Abstract
Purpose
Corneal haze is uncommon after laser assisted in situ keratomileusis (LASIK). Post-LASIK haze and scarring can develop due to different conditions such as infectious keratitis, LASIK flap complications, diffuse lamellar keratitis (DLK), corneal photo disruption and damage to the basement membrane due to effects of femtosecond laser, or unknown causes such as in central toxic keratopathy (CTK). In this report, we describe a patient with bilateral late onset annular subepithelial corneal haze which presented more than 20 years after LASIK.
Observations
A 65-year-old woman who presented with decreased vision in both eyes (Best corrected visual acuity [BCVA] 20/80 in right eye and 20/300 in the left eye) over 20 years after LASIK. The patient had history of gout, chromic kidney disease, dry eyes, and chronic cigarette smoking. Clinical examination and anterior segment optical coherence tomography revealed bilateral annular subepithelial corneal haze in the paracentral and midperipheral zone in an annular pattern. Following superficial keratectomy and mitomycin-C application, the uncorrected corrected visual acuity improved to 20/60 in the right eye at 7 months but the final BCVA decreased to 20/300 at 11 months after the surgery due to recurrence of subepithelial haze. The postoperative BCVA improved to 20/30 in the left eye 7 months after the surgery. Histologic examination of the excised corneal tissue revealed presence of subepithelial fibrous tissue and epithelial basement membrane thickening.
Conclusions and importance
Although uncommon, delayed onset bilateral annular subepithelial haze and scarring can develop after LASIK. Although the reason for this clinical presentation is unknown, it is possible that chronic ocular surface breakdown due to a combination of systemic and local factors such as gout, chronic kidney disease, dry eyes, and chronic cigarette smoking contributed to development of subepithelial haze in this patient.
Keywords: Late onset corneal haze, Corneal haze, LASIK
1. Introduction
Corneal haze and opacity formation is an uncommon complication of laser in situ keratomileusis (LASIK). Post-LASIK haze and scarring can develop due to different conditions such as infectious keratitis, LASIK flap complications, diffuse lamellar keratitis (DLK), corneal photo disruption and damage to the basement membrane due to effects of femtosecond laser, or unknown causes such as in central toxic keratopathy (CTK).1,2
In this article we report a case of late onset bilateral annular subepithelial corneal haze following.
2. Case report
A 65-year-old Caucasian woman presented with progressive worsening of vision, sensitivity to light, and irritation in both eyes for the past two years. She had a history of bilateral LASIK about 20 years ago. The past medical history was significant for hyperlipidemia, hypertension, chronic kidney disease, gout, and long-standing tobacco use. The patient did not have a history of poor wound healing or keloid formation. She was using artificial tears in both eyes as needed for dry eyes.
At presentation, the patient's best corrected visual acuity (BCVA) was 20/80 in the right eye and 20/300 in the left eye. The manifest refraction at presentation was +2.00 + 2.00 x 145 in the right eye and +1.75 + 1.5 x 145 in the left eye. Slit lamp examination revealed bilateral subepithelial corneal haze with overlying negative staining in an annular pattern in the midperipheral and paracentral zone, sparing the central 2 mm of the cornea in both eyes (Fig. 1). Lens examination revealed 1–2+ nuclear sclerosis and 2+ cortical cataract in both eyes. Additional findings included mild punctate epithelial keratitis due to dry eyes.
Fig. 1.
Preoperative and postoperative slit photographs. Preoperative slit photographs demonstrating subepithelial opacities in the paracentral and midperipheral zone in an annular pattern with sparing the central cornea in the right (A) and left eye (B and C). Postoperative slit photographs demonstrating residual subepithelial opacities and scarring in the right (D) and left eye (E and F).
Corneal topography revealed irregular anterior corneal surface profile (Fig. 2). Anterior segment optical coherence tomography (AS-OCT) demonstrated a hyperreflective hypertrophic subepithelial tissue and anterior stromal opacities in the paracentral and midperipheral zone (Fig. 3). The LASIK flap thickness was 135 and 188 μm near the edge of the LASIK flap and 89 and 94 μm at the center in the right and left eye, respectively, consistent with a meniscus shaped flap created by microkeratome (Fig. 4). The haze involved the Bowman's layer and anterior stroma and did not involve the LASIK flap interface. Specular microscopy revealed endothelial cell count to be 2183 cells/mm2 in the right eye. The specular microscopy readings were precluded by the presence of corneal opacity in the left eye.
Fig. 2.
Preoperative topography images. Axial and instantaneous maps of the right (A and B) and axial and instantaneous maps of the left eye (C and D).
Fig. 3.
Preoperative and postoperative AS-OCT scans. Preoperative AS-OCT scans demonstrating subepithelial hyperreflective tissue and anterior stromal hyper-reflective opacities in the paracentral and midperipheral area sparing the central cornea in the right (A and C) and left eye (B and D). The LASIK flap thickness near the edge and at the center in the right eye and left eye are displayed in Figure C and D. The hyper-reflective opacities extend close to the edge of the LASIK flap marked by asterisk sign (C and D). Postoperative AS-OCT scans demonstrating residual subepithelial and anterior stromal hyperreflective opacities in the right (E) and left eye (F). AS-OCT: Anterior segment optical coherence tomography.
Fig. 4.
The postoperative Pentacam demonstrating central and inferior steepening in the right eye in the front axial curvature map 11 months after surgery.
Considering the location of the opacities (mainly subepithelial in AS-OCT), it was decided to proceed with superficial keratectomy (SK) combined with mitomycin-C (MMC) application first the right eye followed by left eye. During the surgery, a 57 blade was used to carefully separate the subepithelial scar tissue at its outer edge from the cornea with care to avoid damage to the edge of the LASIK flap. Then a 0.12 mm Colibri forceps was used to grasp the edge of the scar tissue and gently peel the scar tissue off the cornea, while a tying forceps was placed over the adjacent area of LASIK flap to fixate and support the LASIK flap and minimize the risk of tear or separation of the flap. MMC application was applied for 45 seconds in the right eye. Considering the more severe degree of the haze in the left eye and presence of residual subepithelial haze in the right eye after surgery, a longer application of MMC (90 seconds) was considered in the left eye.
Postoperative management included placement of bandage contact lens for one week, topical antibiotics (moxifloxacin eye drops 4 times a day for two weeks), and topical steroids (prednisolone starting 4 times a tapered to once a day over 1 month, after which the patient was transitioned to Loteprednol 0.5 % twice a day which was continued for 4 months after surgery before stopping the medication.
The subepithelial haze improved with persistence of a mild a residual subepithelial haze in both eyes (Fig. 1). The UCVA initially improved to 20/60 in the right eye at 7 months after the surgery but subsequently decreased to 20/300 at 11 months after the surgery due to subepithelial haze. The postoperative BCVA improved to 20/30 at 7 months after the surgery. The manifest refraction was −2.25 + 2.00 x 145 (with no improvement of vision) 11 months after the surgery in the right eye and +0.25 + 1.75 x 165 seven months after surgery in the left eye. The postoperative tomography (Pentacam, Oculus, Inc) demonstrated central and inferior steepening in the right eye 11 months after surgery (Fig. 4, Fig. 1S (Supplemental)) and central flattening and peripheral steepening in the left eye 7 months after surgery (Fig. 5, Fig. 2S (supplemental)).
Fig. 5.
The postoperative Pentacam demonstrating central flattening and peripheral steepening in the left eye in the front axial curvature map 7 months after surgery.
Histologic examination of the excised corneal tissue revealed stromal scarring immediately beneath the epithelium and focal basement membrane thickening in both eyes. In addition, there was a focal area of spindle cells reactive to anti-smooth muscle antigen consistent with myofibroblasts seen in the sections from the right cornea (Fig. 6).
Fig. 6.
Histologic examination of the excised corneal tissue. A. Hematoxylin and
Eosin (H&E) staining showing subepithelial stromal scarring, B. Masson's trichrome
staining demonstrating haphazard subepithelial fibrous tissue formation, C. Focal
basement membrane thickening (black arrow), H&E stain, D. Focal area of spindle cells
reactive to anti-smooth muscle antigen consistent with myofibroblasts (black arrows).
3. Discussion
This case report describes a case of late onset bilateral annular subepithelial corneal haze and scarring after LASIK. In the following sections, we will discuss the distinctions and similarities of our case to the previously reported causes of scarring and haze after LASIK.
Girgis et al. reported development of corneal scarring after LASIK and PRK in a patient with predisposition to keloid formation.3 Of note, our patient did not have history of keloid formation or abnormal wound healing.
Diffuse Lamellar Keratitis (DLK), also known colloquially as the Sands of Sahara, refers to a post-LASIK haze confined to the LASIK flap interface without extension into the surrounding stroma. The clinical appearance usually begins at the periphery of the LASIK flap. DLK is a non-infectious inflammatory response mediated by chemokines released during epithelial injury from lamellar surgeries.4 Patient related risk factors such as history of atopy and procedure related factors such as larger flap diameter, higher energy level for flap creation, blood in the interface, and endotoxins have been reported as possible risk factors for DLK. DLK has been reported to occur up to months and years after LASIK with ocular inflammation, trauma, or idiopathic etiologies.5 The corneal opacities associated with DLK usually resolve with intense topical and oral steroid treatment.4 The location of the corneal opacities in DLK is at the LASIK-flap interface, unlike our case which was located immediately beneath the epithelium.
Central toxic keratopathy (CTK), refers to a non-inflammatory condition characterized by post-LASIK haze with clinical appearance of central or paracentral corneal opacification with striae, stromal loss, and hyperopic shift that usually presents within a few days of LASIK.2,6 The etiology for CTK is currently unknown. The corneal opacities in our patient did not involve the center of cornea, unlike the central corneal involvement in CTK.
Interface haze occurring in the early postoperative period (3 months after surgery) has been reported following femtosecond laser assisted LASIK for myopia, with ultra-thin femtosecond laser flap creation (90 μm) and younger age being as risk factors.7 This could be likely related to the closer application of the laser to Bowman's layer in those patients with thinner flaps.
Kymionis et al. reported development of a temporary subepithelial haze with myopic regression 1 month after thin flap creation for LASIK using a microkeratome (Schwind Carriazo Pendular 90 μm head) in 10 eyes of 5 patients. A significant improvement of haze formation and residual refractive error was observed during the following postoperative months.8
Early-onset subepithelial and interface haze has been reported after femtosecond-assisted LASIK. Hafezi and Seiler reported a case of persistent subepithelial and LASIK flap interface haze formation in two patients 3 months after thin-flap (90–100 μm) femtosecond-assisted LASIK.9 The haze was localized approximately 20–40 μm below Bowman's layer and resolved slowly during the 3 months following starting of topical steroid treatment. In another study, Vaddavalli et al. reported a case of bilateral haze formation in the interface 4 months after femtosecond LASIK.10 Flap thickness was calculated to be 73 and 81 μm in the right eye and left eye, respectively. Ultrahigh-resolution OCT demonstrated interface haze with areas of focal disruption of the basement membrane and Bowman's layer corresponding to the most significant areas of interface haze. The authors attributed the damage to the basement membrane and Bowman's layer as the likely cause for interface haze formation.
The presence of subepithelial haze in this patient has similarities to Salzmann's nodular degeneration. Moshirfar et al. reported two cases of Salzmann's nodular degeneration after LASIK.11 There are also reports of similar cases with anterior subepithelial opacities after LASIK.12,13 It is hypothesized that damage to the basement membrane and activation of myofibroblasts by transforming growth factor-beta from epithelium and tears that passes through the defective epithelial basement membrane, is implicated in development of Salzmann's nodules in this setting.13 If the injury is associated with damage to the underlying Bowman's layer and stroma, as in LASIK flap generation, then the myofibroblasts and fibrosis can extend into Bowman's layer and the underlying anterior stroma.13 Although the presence of annular pattern of haze in this patient is different from typical Salzmann's nodular degeneration, a similar process cannot be ruled out.
Superficial keratectomy and MMC application were effective in reducing the corneal haze. Extreme care should be taken to avoid complications such as tears or separation of the LASIK flap during the surgery. In particular, care should be taken to minimize the risk of damage to the edge of the LASIK flap. Applying the tractional forces away from the LASIK flap hinge and fixating the LASIK flap with another instrument during the surgery could be useful to minimize displacement of the LASIK flap.
Some degree of residual subepithelial haze was noted after surgery in both eyes. A decline in vision in the right eye was noted in the late postoperative period due to recurrence of the corneal haze. A shorter application of MMC in the right eye could be the underlying cause for decreased vision related to recurrence of corneal haze noted in the follow up period in the right eye. We used prednisolone for 1 month and a lower potency steroid (Loteprednol) thereafter for 4 months after surgery. A longer application of MMC, longer maintenance on contact lens (considering use of MMC), and more intense steroid treatment seems reasonable in similar situations considering development of haze in the right eye of this patient.
Histologic examination of the excised corneal tissue revealed presence of subepithelial fibrous tissue and epithelial basement membrane thickening. The reason for excessive fibrotic response in this patient is unknown. The patient did not have a history of keloid formation or poor wound healing. Chronic ocular surface irritation due to dry eyes and chronic cigarette smoking could be a factor contributing to fibrotic response in this patient. Increased tear levels of TGF-β1, a cytokine implicated in keratocyte activation and corneal scarring, have been reported in patients with chronic cigarette smoking supporting the contribution chronic cigarette smoking to scar formation in this patient.14 Genetic factors may also play a role for increased predisposition to scarring. Further genetic testing such as screening for mutations of TGF-β1 gene could be considered to determine to role of genetic factors associated with increased predisposition to scarring.
There are limitations to our study. Considering the unavailability of the prior records, it is difficult to determine the initial refractive error. It is possible that the initial refractive error was not purely myopic, and a mixed astigmatism or hyperopic treatment was performed for the patient. It is possible that the corneal haze was present for a longer time and the progression of cataracts contributed to further decline and recent change in the vision. The patient's improvement of the vision following superficial keratectomy and subsequent decline in vision in the right eye following development of haze correlates with the contribution of corneal haze to decreased vision. However considering the patient's age, it is likely that cataracts partly contributed to decreased vision in this patient. In addition, the etiology of haze could not be attributed only to LASIK and could be multifactorial with systemic and local factors such as gout, chronic kidney disease, dry eyes, and chronic cigarette smoking contributing to chronic ocular surface breakdown, and leading to epithelial and stromal hyperplasia and development of annular haze in this patient.15
In conclusion, we present a case of a 65-year-old woman who presented over 20 years after LASIK procedure with bilateral subepithelial corneal haze in an annular pattern confined to LASIK flap area. Although the reason for this clinical presentation is unknown, it is possible that chronic ocular surface breakdown due to a combination of systemic and local factors such as gout, chronic kidney disease, dry eyes, and chronic cigarette smoking contributed to development of subepithelial haze in this patient.
CRediT authorship contribution statement
Michelle Y. Ko: Writing – original draft, Data curation. Ben J. Glasgow: Resources, Writing – review & editing, Investigation. Reza Ghaffari: Writing – review & editing, Resources, Conceptualization, Supervision, Investigation.
Patient consent
Written consent to publish this case has not been obtained. This report does not contain any personal identifying information.
Authorship
All authors attest that they meet the current ICMJE criteria for Authorship.
Financial support
Supported by the Edith and Lew Wasserman Professorship (BG) which had no role in design and conduct of the study.
Funding
No funding or grant support.
Declaration of competing interest
The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
Acknowledgements
None.
Footnotes
Supplementary data to this article can be found online at https://doi.org/10.1016/j.ajoc.2025.102371.
Appendix A. Supplementary data
The following are the Supplementary data to this article:
Fig. 1S.
(supplemental). The postoperative Pentacam power distribution map demonstrating inferior paracentral and peripheral steepening in the right eye 11 months after surgery.
Fig. 2S.
(supplemental). The postoperative Pentacam power distribution map demonstrating central flattening and peripheral steepening in the left eye7 months after surgery.
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