Quantitative evaluation of corneal irregularity and scarring after infectious keratitis using anterior segment optical coherence tomography

Infectious keratitis is a condition in which pathogens such as bacteria, viruses, and fungi cause corneal abscess formation and inflammation [1]. In some cases, corneal scarring can develop even with proper antibiotic and anti-inflammatory treatment, leading to long-term visual impairment and necessitating therapeutic or phototherapeutic corneal transplantation. Infectious keratitis is the third most common reason for corneal transplantation among primary diseases [2]. Corneal scarring, a leading cause of blindness worldwide, is caused primarily by infectious keratitis [3, 4].

Corneal astigmatism is an important factor to consider in the maintenance of visual acuity. It is observed not only in patients with corneal diseases but also in those without ophthalmological issues [5, 7]. Scarring after infectious keratitis can affect visual function due to the invasion of the visual axis [8] and increasing higher-order corneal aberrations [8, 12]. Corneal astigmatism has also been increasingly reported in patients with keratitis [1, 13], and previous studies have reported changes in higher-order aberrations of anterior and posterior surfaces after corneal diseases [14]. In our clinical experience, many patients with fungal keratitis have strong corneal opacity, while herpetic keratitis usually results in slight opacity that is localized in the corneal epithelium. This suggests that the degree of the opacity and corneal deformation can be different depending on the cause of keratitis. However, no studies have quantitatively evaluated corneal scars by comparing how different causes of infectious keratitis influenced irregular astigmatism measured with corneal tomography.

Thus, we aimed to evaluate the degree of corneal irregular astigmatism and opacification after infectious keratitis using anterior segment optical coherence tomography (AS-OCT).

The medical charts of 663 eyes were reviewed, and 541 eyes were excluded from the study because of insufficient information or a history of corneal surgery. A total of 61 patients and 122 eyes were included in the study (Fig. 1). The demographic data are summarized in Table 1. Male predominance was observed (n = 37), and the mean age of the patients was 55.3 ± 19.4 years. There was no significant difference in age or sex among the four groups categorized based on the primary causes of keratitis (bacteria, fungi, herpesvirus, and acanthamoeba). Degrees of haziness were negatively correlated with CCT for all patients (Y = -0.04199*X + 119.8, P = 0.033).

A comparison of the corneal data for all patients is summarized in Table 2. BSCVA was significantly worse in affected eyes compared with in healthy eyes (0.93 ± 1.36 and 0.30 ± 0.83 logMAR, P = 0.003). Although no difference was found in AvgK and TCT between the two groups, CCT was significantly higher in affected eyes compared with in healthy eyes (591.8 ± 132.4 and 531.1 ± 46.2 μm, P = 0.001). Haziness was also significantly worse in affected eyes (111.9 ± 19.2 and 84.4 ± 11.8 grayscale units (GSU), P < 0.001). The Fourier harmonic analysis revealed that asymmetry and higher-order (irregular corneal) astigmatism were significantly increased in affected eyes, similar to regular astigmatism (P < 0.001 for all). There were significant positive correlations between BSCVA and the three components of the Fourier harmonic analysis (regular astigmatism: R² = 0.22, P < 0.001, irregular astigmatism: R² = 0.20, P = 0.002, higher-order irregularity: R² = 0.39, P < 0.001). There were no significant differences in changes in BSCVA and AvgK among the four types of keratitis (bacteria, fungi, herpes, and acanthamoeba) (Fig. 2A); however, changes in CCT were significantly different among the groups (40.6 ± 108.1, 106.0 ± 108.9, -5.6 ± 65.1, and 121.6 ± 131.6 D, respectively; P = 0.04) (Fig. 2B). Changes in TCT were also significantly different among the four groups (bacteria, fungi, herpes, and acanthamoeba: -15.7 ± 59.4, 20.0 ± 60.7, -74.0 ± 107.1, and 58.4 ± 136.9 μm, respectively; P = 0.015) (Fig. 2C), and multiple comparisons revealed that TCT changes after fungal and acanthamoeba keratitis were significantly greater than those after herpesvirus (P = 0.03 for both) (Fig. 2C).

We demonstrated that corneal scarring after bacterial, fungal, and acanthamoeba keratitis results in significant visual impairment. Shimizu et al. [17] reported visual acuity after bacterial (0.98 ± 1.01), fungal (1.30 ± 1.17), herpetic (1.08 ± 0.95), and acanthamoeba (0.60 ± 0.91) keratitis. In the present study, BSCVA approximately coincided with these values; however, it was more severe in patients with acanthamoeba keratitis (2.00 ± 0.85). This could be because our center is a tertiary hospital in the inner-city area, where more advanced cases are often referred. Although there was no difference in AvgK in all patients with keratometry values, the Fourier harmonic analysis detected some changes in corneal tomography findings. Our results demonstrated that regular astigmatism, asymmetry components, and higher-order irregularities significantly increased in eyes with infectious keratitis. Since all these factors were significantly related to BSCVA, these three Fourier harmonic analysis parameters are thought to contribute to the maintenance of visual acuity. The asymmetry component and higher-order irregularity cannot be corrected with glasses and require rigid gas-permeable lenses for correction. The results suggest that many patients with corneal scarring need treatment for visual correction even after recovery from infectious keratitis. The AS-OCT in our study was useful for evaluating corneal parameters [18, 19]. Scheimpflug imaging is another modality that is useful for evaluating corneal scars with sufficient reproducibility and repeatability [20]. However, it may underestimate corneal thickness in the presence of central scarring [21]. Therefore, AS-OCT is considered more suitable for evaluating hazy corneas with post-infectious scars.

Anterior and posterior corneal topographic changes were evaluated in our study. The posterior curvature of the cornea, which cannot be treated with a rigid gas-permeable lens, is important for visual function [22]. Although Fourier harmonic components were not different among four causative organisms of infectious keratitis, a high value of asymmetry component was observed in all patients. Therefore, a detailed evaluation of posterior corneal astigmatism for scarring is necessary even after complete recovery. Additionally, after the treatment of infectious keratitis, fabrication of eyeglasses or ophthalmic surgery, such as cataract surgery, require accurate corneal astigmatism analysis, especially for patients with a toric lens inserted for astigmatism correction [23].

We evaluated corneal scarring using densitometry of the images obtained from AS-OCT. Affected eyes exhibited higher values in all four types of infectious keratitis categorized by causal organisms. Corneal densitometry has been shown to be useful for quantitatively evaluating opacity by AS-OCT [24], as well as Scheimpflug imaging [25, 26]. The degree of opacity was traditionally evaluated with slit-lamp microscopic examination, but it was difficult to measure and compare the earlier data of the same patient with that of a different one. Densitometry of AS-OCT can quantitatively evaluate corneal scarring, and it is useful for not only patient-to-patient comparison but also longitudinal comparison of the data of the same patients.

We found that CCT increased in patients after fungal and acanthamoeba keratitis, in contrast to those with bacterial and herpetic keratitis, where no changes were observed. Fungal keratitis can deeply invade the corneal stroma and cause severe persistent inflammation that sometimes requires intrastromal injection of antifungal medications [27]. Additionally, topical medications for fungi, such as chlorhexidine, can cause toxicity to the cornea. Higher-order aberrations have been reported to be prevalent in fungal keratitis [17]. Although herpetic keratitis could affect both the corneal epithelial and stromal layers, where the virus was detected at different depths [28], stromal keratitis accounted for only 29.5% of cases, where superficial keratitis was the main cause [29, 30]. These differences in the depth of the infectious foci could explain the results of our study. Furthermore, densitometry values significantly increased in patients with herpetic keratitis, although CCT did not change. This suggests that the solid corneal opacity remained without thickening even after treatment for keratitis. There was variability in the formation of corneal scars after herpetic keratitis and acanthamoeba keratitis. It should be noted that our study group of patients with herpetic keratitis did not have severe stages of the disease. Patients with herpetic keratitis who are unresponsive to treatment can demonstrate progressive corneal opacity. However, as our institution is a tertiary care hospital located in the central area of the capital city in Japan, patients were typically not left untreated for a long time. This particularly geographical characteristic is a distinctive feature of the patients included in the study.

AS-OCT is useful for understanding corneal astigmatism owing to corneal scarring after treatment for infectious keratitis because the type of persisting corneal astigmatism or corneal haziness is tightly linked to the post-keratitis options for visual correction, such as the use of optical glasses or RGP lens. Patients with mild corneal haziness and high corneal irregular astigmatism can be prescribed RGP lens for correction.

This study has several limitations. First, we compared the affected eyes after keratitis with the contralateral healthy eyes. This is because most of the included patients had not visited our center before they developed keratitis; thus, corneal data and BSCVA of the affected eyes before infectious events were unavailable. Second, it would have been beneficial to factor in the strain of the organism when evaluating corneal tomographic changes and group patients based on specific etiologies such as gram-positive bacteria, gram-negative bacteria, Candida, and Aspergillus. However, this was difficult because of the limited number of patients with sufficient corneal data. Furthermore, in the present study, the number of eyes with herpetic keratitis and acanthamoeba keratitis were small. Further prospective studies including large numbers of eyes, for each of the etiology groups, are required in the future to validate the findings. Lastly, although we observed a statistical difference in corneal thickness in some analyses, the value was not high. Consequently, we had to verify the repeatability of the examination results because of the low visual acuity and insufficient fixation at times. Herein, we performed multiple examinations and adopted only reliable clinical data.

In conclusion, corneal scarring persisted even after treatment for infectious keratitis, and regular and irregular corneal astigmatism increased with visual acuity impairment. AS-OCT with the Fourier harmonic analysis was useful for evaluating corneal topographic changes in patients with corneal scarring after keratitis. Future multi-institutional studies that include data before and after keratitis may be helpful for clarifying how AS-OCT with Fourier harmonic analysis can be used in a clinical setting.