Effect of the Retention Ring-Assisted Continuous Application of Riboflavin in Pulsed-Light Accelerated Corneal Collagen Cross-Linking on the Progression of Keratoconus

doi:10.21203/rs.2.72/v1

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Effect of the Retention Ring-Assisted Continuous Application of Riboflavin in Pulsed-Light Accelerated Corneal Collagen Cross-Linking on the Progression of Keratoconus

https://doi.org/10.21203/rs.2.72/v1

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published 11 Mar, 2019

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Purpose: To investigate the efficacy and safety of the retention ring-assisted continuous application of 0.1% riboflavin in pulsed-light accelerated corneal collagen cross-linking on the progression of keratoconus.

Methods: The medical records of 20 eyes of 18 patients with progressive keratoconus who received collagen cross-linking at Seoul National University Hospital were retrospectively reviewed. Isotonic 0.1% riboflavin was continuously applied for 10 minutes using an 8.0-mm retention ring before the irradiation and accelerated cross-linking was applied with 30-mW pulsed-ultraviolet light at a wavelength 365 nm for eight minutes (1 second on/1 second off; 30 mW/cm2, cumulative dose of 7.2J/cm2) without further intermittent application of riboflavin. Visual acuity, refractive error, topographic index, corneal thickness, and endothelial cell density were evaluated before the operation and at 1, 3, 6, and 12 months.

Results: The best corrected visual acuity in logMAR improved from preoperative 0.43 to 0.18 in 12 months. Maximum keratometry decreased from 51.8 D to 50.4 D at six months (p = 0.015) and 50.3 D at 12 months (p < 0.0001). Astigmatism decreased from preoperative 5.5 D to 4.2 D at 12 months (p < 0.0001). Thinnest corneal thickness decreased at three and six months but recovered in 12 months (p > 0.05). Endothelial cell density decreased at one month (p = 0.02) but gradually recovered in 12 months (p > 0.05).

Conclusions: Continuous application of riboflavin using a retention ring for 10 minutes in an accelerated pulsed-light collagen cross-linking seems to be safe and effective for halting the progression of the keratoconus.

Internal Medicine Specialties

cornea

keratoconus

collagen cross-linking (CXL)

accelerated cross-linking

pulsed-light

retention ring

riboflavin

Keratoconus is a ectatic corneal disorder characterized by progressive thinning and protrusion, accompanied by irregular astigmatism and myopic progression, thereby deteriorating visual function. The conventional standardized treatment is keratoplasty in advanced keratoconus[1].

Corneal collagen cross-linking has recently been introduced to intervene in progression in moderate keratoconus. In corneal cross-linking (CXL), riboflavin (vitamin B2) produces oxygen radicals via a photochemical reaction with ultraviolet A (UV-A) of 365-nm wavelength, and they introduce cross-links between collagen fibrils[2]. Such chemical bonds restore the stability of the keratoconic cornea[3], thereby halting the progression of the disease. The conventional Dresden protocol irradiates UV of 3 mW/cm2 for 30 minutes after intermittent application of the riboflavin every two to five minutes for a total of 30 minutes[4]. It proved to stabilize the cornea in progressive keratoconus for 10 years[5] but, it was considered to be a time-consuming procedure by surgeons.

To shorten the procedure, an accelerated cross-linking protocol was introduced; it uses a shorter radiation time with greater intensity based on the Bunsen-Roscoe law of reciprocity[6]. However, there are debates about whether the accelerated protocol has an effect equivalent to that of the conventional protocol according to different protocols of irradiation and riboflavin application[7-13]. Furthermore, meta-analysis showed a higher treatment efficacy of the standard Dresden protocol compared with the accelerated cross-linking[14, 15].

Meanwhile, reactive oxygen species (ROS) are rapidly depleted by continuous UV irradiation and are replenished by turning the UV off[16]. Pulsing UV irradiation theoretically can therefore restart the photodynamic reaction and can maintain the ROS concentration in the cornea[16]. Accordingly, pulsed-light accelerated cross-linking was adopted to achieve efficacy comparable to that of the conventional Dresden protocoll[17, 18]. However, there is no standardized protocol for the application of riboflavin in pulsed-light accelerated protocol so far. The protocol provided by the manufacturer (Avedro. Inc., Waltham, MA) recommends intermittent application of isotonic riboflavin every two minutes for ten minutes. However recent studies reported different clinical efficacies with various application times of riboflavin (10-30 minutes) and intervals (two to five minutes) in the accelerated protocol[8-11, 18]. Shorter application times (every two minutes for 10 minutes) seem to have lower efficacy, even in pulsed-light accelerated protocol, than that of the conventional protocol[11]. We also recently demonstrated possible damage to the limbal stem-cell area by the exposure to the riboflavin during the cross-linking[19]. Therefore, we newly introduced use of a retention ring in order to (1) reduce exposure of the riboflavin in limbal area and (2) apply riboflavin continuously for better penetration into the cornea. We hypothesized that retention ring-assisted continuous application of 0.1% riboflavin for ten minutes may have better efficacy on the progression of keratoconus in pulsed-light accelerated cross-linking.

Patients

This study was approved by the Institutional Review Board of Seoul National University College of Medicine (IRB No. 1807-139-961, Seoul, South Korea) and adhered to the Declaration of Helsinki. It included 20 eyes of 18 patients with progressive keratoconus who received CXL at a single institution (Seoul National University Hospital) by a single surgeon (M.K. Kim). The medical records of the 18 patients (14 male and 4 female patients) were retrospectively reviewed. The mean age was 28.0 ± 7.3 (range 17- 43) years, and all patients were treated with the same protocol.

Inclusion and Exclusion Criteria

The patients who were diagnosed with progressive keratoconus and underwent accelerated CXL were included in the study. Progression was confirmed by an increase of maximum keratometry (Kmax) of more than 1.5 diopters (D) / year in serial topography. Those with preoperative Kmax greater than 60 D or central corneal thickness (CCT) less than 400 μm or thinnest corneal thickness (TCT) less than 390 μm were excluded. Patients combined with other ocular surface diseases were also excluded.

Clinical Evaluation

Preoperative and postoperative examinations included best-corrected visual acuities (BCVA) as a logarithm of the minimum angle of resolution (logMAR), refractive errors by Auto Kerato-Refractometer (KR-8900, Topcon, Tokyo, Japan), keratometric values including maximum (Kmax ), minimum (Kmin), average (Kavg), and 3 mm and 5 mm irregular index by topography (ORBSCAN IIz, Technolas Perfect Vision GmbH, München, Germany). Corneal thickness (CT) was measured by anterior segment optical coherence tomography (AS-OCT, Visante OCT; Carl Zeiss Meditec, Dublin, CA). Noncontact specular microscopy (SP-8800, Konan, Hyogo, Japan) was used to measure endothelial cell density. Preoperative measurements were compared with the postoperative measurements at 1, 3, 6, 12 months.

Surgical Procedure

Eyes were anesthetized with topical 1% proparacaine (Alcaine; Alcon, Fort Worth, TX) and the central 9.0-mm corneal epithelium was peeled off using a crescent knife (Beaver; Beaver-Visitec, Waltham, MA). Intraoperative pachymetry (Pocket II; Quantel Medical, Bozeman, MT) was performed to make sure that the corneal thickness was greater than 325 μm. A retention ring 8.0 mm in diameter (Frimen, Inc., Jiangsu, China) was applied on the epi-off corneal surface, and 0.1% isotonic riboflavin (Vibex Rapid, Avedro, Inc., Waltham, MA, USA) with dextran-free hydroxypropyl methylcellulose (HPMC; VibeX Rapid, Avedro, Waltham, MA) was continuously applied for ten minutes within the retention ring (Supplementary Figure S1 A). Then, a trephined (inner diameter, 8.5 mm) silicone hydrogel bandage contact lens (ACUVUE OASYS; Johnson & Johnson Vision Care, Jacksonville, FL) was applied to cover the limbus from UV irradiation (Supplementary Figure S1 B and C). Pulsing (1 sec. on/off) 30 mW/cm2 intensity of 365-nm wavelength UV-A (Avedro, Waltham, MA) was irradiated for eight minutes, resulting in a cumulative dose of 7.2J/cm2. During the irradiation, riboflavin was not applied. After irradiation, the corneal surface was irrigated with a balanced salt solution, and the silicone hydrogel bandage contact lens was applied. The bandage contact lens was maintained for seven days with topical 0.5% moxifloxacin and 1% prednisolone four times a day.

Statistical Analysis

Statistical analysis was performed using Prism 5 software (Graphpad Software, Inc., San Diego, CA). The two-tailed Student’s t test was used to compare each of the baseline parameters with the following measurement. The data are presented with mean value ± mean standard deviation (SD), and statistical significance was verified if p < 0.05.

This study analyzed a total of 20 eyes of 18 patients over a mean postoperative follow-up of 12.8 ± 1.0 months. The demographics and baseline characteristics of the study group are shown in Table 1. The mean age at the time of the procedure was 28.0 ± 7.3 years. Mean depth of the demarcation line was 281.0 ± 39.9 µm (minimum 210 µm to maximum 380.0 μm) (Supplementary Figure S2, Table 1). The penetration depth (demarcation line) in our study is comparable to or deeper than that in other studies on accelerated cross-linking protocols (Table 2).

The best corrected visual acuity gradually improved from preoperative 0.43 ± 0.43 logMAR to 0.18 ± 0.16 logMAR at 12 months (p = 0.073, marginally significant) (Figure 1A) and uncorrected visual acuity also improved, from 0.81 ± 0.38 logMAR to 0.49 ± 0.50 logMAR at 12 months, although it was not statistically significant (p = 0.635) (Figure 1B). Refractive errors decreased from -7.40 ± 2.80 D to -6.34 ± 3.16 D in spherical, -4.81 ± 1.36 D to -4.10 ± 2.10 D in cylinder and -9.81 ± 2.93 to -8.39 ± 2.91 in spherical equivalent after 12 months, and remained stable thereafter (p = 0.390, p = 0.069, p = 0.141, respectively) (Figure 1C and D).

Keratometric values were delineated as Kmax (maximum), Kmin (minimum), and Kavg (average). Kmax (Figure 2A) decreased from 51.85± 4.11 D to 50.36 ± 3.55 D at six months (p = 0.015) and 50.31 ± 3.78 D at 12 months (p < 0.0001). Kmin (Figure 2B) also decreased, from 46.40 ± 2.19 D to 46.11 ± 2.37 D at 12 months (p = 0.007). Kavg (Figure 2C) also decreased, from 49.12 ± 2.95 D to 48.55 ± 2.79 D at six months (p = 0.045) and 48.21 ± 2.80 D (p = 0.0001) at 12 months. Topographic astigmatism was significantly reduced, from preoperative 5.45 ± 2.90 D to 4.23 ± 2.27 D at six months (p = 0.006) and 4.19 ± 2.90 D at 12 months (p < 0.0001) (Figure 2D). Irregular index at 3 mm and 5 mm decreased from preoperative 6.27 ± 2.16 D to 5.11 ± 1.58 D and 6.11 ± 1.82 D to 5.44 ± 1.44 D, respectively. The reductions were statistically significant at 12 months (p = 0.002, p = 0.0007, respectively) (Figure 2E and F).

Central corneal thickness showed a significant decrease, from 495.9 ± 36.1 μm to 481.8 ± 43.5 μm in 12 months (p = 0.027) (Figure 3A). Thinnest corneal thickness was temporarily decreased at six months (p = 0.0005), but eventually recovered to 457.9 ± 40.1 μm in 12 months, resulting in no statistical difference compared with the preoperative level (p > 0.05) (Figure 3B).

Endothelial cell density decreased, from preoperative 2693 ± 223 cells/mm2 to 2434 ± 460 cells/mm2 at one month (p = 0.018), but gradually recovered in 12 months (2640 ± 481 cells/mm2) without any significance (p = 0.392) (Figure 3C).

In this study, we report that retention ring-assisted continuous application of riboflavin for ten minutes in pulsed-light accelerated cross-linking seems is safe and effective in halting the progression of keratoconus in 12 months.

To date, there is no consensus on a standardized protocol for accelerated cross-linking comparable to the conventional protocol, which was documented to be effective in treating progressive keratoconus by improving corrected distance visual acuity, decreasing keratometric values, and preserving endothelial cells in a ten-year follow-up study[5]. To improve efficacy, a pulsed-light accelerated protocol was first introduced, showing better functional outcomes in one year by optimizing intraoperative oxygen availability than did the conventional protocol [17], and effectiveness in a two-year follow-up [20]. Nevertheless, recent meta-analysis studies generally indicate better efficiency for the conventional protocol than for the accelerated protocol with a deeper demarcation line [14, 15]. From these analyses, protocol modification is still required to improve the outcomes for the accelerated protocol. That is why we tried continuous application of riboflavin using a retention ring for deeper penetration and better efficacy.

In our study, to shorten the procedure time without reducing the efficacy, we aimed to modify the application method of the riboflavin by continuously using a retention ring before irradiation. The overall clinical effect of our modified protocol on visual acuity, topographic parameters and demarcation line depth was comparable to or better than other studies on accelerated cross-linking (Table 2). The depth of demarcation line was the greatest among the pulsed-light accelerated protocols reported and was still comparable with other continuous accelerated protocols. The mean reduction of maximum keratometry was -1.54 D in our study, and the reduction was greater than those of other accelerated protocols (Table 2) and comparable to those of conventional protocol [15]. Therefore, our modified ten-minute continuous application of riboflavin in a pulsed-light accelerated protocol has better efficacy than other accelerated protocols and efficiency comparable to that of the conventional protocol in halting the progression of keratoconus.

Because of the possibility of limbal stem cell damage during the riboflavin application and UV irradiation[19], modification of the previous protocol was regarded as essential. In our in vivo experiments[19], a significantly greater decrease of p63+ stem cells was observed when the riboflavin was dropped on the whole corneal surface in accelerated cross-linking when compared with the protocol using the retention ring to confine the riboflavin to only the central cornea. We believe that protecting the limbal stem cells by minimizing their exposure to riboflavin and UV is very important, given their crucial role in regeneration of cells. Further experimental studies on concentration- and duration-dependent toxicity of riboflavin are needed to elucidate cellular injury and to standardize the protocol. In our study, there was no significant reduction of endothelial cell density. There was a single case of delayed wound healing, which spontaneously resolved in 14 days with conservative treatments using preservative artificial tear; otherwise, there were no serious complications related to the procedure. Therefore, retention ring-assisted continuous application of riboflavin for ten minutes seems to be clinically safe.

The limitations of our study are that it was not comparative and the sample size was small. Nevertheless, we believe it is worthy of notice as being the first report on a novel method and a clinically significant one-year follow-up result.

In conclusion, ten minutes of continuous riboflavin application with a retention ring in pulsed-light accelerated CXL is safe and effective in halting the progression of keratoconus in 12 months, and the procedure can be shortened without disturbing its efficacy.

Ethics approval and consent to participate : This retrospective study adhered to the tenets of the Declaration of Helsinki and was approved by the Institutional Review Board of Seoul National University Hospital (IRB No. 1807-139-961).

Consent for publication : Not applicable

Availability of data and material : The datasets supporting the conclusions of this article are included within the article and available from the corresponding author on reasonable request.

Competing interests : The Authors declare that there is no conflict of interest

Funding : This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.

Authors' contributions : CYK collected and analyzed the data, wrote the manuscript, and gave final approval of the manuscript to publish. MKK designed the study, wrote the manuscript, and gave final approval of the manuscript to publish.

Acknowledgements : None

Table 1. Baseline characteristics of the patients who underwent pulsed accelerated cross-linking in this study.

Demographic factors
Eyes	20 eyes of 18 patients
Sex	14 male (77.7%), 4 female (22.3%)
Age (year)	28.0 ± 7.3
FU (month)	61.3 ± 53.6
POD (month)	12.8 ± 1.0
BCVA (logMAR)	0.43 ± 0.43
UCVA (logMAR)	0.81 ± 0.38
Refractive error
Spherical (diopter)	-7.40 ± 2.80
Cylinder (diopter)	-4.81 ± 1.36
SE (diopter)	-9.81 ± 2.93
Topography
Kmax (diopter)	52.20 ± 4.32
Kmin (diopter)	46.50 ± 2.18
Kavg (diopter)	49.35 ± 3.06
Astigmatism	5.71 ± 3.07
IR, 3mm	6.38 ± 2.17
IR, 5mm	6.23 ± 1.86
AS-OCT
CCT (μm)	492.1 ± 39.1
TCT (μm)	466.6 ± 37.1
ECD (cells/ mm²)	2731 ± 279.5
Depth of demarcation line after 1mo of cross-linking (μm)	281.0 ± 39.9

Values are presented as mean ± SD, FU, follow up; POD, postoperative date; BCVA, best-corrected visual acuity; UCVA, uncorrected visual acuity; logMAR, logarithm of minimum angle of resolution; SE, spherical equivalent; IR, irregular astigmatism; CCT, central corneal thickness; TCT, thinnest corneal thickness; AS-OCT, anterior segment optical coherence tomography; ECD, endothelial cell density

Table 2. Comparison of the application method of UV / riboflavin and subsequent efficacy in accelerated cross-linking with previous studies. The first three studies used pulsed UV, while the others used continuous UV.

	Irradiation	Total dose (J/cm²)		Riboflavin application: before/during irradiation	FU (mo.)	N	Δ BCVA (logMAR)	Δ Kmax (diopter)	Δ CCT (μm)	Δ ECD (cells/cm²)	DDL (μm)
Our study	30mW/cm² for 8 min (1sec. on/off)	7.2	with HMPC for 10 min, continuous / Not applied		12	20	-0.25	-1.54	-10.3	-91	281
Mazzotta[20]	15mW/cm² for 12 min (1sec. on/off)	5.4	with HMPC every 1 min for 10 min / NR		24	132	-0.14	-0.42	5.03	NR	280
Jiang[18]	30mW/cm² for 8 min (1sec. on/off)	7.2	with HMPC every 2 min for 10 min / every 3 min		12	36	-0.09	-1.31	NR	-247	202
Bouheraoua[21]	30mW/cm² for 3 min	5.4	20% dextran every 1 min for 10 min / NR		6	15	-0.01	0.5	-3	20	184
Brittingham[22]	9mW/cm² for 10 min	5.4	20% dextran every 5 min for 20 min / every 2 min		12	50	NR	0.72	NR	NR	245
Hagem[23]	9mW/cm² for 10 min	5.4	with HPMC for 20 min / every 2 min		12	20	-0.09	-0.5	NR	-54	160
Ng[24]	9mW/cm² for 10 min	5.4	20% dextran every 2 min for 25 min / every 5 min		13.9	12	0.02	-0.3	2.1	NR	209
Pircher[25]	9mW/cm² for 10 min	5.4	with HPMC for 10 min / NR		12	36	NR	-0.77	NR	NR	169
Shetty[7]	18mW/cm² for 5 min	5.4	20% dextran every 2 min for 30 min / every 2 min		15.3	33	0.10 (decimal)	-0.52	-16	-162	203
Tomita[26]	30mW/cm² for 3 min	5.4	with HPMC for 15 min / NR		12	30	-0.09	-0.62	NR	106.6	294

Values are presented as mean, FU, follow up; N, number; mo, months; BCVA, best-corrected visual acuity; logMAR, logarithm of minimum angle of resolution; Kmax, maximum keratometry; CCT, central corneal thickness; ECD, endothelial cell density; DDL, depth of demarcation line; NR, not reported; ΔBCVA (logMAR), BCVA at last FU - preoperative BCVA; ΔKmax, Kmax at last FU - preoperative Kmax; ΔCCT, CCT at last FU - preoperative CCT; ΔECC, ECC at last FU - preoperative ECC

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Effect of the Retention Ring-Assisted Continuous Application of Riboflavin in Pulsed-Light Accelerated Corneal Collagen Cross-Linking on the Progression of Keratoconus

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