A case report of late-onset central toxic keratopathy following femtosecond laser-assisted in situ keratomileus

Abstract

Background

CTK is a rare, acute, noninflammatory, self-limiting corneal condition that occurs after refractive surgery and is characterized by dense central stromal opacification. Clinical hallmarks include significant central corneal haze, stromal thinning, Descemet’s membrane folds, and a significant hyperopic shift within 3–9 days postoperatively. We reported a case of CTK occurring 5 years after refractive surgery.

Case report

A myopic patient who underwent Femtosecond Laser-Assisted In Situ Keratomileusis (FS-LASIK) five years prior presented with pain and blurred vision after rubbing his right eye. Initially, diagnosed with Stage III diffuse lamellar keratitis (DLK), the patient was treated with topical corticosteroids (prednisolone acetate and fluorometholone), antibiotics (tobramycin), intravenous vitamin C, and corneal lesion debridement. After treatment, the patient’s vision improved. The diagnosis was later revised to corneal toxic keratopathy (CTK).

Conclusions

Early and correct differentiation between CTK and DLK could lead to a good prognosis. Corneal confocal microscopy is helpful in diagnosis. A reduction in the use of corticosteroids and antibiotics led to further ocular amelioration. Moreover, this treatment should actively promote corneal epithelial repair, and in the future, the use of vitamin C in the early stage of the disease can be considered.

Background

CTK is a rare, acute, noninflammatory, self-limiting corneal condition that occurs postrefractive surgery [1] and is characterized by dense central stromal opacification. First described in 1998 by Fraenkel et al. [2], CTK has an estimated incidence of 0.0076–0.016% in patients undergoing refractive surgery [3, 4]. Clinical hallmarks include significant central corneal haze, stromal thinning, Descemet’s membrane folds, and a significant hyperopic shift within 3–9 days postoperatively [5]. To date, reports of late-onset CTK after refractive surgery have been rare. Recently, a case of CTK occurring 5 years after refractive surgery was reported in the refractive clinic of Fuzhou Eye Hospital.

Case presentation

A 29-year-old male underwent bilateral FS-LASIK on August 9, 2016. Preoperatively, his uncorrected visual acuity (UCVA) was LogMAR 1.30 bilaterally, improving to LogMAR 0 with a -3.75 diopter sphere (DS) correction. Central corneal thickness (CCT) was 530 μm and 531 μm in the right and left eyes, respectively. During the procedure, a corneal flap with a depth of 110 μm and a diameter of 7.3 mm was created, with an effective ablation diameter of 6.50 mm and a laser energy ranging from 2.36 to 4.60 mJ. The postoperative CCT was 478 μm and 480 μm in the right and left eyes, respectively. Regular follow-up examinations remained unremarkable until July 3, 2021, when the patient presented with complaints of right eye discomfort upon waking, exacerbated by accidental eye rubbing, leading to pain and blurred vision. The patient denied any history of chemical exposure. Examination revealed corneal epithelial defects and mild stromal edema, approximately 7 mm in diameter. Anterior segment optical coherence tomography (AS-OCT) revealed stromal opacification with a CCT of 530 μm (Fig. 1). The patient received copious conjunctival irrigation with balanced salt solution and a therapeutic bandage contact lens (BCL, PureVision, Bausch & Lomb, USA). On July 13, 2021, persistent pain, photophobia, and blurred vision prompted his return. UCVA in the right eye had deteriorated to LogMAR 0.92, with an intraocular pressure (IOP) of 7.0 mmHg. Manifest refraction measured + 5.00–1.25 × 105, with no improvement in best-corrected visual acuity (BCVA). Slit-lamp biomicroscopy revealed diffuse, pale white stromal opacification in the right cornea. AS-OCT and corneal topography confirmed stromal opacification and thinning, with a CCT of 296 μm (Fig. 2b), which was corroborated by corneal topography (Fig. 3a). A presumptive diagnosis of Stage III DLK in the right eye was established. Treatment included BCL removal, topical prednisolone acetate 1% eye drops eight times daily, fluorometholone 0.1% eye drops twice daily, and tobramycin 0.3% eye drops four times daily.

Fig. 1

(a) Slit-lamp examination reveals conjunctival injection, corneal epithelial defects, and corneal stromal edema. (b) Corneal fluorescein staining showing a central corneal epithelial defect with positive staining. (c) AS-OCT reveals corneal edema extending through all corneal layers, with a central corneal thickness of 530 μm

Fig. 2

Shows the AS-OCT images taken on the day of onset and at 10 days, 13 days, 19 days, 4 weeks, 4 months, 26 months, and 29 months. (a) On the day of onset, there was an epithelial defect with the cornea exhibiting full-thickness edema and thickening. (b, c) Within 13 days, the corneal epithelium began to be repaired, but the cornea rapidly thinned and flattened, with worsening opacity. (d-h) After 19 days, the corneal epithelium was fully restored, the corneal thickness began to increase, the degree of haziness gradually diminished, and ultimately, the cornea became transparent

Fig. 3

Presents the corneal topography images taken at 10 days, 19 days, 4 weeks, and 29 months postonset. (a, b): At 10 and 19 days, there was a reduction in the curvature of both the anterior and posterior corneal surfaces, with the cornea thinning and flattening and the mean keratometry (km) decreasing from 28.8 to 31.9. (c) At 4 weeks, there was an increase in the curvature of both surfaces, with the cornea thickening and steepening and the km reaching 32.3. (d) At 29 months, the corneal shape returned to normal, exhibiting circular symmetry, with increased corneal thickness and a km of 38.3

The patient presented with persistent central corneal edema and a distinctive grid-like pattern of opacification (Fig. 4b). AS-OCT revealed further central corneal thinning (277 μm) (Fig. 2c). Confocal microscopy revealed enlarged and pleomorphic epithelial cells with indistinct cell borders, extensive dendritic cell aggregation (43 μm), irregular pleomorphic reflections at Bowman’s layer (50–65 μm), and obscured superficial keratocytes. Deeper stromal keratocyte morphology remained satisfactory, although endothelial cell imaging was suboptimal (Fig. 5a). On July 19, 2021, the patient underwent corneal lesion debridement with removal of necrotic epithelial tissue and placement of a therapeutic BCL at another hospital. Postoperatively, he received fortified topical antibiotics (levofloxacin 0.5% and dexamethasone 0.3%) four times daily and intravenous vitamin C (2 g daily). Follow-up AS-OCT revealed an increase in the CCT (342 μm) (Fig. 2d), and the corneal topography indicated increased corneal steepness and thickness (Fig. 3b). He was subsequently discharged on July 23, 2021. Between discharge and August 11, 2021, the patient continued to experience suboptimal visual acuity and consulted multiple ophthalmologists, exhibiting a characteristic grid-like pattern of opacification (Fig. 4c). AS-OCT revealed that the epithelium was restored, and the corneal thickness began to increase (343 μm) (Fig. 2e), as corroborated by the corneal topography (Fig. 3c). Confocal microscopy revealed enlarged and deformed corneal epithelial cells, although with reduced folding. The number of superficial stromal cells decreased alongside less edema, whereas deep stromal and endothelial cells displayed acceptable morphology (Fig. 5b). Penetrating keratoplasty was recommended but was declined by the patient. During this period, he continued topical levofloxacin, tobramycin, dexamethasone, and artificial tears four times daily. By August 11, 2021, his UCVA had improved to LogMAR 0.82.

Fig. 4

Displays slit-lamp photographs taken on the day of onset and at 2, 3, 4, 6, 10, and 29 months. (a) On the day of onset, there was an epithelial defect on the cornea with stromal edema. (b-d) The corneal epithelium gradually healed, but the stroma transitioned from an edematous state to grid-like opacification, then to striate opacification, and ultimately to fading and disappearance of the haziness. (e-g) The corneal epithelium fully recovered, restoring corneal transparency

Fig. 5

Displays the corneal confocal microscopy images at 13 days, 5 weeks, 4 months, and 29 months postonset. (a) At 13 days, the corneal epithelial cells were enlarged and deformed with unclear boundaries (I) and indistinct boundaries, and a patchy, uneven, folded appearance with high reflectivity was observed at 50–65 μm (II). The superficial stromal cells were swollen and blurred (III), while the deep stromal cells maintained a relatively normal morphology (IV), and the endothelial cells were not clearly imaged (V). (b) At 5 weeks, the corneal epithelial cells were still enlarged and deformed (I), but the degree of folding had decreased (II). The number of superficial stromal cells was reduced, with less edema (III), and the deep stromal (IV) and endothelial cells (V) showed acceptable morphology. (c) At 4 months, the corneal epithelial cells had a complete structure (I), and scar tissue was visible in the superficial stroma (II). The nuclei of the superficial stromal cells were clearly visible (III), and the deep stromal layer showed linear low reflectivity (IV), with an acceptable endothelial cell morphology (V). (d) At 29 months, the corneal epithelial cells had a normal morphology, with localized clumps of high reflectivity (I). The corneal folds persisted (II), and the superficial stromal (III), deep stromal (IV), and endothelial (V) cells all had an acceptable morphology

On August 12, 2021, the patient returned to our clinic and exhibited a significant reduction in corneal opacification. On the basis of the clinical improvement, gradual tapering of the topical steroids was initiated. From January 19, 2022, to December 25, 2023, follow-up examinations revealed progressive visual acuity restoration from LogMAR 0.82 to LogMAR − 0.08, marked corneal clearing (Fig. 4d-g), resolution of the hyperopic shift, and gradual CCT recovery (Fig. 2f-h). Corneal topography revealed a return toward normal corneal morphology, with increased anterior surface curvature (Fig. 3d). Confocal microscopy revealed resolution of epithelial edema and folds, with a clear morphology of superficial and deep stromal keratocytes and endothelial cells (Fig. 5c-d). Topical steroid therapy was discontinued on January 19, 2022, and the diagnosis was revised to CTK. The patient remains under observation. The comprehensive follow-up data are summarized in Table 1, and the evolutions of the sphere equivalent (SE) and CCT are illustrated in Fig. 6.

Table 1 Follow-up status of the CTK patient’s right eye

Fig. 6

Shows that the CCT rapidly decreased within 10 days of onset, followed by gradual thickening. SE exhibited a hyperopic shift after onset, which persisted until the corneal thickness reached normal levels

Discussion

The precise etiology and pathophysiology of CTK remain elusive. Potential contributing factors include hypersensitivity reactions to marking ink [3], photoactivated substances generated by the excimer laser, meibomian gland secretions, talc from surgical gloves, and postoperative debris catalyzing a toxic reaction within the corneal stroma [5]. Prolonged laser exposure and the specific laser platform utilized may also play a role.

Differentiating CTK from DLK is a critical clinical challenge, as they can present with overlapping features. However, their management methods differ significantly, underscoring the importance of accurate diagnosis to avoid potential iatrogenic complications from corticosteroid treatment in CTK. Onset timing and distinctive clinical features aid in differentiation. DLK typically manifests within 1–2 days postoperatively and resolves within a week, whereas CTK presents 3–9 days after refractive surgery, with corneal haze persisting for 2–18 months before resolving spontaneously [5–6]. DLK tends to be localized between the corneal flap interface and stromal bed, progressing centripetally from the periphery toward the central optical zone and responding favorably to topical corticosteroids, independent of refractive changes. Conversely, CTK is centrally located, extends anteriorly and posteriorly, is unresponsive to corticosteroids, and is associated with significant hyperopic shifts due to central corneal thinning [7]. Given the absence of inflammatory cells in CTK on confocal microscopy and the potential inhibitory effect of corticosteroids on corneal epithelial and keratocyte proliferation and stromal matrix reconstruction, a conservative approach, allowing natural healing without intervention, is generally recommended for CTK [1].

Our patient developed CTK five years after FS-LASIK and experienced rapid corneal thinning and flattening within 10 days, accompanied by a rapid decline in visual acuity, conjunctival injection, and pain. The etiology could be twofold: mechanical trauma from rubbing the eyes upon waking, which might lead to peeling of the corneal epithelium and the entry of ocular secretions into the stromal layer, or irrigation during an emergency, which could stimulate the stroma and trigger CTK. Ronald J. Smith et al. [8] reported that the excimer laser is not the cause of CTK, as one case occurred after FS-LASIK surgery, and two cases occurred after epithelial ingrowth removal following FS-LASIK surgery. Majid Moshirfar et al. [9] reported a case of CTK resembling central toxic keratopathy syndrome induced by overwearing contact lenses. Overwearing contact lenses can lead to corneal hypoxia, causing lactate accumulation, acid shift, and reduced cell synthesis in epithelial cells, resulting in epithelial defects. Additionally, overwearing contact lenses can cause corneal stromal acidosis, edema, and striae, which can thin the corneal stroma, infiltrate, and induce neovascularization. We postulate that CTK onset is not confined to the immediate 3–9-day postoperative period but can occur at any time following refractive surgery if corneal epithelial integrity is compromised. When the corneal epithelium or endothelium is injured due to trauma, surgery or infection, damaged or dying cells release cytokines that penetrate the stroma and induce the apoptosis of keratocytes via the Fas‒FasL pathway [10, 11]. The degree of epithelial and stromal injury correlates with the extent of keratocyte apoptosis [12]. Hence, the onset of most CTK cases occurs 3–9 days after refractive surgery. Moreover, we propose that any insult to the corneal epithelium, whether from refractive surgery or subsequent damage, may predispose patients to the development of CTK. In the nascent understanding of CTK, misdiagnosis as DLK is frequent, leading to inappropriate corticosteroid therapy. In a different treatment approach, superficial keratectomy was performed to remove opaque corneal tissue, and systemic vitamin C was administered, resulting in increased CCT. Vitamin C has demonstrated efficacy in promoting alkali burn corneal healing and may facilitate corneal epithelial stem cell proliferation and differentiation [13], preserving corneal stromal microenvironment stability and facilitating wound healing [14]. Therefore, systemic vitamin C therapy may warrant consideration in the early management of CTK.

Conclusions

This report describes a clinical case of late-onset CTK after refractive surgery. Although this condition is rare, early and correct differentiation between CTK and DLK could lead to a good prognosis. Corneal confocal microscopy is helpful in diagnosis. A reduction in the use of corticosteroids and antibiotics led to further ocular amelioration. Moreover, this treatment should actively promote corneal epithelial repair, and in the future, the use of vitamin C in the early stage of the disease can be considered.