Epidemic keratoconjunctivitis is a contagious adenoviral infection that is considered the most common ocular infectious disease.1–4 Subepithelial infiltrates may present within the second or third week of epidemic keratoconjunctivitis as multifocal, elevated, nummular opacities with inflammatory infiltrate in the anterior stroma. They are frequently associated with photophobia, conjunctival hyperemia, and ocular discomfort. Topical treatment with low-dose steroids, cyclosporin A 1%, or tacrolimus 0.03% reduces infiltrates and their associated symptoms in most cases, although they frequently recur after discontinuation of therapy, even when slowly tapered.1–5 However, some cases evolve with chronic persistent opacities, or scars, in the anterior stroma; these do not respond to topical immune modulators, thus causing permanent visual loss due to surface irregularity and central corneal opacity. A conservative approach in these cases includes the fitting of rigid gas-permeable (RGP) contact lenses, which can greatly improve visual acuity by neutralizing surface irregularities, and clinical follow-up, with which many cases show significant improvement of the stromal opacities over time.
Phototherapeutic keratectomy (PTK) with excimer laser has been widely used in the treatment of anterior stromal corneal opacities, scarring, and corneal surface irregularities,6–16 with a few published studies4,17–19 in the peer-reviewed literature reporting its efficacy and safety for the treatment of corneal opacities following epidemic keratoconjunctivitis. However, to date, no study has evaluated visual and refractive outcomes of excimer laser keratorefractive surgery in comparison to long-term clinical follow-up for the management of adenoviral corneal scars. Because these corneal scars and visual acuity may slowly improve over time without treatment, it is important to include a control group to better assess the relative value of treating these patients.
The aim of this study was to evaluate the long-term visual and refractive outcomes of transepithelial corneal surface ablation (PTK and photorefractive keratectomy [PRK]) with mitomycin C (MMC) 0.02% for the treatment of central corneal scars following epidemic keratoconjunctivitis, and to compare these results to a control group treated with refractive correction (glasses or RGP contact lenses) and clinical follow-up.
Patients and Methods
This retrospective comparative case series included 35 eyes of 27 patients presenting with central corneal scars following adenoviral subepithelial infiltrates. Inclusion criteria were: presence of central adenoviral scar for 2 or more years; inactivity of subepithelial infiltrates (no cellular infiltrate) for at least 1 year; corrected distance visual acuity (CDVA) of 20/25 or worse, or 20/20 if complaining of poor vision quality; no use of steroid drops in the past 6 months; minimum age of 18 years; and minimum central corneal thickness (CCT) of 400 µm measured by ultrasonic pachymetry. Written informed consent was obtained from each patient. The study was approved by the institutional review board and local ethics committee, and adhered to the tenets of the Declaration of Helsinki.
Patients were divided into two groups: (1) control group, comprising patients who refused treatment with PTK and therefore were clinically treated with refractive correction with glasses or RGP contact lenses when necessary; and (2) treatment group, comprising patients who underwent transepithelial PTK with MMC 0.02%, with associated PRK in the same procedure in eyes that presented with a previous refractive error.
All patients underwent complete ophthalmic examination including: slit-lamp biomicroscopy, uncorrected distance visual acuity (UDVA) and CDVA in logMAR units, manifest and cycloplegic refraction, CCT with ultrasonic pachymetry (AccuPach V; Accutome Inc, Malvern, PA), and corneal topography (Medmont E300; Medmont Intl., Nunawading, Australia). Complications were also registered during the follow-up, such as recurrence of subepithelial infiltrates, haze, loss of CDVA, and presence of symptoms (ocular discomfort, photophobia, and photic phenomena).
Safety and efficacy of the surgery were assessed by the following: (1) safety index (preoperative CDVA divided by postoperative CDVA) and (2) efficacy index (preoperative CDVA divided by postoperative UDVA). Desirable values are higher than 1.00.
Surgical Technique
All surgeries were performed by two corneal specialists (VCG and RCG) following the same protocol. Transepithelial PTK was performed using a Schwind Esiris excimer laser (SCHWIND eye-tech-solutions, Kleinostheim, Germany), with a 2.4- to 3-mJ pulse energy, 0.8-mm beam diameter, and 300-Hz eye tracking system. Optical zone varied from 8 to 9 mm, with a fixed 1-mm transition zone. The ablation depth was determined by subtracting 20% from the estimated depth of the corneal opacity based on slit-lamp biomicroscopy. In the last 10 µm of the programmed ablation, balanced salt solution was used as a fluid-masking agent to regularize the surface (“smoothing”). After ablation was complete, MMC 0.02% was applied to the treated area for 20 to 40 seconds. MMC was applied for 40 seconds when ablation was deeper than 80 µm. The ocular surface was then washed with 5 mL of balanced salt solution, and a bandage contact lens (Acuvue Oasys; Johnson & Johnson, São José dos Campos, Brazil) was used until complete reepithelialization.
Postoperatively, patients were instructed to instill one drop of gatifloxacin 0.3% with prednisolone acetate 1.0% (ZYPRED; Allergan, São Paulo, Brazil) four times daily for 7 days, followed by prednisolone acetate 1.0% drops (PredFort; Allergan) tapered for 30 days, and lubricating eye drops (Optive UD; Allergan) for 90 days. Aceclofenac 100 mg twice daily was prescribed to control postoperative pain. Follow-up was scheduled for 1 week, then 1, 3, 6, and 12 months.
Statistical Analysis
Collected data were included in a Microsoft Excel spreadsheet (Microsoft Corporation, Redmond, WA), and statistical analysis was performed using the IBM SPSS Statistics 20 software (IBM, Armonk, NY). Normality distribution was tested with the Shapiro–Wilk test. The Student's t test and Mann–Whitney U test were used to compare independent means. To compare paired means, the paired t test and the Wilcoxon test were used. To analyze the effect of the intervention, the one-way analysis of covariate test with the initial values as covariates with Bonferroni correction was used because the groups were not randomized. A P value of less than .05 was considered statistically significant.
Results
Thirty-five eyes of 27 patients (11 men [40.7%] and 16 women [59.3%]) with central corneal scars following epidemic keratoconjunctivitis were included in the study. There were 18 eyes of 13 patients in the control group. The treatment group comprised 17 eyes of 14 patients who underwent PTK only in the treatment group and 11 eyes of 8 patients who had PTK+PRK.
The mean age in the control and treatment groups was 32.4 ± 12.0 and 34.3 ± 12.5 years, respectively (P = .546). Mean lengths of follow-up were 54.4 ± 19.7 and 27.5 ± 22.8 months in the control and treatment groups, respectively (P = .001).
Mean CCT measured by ultrasonic pachymetry in the treatment group was 508 ± 46 µm (range: 403 to 580 µm). Mean total depth of corneal ablation (epithelial + stromal) was 109 ± 31.6 µm (range: 80 to 150 µm) in patients undergoing PTK only, and 129.9 ± 32.7 µm (range: 82.0 to 209.6 µm) in patients undergoing PTK+PRK, with significantly deeper ablation in the latter (P = .048). There was no statistically significant correlation between depth of ablation and improvement of visual acuity (P = .214).
Visual and refractive results of both groups are summarized in Table 1. Figure 1 shows the initial and final cumulative CDVA in each group.
In the control group, mean CDVA improved from 0.30 ± 0.19 to 0.17 ± 0.18 logMAR (P = .007) during the follow-up, which corresponds to a gain of 1.3 ± 1.7 lines on the Snellen chart. The UDVA improved from 0.50 ± 0.30 to 0.34 ± 0.28 logMAR (P = .003).
In the treatment group, mean CDVA improved from 0.34 ± 0.24 logMAR preoperatively to 0.06 ± 0.10 logMAR (P = .001) at the last follow-up visit, corresponding to a gain of 2.9 ± 2.4 lines on the Snellen chart. The UDVA improved from 0.64 ± 0.30 to 0.24 ± 0.27 logMAR (P = .001).
Intergroup comparison found significantly better UDVA and CDVA in the treatment group (0.34 vs 0.24, P = .031; and 0.17 vs 0.06, P = .013, respectively), as evaluated by the one-way analysis of covariance test. In addition, there was a greater gain of Snellen chart lines with correction in the treatment group (1.3 vs 2.7, P = .041) (Figure 2). Moreover, no eyes lost vision in the treatment group, and even the two patients who had no gain of vision reported improvement in visual quality with the resolution of photic phenomena.
Considering the refractive target in the treatment group, results indicate a mean hyperopic shift of +0.48 ± 0.91 diopters (D) in spherical equivalent, with no significant difference between patients undergoing PTK only or PTK+PRK (P = .884).
The treatment group showed good (> 1.0) safety and efficacy indexes of 1.81 ± 1.10 and 1.32 ± 0.88 in the PTK only and PTK+PRK subgroups, respectively, with no statistically significant difference between them (P = .525).
In the control group, 14 (77.7%) had at least one episode of reactivation of subepithelial infiltrates during follow-up. However, the recurrence was significantly lower (P < .001) in the treatment group, with only 2 (11.7%) eyes having recurrence of subepithelial infiltrates at 3 and 41 months postoperatively. Both had complete resolution of the infiltrates with the use of topical steroids, reestablishing 20/20 UDVA (Figure 3). Fifteen (88.8%) eyes remained asymptomatic during the follow-up in the treatment group. One patient (5.5%) reported discomfort and foreign body sensation, and only the patient with central haze reported decreased visual acuity. In the control group, 4 (22%) patients remained asymptomatic during the follow-up, 9 patients (50%) reported persistence of low visual acuity, and 6 patients (33.3%) reported foreign body sensation.
The eye presenting central corneal haze 6 months after PTK had a preoperative dense stromal scar, intraepithelial cysts, and central corneal thinning. Despite the haze, CDVA improved from 0.3 to 0.2 logMAR, and the patient refused re-treatment (Figure 4).
On slit-lamp biomicroscopy, 6 eyes (35.2%) in the treatment group were considered free of residual opacities, 10 (58.8%) had a faint remaining opacity, and only 1 (5.8%) presented haze. The large proportion of eyes with subtle residual opacity was due to the adoption of a conservative approach, with partial ablation of the opacities' depth.
Discussion
This study demonstrates that transepithelial corneal surface ablation with excimer laser (PTK with or without associated PRK) is an effective option in the management of subepithelial infiltrates after epidemic keratoconjunctivitis, with greater improvement in UDVA and CDVA compared to clinical management and a low complication rate.
Corneal subepithelial infiltrates are a frequent complication of epidemic keratoconjunctivitis. They occur likely due to the penetration of adenoviral antigens into the corneal anterior stroma with subsequent inflammation. This triggers myofibroblast-associated fibrosis due to epithelial basement membrane injury and defective regeneration, leading to scar formation.20
After multiple recurrences of subepithelial infiltrates, some patients can develop anterior stromal scars that do not respond to topical immune modulators, thus causing permanent visual loss due to central opacity, corneal surface irregularity, and higher order aberrations.
PTK has been shown to be effective for the treatment of superficial corneal diseases involving the Bowman's layer and anterior stroma, such as corneal dystrophies, opacities, and surface irregularities.6–16 The transepithelial PTK approach uses the epithelium as a natural masking agent to regularize the corneal surface and improve transparency. PTK has been used for the treatment of persistent adenoviral corneal subepithelial opacities, with studies in the literature showing favorable results regarding the efficacy and safety of this method. Potential complications of this technique include: hyperopic shift, haze formation, and recurrence of opacities.4,17,18,21 Intraoperative MMC is widely used in eye surgery and particularly in refractive surgery (eg, PRK and PTK) to prevent the formation of subepithelial fibrosis (haze) and to improve the overall quality of corneal healing.4,17,18,22–26
Patients with central corneal scars after epidemic keratoconjunctivitis were retrospectively included in this study to evaluate the visual and refractive results after transepithelial corneal surface ablation with MMC 0.02%. A mean postoperative follow-up of 27.5 months was important for allowing assessment of long-term visual and refractive outcomes, recurrence rate, and possible effects of excimer laser ablation in adenoviral corneal disease.
In the current study, we used a conservative approach, avoiding deep ablations that could lead to higher hyperopic shift. Shallow ablations correct corneal surface irregularities, thus improving vision without complete removal of opacities, which can vary in intensity, depth, and distribution. Factors that contributed to minimization of the corneal surface ablation-induced hyperopic shift in this study include: shallow, partial ablation of the scar depth; wide optic zone of 8 to 9 mm; transition zone profile at the edge of the treatment area; and associated PRK in selected cases.4,17–19,27 A transepithelial PTK mode is also available in one laser system that compensates for a different epithelial thickness profile, thus avoiding hyperopic shift.28
Quentin et al.18 reported a case series of 13 eyes with persistent and recurrent opacities after epidemic keratoconjunctivitis who underwent PTK. In agreement with our findings, the authors reported improvement in visual acuity in 11 (84.6%) eyes with a mean follow-up of 33 months, reduction of glare, and recurrence of infiltrates in 2 eyes of the same patient 6 weeks after PTK. They also reported faint haze in the first weeks after surgery and hyperopic shift as side effects, but did not use MMC as in our study.18
Yamazaki et al.4 reported a prospective case series enrolling 31 eyes of 23 patients who underwent PTK with MMC 0.002% for the treatment of corneal opacities after epidemic keratoconjunctivitis. According to this study, CDVA improved two or more lines in 78% of the patients at 12 months, with a hyperopic shift of 1.52 ± 0.91 D and significant improvement on contrast sensitivity and photophobia.2
Recurrence of post-adenoviral subepithelial infiltrates after PTK has been described in the literature. According to Starr,29 subepithelial infiltrates may result from the penetration of antibodies into the corneal stroma, and by performing PTK, viral antigens located deeper in the stroma would become more superficial and therefore closer to tear film antibodies, leading to a greater chance of subepithelial infiltrate recurrence. The findings in our study do not support this hypothesis because a reduced rate of recurrence was observed in the treatment group, supporting the idea that corneal surface excimer laser ablation may remove some of the immunogenic factors that trigger the formation of subepithelial infiltrates.
In this retrospective study, CCT was measured by ultrasound pachymetry and corneal scar depth was estimated based on slit-lamp biomicroscopy. Currently, more objective and accurate methods for such measurements are available, such as high-resolution corneal optical coherence tomography, which was not available when these patients were treated. Khurana et al.27 showed that optical coherence tomography and ultrasound pachymetry provide statistically equivalent measurements of CCT in eyes with central corneal opacities, therefore being reliable for planning the amount of corneal tissue ablation in PTK. Other limitations of this study include its retrospective, non-randomized design and significant difference in follow-up period between groups. The variable follow-up may have influenced the analysis of subepithelial infiltrate recurrence rate and, to a lesser extent, visual and refractive results.
This is the first study to compare excimer laser corneal surface ablation with long-term clinical follow-up in the management of adenoviral corneal scars. We conclude that transepithelial corneal surface ablation with MMC 0.02% is a safe and effective method for treating adenoviral corneal scars. Corneal surface ablation has been shown to be superior to conservative clinical follow-up in terms of improvement in visual acuity, resolution of symptoms, and recurrence rate of subepithelial infiltrates.
References
- Jeng BH, Holsclaw DS. Cyclosporine A 1% eye drops for the treatment of subepithelial infiltrates after adenoviral keratoconjunctivitis. Cornea. 2011;30(9):958–961. doi:10.1097/ICO.0b013e31820cd607 [CrossRef]21673568
- Levinger E, Slomovic A, Sansanayudh W, Bahar I, Slomovic AR. Topical treatment with 1% cyclosporine for subepithelial infiltrates secondary to adenoviral keratoconjunctivitis. Cornea. 2010;29(6):638–640. doi:10.1097/ICO.0b013e3181c33034 [CrossRef]20458220
- Meyer-Rüsenberg B, Loderstädt U, Richard G, Kaulfers PM, Gesser C. Epidemic keratoconjunctivitis: the current situation and recommendations for prevention and treatment. Dtsch Arztebl Int. 2011;108(27):475–480.21814523
- Yamazaki ES, Ferraz CA, Hazarbassanov RM, Allemann N, Campos M. Phototherapeutic keratectomy for the treatment of corneal opacities after epidemic keratoconjunctivitis. Am J Ophthalmol. 2011;151(1):35–43 e1. doi:10.1016/j.ajo.2010.07.028 [CrossRef]
- Ghanem RC, Vargas JF, Ghanem VC. Tacrolimus for the treatment of subepithelial infiltrates resistant to topical steroids after adenoviral keratoconjunctivitis. Cornea. 2014;33(11):1210–1213. doi:10.1097/ICO.0000000000000247 [CrossRef]25188789
- Ayres BD, Rapuano CJ. Excimer laser phototherapeutic keratectomy. Ocul Surf. 2006;4(4):196–206. doi:10.1016/S1542-0124(12)70166-0 [CrossRef]17146575
- Campos M, Nielsen S, Szerenyi K, Garbus JJ, McDonnell PJ. Clinical follow-up of phototherapeutic keratectomy for treatment of corneal opacities. Am J Ophthalmol. 1993;115(4):433–440. doi:10.1016/S0002-9394(14)74443-5 [CrossRef]8470713
- Chow AM, Yiu EP, Hui MK, Ho CK. Shallow ablations in phototherapeutic keratectomy: long-term follow-up. J Cataract Refract Surg. 2005;31(11):2133–2136. doi:10.1016/j.jcrs.2005.03.079 [CrossRef]
- Dogru M, Katakami C, Miyashita M, et al. Ocular surface changes after excimer laser phototherapeutic keratectomy. Ophthalmology. 2000;107(6):1144–1152. doi:10.1016/S0161-6420(00)00113-5 [CrossRef]10857835
- Fagerholm P. Phototherapeutic keratectomy: 12 years of experience. Acta Ophthalmol Scand. 2003;81(1):19–32. doi:10.1034/j.1600-0420.2003.00015.x [CrossRef]12631015
- Maloney RK, Thompson V, Ghiselli G, et al. The Summit Phototherapeutic Keratectomy Study Group. A prospective multicenter trial of excimer laser phototherapeutic keratectomy for corneal vision loss. Am J Ophthalmol. 1996;122(2):149–160. doi:10.1016/S0002-9394(14)72006-9 [CrossRef]8694083
- Moniz N, Fernandez ST. Efficacy of phototherapeutic keratectomy in various superficial corneal pathologies. J Refract Surg. 2003;19(2)(suppl):S243–S246.12699182
- Rapuano CJ. Excimer laser phototherapeutic keratectomy in eyes with anterior corneal dystrophies: short-term clinical outcomes with and without an antihyperopia treatment and poor effectiveness of ultrasound biomicroscopic evaluation. Cornea. 2005;24(1):20–31. doi:10.1097/01.ico.0000134184.47687.bb [CrossRef]
- Rapuano CJ. Phototherapeutic keratectomy: who are the best candidates and how do you treat them?Curr Opin Ophthalmol. 2010;21(4):280–282. doi:20467315
- Sharma N, Prakash G, Sinha R, Tandon R, Titiyal JS, Vajpayee RB. Indications and outcomes of phototherapeutic keratectomy in the developing world. Cornea. 2008;27(1):44–49. doi:10.1097/ICO.0b013e318157a111 [CrossRef]18245966
- Zuckerman SJ, Aquavella JV, Park SB. Analysis of the efficacy and safety of excimer laser PTK in the treatment of corneal disease. Cornea. 1996;15(1):9–14. doi:10.1097/00003226-199601000-00003 [CrossRef]8907374
- Alevi D, Barsam A, Kruh J, Prince J, Perry HD, Donnenfeld ED. Photorefractive keratectomy with mitomycin-C for the combined treatment of myopia and subepithelial infiltrates after epidemic keratoconjunctivitis. J Cataract Refract Surg. 2012;38(6):1028–1033. doi:10.1016/j.jcrs.2011.12.039 [CrossRef]22624902
- Quentin CD, Tondrow M, Vogel M. [Phototherapeutic keratectomy (PTK) after epidemic keratoconjunctivitis]. Ophthalmologe. 1999;96(2):92–96. doi:10.1007/s003470050381 [CrossRef]10095355
- Kepez Yildiz B, Urvasizoglu S, Yildirim Y, et al. Changes in higher-order aberrations after phototherapeutic keratectomy for subepithelial corneal infiltrates after epidemic keratoconjunctivitis. Cornea. 2017;36(10):1233–1236. doi:28742618
- Medeiros CS, Marino GK, Santhiago MR, Wilson SE. The corneal basement membranes and stromal fibrosis. Invest Ophthalmol Vis Sci. 2018;59(10):4044–4053. doi:10.1167/iovs.18-24428 [CrossRef]30098200
- Fite SW, Chodosh J. Photorefractive keratectomy for myopia in the setting of adenoviral subepithelial infiltrates. Am J Ophthalmol. 1998;126(6):829–831. doi:10.1016/S0002-9394(98)00224-4 [CrossRef]9860010
- Carones F, Vigo L, Scandola E, Vacchini L. Evaluation of the prophylactic use of mitomycin-C to inhibit haze formation after photorefractive keratectomy. J Cataract Refract Surg. 2002;28(12):2088–2095. doi:10.1016/S0886-3350(02)01701-7 [CrossRef]12498842
- Ghanem RC, Ghanem EA, Kara-José N. [Corneal wavefront-guided photorefractive keratectomy with mitomycin-C for consecutive hyperopia after radial keratotomy]. Arq Bras Oftalmol. 2010;73(1):70–76. doi:10.1590/S0004-27492010000100013 [CrossRef]20464118
- Ghanem RC, Ghanem VC, Ghanem EA, Kara-José N. Corneal wavefront-guided photorefractive keratectomy with mitomycin-C for hyperopia after radial keratotomy: two-year follow-up. J Cataract Refract Surg. 2012;38(4):595–606. doi:10.1016/j.jcrs.2011.11.032 [CrossRef]22440434
- Thornton I, Puri A, Xu M, Krueger RR. Low-dose mitomycin C as a prophylaxis for corneal haze in myopic surface ablation. Am J Ophthalmol. 2007;144(5):673–681. doi:10.1016/j.ajo.2007.07.020 [CrossRef]17889818
- Thornton I, Xu M, Krueger RR. Comparison of standard (0.02%) and low dose (0.002%) mitomycin C in the prevention of corneal haze following surface ablation for myopia. J Refract Surg. 2008;24(1):S68–S76. doi:10.3928/1081597X-20080101-13 [CrossRef]18269154
- Khurana RN, Li Y, Tang M, Lai MM, Huang D. High-speed optical coherence tomography of corneal opacities. Ophthalmology. 2007;114(7):1278–1285. doi:10.1016/j.ophtha.2006.10.033 [CrossRef]17307254
- Guglielmetti S, Kirton A, Reinstein DZ, Carp GI, Archer TJ. Repair of irregularly irregular astigmatism by transepithelial phototherapeutic keratectomy. J Refract Surg. 2017;33(10):714–719. doi:10.3928/1081597X-20170721-04 [CrossRef]28991341
- Starr MB. Recurrent subepithelial corneal opacities after excimer laser phototherapeutic keratectomy. Cornea. 1999;18(1):117–20. doi:10.1097/00003226-199901000-00018 [CrossRef]9894948
Visual and Refractive Results of Both Groupsa
| Parameter | Control Group | Treatment Group | P (Between Groups)c |
|---|
|
|
|---|
| Initial | Last Follow-up | Pb | Preoperative | Postoperative | Pb |
|---|
| UDVA (logMAR) | 0.50 ± 0.30 | 0.34 ± 0.28 | .003 | 0.64 ± 0.30 | 0.24 ± 0.27 | .001 | .031 |
| CDVA (logMAR) | 0.30 ± 0.19 | 0.17 ± 0.18 | .007 | 0.34 ± 0.24 | 0.06 ± 0.10 | .001 | .013 |
| Sphere (D) | 0.37 ± 1.14 | 0.01 ± 1.14 | .008 | −0.19 ± 3.66 | 0.06 ± 2.75 | .694 | .358 |
| Cylindral (D) | −0.91 ± 0.74 | −0.90 ± 0.87 | .926 | −1.76 ± 1.34 | −0.93 ± 1.34 | .026 | .232 |
| Spherical equivalent (D) | −0.89 ± 1.38 | −0.43 ± 1.42 | .040 | −1.07 ± 3.88 | −0.40 ± 3.13 | .341 | .302 |