Long-term results of corneal collagen crosslinking with ectatic forms of corneal dystrophy

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BACKGROUND

The introduction of effective and minimally invasive treatment methods for corneal pathologies, including ectatic dystrophies, to clinical practice is currently very important [3]. Studies of the treatment of ectatic diseases of the cornea are warranted for multiple reasons. First, there has been a steadily increasing trend in the incidence of corneal diseases in recent years, and these diseases have led to the consequent transformation and destruction of collagen, and to an increase in severe consequences of eye injuries. Second, the number of refractive surgeries has increased and diagnostic capabilities have improved because of the widespread introduction of modern computerized cornea examination methods [4].

Regarding corneal pathologies, keratectasia is a main cause of poor vision and blindness. Corneal ectasia is characterized by a progressive course characterized by corneal thinning and protrusion. Various types of keratectasias have been identified, including keratoconus, keratoglobus, pellucidal marginal degeneration (PMD), pellucid marginal corneal degeneration, and iatrogenic keratectasia; of these, keratoconus is the most common [2]. As the ectatic process is frequently bilateral, often leads to visual disability and affects younger patients of working age, it is a particularly significant medical and social issue [6].

According to studies on the epidemiology of keratoconus, the reported incidence and prevalence ranges are 1.3–22.3 and 0.4–86 cases per 100,000 patients, respectively [12]. The frequency of secondary corneal ectasia after refractive surgery (e.g., Laser Assisted in Situ Keratomileusis, LASIK) is 0.04%–0.6% [9]. PMD, which affects the lower periphery of the cornea, is less common than keratoconus. The disease refers to sporadic ones (single). Here, the cornea thins between the 4 and 8 o’clock positions at a distance of 1 mm from the limbus. In such cases, a typical “butterfly” or “crab claw” pattern with a noticeable flattening of the vertical axis is observed on the corneal topogram [10, 15].

Corneal collagen crosslinking (CXL), which uses riboflavin as a photosensitizer and initiator of photochemical modifications induced by monochromatic ultraviolet radiation, was designed and implemented by Seiler et al. in the late 1990s. CCC has since been recognized as the only treatment method that helps to slow the progression of keratoconus by improving the biomechanical properties of the cornea [2, 20]. In previous studies of CXL, researchers noted several positive biomechanical, biochemical, anti-hydration, and antimicrobial effects, as well as increases in resistance to heat and the resistance of corneal tissue to collagenase [1, 2, 13, 16, 17]. Accordingly, the indications for CXL have expanded significantly [5].

INTRODUCTION

Ectatic forms of corneal dystrophy are among the main indications of keratoplasty. Corrective glasses and contact lenses do not affect the course of this disease. Corneal transplantation is the main treatment option for severe forms of ectasia, and this option is associated with the risk of complications [6–8, 11, 18]. Currently, CXL is the only pathogenetically substantiated method that can block the progression of early-stage corneal ectasia [15, 19, 20, 21]. Changes in the biochemical and biophysical properties of the collagen frame of the cornea induce the development and progression of ectatic forms of corneal dystrophy. CXL is a particular example of photodynamic therapy that has been subjected to extensive study over the past 15 years. The mechanism of action of CXL is based on the photochemical effects of riboflavin and ultraviolet (UV) radiation at a wavelength of 365 nm on the cornea [20]. During CXL, photosensitive riboflavin molecules absorb UV radiation energy, reach an excited state, and produce reactive oxygen species that induce photochemical interactions in the corneal tissues. The resulting crosslinking of collagen molecules with main components of the stroma increases the mechanical strength of the cornea [2]. A similar crosslinking effect is used to increase the elasticity and strength of materials in polymer chemistry applications [12].

MATERIALS AND METHODS

This study was conducted at St. Petersburg City Diagnostic Center No. 7. The sample included 90 eyes of 90 patients aged 13–50 years (mean age: 26.53 ± 7.69 years). Written informed consent for the processing of personal data was obtained from each patient. All patients were divided into three groups depending on the diagnosed ectatic process: keratoconus, secondary ectasia and PMD of the cornea. The first two groups each included 30 eyes of 30 patients. In the third group, the treatment results of 30 eyes of 30 patients with PMD were analyzed. Patients with a corneal thickness <400 microns, stage 3–4 keratoconus, or a history of herpetic keratitis, parallel infectious or autoimmune disease and/or an abnormal endocrine profile were excluded.

CXL was performed during the first or second year of follow-up, after which the corneal state and visual acuity were monitored for 6 years. All patients underwent a comprehensive examination, including biomicroscopy, ophthalmoscopy, ophthalmometry, refractometry, visometry, tonometry, perimetry, and ultrasound pachymetry. Particular attention was paid to the results of corneal topography performed on a TOMEY TMS-4 corneal topograph. CXL was performed using a UV-X device (version 1000; IROC Innocross, Switzerland) with a UV wavelength of 365 nm and a radiation power on the corneal surface of 3 mW/cm2 when used with a solution of 0.1% riboflavin in 20% solution of dextran (Dextralink, Ufa) according to the standard method (Dresden protocol). Silicone hydrogel soft contact lenses were prescribed to all patients before re-epithelialization. Data from the first visit and from 6 years of subsequent annual examinations were included in the analysis. The best corrected visual acuity, corneal surface asymmetry index (SAI) and refractive corneal power in the center of the corneal ectasia were evaluated.

The Wilcoxon test (V-statistics) was used to assess the dynamics of changes over 6 years since the time of surgery. A mixed-effects beta regression analysis was used to provide a comprehensive description of the dynamics of the studied variables after adjustment for the pathology, sex and age of the patients [14]. The beta regression analysis was selected because an initially strong assumption about the normal distribution of residues was not needed. Beta regression is used to model data distributed in an interval of (0; 1). The characteristics of the random effect and the additional parameter are presented as values with corresponding 95% confidence intervals. The Benjamini–Hochberg adjustment was used to correct p-values when multiple hypotheses were tested. The results were considered statistically significant at a p value < 0.05. All calculations were performed using the R programming language v3.6.1. Data are presented as medians and quartiles (Me [Q1; Q3]).

RESULTS

Our data demonstrated an increase in the best corrected visual acuity, a decrease in the refractive corneal power in the center of ectasia, and a decrease in the SAI index in all groups of patients. However, most significant results were observed in the group of patients with keratoconus (Fig. 1–3). Our results were consistent with those obtained by Raiskup-Wolf et al. [14] in an analysis of the results of CXL in patients with keratoconus.

In patients with keratoconus, best corrected visual acuity (BCVA) values before and 6 years after surgery were 0.55 [0.42; 0.70] and 0.75 [0.70; 0.80], respectively (V = 0.0, p < 0.001). In patients with secondary ectasia, BCVA values before and 6 years after CXL were 0.50 [0.40; 0.60] and 0.70 [0.60; 0.70], respectively (V = 0.0, p < 0.001). In patients with PMD before surgery, BCVA values before and 6 years after CXL were 0.60 [0.52; 0.70] and 0.70 [0.60; 0.80], respectively (V = 0.0, p < 0.001).

 

Fig. 1. The dynamics of the most corrected visual acuity

Рис. 1. Динамика максимально корригированной остроты зрения. Вертикальные линии — 95 % доверительный интервал среднего

 

Fig. 2. The dynamics of the refractive power of the cornea in the center of ectasia

Рис. 2. Динамика преломляющей силы роговицы в центре эктазии. Вертикальные линии — 95 % доверительный интервал среднего

 

Fig. 3. The dynamics of the topographic index of the asymmetry of the cornea

Рис. 3. Динамика топографического индекса асимметрии поверхности роговицы. Вертикальные линии — 95 % доверительный интервал среднего

 

In patients with keratoconus, refractive corneal power values before and 6 years after CXL were 53.06 [52.52; 53.72] and 52.06 [51.44; 52.67], respectively (V = 465.0, p < 0.001). In patients with secondary ectasia, refractive power values before and 6 years after CXL were 53.20 [53.08; 54.01] and 52.80 [52.16; 52.98], respectively (V = 465.0, p < 0.001). In patients with PMD, refractive power values before and 6 years after CXL were 53.13 [52.53; 53.30] and 52.81 [52.14; 53.05], respectively (V = 438.0, p < 0.001).

In patients with keratoconus, SAI index values before and 6 years after CXL were 5.89 [4.19; 6.01] and 4.13 [3.69; 4.77], respectively (V = 465.0, p < 0.001). In patients with secondary ectasia, SAI index values before and 6 years after CXL were 5.94 [5.89; 6.09] and 5.11 [4.89; 5.29], respectively (V = 465.0, p = 0.008). In patients with PMD, SAI index values before and 6 years after CXL were 5.38 [3.97; 5.82] and 5.12 [3.80; 5.73], respectively (V = 465.0, p < 0.001).

CONCLUSION

Our analysis of the long-term effectiveness of CXL revealed positive outcomes in all groups, as evidenced by both the suspension of progression and, in many cases, a complete stabilization of the pathological process and improvements in visual functions. Significant flattening of the ectasia zone and increases in the BCVA were noted in some cases. However, no significant flattening of ectasia or increases in BCVA were observed in patients with PMD. These results will facilitate the development of criteria for the monitoring of cases and staging of therapeutic measures.

SUMMARY

CXL can effectively treat ectatic forms of corneal dystrophy. This technique yields additional benefits by enhancing visual function and improving young patients’ quality of life and ability to work.

Transparency of financial activity: None of the authors has a financial interest in the materials or methods presented.

There are no conflicts of interest.

Authors’ contributions: S.Yu. Astakhov and S.A. Novikov created the research concept and design; O.A. Frolov collected and processed the materials, analyzed the data and wrote the manuscript.

About the authors

Oleg A. Frolov

Diagnostic Center No. 7 (Eye) for Adults and Children; Pavlov First Saint Petersburg State Medical University

Author for correspondence.
Email: oleg524@mail.ru

Post-Graduate Student, Department of Ophthalmology with the Clinic; Head of the Department of Complex Optical Correction

Russian Federation, Saint Petersburg

Sergey Yu. Astakhov

Pavlov First Saint Petersburg State Medical University

Email: astakhov73@mail.ru

MD, PhD, DMedSc, Professor, Head of Ophthalmology Department

Russian Federation, Saint Petersburg

Sergey A. Novikov

Pavlov First Saint Petersburg State Medical University

Email: serg2705@yandex.ru

MD, PhD, DMedSc, Professor, Ophthalmology Department

Russian Federation, Saint Petersburg

References

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