Long-Term Visual, Refractive and Topographic Outcomes of KeraRings Combined with Accelerated Transepithelial Crosslinking for Management of Different Grades of Progressive Keratoconus: A Retrospective Cohort Study

1. INTRODUCTION

Keratoconus (KC) is a bilateral progressive asymmetrical ectatic disease of the cornea with multifactorial etiological factors lead to stromal thinning and corneal protrusion [1]. Vernal keratoconjunctivitis [2], chronic eye rubbing [3], thyroid disease [4, 5], pregnancy, and lactation [6] are known risk factors that could promote keratoconus progression (KCP) [7, 8].

The first known effective treatment that halts KCP is the corneal collagen standard cross-linking (SCXL) that was introduced by Wollensak et al. in 2003 [9]. Accelerated epithe- lium-off CXL (ACXL) and accelerated epithelium-on, also known as transepithelial CXL (TCXL), are the two major modifications aimed to achieve the previously mentioned objectives [10-15]. However, several other studies proved the superiority of SCXL versus both ACXL and TCXL in adult and pediatric KC patients [16-23].

Intracorneal ring segments (ICRS) are introduced as a refractive device that helps to support the cone, flatten the corneal surface, and improve the spherical and astigmatic status, thus improving the patients’ visual acuity and quality [24, 25]. The ICRS advantages, disadvantages, timing, indications, evolving nomograms, and their ability to stabilize the ectatic cornea, thus preventing KCP, are still being debated [26, 27]. Meanwhile, combination procedures known as cross-linking plus (CXL-Plus) have become popular among corneal surgeons [28-35]. Keraring segments (Mediphacos Inc., Belo Horizonte, Brazil) are common ring segments that are used as corneal implants worldwide [35, 37].

Over the last decade, several studies recommended the use of Kmax as the main parameter besides other parameters for documentation of KCP, i.e., KCP is documented when Kmax≥1 D [38-42]. However, in 2015, based on the global consensus on keratoconus and ectatic diseases, the panel defined keratoconus progression as the occurrence of 2 of the 3 identified parameters of KCP, which causes an increase in the steepening of the anterior corneal curvature, the posterior corneal curvature, and the corneal thinning [43]. Belin ABCD progression display and the Belin-Ambrosio Enhanced Ectasia Display (BAD) are recently introduced as new accurate topographic tools for screening and documenting KC progression [44-47].

The primary aim of this study was to compare the effectiveness of Keraring segments implantation combined with TCXL in low-grade (grades 1 and 2 Amsler-Krumeich) versus high-grade keratoconus (grades 3 and 4 Amsler-Krumeich). The secondary aim was to evaluate the long-term stability in both groups with the demonstration of the prognostic and diagnostic parameters of post-ring implantation keratoconus progression (PR-KCP).

2. METHODS

3. RESULTS

This study included 70 eyes of 70 keratoconus patients (51% male, 49% female). The mean age of patients in group A (n=37) was 26.35±5.83 years, and in group B (n=33) was 28.55±6.06 years. Table 1 shows the characteristics of the studied patients and their eyes descriptive statistics. We recorded no statistically significant differences between both groups regarding these values; however, there were significant differences between S, I, and P subgroups (p=0.004).

4. DISCUSSION

This study included 70 eyes 70 keratoconus patients that underwent TCXL combined with Keraring segment implantation. All eyes completed at least 5 years of follow-up to be included in this study. We exhibited a high rate of complications in 20 eyes at the end of this study. Nineteen eyes with KCP, two of these 19 eyes were also complicated with additional segments' migration. Meanwhile, the twentieth eye was complicated with vascularization, opacification of the tunnel, and also segments' migration.

Our study demonstrated that high-grade keratoconus (grades 3 and 4 AK) yielded better postoperative outcomes in all parameters than the low-grade keratoconus (grades 1 and 2 AK). However, the high-grade keratoconus exhibited a higher rate of postoperative progression than the low-grade keratoconus (45% versus 11% respectively, P<0.0001). In particular, grades 1, 2, 3, and 4 revealed 1, 3, 5, and 10 cases of postoperative progression, respectively. Therefore, we recommend avoiding implantation of ICRS in grade 4 AK keratoconus as it has a high tendency to continue its progression postoperatively. Alternatively, if the surgeon's decision was to implant ICRS, we recommend avoiding TCXL and perform epithelium off CXL considering the use of hypotonic riboflavin solution in high-grade keratoconus.

Our findings suggest that the values regularly used to document preoperative KCP were not ideal to document postoperative KCP, especially in eyes implanted with ICRS. We could possibly have earlier documentation of PR-KCP with earlier surgical interference if the parameters were diagnostic at lower postoperative values than preoperative ones. It was discovered that all eyes that exhibited deterioration of Kmax≥0.71 D finally revealed more deterioration to exceed 1D within a few months later. Therefore, we suggested that if Kmax increases ≥0.75 D, then postoperative KCP should be documented at this level, and another retreatment option should be performed.

Furthermore, we also suggest that PR-KCP should be documented by one of two methods. The first method to document PR-KCP is based on one sole parameter only, which is either Kmax if deteriorated ≥0.75 D. The second method to document PR-KCP is based on the existence of two or more of the following parameters: Kmax≥0.50 D, Kaverage_anterior≥0.50 D, Kaverage_posterior ≥0.25 D, CTT ≥ 1.5% thickness reduction and UDVA or CDVA ≥0.10 logMAR (loss of one or more lines on acuity chart).

Nevertheless, at 48m, we failed to expect early PR-KCP as we depended on prior known parameters and criteria published in the literature to document progression. Unfortunately, none of the values of the current study had achieved the already known prior criteria to document KCP at 48m. Therefore, an early chance was missed to diagnose and retreat KCP. In short, UDVA showed early significant changes in P-subgroup eyes at 48m when the other known parameters did not achieve the known values that were used to document KCP. In other words, patients presented with a postoperative deterioration of UDVA should be scheduled for close follow-up on a 6-monthly basis to avoid missing early postoperative KC progression.

Alio et al. [27] reported the 5-year outcomes of their patients in a retrospective study. They determined their own criteria of success, including UDVA or CDVA gain of one or more lines, while their failure criteria included UDVA or CDVA loss of one or more lines. They concluded ICRS that revealed good results in advanced KC. However, they believed that early KC with good UDVA is a contraindication to ICRS implantation to avoid losing lines of visual acuity. They also recommended avoiding ICRS implantation in progressive KC cases and shifting to other treatment options. Their outcomes were close to ours as we also demonstrated better outcomes in high-grade than in low-grade KC. Furthermore, we demonstrated that UDVA was an early sensitive parameter to document KCP. The main difference between both studies was simply that they implanted Keraring segments in stable and progressive KC cases while we implanted Keraring segments in progressive KC cases only. In addition, we performed TCXL for all our studied eyes, which was not the case in their studied eyes.

As regards the efficacy of combined treatment with TCXL, although postoperative stability is achieved in the first few years, we demonstrated that nineteen eyes (27%) showed definite KCP at the fifth postoperative year. The only explanation of these results is the use of TCXL in our study, which maintains stability for a shorter period of time than standard Cxl.

On the other hand, in a previous study, we (Iqbal et al.) [8] documented no KCP cases for complete postoperative five years following SCXL. This significant difference in the postoperative rate of KCP in both studies proves that SCXL is more effective in the stabilization of ectatic cornea and halting KCP.

Several studies reported different rates of KCP following ICRS implantation. Saleem et al. [31] documented a 14% postoperative rate of KCP. They also reported that 2% of cases revealed spontaneous ring exposure. Our team, in previous research [37], demonstrated a 6% progression rate and 3% segments' migration rate in pediatric patients in postoperative month 18. In a couple of studies of Mounir et al. [48, 49], they reported lower segments' migration rate of 1.5% but documented no cases of postoperative progression in one study; however, their second study revealed 2% segments' extrusion rate but also documented no cases with postoperative progression. On the contrary, to our outcomes, Wild et al. [50] concluded the outcomes of implanting Keraring segments in 70 eyes. They concluded that their implantation outcomes were better in mild KC (mean K<48 D) than in severe KC (mean K>55 D). In their series eyes, they reported that 4% of cases underwent segments explantation because of corneal vascularization; however, they reported no KCP cases in 12 months follow-up period. Nevertheless, 3% of our studied eyes underwent segment explantation, while 27% of the studied eyes were documented with KCP in 60 months follow-up period.

Moreover, Elsaftawy et al. [51] compared Keraring implantation alone versus implantation of Keraring combined with TCXL in a short-term 6 months study. They finally concluded that the addition of TCXL was superior and more advantageous in postoperative improvements and halting KCP. On the contrary, we concluded that TCXL is not effective in halting KCP on long-term follow-up

An important question remains. Why did we choose TCXL instead of SXCL in this present study? The answer is simply related to the time when we operated the studied eyes. Actually, Keratoconus disease is being treated in our localities in Egypt for more than 15 years, and we now have reasonable experience in this field [8, 18, 29, 30, 35]. We started the cross-linking procedures in 2009 using SCXL alone that showed the best CXL outcomes ever in halting KCP. Unfortunately, TCXL was our main CXL procedure for almost 3 years (years 2012 to 2015) because we thought that TCXL was an equivalent procedure to SCXL in efficacy, thus avoiding the potential SCXL postoperative complications. . We acknowledge that we were wrong, and TCXL is less efficient than SCXL. The studied eyes were operated during this time-period shift and discovered that the main disadvantage of TCXL was its weak ability to halt KCP for long-term postoperative periods despite its apparent good outcomes in the early short-term postoperative period. Therefore, the SCXL treatment was again used for patients as the main CXL procedure, especially in young and pediatric patients [18].

Another important question remains. Was KCP the cause of the segments' migration in the current study? Or did the segments' migration accelerate KCP? In other words, Can the cone protrusion and displacement cause migration of the segments? Is the reverse correct? We are not sure if the postoperative progression was responsible for the segments’ migration in this study. Nevertheless, It was believed that the nature of preoperative KCP is different from postoperative one. It was observed that ICRS implantation somehow affects postoperative KCP by either slowing, masking, or accelerating it; however, the underlying mechanism of action of ICRS in the active postoperative progression is not fully understood. Several studies [27, 52, 53] demonstrated that ICRS actually induced corneal remodelling. Alio et al. [27] explained this action by the reduction in the optical aberrations due to improvement of optical properties following ICRS implantation. In addition, Ly et al. [52] used the in vivo confocal microscopy in their study and concluded that ICRSs caused the migration of the fibroblasts with lipid deposition in the extracellular matrix due to their mechanical stresses, thus inducing corneal remodelling. Moreover, Samimi et al. [53] reported that ICRS was associated with keratocyte apoptosis that might be reversible after removal of the implants. The previously reported findings also suggest fibrosis of the tunnel during the wound healing process that could partially induce corneal remodelling. However, we believe that ICRS can help either to stabilize the ectatic cornea or to accelerate postoperative KCP depending on two main factors. The first factor is associated with CXL, while the second is the accurate site and depth of ICRS implantation. TCXL had been found to be effective in halting keratoconus by many studies. This technique overcomes the limitations of a conventional protocol with higher safety and acceptable efficacy [54-56].

On the other hand, Flecha-Lescún et al. [57] theoretically hypothesized that implantation of the segments in the posterior corneal stroma could halt KCP while their implantation in the anterior corneal stroma could properly accelerate KCP. On the contrary, to this theory, Abd Elaziz et al. [58] evaluated the implantation of 355° Keraring segment in the treatment of advanced KC with central cones. They concluded that this type of segment was effective and revealed marked visual and refractive improvements. However, they stated that the actual mean 61% tunnel depth of segment insertion was superficial to their primary intension, 80% tunnel depth. Their findings oppose the theory introduced by Flecha-Lescún et al. [57], as discussed earlier.

The main limitation of our study was the unavailability of patients’ topographic data for the second and third postoperative years. Another limitation was the small number of the studied eyes. Unfortunately, both Belin [59] ABCD grading system 2016 and the new manufacturer’s Keraring nomogram version 2018 were not available when studied eyes operated before 2016. Therefore, an older Amsler-Krumeich grading system and the manufacturer’s Keraring nomogram version 2009 were used. In addition, several studies [44-47], [60-64] recommended the use of the recent Belin ABCD progression display and the BAD for diagnosis of KC progression. We actually did not test the BAD tool as it is unfortunately incorporated only in Pentacam HR (Oculus Inc., Wetzlar, Germany) while we used other types of topographers in our study.

CONCLUSION

We believe that TCXL should not be the first choice for the treatment of progressive KC. In addition, we think that ICRS implantation should not be a basic choice for the treatment of progressive KC until the condition becomes stable for a long period. We also recommend that the indication of ICRS implantation in KC is better to be limited in cases with contact lens intolerability. Furthermore, we believe that ICRS could be considered as supporting implants if the segments’ size and thickness were properly chosen and appropriately implanted. On the other hand, we think that ICRS can act as traumatising implants if not properly selected or perfectly implanted. In the two previous conditions, ICRS could help to stabilize or accelerate KCP; thus the ideal ICRS implants do not exist. Moreover, we think that grade 4 KC should be considered as a contraindication to ICRS implantation as we documented 52.6% of KCP eyes (10 out of 19 eyes) in this grade 4 alone in comparison to other grades. We now believe that the prior known values of the parameters determining preoperative KCP are actually underestimating the real postoperative progression. Therefore, we recommend lowering these values for documenting postoperative KCP to start an early second intervention to halt such progression.

REFERENCES