Two-year topographic and densitometric outcomes of accelerated (45 mW/cm²) transepithelial corneal cross-linking for keratoconus: a case-control study

Keratoconus (KC) is a chronic ectatic corneal disease characterized by progressive corneal thinning and steeping which lead to irregular astigmatism and visual impairment [1]. Treatment options, including spectacles, rigid gas permeable contact lenses (RGP) [2], intrastromal corneal rings (ICR) [3], keratoplasty [4, 5] and riboflavin ultraviolet-A (UV-A) corneal cross-linking (CXL) [6], are available for improving visual acuity or (and) retarding the progression of KC. Spectacles and RGP correct refractive error but do not change the course of the disease. CXL is effective for slowing or stopping the progression of KC [7]. Literatures have reported that CXL results in increased collagen fiber diameter [8] and enhances biomechanical stiffness [9] through the induction of increased formation of covalent bonds within or between collagen fibers in the corneal stroma [10]. Greenstein SA [11] reported a significant increase in corneal densitometry after conventional (3 mW/cm²) corneal crosslinking (C-CXL), and transient sub-epithelial haze is frequently detected after C-CXL [12, 13]. Accelerated (45 mW/cm²) trans-epithelial corneal cross-linking with pulsed UV (ATE-CXL) is a novel and minimally invasive corneal cross-linking procedure. Higher irradiance, pulsed UV light is used to dramatically shorten treatment duration as compared with the C-CXL (3 mW/cm²) procedure. As the epithelium layer remains intact during ATE-CXL, risk of infection is minimized, and milder ocular surface inflammatory reactions may be triggered, and hence, post-operative complications may be reduced [14]. One of our previous studies [15] investigated one-year outcomes of corneal topographic parameters and corneal densitometry after ATE-CXL for KC. Our results demonstrated decreased corneal densitometry and stable keratometry values at post-operative year 1 [15]. Corneal densitometry, which is also known as corneal backscattering, is considered as a proxy for corneal transparency [16]. It is important to determine whether CXL would lead to loss of transparency when assess the safety of CXL protocols. However the long-term effects of ATE-CXL on corneal densitometry and keratometry remain unknown. In the current study, we investigated 2-year changes in corneal topographic parameters and densitometry values after ATE-CXL for KC.

In KC group, all procedures were uneventful (n = 25). Two patients failed to attend the follow-up of post-operative month 6 (n = 23). At post-operative month 12, 1 patient withdrew from the study, and 1 additional patient did not come for the visit (n = 23). At post-operative month 24, another 2 patients failed to attend the last visit (n = 22). The reasons for loss of follow-up included inconvenient traffic and personal affairs (work- or school-related problems). No statistically significant difference was detected in the mean values of age between the two groups (t = − 0.440, P = 0.664).

A normal cornea is transparent and maintains a smooth and stable curvature [19]. Keratoconus compromises corneal biomechanical stability, leading to progressively increasing corneal keratometry and decreasing corneal thickness.

C-CXL is effective for retarding the progression of KC [20]. However, disadvantages to the standard therapy include the long procedure duration, the removal of the corneal epithelium, and the risks of infection and haze [12, 21, 22], which may lead to increased corneal densitometry and compromised transparency [11]. In the present study, we found the mean values of K1, K2, Km, Kmax, CA, CCT, TCT, ACE and PCE were unchanged over time, indicating that corneal structure remained stable during the 24-month follow-up. Moreover, as we expected [15], the pre-operative densitometry values of the full thickness of the cornea over annular regions Φ0-2 mm and Φ2–6 mm were higher than those of the control group (Figs. 3 and 4), but at post-operative month 24, these values remarkably decreased to normal levels. Strong evidence has shown that corneal collagen diameter increases and the gap between corneal collagen fasciculi narrows significantly after corneal crosslinking using riboflavin and UVA [8]. We hypothesize that the decreased corneal backscattering (densitometry) values are mainly due to the more tightly arranged corneal collagen fasciculi after ATE-CXL. In addition, we did not reveal any correlations between corneal densitometry values and ΔACE, or between the corneal densitometry values and ΔPCE. These results all imply that the densitometric variation might have little relationship with the changes in corneal shape.

So far, many protocols have been suggested for corneal cross-linking. The original cross-linking procedure, Dresden protocol (epithelium off, 3mw/cm² UV-A irradiation for 30 min), demonstrated that both Kmax and Km readings kept stable, and ACE and PCE values continued to decrease up to 5 years after C-CXL [23]. Trans-epithelial corneal cross-linking (TE-CXL) procedure avoids epithelial removal. Magli A et al. [24] compared C-CXL and TE-CXL in progressive KC pediatric patients. They found TE-CXL provided similar efficacy and fewer complications than C-CXL at 1-year follow-up. Accelerated accelerated corneal cross-linking (A-CXL) protocols increase the power intensity of UV-A (9mw/cm², 18mw/cm², 30mw/cm² and 45mw/cm²) and shorten the exposure time to achieve equal dosage. Meanwhile, A-CXL procedures could be performed with or without epithelium [15, 25]. A meta-analysis [26] concluded that, in general, ATE-CXL is effective and safe for KC stabilization, however, C-CXL results in greater flattening of corneal curvature. In the present study, we noticed that at post-operative month 24, 12 of 25 eyes (48%) had decreased Kmax values, 3 eyes (12%) had less than 1.00D shift in Kmax values, but the remaining 7 eyes had progressive KC (Kmax value increased more than 1.00D), implying that ATE-CXL may have insufficient efficacy in some specific KC patients. Interestingly, further analysis revealed that ΔKmax values were positively correlated with pre-operative ACE values (R = 0.436,P = 0.043), moreover, the Log-rank tests also showed that the subgroups with Km ≥ 50.30D or ACE ≥35.3 μm progressed significantly when compared with those with Km < 50.30D or ACE< 35.3 μm, indicating that severer KC patients (Amsler-Krumeich classification above Stage 2) may tend to have poorer outcomes (greater progression). Olivo-Payne A et al. [27] also reported that trans-epithelial accelerated corneal cross-linking demonstrated poorer long-term outcomes in severer cases, which was consistent to our findings.

CXL achieves its effect through increased formation of crosslinks in the corneal stroma, thus enhancing corneal biomechanical stiffness [28]. In severe KC, the cornea is generally thinner and less biomechanically stable [29] compared with mild KC. We hypothesize that, in advanced KC, there is greater stromal degeneration and fewer intact corneal collagen fibrils are available to be cross-linked [30] with ATE-CXL; hence, the effect of ATE-CXL on KC control in severe KC patients may be limited. Alternatively, more crosslinking formation (stronger treatment) may be required in severe cases to stabilize the biomechanically unstable cornea.

The current study had some limitations. First, we only assessed the 2-year changes in topographic parameters and densitometry values following ATE-CXL. The photopic, mesopic and scotopic visual acuity and higher order aberrations were not evaluated. It would be prudent to investigate the effects of ATE-CXL on visual quality in further studies. Second, the sample size is relatively small, however, we mainly investigate the changes in topographic and densitometric parameters before and after ATE-CXL, moreover, the KC patients and the myopes were matched for gender and age and thus, the selection bias should be limited.

Topographic parameters, including K1, K2, Km, CA, Kmax, CCT, TCT, ACE, and PCE values, may all remain stable while the densitometry values of the total layer (over Φ0mm–2 mm and Φ2mm–6 mm) may decrease to normal levels at 2 years after ATE-CXL for KC. Patients with more severe KC may tend to have poorer outcomes. Further studies are essential to shed light on the optimal patient selection criteria for ATE-CXL.