is a reliable and validated 12-item questionnaire used to assess subjective symptoms in ocular surface diseases and the impact on visual functioning.22 In addition, patients were asked to answer yes or no to the following questions: 1) Do you have dry eyes, and 2) Would you choose LASIK surgery again?
CORNEAL NON-CONTACT ESTHESIOMETER
The central corneal mechanical sensitivity was assessed with modified Belmonte Non-Contact Esthesiometer, developed by the Cooperative Research Center for Eye Research and Technology, Sydney, Australia, based on an instrument previously designed by Dr Carlos Belmonte, which has been extensively used in assessing corneal sensation in animals and humans.23'24 The instrument is mounted on the frame of an air tonometer, and it has a box controller and two gas tanks, which contain 100% air and 100% CO2, respectively. The tip of the esthesiometer is adjusted to a distance of 4 mm in front of the cornea, using a focusing mechanism.
Characteristics of LASIK Patients and Controls Assessed for Subjective and Clinical Symptoms of Dry Eye and Corneal Sensitivity
Study participants were seated in front of the gas esthesiometer, with their chin placed in a cup and their forehead against a band. An audible click produced by the opening of the gas valve identified the onset of the stimulus. After each pulse, the individual was asked to report if the stimulus was felt independently of the sensation evoked. Sequential stimulus was only performed after the patient reported no sensation from the previous stimulation. The patients were asked to blink freely between the stimuli.
Mechanical stimulation consisted of a series of pulses of warmed air (constant temperature of 42°C at the tip of the probe) with flow varying from 0 to 160 mL/min, applied to the central corneal surface. Sensation caused by the mechanical stimulation was determined using the visual analog scale. Briefly, a series of two-second pulses were applied randomly in 20 mL/min increments from 160 mL/min to 20 mL/min. After the negative answer, the next stimulus was 10 mL/min higher until the lowest positive value was achieved. The lowest airflow that elicited a response, even weakly, was recorded as the mechanical threshold.
For statistical analysis, Snellen acuity was converted to the logMAR value of acuity. Statistical comparisons between groups were performed either with the t test or with the Mann-Whitney U test using SPSS for Windows (version 11.0; SPSS Ine, Chicago, 111). Pvalues <.05 were considered statistically significant.
The demographic data and data concerning subjective dry eye symptoms and objective signs are shown in the Table. No difference was found in objective dry eye tests: Schirmer's test values did not differ between patients and controls; LASIK patients showed higher scores (the opposite could be supposed); however, they were not statistically significant. Tear BUT was equal, and none of the patients or controls showed corneal fluorescein staining.
The preoperative spherical equivalent refraction in the LASIK group was -11.40±1.40 D (range: -9.10 to -14.00 D) and the spherical equivalent refraction of intended correction was -10. 40 ±1.10 D (range: -8.30 to -12.50 D). At last postoperative follow-up, the mean manifest refraction was -1.90±1.60 D and the UCVA was 20/40 or better in 6 (60%) of 10 eyes that were targeted for emmetropia. The difference between the spherical equivalent refraction and the target spherical equivalent refraction was within ±1.00 D in 55% of all patients. No patient lost any Snellen lines of BSCVA.
The mean corneal sensitivity thresholds did not differ between the groups. Threshold values were 73.5 ±2 9. 6 mL/min in LASIK patients and 78.0 ±18. 7 mL/min in controls [P=. 66 6). No correlations were found between corneal sensitivity threshold values and OSDI scores. Even when patients were divided into two groups - patients who claimed to have dry eyes and patients who claimed not to have dry eyes - no significant difference was found between sensitivity threshold values. No significant correlation appeared between corneal sensitivity thresholds and objective dry eye signs (Schirmer's test or BUT).
The majority of patients (55%) reported dry eye symptoms when they were asked a simple question: do you have dry eyes? Ocular Surface Disease Index score, indicating degree of dry eye symptoms, was significantly higher in LASIK patients (18.6 ±6.4%) compared to controls (7.5 ±5. 7%; P=. 022). However, almost all patients (95%) were satisfied with the overall outcome and would have chosen the operation again. The patient who was not entirely satisfied experienced epithelial erosion during the surgery and subsequent DLK in both eyes. A predisposing factor seemed to be loose epithelium due to basement membrane dystrophy; however, the patient did not have a history of erosions and preoperative examination did not reveal any abnormalities.
Corneal sensitivity is mediated by stromal nerves originating from the long ciliary nerves that penetrate the cornea and run forward in a radial fashion toward the center of the cornea. They form a network of nerves called the subbasal nerve plexus.25"27 Intact innervation is mandatory for normal corneal function. Ocular surface, lacrimal glands, and interconnecting nerves form a functional unit. A compromise in one portion of this reflex arch may result in ocular surface disease.28 In addition, corneal innervation has a trophic effect on corneal epithelial cells.27 Several neuropeptides and growth factors have been demonstrated in corneal nerves such as substance P and calcitonin gene-related peptide, which regulate corneal epithelial proliferation, integrity, and wound healing.29,30
In the current study, we have shown that corneal mechanical sensitivity thresholds in the long term after high myopic LASIK did not differ from those of normal controls. Accordingly, the results of objective dry eye tests were similar to those of controls. However, patients reported ongoing ocular discomfort and symptoms resembling dry eye (photophobia, grittiness, foreign body sensation, and ocular irritation) significantly more than age- and sex-matched controls. Loss of sensitivity and recovery of sensitivity after LASIK have been shown to correlate with high corrections.13'18 Therefore, it is logical to presume that corneal nerves are implicated in this process in some way. On the other hand, high correction seems to be one of the risk factors for patients developing so-called chronic dry eye syndrome after LASIK.4
De Paiva and Pflugfelder31 observed decreased corneal sensitivity after LASIK in patients without dry eye. They also found corneal hypersensitivity in patients with dry eye after LASIK compared with normal controls. They used the same Belmonte non-contact gas esthesiometer used in the present study. The LASIK group consisted of 20 patients 1 to 40 months after myopic or hyperopic correction; data of refractive corrections were not described. Dry eye after LASIK group included 6 patients who reported dry eye symptoms and had ocular signs compatible with dry eye after a mean interval of 12 months (range: 3 to 36 months) following myopic LASIK. They suggested that corneal hypersensitivity observed in dry eye patients is due to compromised ocular surface barrier function and hypersensitivity to air jet. Differences found in our study may be explained by the following: 1) inclusion of patients with high myopic corrections, and 2) a longer mean interval after surgery (44.2 ±11.3 months, range: 23 to 58 months).
Wilson32 suggested that LASIK dry eye represents a neurotrophic epitheliopathy rather than a real dry eye syndrome. This is supported by the data presented in the current study of high myopic LASIK patients. The majority of patients report ocular discomfort resembling dry eye symptoms although clinical dry eye tests are normal and corneal sensitivity is within normal limits. We hypothesize that these symptoms of ocular discomfort could be in part derived from aberrantly regenerated corneal nerves. The LASIK dry eye syndrome may actually be a sort of "phantom pain," and thus corneal neuropathy would be a more appropriate classification of this phenomenon.
Other issues possibly contributing to dry eye symptoms after LASIK include differences in corneal curvature, whereas normal corneas show prolate profiles (ie, steeper in the center) and high conventional myopic LASIK produces oblate corneas. These changes in corneal curvature may interfere not only with even tear distribution, but also mechanical rubbing due to the actual change in anatomy. Moreover, patients who seek refractive surgery are often contact lens intolerant and may have preclinical dry eye before surgery. Unfortunately, our study was cross-sectional and we were not able to perform preoperative examinations.
An individual patient is not able to differentiate between symptoms from ocular dryness or "sore eyes" due to any other basic conditions. Eventually, the most important aspect is the subjective symptoms experienced by the patient. Patients report relief in symptoms when using artificial tears, which may be explained by lowering the frictional forces between lids and ocular surface and thus corneal afferent nerves are less activated.
The new insight into the pathogenesis of LASIK dry eye syndrome as a form of corneal neuropathy provides clinical implications as well as novel therapeutic possibilities. Patients should be informed of the possibility of developing chronic dry eye symptoms especially after deep ablations. In severe cases of disabling chronic pain after LASIK, when conventional therapeutic possibilities do not offer relief, consultation of a physician specialized in treating pain is recommended. Novel high resolution corneal imaging techniques, eg, scanning slit confocal microscopy, might provide more information on the subject, and new studies on corneal nerve morphology in the long term after LASIK are warranted.
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Characteristics of LASIK Patients and Controls Assessed for Subjective and Clinical Symptoms of Dry Eye and Corneal Sensitivity