Journal of Refractive Surgery

Original Article 

Transepithelial Corneal Cross-linking With Supplemental Oxygen in Keratoconus: 1-Year Clinical Results

Alex Matthys, FRCOphth; Myriam Cassagne, MD, MSc; Stéphane D. Galiacy, PhD; Safa El Hout, MD; Pierre Fournié, MD, PhD; François Malecaze, MD, PhD

Abstract

PURPOSE:

To evaluate the efficacy and safety of transepithelial corneal cross-linking (CXL) with supplemental oxygen.

METHODS:

This was a prospective, non-comparative, pilot cohort study conducted at the National Reference Center for Keratoconus (Toulouse, France) on patients with progressive keratoconus. Transepithelial, pulsed, accelerated CXL was performed in an oxygen-rich atmosphere. Oxygen goggles were applied to the eyes to maintain a high level of oxygen during treatment. The main efficacy outcome was the mean change from baseline in maximum keratometry (Kmax) and the secondary outcomes were the mean changes in flat keratometry (K1), steep keratometry (K2), mean keratometry (Km), corrected distance visual acuity (CDVA), uncorrected distance visual acuity (UDVA), and demarcation line depth. The safety outcomes were the incidence of adverse events, the mean change in pachymetry, and endothelial cell count.

RESULTS:

Thirty-four eyes of 34 patients were included. At 12 months postoperatively, the Kmax decreased by 1.56 ± 1.71 diopters (D) (P < .0001) and CDVA improved by 0.093 ± 0.193 logMAR (P < .02). The K2 and Km decreased by 0.51 ± 1.03 D (P < .02) and 0.40 ± 0.78 D (P < .01), respectively. There was no change in K1 and UDVA. The most frequent adverse event was corneal haze (64.78%). There were neither cases of infectious keratitis or loss of more than two lines in CDVA nor changes in pachymetry or endothelial cell count.

CONCLUSIONS:

Transepithelial CXL performed in an oxygen-rich atmosphere results in improved Kmax and CDVA with good safety. These promising findings suggest that this procedure could be safe and capable of halting the progression of keratoconus.

[J Refract Surg. 2021;37(1):42–48.]

Abstract

PURPOSE:

To evaluate the efficacy and safety of transepithelial corneal cross-linking (CXL) with supplemental oxygen.

METHODS:

This was a prospective, non-comparative, pilot cohort study conducted at the National Reference Center for Keratoconus (Toulouse, France) on patients with progressive keratoconus. Transepithelial, pulsed, accelerated CXL was performed in an oxygen-rich atmosphere. Oxygen goggles were applied to the eyes to maintain a high level of oxygen during treatment. The main efficacy outcome was the mean change from baseline in maximum keratometry (Kmax) and the secondary outcomes were the mean changes in flat keratometry (K1), steep keratometry (K2), mean keratometry (Km), corrected distance visual acuity (CDVA), uncorrected distance visual acuity (UDVA), and demarcation line depth. The safety outcomes were the incidence of adverse events, the mean change in pachymetry, and endothelial cell count.

RESULTS:

Thirty-four eyes of 34 patients were included. At 12 months postoperatively, the Kmax decreased by 1.56 ± 1.71 diopters (D) (P < .0001) and CDVA improved by 0.093 ± 0.193 logMAR (P < .02). The K2 and Km decreased by 0.51 ± 1.03 D (P < .02) and 0.40 ± 0.78 D (P < .01), respectively. There was no change in K1 and UDVA. The most frequent adverse event was corneal haze (64.78%). There were neither cases of infectious keratitis or loss of more than two lines in CDVA nor changes in pachymetry or endothelial cell count.

CONCLUSIONS:

Transepithelial CXL performed in an oxygen-rich atmosphere results in improved Kmax and CDVA with good safety. These promising findings suggest that this procedure could be safe and capable of halting the progression of keratoconus.

[J Refract Surg. 2021;37(1):42–48.]

Keratoconus is a bilateral corneal ectatic disease characterized by progressive thinning and steepening of the cornea.1 Standard management of progressive keratoconus includes corneal cross-linking (CXL) to limit ectatic progression. In the conventional CXL procedure first described by Wollensak et al2 in 2003, the central corneal epithelium is debrided and the stroma is loaded with riboflavin and irradiated with ultraviolet-A light (UVA) at 3 mW/cm2 for 30 minutes. Epithelial debridement enables permeation of the riboflavin to the stroma, where UVA photoactivation generates singlet oxygen and leads to the formation of covalent bonds.3 The efficacy of conventional CXL has been shown through ex vivo experiments4 and multiple randomized clinical trials.5,6

Transepithelial CXL has been proposed to reduce potential complications such as pain, delayed epithelial healing, or infectious keratitis by eliminating the epithelial debridement step.7,8 Despite treatment modifications to improve riboflavin permeation,9,10 prior attempts at transepithelial CXL have shown reduced efficacy compared to conventional CXL.11,12 The epithelium also acts as a barrier to oxygen and UVA, key components of the photochemical reaction. Ex vivo studies indicate that oxygen is rapidly consumed during the UVA irradiation under atmospheric conditions,13 and that corneal stiffening is reduced when CXL is performed in a low oxygen environment14 and increased in high oxygen environments.15 Two mechanisms have been proposed to improve oxygen bioavailability in the stroma during CXL: pulsed illumination to slow the rate of oxygen consumption16–18 and oxygen supplementation to increase the rate of oxygen replenishment.15

Thus, we initiated a study to evaluate an accelerated transepithelial CXL procedure combining high-irradiance, high-dose, pulsed UVA illumination and supplemental oxygen delivery through Boost Goggles (Avedro, Inc). We previously published a clinical study applying a pulsed, oxygen-enriched transepithelial CXL procedure for the treatment of low myopia in patients without ectasia, demonstrating significant flattening of corneal curvature.19 To our knowledge, this is the first study of pulsed, oxygen-enriched transepithelial CXL in patients with progressive keratoconus.

Patients and Methods

Study Design

This prospective, non-comparative, single-center, pilot cohort study was conducted at the National Reference Center for Keratoconus (Department of Ophthalmology) at Purpan Hospital, Toulouse, France. Approval was obtained from the Ethical Committee (ID-RCB: 2017-A02661-52) and in accordance with the tenets of the Declaration of Helsinki.

Patient Population

Patients with progressive keratoconus were enrolled between January 2018 and February 2019. Inclusion criteria were as follows: at least 18 years old, progressive keratoconus (defined by an increase of 1.00 diopters [D] or greater in maximum keratometry [Kmax] over a period of 1 year or less), and pachymetry of at least 400 µm. Exclusion criteria included history of corneal surgery or other corneal disease, aphakic or pseudophakic eyes without a UV-filtering intraocular lens, nystagmus, known allergy to any component used, pregnancy, and lactation. Patients who reported eye rubbing during screening evaluation were asked to cease eye rubbing and scheduled for an additional evaluation. If progression continued after cessation of eye rubbing, the patient was included. The aim of this delayed indirect recruitment was to obtain a uniform population of progressive keratoconus. Contact lens wearers were required to remove contact lenses for 1 week before the screening and follow-up visits. All patients signed an informed consent form prior to enrollment in the study.

Patient Examination

Patients were examined preoperatively, at 2 days postoperatively to remove the bandage contact lens and check for early complications, at 7 days postoperatively, and at 1, 3, 6, and 12 months postoperatively.

Surgical Procedure

After administration of a topical anesthetic (Tetra-caine; Thea), the mucin layer of the tear film was gently removed with a surgical spear (Wek Cell Sponge; Beaver-Visitec) moistened with 0.25% riboflavin solution with benzalkonium chloride in hydroxypropyl methylcellulose (ParaCel Part 1; Avedro, Inc). Then, additional drops of the 0.25% riboflavin solution were applied every 60 seconds for 4 minutes. At 4 minutes, the Part 1 formulation was rinsed from the eye with 0.22% riboflavin solution without benzalkonium chloride (ParaCel Part 2; Avedro, Inc). Additional drops of the 0.22% riboflavin solution were applied every 30 seconds for 6 minutes. Excess riboflavin was then rinsed from the surface with 5 mL of balanced salt solution. To create a high oxygen level at the surface of the cornea, oxygen goggles (Boost Goggles) were placed and connected to a humidified medical grade oxygen source. The flow rate was set to obtain an oxygen concentration of 90% or greater within the goggles, confirmed using an oxygen analyzer (NTH-PSt7 sensor with OXY-4 meter; PreSens Precision Sensing GmbH). The central 9 mm of the cornea was irradiated, through the front opening of the goggles, with 30 mW/cm2 365-nm UVA, pulsed at 1-second intervals for 11 minutes and 6 seconds using a CE-marked (EU1504407) UVA delivery device (Mosaic; Avedro, Inc). The total UVA dose was 10 J/cm2. Balanced salt solution was instilled onto the cornea through the front opening of the goggles as needed to maintain corneal hydration during UVA irradiation, at least once every 2 minutes. After the irradiation period, another measure of oxygen concentration in the goggles was performed. At the end of the procedure, the cornea was rinsed with 5 mL of balanced salt solution and a bandage lens was applied.

Postoperative Care

Postoperative medications included an antibiotic (Azyter; Thea) for 3 days and nonsteroidal anti-inflammatory drug (NSAID) (Ocufen; Horus Pharma) for 3 days. When the bandage contact lens was removed, preservative-free lubricant eye drops (Vismed; Horus Pharma) were used as needed.

Outcome Measures

The main outcome measure was the mean change from the preoperative baseline in maximal curvature (Kmax) measured on elevation Scheimpflug tomography (Pentacam HR; Oculus Optikgeräte GmbH).

For efficiency, the secondary outcome measures were: (1) the mean change from the preoperative baseline in flat keratometry (K1), steep keratometry (K2), and mean keratometry (Km); (2) the mean change from preoperative baseline in corrected (CDVA) and uncorrected (UDVA) distance visual acuity measured by the logMAR scale; (3) the mean change from the preoperative baseline in manifest refraction spherical equivalent; (4) central demarcation line depth measured using the flap tool from anterior segment optic coherence tomography (AS-OCT) (Spectralis; Heidelberg Engineering); and (5) the mean change from preoperative baseline in pachymetry of the thinnest point measured by Scheimpflug tomography (Pentacam HR).

For safety, the secondary outcome measures were: (1) the incidence of adverse events such as ulcer, superficial punctuate keratitis assessed according to the Oxford scale by a single investigator, haze, and infiltrate; (2) the subjective patient evaluation with a visual analog scale ranked from 0 to 10 regarding pain, foreign body sensation, watering, and photophobia (1 to 3 = mild; 4 to 6 = moderate; 7 to 10 = severe); (3) the percentage of eyes with loss of more than two lines of CDVA from preoperative baseline; (4) the mean change from preoperative baseline in endothelial cell count (SP 2000P; Topcon Corporation); and (5) the occurrence of infectious keratitis or loss of more than two lines of CDVA was defined as serious side effects.

Statistical Analysis

Comparisons of different parameters between the 12-month follow-up visit and the baseline were performed using the t test. The data were expressed as average and standard deviation. A P value less than .05 was considered statistically significant.

Results

Population

Thirty-four eyes (22 [64.7%] right and 12 [35.3%] left) of 32 patients were enrolled. The mean patient age was 24.2 ± 4.5 years (range: 19 to 40 years). There were 28 men (82.4%) and 6 women (17.6%). A total of 58.8% of patients were included directly and 41.2% were included on confirmation of continued progression after eye rubbing cessation. The average oxygen concentration in the goggles was 94.6 ± 2.2% (range: 90.3 to 99.1%) at the start of the procedure and 95.1 ± 2.4% (range: 89 to 98.9%) at the end. Three eyes from three patients were lost to follow-up and could not be evaluated at 12 months postoperatively.

Topography Outcomes

Mean preoperative Kmax progression was 1.54 ± 1.21 D within the 12 months prior to the screening visit (baseline). The tomographic changes are depicted in Table 1. Kmax decreased significantly by 1.56 ± 1.71 D (P < .0001) at 12 months postoperatively. The time course of the change in Kmax is reported in Figure 1. Other tomographic outcomes showed a significant decrease of 0.51 ± 1.03 D (P < .02) in K2 and 0.40 ± 0.78 D (P < .01) in Km at 12 months postoperatively. There was no significant change in K1 (P = .061).

Tomographic and Visual and Refractive Outcomes

Table 1:

Tomographic and Visual and Refractive Outcomes

Maximum keratometry (Kmax) evolution preoperatively and at 1, 3, 6, and 12 months postoperatively after transepithelial pulsed corneal cross-linking with high oxygen concentration.

Figure 1.

Maximum keratometry (Kmax) evolution preoperatively and at 1, 3, 6, and 12 months postoperatively after transepithelial pulsed corneal cross-linking with high oxygen concentration.

Visual and Refractive Outcomes

At 12 months postoperatively, there was a statistically significant improvement in mean CDVA of 0.093 ± 0.193 logMAR (P < .02) (Table 1). There was no statistically significant change in UDVA. CDVA improved by one line or more in 47% of patients, remained stable in 32.4% of patients, and decreased by one or two lines in 11.7% of patients (Figure 2). The manifest refraction spherical equivalent decreased significantly by 1.00 D (P = .033).

Changes in lines of corrected distance visual acuity (CDVA) over 12 months.

Figure 2.

Changes in lines of corrected distance visual acuity (CDVA) over 12 months.

Demarcation Line Depth

A visible demarcation line was observable on ASOCT in 29 eyes (85%) at 1 month postoperatively with a mean depth of 316 ± 63 µm. At 3 months postoperatively, it was observed in 22 eyes (64.7%) with a mean depth of 288 ± 64 µm. At 6 months postoperatively, it had resolved in the majority of cases (remained detectable in 3 patients), as already described.20

Pachymetry

There was no significant change in minimum corneal thickness at 12 months postoperatively (456 ± 33 µm at baseline and 451 ± 35 µm at 12 months postoperatively, P = .172).

Safety

No serious side effects were observed during the 12-month follow-up period. Superficial punctuate keratitis was observed in 27 eyes (79.4%) at 2 days postoperatively: 10 eyes (29.4%) at stage 3, 6 eyes (17.6%) at stage 2, and 11 eyes (32.4%) at stage 1. By 7 days postoperatively, superficial punctuate keratitis was resolved in 82.4% of cases and continued with stage 3 in 1 eye (2.9%) and stage 1 in 5 eyes (14.7%). Superficial punctuate keratitis resolved in all eyes by 1 month, and no corneal ulcers occurred. Sterile infiltrates were observed in 4 eyes (11.8%). Considering that that they could be induced by the NSAIDs, they were treated, as deviation from protocol, with topical steroids and antibiotics.

On the subjective patient assessment questionnaire, patients reported an average of 1.7 ± 1 days of postoperative pain. Subjective outcomes are reported in Table 2. One patient could not be evaluated at 2 days postoperatively, and 2 patients could not be evaluated at 7 days postoperatively. Most patients reported tearing (85.3%), photophobia (91.2%), and foreign body sensation (73.5%) immediately following the procedure, with reduction in symptoms at 2 days postoperatively and over the first postoperative week (Table 2). No patients required the addition of oral medications for pain management.

Subjective Patient Assessment Questionnaire Distribution

Table 2:

Subjective Patient Assessment Questionnaire Distribution

Corneal Haze

Transient postoperative anterior stromal haze was observed in 22 eyes (64.7%) at 1 month postoperatively and decreased over the following months. The haze was visible in 17 eyes (50%) at 3 months postoperatively and 8 eyes (23.5%) at 6 months postoperatively, and completely resolved for all patients at 12 months postoperatively. Topical steroid treatment was introduced for 13 patients (38.2%): 4 patients (11.8%) received steroid treatment for sterile infiltrates and 9 patients (26.5%) for corneal haze. The choice of steroid, duration, and dose were prescribed according to the intensity of the corneal haze.

Endothelial Cell Count

There was no statistically significant difference between the preoperative measurements and the 12-month visit (2,666 ± 309 vs 2,702 ± 259 cells/mm2, respectively, P = .09).

Discussion

Previous work has demonstrated the important role of oxygen in the CXL photochemical reaction, which can follow either an aerobic or an anaerobic pathway.13 Although cross-link formation is possible under both conditions, the aerobic pathway leads to more efficient generation of oxygen radicals. An ex vivo study comparing the biomechanical effect of epithelium-off accelerated CXL in different oxygen environments showed that Young's modulus significantly increased in corneas treated in normal atmosphere, whereas corneas treated in a low oxygen environment did not show any significant increase compared to untreated controls.14 Furthermore, ex vivo results with epithelium-on pulsed CXL in a high oxygen environment increased the efficacy of CXL,15 as suggested by Kling and Hafezi.21

In our protocol, aerobic CXL is favored by two mechanisms. First, the oxygen concentration over the surface of the eye is held at greater than 90% throughout the procedure through continuous delivery of high-purity, humidified oxygen using the goggles system. The high oxygen environment increases the rate of oxygen diffusion into the corneal stroma to balance the supply of stromal oxygen versus the consumption during CXL. Second, our protocol applied pulsed UV irradiation. Pulsing decreases the average consumption rate by lowering the average irradiance and allows time for partial replenishment of oxygen. These two factors in combination have been shown to result in stable and aerobic conditions in the stroma during epithelium-on CXL.15

The objective of our study was to evaluate the effectiveness of a transepithelial CXL procedure performed in an oxygen-rich atmosphere to stabilize progressive keratoconus. The results at 12 months postoperatively show a statistically significant decrease in Kmax (1.56 ± 1.71 D; P < .0001) and a statistically significant improvement in CDVA (0.093 ± 0.193 logMAR; P < .02). The outcomes of our study compare favorably to previously reported outcomes of conventional CXL in a comparable French population.22 In the French study, Kmax was decreased by 0.49 D and CDVA was improved by 0.01 log-MAR at 12 months postoperatively. An Australian randomized controlled study of conventional CXL showed a decrease in Kmax of 1.45 D at 12 months postoperatively and CDVA was improved by 0.12 logMAR.23 In the United States, a multicenter randomized controlled trial showed a decrease in Kmax of 1.60 D at 12 months postoperatively in the conventional CXL group.5 Therefore, the results of our transepithelial CXL study appear comparable to previous results obtained at several international centers using conventional CXL and better than previous transepithelial CXL studies that did not use supplemental oxygen.9,12,24 In a randomized study, Soeters et al25 showed that Kmax remained significantly unchanged at 12 months postoperatively with transepithelial CXL compared to a decrease by 1.50 D with conventional CXL. In a prospective study, Ziaei et al26 assessed an accelerated and pulsed transepithelial CXL, with the same riboflavin formulations applied in our study, and found no change in Kmax or CDVA at 12 months postoperatively. Finally, Vinciguerra et al27 observed at 12 months postoperatively a non-significant decrease in Kmax (0.31 D) and a significant increase in CDVA of 0.10 logMAR in the transepithelial CXL using iontophoresis group compared to conventional CXL. The significant decrease of Kmax observed in our study at 12 months postoperatively is comparable to the effect observed with conventional CXL at the same postoperative visit, while still preserving visual acuity. Because variable Kmax results have been observed with other transepithelial CXL protocols, further studies of our oxygen-supplemented transepithelial CXL protocol are recommended to confirm our results.

The demarcation line is thought to represent the transition zone between the CXL-treated cornea and the untreated cornea below and is used as a clinical indicator to evaluate the relative treatment depth. Confocal microscopy studies have demonstrated that cellular apoptosis and stromal edema are responsible for changes in reflective properties of the stroma that produce a line that is visible with the slit lamp and AS-OCT.28 Mazzotta et al29 found that the mean demarcation line depth was approximately 100 ± 20 µm for transepithelial CXL, 200 ± 20 µm for accelerated CXL, 250 ± 20 µm for pulsed CXL, and 350 ± 20 µm for conventional CXL. Oxygen has been described as a factor that affects the depth of the demarcation line: it is more shallow when CXL is performed at altitudes higher than 1,600 m.30 Other factors (eg, the formulation of the riboflavin, irradiation system, duration, power, and mode of irradiation) influence the depth. To limit their influence, we performed all procedures with the same treatment protocol in the same operating room under stable oxygen saturation. In our study, we found a mean demarcation line depth of 316 ± 63 µm at 1 month. This is an interesting finding because it significantly exceeds the depth of previous transepithelial CXL (100 µm) and more closely matches the depth typically reported following conventional CXL (350 µm).29 Although a direct correlation between the depth of the demarcation line and topographic change has not been demonstrated, it may be a useful indicator to compare the relative impact of treatment protocols on stromal cellular components.31 Therefore, the increase in the depth of the demarcation line compared to the transepithelial CXL is the first evidence of the increased formation of oxygen radicals, also responsible for the formation of cross-link bonds.

No patient in our study developed serious adverse events (lost more than two lines of CDVA or had infectious keratitis). The most frequent complaints (eg, foreign body sensation) were transient. One patient described the persistence of severe pain at 7 days postoperatively due to sterile infiltrates that resolved completely at 1 month. Moreover, although superficial punctuate keratitis was noted in 79.4% of corneas at 2 days postoperatively, no patient experienced significant epithelial defects, whereas several studies have reported ulcers after various transepithelial CXL procedures.32,33 We took care with the epithelium throughout the procedure: minimal applications of tetracaine, gentle blepharostat removal, protective contact lens postoperatively, and limited exposure to benzalkonium chloride using a two-part riboflavin formulation. Taneri et al32 observed that this two-part formulation reduced the epithelial defects rate compared to use of Part 1 alone. The most common adverse event was haze in 22 patients (64.78%). It gradually declined and was only visible in 8 patients (23.5%) at 6 months postoperatively. Mazzotta et al28 demonstrated that the haze was related to keratocyte loss and edema and consequently to the relative depth of the reaction and the demarcation line. We observed a higher rate of sterile infiltrates (4 patients, 11.8%) than typically reported after conventional CXL (from 3.2 to 7.6)7,34 and transepithelial CXL (2.4%).35 In our study, the relevant risk factors were the use of a contact lens, NSAID, and atopic disease. The mechanisms suggested are an immune response due to antigenic reaction (for 3 cases) or an excessive scarring response leading to corneal fibrosis (for 1 case).36 In future studies, it would be interesting to use steroids instead of NSAIDs, carefully select the patients (regarding atopic stability), and not use a bandage contact lens.

Accelerated transepithelial CXL with supplemental oxygen resulted in statistically significant flattening of Kmax of 1.56 D at 12 months postoperatively with an increase in visual acuity in patients with progressive keratoconus. This new epithelium-on CXL protocol boosted by oxygen appears to be effective and safe. A future randomized study is warranted to compare it with alternative techniques, particularly conventional CXL.

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Tomographic and Visual and Refractive Outcomes

ParameterBaseline1 Month3 Months6 Months12 MonthsP
No. of eyes3432293331
Tomographic
  Kmax (D)56.43 ± 4.6055.50 ± 4.4655.38 ± 4.0555.08 ± 4.1854.91 ± 3.97< .0001
  K1 (D)45.27 ± 2.4145.27 ± 2.2644.96 ± 2.3245.22 ± 2.1145.20 ± 2.14.061
  K2 (D)48.95 ± 2.9049.36 ± 2.8148.74 ± 2.6648.75 ± 2.5648.68 ± 2.53< .02
  Km (D)47.03 ± 2.4747.23 ± 2.3746.76 ± 2.3546.89 ± 2.1646.87 ± 2.20< .01
Visual and refractive
  CDVA (logMAR)0.19 ± 0.240.15 ± 0.150.13 ± 0.140.12 ± 0.140.11 ± 0.11< .02
  UDVA (logMAR)0.54 ± 0.350.57 ± 0.300.55 ± 0.340.51 ± 0.380.62 ± 0.40.132
  MRSE (D)−1.44 ± 1.951.67 ± 2.35−1.54 ± 2.52−1.57 ± 2.54−2.48 ± 3.59.03

Subjective Patient Assessment Questionnaire Distribution

ParameterDay 2Day 7


NoneMildModerateSevereNoneMildModerateSevere
Pain or discomfort6 (17.6%)13 (38.2%)11 (32.4%)3 (8.8%)20 (58.8%)11 (32.4%)1 (2.9%)
Foreign body sensation8 (23.5%)10 (29.4%)7 (20.6%)8 (23.5%)17 (50%)10 (29.4%)4 (11.8%)1 (2.9%)
Tearing4 (11.8%)3 (8.8%)11 (32.4%)15 (44.1%)9 (26.5%)16 (47.1%)5 (14.7%)2 (5.9%)
Photophobia2 (5.9%)4 (11.8%)12 (35.3%)15 (44.1%)5 (14.7%)10 (29.4%)12 (35.3%)5 (14.7%)
Authors

From the Ophthalmology Department, CNRK, Purpan Hospital, Toulouse, France (AM, MC, SE, PF, FM); and UDEAR, Inserm University of Toulouse III, Toulouse, France (MC, SDG, PF).

The authors have no financial or proprietary interest in the materials presented herein.

Drs. Matthys and Cassagne contributed equally to this work and should be considered as equal first authors.

AUTHOR CONTRIBUTIONS

Study concept and design (MC, SDG, PF, FM); data collection (AM, SE); analysis and interpretation of data (AM, MC, FM); writing the manuscript (AM, MC, FM); critical revision of the manuscript (MC, SDG, SE, PF, FM); statistical expertise (MC, SDG); administrative, technical, or material support (MC); supervision (MC, PF, FM)

Correspondence: Myriam Cassagne, MD, MSc, Department of Ophthalmology, Purpan Hospital, 1 Place du Dr Baylac, Toulouse 31059, France. Email: cassagnemyriam@gmail.com

Received: April 02, 2020
Accepted: October 30, 2020

10.3928/1081597X-20201111-01

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