Purpose
To assess visual results and compare methods of measuring central corneal thickness (CCT) and corneal opacity thickness (COT) in patients with corneal opacities induced by epidemic keratoconjunctivitis (EKC) and treated with phototherapeutic keratectomy (PTK) using low-dose mitomycin C (MMC).
Design
Prospective consecutive case series.
Methods
Patients with chronic adenoviral corneal opacity underwent transepithelial PTK with MMC 0.002% for 1 minute. The presence of photophobia, the best spectacle-corrected visual acuity (BSCVA), and the contrast sensitivity were evaluated. CCT measurements were obtained with ultrasound pachymeter (US), ultrasound biomicroscopy (UBM), Scheimpflug tomography (Pentacam Oculus), and optical coherence tomography (OCT Visante). COT measurements were obtained with UBM, Pentacam, and OCT.
Results
Thirty-one eyes of 23 patients, comprising 15 women (65.2%) and 8 men (34.8%), mean age 41.8 years, were enrolled in the study. Duration of visual disturbance was 19.1 ± 14 months. The number of patients with photophobia was reduced from 100% to 29% after surgery. BSCVA improved 2 or more lines in 78% of the patients at 12 months. A hyperopic shift of 1.52 ± 0.91 diopters was achieved. Contrast sensitivity improved in both photopic and mesopic conditions. For each of the instruments, the CCT postoperative mean was significantly smaller than the preoperative measurement ( P < .0001) and COT values were significantly reduced in comparison to the preoperative values ( P < .001).
Conclusion
Improvements in photophobia, BSCVA, and contrast sensitivity were observed in patients treated using excimer laser PTK with low-dose MMC for subepithelial infiltrates.
Epidemic keratoconjunctivitis (EKC) is a contagious eye disease caused by an adenovirus with history of outbreaks worldwide. Some patients develop central and nummular subepithelial infiltrates after EKC, causing serious visual disturbances. The adenoviral corneal signs may persist for months to years. Topical treatment with corticosteroids, cyclosporin, and antiviral drugs may fail to reduce symptom severity or to restore corneal transparency because of recurrence after the discontinuation of drug therapy.
Phototherapeutic keratectomy (PTK) is a safe and effective method for treating corneal opacities localized over one-third of the superficial stroma. PTK is also used to smooth irregular corneal surfaces caused by corneal disease, thereby improving the cornea’s optical qualities and resulting in better vision. Some difficulties of excimer laser PTK are preoperative prediction of the depth of pathology to determine whether the patient is a good candidate for this procedure, as well as determination of the amount of tissue to be removed during the procedure. These difficulties can be helped by new technologies that analyze the anterior segment of the eye without contact, such as the Pentacam device (Pentacam, Oculus, Inc, Lynnwood, Washington, USA) and optical coherence tomography (OCT; Visante OCT, Carl Zeiss Meditec, Inc, Dublin, California, USA).
Another technology that involves a certain degree of contact using high-frequency ultrasound (50 MHz) is ultrasound biomicroscopy ([UBM]; Ultrasound Biomicroscope Model 840; Humphrey Instruments, Carl Zeiss, Inc, San Leandro, California, USA).
Mitomycin C (MMC) is used in refractive surgeries to enhance the corneal wound healing process and to prevent subepithelial fibrosis. Beneficial effects of decreasing myofibroblast activation in rabbits after the use of low-dose MMC and efficacy of MMC when using concentrations of 0.002% in photorefractive keratectomy (PRK) surgery deeper than 50 μm were reported in literature. Corneal haze prophylaxis was described with low-dose MMC in myopic surface ablation.
The purpose of this study was to assess visual symptoms of photophobia, visual acuity, refractive errors, and contrast sensitivity, and to measure central corneal thickness (CCT) and corneal opacity thickness (COT) in patients with chronic epidemic EKC preoperatively and postoperatively who underwent PTK with MMC.
Patients and Methods
Patients were enrolled in a prospective case series. Eyes were treated between July 3, 2006 and December 21, 2007 at the Refractive Surgery Service at the Federal University of São Paulo, Brazil. The inclusion criteria were eyes with anterior corneal opacities caused by EKC that were sufficiently severe to reduce visual acuity to 20/40 (uncorrected visual acuity) or less and presented disabling symptoms after topical treatment failure. At the time of inclusion, all patients presented central corneal scars related to fibrosis and no fluorescein staining attributable to epithelium damage. Some patients required steroid tapering that depended on drug concentration, pharmacologic class, and dosing in use. The mean use of steroids was estimated to be 42.4 days (SD 17.5). Washout period for inclusion was about 1 month. Only after 3 months of steroid discontinuation without active keratitis recurrence would the patient be included. All patients were at least 18 years of age and required a minimum of 400 μm of central corneal thickness by US. At the time of inclusion, the presence of an active keratitis, as determined by the pattern of fluorescein staining and clinically detectable stromal edema, represented exclusion criteria. The other exclusion criteria were eyes with ongoing use of immunosuppressive medication, active uveitis, glaucoma, dry eye, herpetic corneal ulcer, diabetes, autoimmune diseases, or pregnancy.
All patients underwent a complete preoperative ophthalmologic examination. They were asked about the presence or absence of photophobia. Examinations included uncorrected visual acuity (UCVA) and best spectacle-corrected visual acuity (BSCVA) using Snellen charts; contrast sensitivity (FACT OPTEC 6500, Stereo Optical Co, Inc, Chicago, Illinois, USA) was determined in each eye with the BSCVA at spatial frequencies of 1.5, 3, 6, 12, and 18 cycles per degree in mesopic and photopic conditions. The log base 10 contrast sensitivity values were used to construct a graph for each spatial frequency tested. CCT was measured with ultrasound pachymetry (Sonogage, Cleveland, Ohio, USA) after instillation of anesthetic drops (Anestalcon; Alcon Laboratories, Inc., Fort Worth, Texas, USA); 3 central thickness measurements were taken and the average value was calculated. UBM (Ultrasonic Biomicroscope, model 840; Humphrey Instruments) was performed using a 50-MHz transducer with the patient lying in the dorsal decubitus position. Local anesthesia was administered and a transparent acrylic eye cup was placed between the eyelids and filled with viscoelastic substance (methylcellulose solution 2.0%; Ophthalmos, Inc., São Paulo, Brazil) to allow immersion of the transducer. COT was also measured with UBM. Those examinations were performed on a different date from the other methods because this test requires contact, which could interfere with the measurements obtained using the other techniques.
Pentacam examination (Pentacam Oculus, version 1.09b02; Oculus, Inc) was performed in a dark room, with the patient seated, chin supported in the device, and fixating on a central target where the first camera was located. A second camera rotated 360 degrees around the central axis to capture multiple images of the anterior segment. The device uses the Scheimpflug principle to reconstruct the images and several maps are available such as keratometry, the anterior coefficient of aberrometry, Scheimpflug photographs, COT, and CCT. COT was measured in the Scheimpflug image applying the 2X zoom setting using the same scale of brightness and contrast in all of the examinations. Manual measurements of the opacities were registered at 4 meridians (0, 45, 90, and 135 degrees of rotation) for both Pentacam and OCT. OCT (Visante OCT, version 1.0.12.1896; Carl Zeiss Meditec, Inc) was performed with the patient seated with the chin supported; the patient was asked to fixate on a light beam. CCT was obtained using pachymetry maps calculating the average value, and COT was obtained using the high-resolution option (quad scans) in 4 image slices at the same meridians. The device software measures the opacities using a “flap tool,” with which the cursor can be placed on the opacity to graphically illustrate the measurement.
All measurements were performed by the same examiner in the morning without predefined sequence, but on different days because the US and UBM are considered contact methods.
PTK was performed using an argon fluoride (193-nm) excimer laser (LADARVISION 4000; Alcon), which operates with a pulse energy of 2.4 to 3.0 mJ, a beam diameter of 0.8 to 0.9 mm, an average fluence of 180 to 240 mJ/cm 2 , and a repetition rate of 60 Hz. The ablation was performed under topical anesthesia and with 7-mm diameter without a transition zone. After transepithelial laser removal, a conservative subepithelial tissue removal approach was performed (less than 25 μm was used in all eyes). The ablation depth was determined by taking the average values of COT measurements with UBM, Pentacam, and OCT, including the epithelial thickness, which was assumed to be 50 μm, and then adding 10% of the final COT value. For example, if the patient presented a final average COT of 120 μm, 10% of this value, which is 12 μm, was added to the 50 μm of the epithelium, resulting in an ablation depth of 62 μm. When the anterior stroma was achieved, a balanced salt solution (BSS) fluid mask was applied 3 times during the ablation to smooth the cornea. After the ablation was completed, MMC 0.002% was applied inside an 8.0 mm PRK cornea marker (Baucsh & Lomb, Irvine, California, USA) and removed with a dry sponge after 1 minute. The eyes were profusely irrigated with 20 mL BSS. At the end of the surgery, a therapeutic contact lens was used until re-epithelialization was complete and the patient was given a prescription for antibiotics (7 days), corticosteroids (30 days), and artificial tears (90 days). Follow-up was scheduled for postoperative days 1, 3, and 7, and for 1, 3, 6, and 12 months postoperatively, when examinations with instruments were repeated, except for UBM, which was obtained preoperatively and at postoperative months 1 and 3.
For statistical analysis, UCVA and BSCVA were converted to logMAR units and contrast sensitivity to log base 10, and nonparametric tests (Friedman test and Dunn test for multiple comparisons) were applied to the comparisons between different moments of the variables. Data regarding the presence or absence of photophobia were submitted to Fisher test. CCT and COT variables presented normal distribution and parametric ANOVA test was used. The results are presented as median, means, and SD. Spearman and Pearson correlation test was used to determine correlations using SPSS ver.15 (SPSS Inc, Chicago, Illinois, USA). Probabilities of less than 5% were considered statistically significant.
Results
Thirty-one eyes of 23 patients (15 women [65.2%], 8 men [34.6%]) were treated. Mean patient age was 41.8 years (range, 18-74 years). Visual symptoms and cornea disturbance had a duration of 19.1 ± 14.2 months (mean value, range of 4-48 months). The last follow-up ranged from 3 to 12 months (mean, 10.4 ± 3.1 months) ( Table 1 ). All patients (31 eyes; 100%) returned for follow-up at 1 and 3 months after surgery, followed by 90% (28 eyes) at 6 months and 74% (23 eyes) at 12 months.
| No. of eyes | 31 |
| Age (years) | 41.8 ± 16.1 (18 to 74) |
| Gender (male/female) (%) | 8/15 (35%/65%) |
| Time of onset (mo) | 19.1 ± 14.2 (4 to 48) |
| Follow-up (mo) | 10.4 ± 3.1 (3 to 12) |
| Ablation depth (μm) | 65.4 ± 2.6 (62 to 75) |
| CCT by US (μm) | 508.4 ± 36.8 (439 to 585) |
| Spherical equivalent (D) | 0.05 ± 0.82 (−1.5 to 2) |
| Cylinder (D) | −1.2 ± 0.8 (−4.0 to −0.3) |
| Keratometry (D) | 43.1 ± 1.9 (39.4 to 46.2) |
| Keratometric astigmatism (D) | 1.4 ± 0.8 (0.2 to 4.1) |
| Anterior corneal aberration by Pentacam | 1.6 ± 0.5 (1.2 to 3.7) |
a Data are presented as mean ± standard deviation (range), except for no. of eyes and gender.
All patients presented with marked photophobia prior to surgery, but at the last examination there was a significant decrease in all symptoms ( P < .0001 by Fisher test) and 29% (9 eyes) continued to complain of a certain degree of photophobia. One patient had, in both eyes, symptoms of conjunctivitis followed by persistent corneal opacities for 12 months. This patient developed EKC after 7 years of laser in situ keratomileusis (LASIK) correction. A representative slit-lamp photograph of the clinical presentation before and after PTK is shown in Figure 1 . In this patient, slit-lamp preoperative photographs presented nummular, or coinlike, gray subepithelial opacities in the LASIK flap. The subjective impression of an improvement in corneal transparency, as seen at the slit lamp, was observed in all patients after surgery.
Re-epithelialization occurred in 30 of 31 eyes (96.7%) by postoperative day 4, and only 1 eye (3.2%) presented an epithelial defect until day 11. Infiltrate recurrences were observed in 3 eyes (9.6%) at 4 to 5 weeks after surgical treatment and occurred simultaneously with the discontinuation of the corticosteroid eye drops. Episodes of recurrence were characterized by the presence of acute symptoms such as foreign body sensation, red eye, photophobia, watering, keratitis, and increased infiltrates.
Preoperative and postoperative logMAR values for both UCVA and BSCVA were statistically significant ( P < .0001). Comparison of the values from each postoperative visit with the preoperative values indicated a significant trend towards improvement ( P < .05). There were no significant differences between any of the postoperative values. An improvement in UCVA was observed after surgery. No eyes presented UCVA worse than >20/100 at 6 and 12 months postoperatively, compared with 13% preoperatively ( Figure 2 ). A consistent improvement of 2 or more Snellen lines in BSCVA was achieved, ranging from 61.2% to 78.5% at follow-up. A loss of lines was observed only in the first month ( Figure 3 ). Gain of 3 or more lines was observed in 11 of 31 eyes (35%) at the last postoperative visit and 1 patient had improved 7 lines with BSCVA.
Eyes showed a tendency towards hyperopic refraction. At the final 12-month examination, the mean induced hyperopia shift was 1.52 ± 0.91 diopters (D). In 21.7% (5 eyes), a hyperopic shift of less than +1D was induced and in 78.2% (18 eyes), a hyperopic shift of more than +1D was observed ( Table 2 ). The correlation between CCT variation (measured by US) and spherical equivalent variation was significant only in the first postoperative month (r = 0.3568, P = .048). It was inverse and nonsignificant for 3 (r = −0.0169, P = .929), 6 (r = −0.2504, P = .1987), and 12 months (r = −0.274, P = .2057). At each postoperative examination, the change in magnitude of net astigmatism from baseline was calculated. The mean magnitude of astigmatism decreased slightly at all visits, reaching −0.9 D at 12 months, and it was nonsignificant between different moments. Keratometric readings obtained from Pentacam revealed minimal change in the keratometric cylinder at 6 and 12 months postoperatively, with no significance, and the mean keratometry value decreased about 1 D at 12 months, which was significant ( P < .05). The coefficient of aberrometry from the anterior cornea did not change significantly during follow-up visits ( Table 2 ).
| Postop 1 m | Postop 3 m | Postop 6 m | Postop 12 m | |
|---|---|---|---|---|
| ▵ Spherical equivalent | 1.23 ± 1.15 | 1.44 ± 1.03 | 1.43 ± 0.99 | 1.52 ± 0.91 |
| <1 D, N (%) | 14 (45.2) | 8 (25.8) | 11 (39.2) | 5 (21.7) |
| >1 D, N (%) | 17 (54.8) | 23 (74.2) | 17 (60.8) | 18 (78.2) |
| Cylinder (D) | −0.9 ± 0.9 | −1.0 ± 0.7 | −0.8 ± 0.6 | −0.9 ± 0.7 |
| Keratometric astigmatism (D) | 1.4 ± 0.8 | 1.4 ± 0.7 | 1.3 ± 0.7 | 1.2 ± 0.7 |
| Keratometry (D) | 42.1 ± 2.3 | 42.2 ± 2.3 | 42.3 ± 2.4 | 41.7 ± 2.3 |
| Aberration a | 1.6 ± 0.3 | 1.5 ± 0.4 | 1.5 ± 0.3 | 1.6 ± 0.3 |
a Anterior corneal coefficient of aberration provided by Pentacam.
Contrast sensitivity, both photopic and mesopic, revealed strong improvement in postoperative results when compared to the preoperative values ( Figure 4 ). A significant change was found from the preoperative level to the postoperative values at 1.5, 3, and 6 cycles for both luminance conditions. In the mesopic conditions, comparisons between the postoperative values at 1 month and those at 12 months revealed a significant difference at 3 ( P < .05) and 6 ( P < .01) cycles per degree. In photopic conditions at 12 cycles, a statistically significant difference was observed at both 6 ( P < .05) and 12 months ( P < .01). The differences between the postoperative values at 3 and 12 months at 6 cycles per degree were also significant ( P < .01).
The pachymetric values of CCT with different devices over time are shown in Figure 5 . For each instrument, the postoperative measurement was significantly smaller than the preoperative measurement ( P < .0001). Preoperatively, OCT (504.2 μm) and US (508.4 μm) measurements were larger than the measurements obtained with the Pentacam (491.3 μm) and UBM (493.9 μm). After surgery the amount of tissue removed centrally ranged from 46.4 to 44.3 μm with UBM, 45.9 to 29.9 μm measured by US, 43.7 to 34.3 μm with OCT, and 40.7 to 23.6 μm with Pentacam.
The preoperative COT measurements were 140, 165, and 167 μm, including the epithelium, with OCT, UBM, and Pentacam respectively. For each of the instruments, the postoperative mean COT values were significantly reduced in comparison to the preoperative values ( P < .001) ( Table 3 ). The differences between the mean COT values before and 3 months after surgery were 35.3 μm with OCT, 35.9 μm with UBM, and 49 μm with Pentacam.
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