Lead author
Year
Number (eyes)
Follow-up (months)
UDVA change (LogMar)
CDVA change (LogMar)
MSE change (D)
K max change (D)
Pachymetry change (μm)
Failure (%)
Raiskup
2008
33
>36
−0.15
−2.57
6
Caporossi A
2010
44
48
−0.37
−0.14
+2.15
−2.26
+0.6
0
Kampik D
2011
46
24
−0.05
−1.23
−21.6
Vinciguerra A
2012
40
24
−0.21
−0.19
+1.57
−1.27
+14.0
Goldich Y
2012
14
24
−0.08
−2.40
0
O’Brart D
2013
30
>48
−0.01
−0.1
+0.8
−1.06
+2.0
0
Theuring A
2015
34
120
−0.13
−3.64
−46.0
6
Raiskup F
Poli M
2015
36
72
−0.08
−0.14
+0.11
−16.4
11
O’Brart D
2015
36
78
−0.14
−0.13
+0.78
−0.9
−3.0
0
19.2.4 Description of the Standard Epithelium-Off CXL Procedure
As described earlier, all long-term data over 5 years, together with the vast majority of prospective cohort case series with reported follow-up between 12 and 24 months and most published randomized prospective studies are with epithelium-off CXL using the standard UVA exposure of 3 mw/cm2 for 30 min (total UV dosage 5.4 J/cm2). As more has been published and is known about this particular CXL methodology and as its efficacy and safety is supported by the current scientific literature it must be regarded as the gold standard technique. The following section describes this operative technique.
Prior to CXL, it is typically necessary to obtain documented evidence of progression of ectasia . The precise and best parameters to define progression are not agreed and remain undefined and indeed undetermined. However, many studies and surgeons define progression as an increase in K max/average keratometry and/or refractive astigmatism of over 1.0D and/or decrease in pachymetry greater than 10 % over the preceding 12–18 months [64, 74, 79]. In addition, many surgeons will offer CXL in all adolescent and paediatric keratoconus patients and all with iatrogenic ectasia, even in the absence of documented progression, because of the high risk of worsening of ectasia in such eyes and the improvements in corneal shape and vision documented in most eyes after CXL with time.
To minimize the risk of endothelial damage and corneal decompensation it should be ensured that prior to surgery the corneal thickness is greater than 450 micrometers (μm) (400 μm with the epithelium off) at its thinnest point [38–40]. Following fully informed consent, CXL is typically performed under topical anaesthesia. In the standard epithelium-off technique the central 9 millimetre (mm) of the corneal epithelium is debrided to enable adequate stromal Riboflavin absorption [24, 42–79]. Following epithelial debridement, Riboflavin 0.1 % is applied every 2–3 min for at least 30 min to allow sufficient and homogeneous stromal uptake prior to UVA exposure [81]. In the initial studies the Riboflavin was suspended in a 20 % dextran solution. Whilst this is still used, many formulations now used clinically are isotonic to avoid stromal dehydration and inadvertent corneal thinning during the procedure and contain hydroxypropyl methylcellulose instead of dextran [82]. Intraoperative pachymetry is advocated by many surgeons to monitor corneal thickness prior to UVA exposure and to administer hypotonic Riboflavin drops if the cornea thins excessively (below 400 μm) during Riboflavin administration. The central 8 to 9 mm of the cornea is then irradiated with UVA at 3 mW/cm2 for 30 min. During this time, Riboflavin 0.1 % drops are applied to the stromal surface every 3–5 min during the 30-min irradiation period. Following irradiation, topical antibiotics and corticosteroids are prescribed until corneal re-epithelialization. Systemic analgesic and bandage soft contact lenses can be used for pain management . Topical anaesthetics in limited dosage, no more than 2 hourly and only for 48 h may also be of benefit [83]. Significant ocular pain is typically experienced for the first 24–48 h following surgery and vision is blurred for 1–2 weeks. Patients need to be carefully counselled concerning the expected occurrence of post-operative pain and slow visual recovery in the early post-operative period to avoid unnecessary distress. Contact lens wear can be resumed once the epithelium has fully healed, typically at about 3 weeks.
19.2.4.1 Wound Healing Changes and Confocal Microscopy During the First 12 Months After CXL
Studies using confocal microscopy have identified oedema, superficial nerve loss, rarefaction of keratocytes in the anterior and mid-stroma and isolated endothelial damage in the immediate post-operative period [84–86]. During the first 3 months after surgery there is keratocyte re-population, which is usually complete by 6 months. An increased density of the extracellular matrix occurs to a depth of 300–350 μm, which forms the so-called demarcation line which can be observed on slit lamp examination [87]. Regeneration of nerve fibres, with re-establishment of the sub-epithelial plexus occurs usually within 12 months with return of full corneal sensitivity. Confocal investigations have confirmed the lack of endothelial damage, with no alterations of cell density changes or hexagonality [84–86]. These in vivo confocal microscopic changes after epithelium-off CXL have been confirmed by histological examination of corneal buttons after keratoplasty [87–90] and corroborate keratocyte loss and damage, which can be prolonged [87], with an increase in collagen fibril diameter [87–90].
19.2.4.2 Epithelium-On Versus Epithelium-Off Techniques
Riboflavin is a hydrophilic and is unable to pass through the tight junctions of the intact corneal epithelial barrier. Spoerl et al. confirmed the requirement for full central epithelial debridement to allow sufficient stromal uptake of Riboflavin. They found no modifications in the biomechanical properties of corneal tissue where the CXL was performed with the epithelium intact [22, 23]. These findings were confirmed by a series of ex vivo laboratory investigations, utilizing photospectrophotometry to indirectly measure stromal Riboflavin concentration, which demonstrated the necessity with standard 0.1 % solutions to completely remove all layers of epithelium to achieve adequate stromal Riboflavin concentrations [91–93]. Superficial epithelial trauma, pre-operative, multiple administration of topical Tetracaine 1 %, application of 20 % Alcohol solution, grid pattern epithelial removal were all found to be insufficient to attain significant and/or homogeneous Riboflavin stromal absorption [91–93]. On the basis of such studies, the epithelium was debrided prior to Riboflavin administration in the first clinical investigations and became the gold standard CXL methodology as described earlier [24, 42–79]. In an attempt to reduce post-operative pain, speed visual recovery, reduce risks of infection, reduce corneal scarring (by decreasing epithelial/stromal cytokine interaction) and limit potential endothelial damage (by having a greater overall corneal thickness and preventing perioperative stromal dehydration and thinning), some investigators postulated performing CXL with the epithelium on . Research has been directed at methodologies to enhance epithelial permeability by using multiple applications of topical anaesthesia [94], the addition of chemical additives to the Riboflavin solution such as trometamol (Tris-(hydroxymethyl)aminomethane) [96], Sodium Ethylenediaminetetraacetic acid (EDTA) [95], Benzalkonium Chloride (BAC) and Sodium Chloride [96], partial mechanical disruption [97], iontophoresis [98], increased Riboflavin concentrations, reduced solution osmolarity [99] and/or increased application times.
19.3 Partial Mechanical Epithelial Disruption
Partial Mechanical Epithelial Disruption may be achieved using superficial scratches or specially designed surgical instruments [100]. Rechichi used a corneal disruptor to create pockmarks in the epithelium in 28 patients and reported an improvement in vision and to a certain extent in refraction and corneal topography at 12 months [100]. Similarly, Hashemi in 40 eyes using a technique with 3–4 vertical strips of complete debridement with intact islands of epithelium in-between, reported significant improvements in CDVA and anterior and posterior corneal elevation at 5 years but no changes in K max, refraction or pachymetry [75]. However, whilst these two studies show some efficacy, two comparative studies, Hashemi in a retrospective study of 80 eyes in 65 patients [101] and Razmjoo in a randomized controlled study in 44 eyes of 22 patients [102], suggested that while visual outcomes in terms of CDVA may be better with partial disruption, improvement in topographic indices are superior with complete epithelial debridement [101, 102]. Clearly, long-term comparative studies are needed to compare these two approaches in terms of stability of outcomes and cessation of progression of ectasia, before partial disruption can be considered as efficacious as the gold standard epithelium-off technique .
19.4 Epithelium-On CXL: Chemical Enhancers
The use of Trometamol and EDTA in Riboflavin solutions to enhance transepithelial CXL is equivocal. Filippello in a prospective case series reported rapid visual recovery, little post-operative pain and outcomes in terms of reduction in K max comparable to epithelium-off CXL albeit with a shallower demarcation line [96]. Such results were also seen in 22 eyes of paediatric cases by Salman, who observed a 2.0D decrease in keratometry, improved vision and no progression at 12 months with a worsening of topographic parameters in untreated control eyes [103] and by Magli in a retrospective comparative study who found little difference between epithelial-on and epithelial-off CXL [104]. However, Buzonetti in 13 eyes treated with epithelium-on CXL with solutions containing Trometamol and EDTA , reported that although CDVA had improved, keratometry and higher order aberrations were worse at 12 months [105]. Similarly, Caporossi documented failure of treatment and had to retreat 50 % of his cases with epithelium-off CXL at 24 months, suggesting little efficacy with the use of these chemical “enhancers” [106].
Correspondingly, the use of BAC and multiple administration of topical anaesthetics has shown limited efficacy, despite some encouraging results in ex vivo pre-clinical studies [96]. Leccisotti and Islam in a prospective, paired-eye study in 51 patients, with the eye with more severe keratoconus being treated and the fellow acting as a control, showed an improvement in CDVA, refraction and keratometry in treated compared to control eyes, but with less effect than that reported with epithelium-off CXL [107], while Koppen in 53 similarly treated eyes of 38 patients showed an improvement in CDVA at 12 months, but with progression of K max and pachymetry [108]. In an as yet unpublished study (Gatzioufas, personal communication) reported a high failure rate in epithelium-on treated eyes using Riboflavin 0.25 % with BAC. Not only did 24 % of eyes progress with an increase in K max greater than 1.0D at 12 months but almost 50 % of eyes had epithelial defects on the first day following surgery due to epithelial toxicity from prolonged BAC application. Such findings are consistent with those of Yuksel et al., who found higher pain scores on day 1 and longer epithelialization with epithelium-on treatments [109].
In terms of comparative studies of epithelium-on CXL, with chemical enhancers and solution modification, with epithelium-off treatment, results are equivocal. Whilst a few showed little difference between techniques some clearly indicate better results with epithelial debridement. Rossi in a limited randomized prospective study of 20 eyes (10 per treatment group) utilizing an epithelium-on technique with EDTA and Trometamol reported no differences between the two treatments at 12 months [110]. Likewise Nawaz et al. in a non-randomized study of 40 patients using an isotonic Riboflavin solution found no differences in outcomes between epithelium-off or on CXL at 6 months [111]. However, Al Fayez et al. in a randomized study of 70 patients with 3-year follow-up reported better results with epithelium-off CXL with no progression and an average reduction of K max of 2.4D, while 55 % of eyes with epithelium-on CXL showed progression and an average increase of K max by 1.1D [112]. Similarly, Soeters in a randomized study of 51 eyes documented better reduction of K max with epithelium-off CXL, with progression being reported in 23 % of epithelium-on treated eyes, utilizing EDTA and Trometamol , at 12 months, although improvement in CDVA with epithelium-on CXL was better and complications were less [113]. Finally, Kocak in a retrospective study in 36 eyes with 12-month follow-up showed a greater reduction in cone apex power with epithelium-off CXL, while there was progression in 65 % of epithelium-on treatments [114].
It therefore appears that there still remains a great deal of uncertainty concerning the efficacy of current commercially available epithelium-on CXL methodologies using Riboflavin solution modifications and the addition of chemical enhancers, with many studies reporting high rates of treatment failure. This is probably due to limited stromal Riboflavin penetration through the intact hydrophobic epithelial barrier as seen in photospectrometry studies [91–93] and confirmed recently by a series of published investigations conducted with 2-photon fluorescence microscopy to more directly measure Riboflavin concentration within the stroma [115, 116]. These studies by Gore et al. show very limited uptake with the use of epithelium-on CXL with chemical enhancers with at best only 20–50 % of the Riboflavin concentrations achieved with the standard epithelium-off technique within the first 100 μm of stroma, which falls further at increasing depths [116]. In addition with BAC-containing compounds, significant epithelial damage was observed after 30 min of solution application time and there appeared to be considerable loading of the epithelium with Riboflavin with all solutions that must cause shielding of the stroma from UVA during irradiation [116]. This shielding of UVA reaching the stroma is likely to further limit the efficacy of epithelium-on treatments.
19.5 Iontophoretic Epithelium-On CXL
In addition to the novel formulations discussed earlier, laboratory investigations have shown enhanced transepithelial Riboflavin absorption using iontophoretic delivery [117–121]. Riboflavin is an effective molecule for iontophoretic transfer as it is small, negatively charged at physiological pH and is easily soluble in water. Cassagne using 0.1 % Riboflavin and 1 mA current for 5 min reported 50 % of the stromal concentration seen with epithelium-off CXL in a Rabbit eye model with similar enhancements in extensiometry and collagenase digestion [117]. In a rabbit eye and human cadaver model, Vinciguerra et al. reported better Riboflavin uptake and increased extensiometry changes with iontophoresis compared to epithelium-on CXL without iontophoresis but less than epithelium-off treatments [118]. Mastropasqua et al. documented increased stiffening of human cadaver corneas following iontophoretic CXL using a noncontact air pulse tonometer [119] and Lombardo found comparable stiffness to that seen with epithelium-off CXL using an inflation methodology of ex vivo human globes [120].
Published clinical studies of iontophoretic CXL are limited but encouraging. Bikbova and Bikbov treated 22 eyes using Riboflavin 0.1 % and 1 mA for 10 min and reported a mean reduction of K max of 2.0D at 12 months [121]. Vinciguerra treated 20 eyes, using Riboflavin 0.1 % and 1 mA for 5 min and showed an improvement in CDVA and stable keratometry, higher order aberrations, pachymetry and endothelial counts at 12 months [122]. Similarly, Li using Riboflavin 0.1 % and 1 mA for 5 min in 15 eyes, documented improvement in visual and topographic parameters, with a demarcation line with an average depth of 288 μm at 6 months [123], while Buzzonetti et al. in 14 paediatric cases showed an improvement in CDVA, stability of refraction and topography at 15 months but with an average demarcation line depth of 180 μm [124].
These results are encouraging, but at present there are no published comparative studies with epithelium-off CXL so this technique must be regarded as investigative at present. In addition, iontophoresis is currently being utilized to provide reduced application times of 5–10 min, instead of the usual 30 min epithelium-off application time. In a series of laboratory investigation, O’Brart and colleagues have shown that by increasing Riboflavin concentration, iontophoresis application times and allowing short periods of time for the Riboflavin, which is initially deposited only into the epithelium and anterior stroma by the iontophoresis, to diffuse deeper into the stroma, concentrations of up to 60–80 % of that achieved with epithelium-off application with a homogeneous distribution throughout the stroma can be achieved [125, 126]. With such improved transepithelial Riboflavin penetration it is hoped that results similar to epithelium-off CXL may be achieved. Randomized, prospective, comparative studies are currently being undertaken (O’Brart, personal communication, ISRCT No: 04451470).
19.5.1 Epithelium-on CXL Other Methodologies
As well as iontophoresis, other methodologies currently under pre-clinical investigation to facilitate transepithelial Riboflavin stromal absorption include the use of ultrasound [127], nano-emulsion systems [128], other epithelial permeation enhancers such as d-Alpha-tocopheryl poly(ethylene glycol) 1000 succinate (Vitamin E-TPGS) [129] and the creation of femto second laser intrastromal pockets [130]. At present there are no large case series or comparative studies of these techniques which are only at an investigational stage but might hold promise in the future.
19.5.2 Rapid (Accelerated/High-Fluence) CXL Techniques
Current protocols utilize UVA energies of 3 mW/cm2 and require 30 min of UVA exposure to achieve the desired clinical effect [24, 42–79]. It has been hypothesized that by increasing the UVA fluence while simultaneously reducing the exposure time (the Bunsen–Roscoe law of reciprocity), the same sub-threshold cytotoxic corneal endothelial UVA dosage can be delivered (5.4 J/cm2), thereby maintaining efficacy and safety, but with a reduced treatment time. Reduced treatment time as well as improving case throughput and surgeon convenience may offer improved patient comfort as well as shortened keratocyte exposure time, which it has been postulated may result in less keratocyte damage and apoptosis.
Preclinical ex vivo studies were encouraging, with similar biomechanical changes as measured by scanning acoustic microscopy and extensiometry, seen between the standard UVA exposure of 3 mw/cm2 for 30 min (SCXL) compared with higher fluencies with shorter exposure times [131–133], albeit with a sudden decrease in efficacy with very high intensity UV light greater than 45 mW/cm2 [133]. This decrease in efficacy with higher fluencies is not understood but might be related to oxygen consumption and availability, which has been shown to limit the photochemical cross-linking process [25].
Published clinical studies at present are limited. Cinar et al. in a study of 23 eyes showed that accelerated CXL (ACXL) produced a significant reduction in topographic keratometry values and an improvement in corrected distance acuity with a limited follow-up of 6 months [134]. Shetty et al. in 30 eyes of 14 paediatric cases with a UVA dosage 9 mW/cm2 for 10 min documented an improvement in vision and refractive cylinder at 24 months [135], while using the same accelerated protocol, Marino in 40 eyes with post-LASIK ectasia reported stabilization in all eyes at 2 years [136] and Elbaz et al. documented stability in 16 keratoconic eyes at 12 month with an improvement in UDVA [137].
Comparative studies of ACXL and SCXL have been conflicting. Ng in a comparative study of 26 eyes found a greater reduction in K max and K mean with SCXL at 6–18 months compared to ACXL (9 mW/cm2 for 10 min) [138], while Brittingham in 131 eyes found a reduction of K max in SCXL but not ACXL at 12 months, with a similar high fluence protocol [139]. In contrast, Kanellopoulos in a randomized, bilateral study of 21 eyes using a UVA power of 7 mW/cm2 for 15 min demonstrated similar results to SCXL at 18–56 months [140]. Similarly, comparable results between ACXL and SCXL were reported by Hashemian et al. in 153 eyes of 153 patients with 15-month follow-up [141], Hashemi in 62 eyes with 6-month follow-up, and an ACXL of 18 mW/cm2 for 5 min [142], Shetty et al. in 138 eyes of 138 patients with 12-month follow-up, who found ACXL protocols of 9 mW/cm2 for 10 min and 18 mW/cm2 for 5 min had similar outcomes to SCXL but 30mWcm2 for 3 min was not as efficacious [143], and Sherif who in 25 eyes of 18 patients comparing 30 mW/cm2 for a 4 min 20 s (to give an 33 % increased total UVA dose of 7.2 J/cm2) found comparative results at 12 months with SCXL [144]. Such outcomes are somewhat confusing but do cast some doubt on ACXL protocols especially with fluencies greater than 18 mw/cm2. The reasons for this possibly reduced efficacy seen in some studies with ACXL are uncertain but may, as discussed earlier, be related to excessive oxygen consumption with higher fluencies of UVA and subsequent reduced oxygen availability, which has been shown to be central to the CXL process [25]. Certainly recently published ex vivo pepsin digestion studies have suggested reduced CXL efficacy with increasing UVA fluencies despite the total UVA dosage remaining unchanged at 5.4 J/cm2 [145].
This uncertain efficacy has led some investigators to postulate the need to increase UVA exposure time by 30–40 % [144, 146] or employ fractionated/pulsed treatments [147, 148]. Thus far, there is little clinical data but as discussed earlier Sherif found comparable results with SCXL by increasing exposure time by one-third with 30 mW/cm2 exposure [144] and Kymionis found the same depth of demarcation line by increasing exposure time by 40 % from 10 to 14 min with the 9 mW/cm2 protocol [146]. Mazotta et al. in a comparative non-randomized study of 20 eyes found a greater reduction in keratometry with pulsed treatment compared to non-pulsed with a UVA fluence of 30 mW/cm2 at 12 months [147], while Moramarco et al. found significantly deeper demarcation lines with pulsed treatments using the same protocol. Whilst interesting these studies with differing ACXL protocols are at an investigational stage at present and the efficacy uncertain further randomized controlled, long-term studies are clearly indicated to ascertain their efficacy to the gold-standard SCXL.
19.5.3 Treatment of Thin Corneas
Due to potential UVA endothelial toxicity, CXL using the standard protocol is contraindicated for individuals with corneas thinner than 400 μm. However, it is not uncommon in the clinical setting to see eyes which meet the criteria for cross-linking in terms of progression and good visual rehabilitation with contact lenses whose corneas are less than 400 μm at their thinnest points. This has led investigators to develop a number of protocols to treat such eyes. In a number of studies, hypo-osmolar Riboflavin solutions have been used to swell the cornea intraoperatively to over 400 μm and enable CXL to be undertaken. Raiskup and Spoerl in a series of 32 eyes with corneas thinner than 400 μm showed stability of vision and keratometry with no adverse events at 12 months [149], whilst Nassaralla et al. in 18 eyes demonstrated swelling of the cornea with the intraoperative administration of hypo-osmolar 0.1 % Riboflavin with no post-operative complications [150]. However, in one study of CXL in thin corneas endothelial counts were shown to be somewhat reduced, although vision and keratometry were improved [151] and in one case report, progression continued after CXL in an eye with a central thickness of less than 330 μm [151]. In addition to the use of hypo-osmolar Riboflavin, Spadea and Mencucci demonstrated efficacy with no endothelial damage with transepithelial CXL in corneas as thin as 331–389 μm [152, 153]. Other proposed techniques for CXL in thin corneas include the use of Riboflavin-soaked, non-UVA filtering bandage contact lenses to be placed on the cornea during UVA irradiation [154] and the avoidance of epithelial debridement over the corneal thinnest point [155]. As yet all these published case series of novel CXL techniques in thin corneas contain small number of treated eyes with limited follow up. Undoubtedly, there is a need to cross-link such eyes and larger clinical series with further long-term follow-up are required to establish if these procedures in thin corneas are as effective and safe as standard CXL in corneas with thicknesses greater than 400 μm.
19.5.4 CXL in Combination with Other Treatment Modalities
As well as an isolated treatment, CXL has been used in combination with other treatment modalities to optimize visual outcomes in keratoconic and post-laser ectasia. Excimer laser epithelial removal has been postulated as a more efficacious methodology than mechanical epithelial debridement in standard epithelium-off CXL. Reinstein et al. using high resolution ultrasonic mapping, showed the epithelium to some extent masks the severity of any ectasia by showing hypoplasia/thinning over the cone apex and hyperplasia/thickening around the cone base [156]. Hence phototherapeutic laser removal could theoretically improve outcomes as the cone would be slightly flattened due to superficial stromal tissue removal over its apex during laser ablation. Kapasi et al. in a comparative study of 34 patients comparing excimer laser with mechanical debridement demonstrated better improvement in refractive error and astigmatism with laser removal [157]. Similarly, superior visual and refractive outcomes with laser removal were reported in a comparative study by Kymionis in 38 eyes [158]. Kymionis et al. also published long-term follow-up utilizing this technique of up to 4 years with an average reduction in K max of 3.4D in 23 eyes [159]. This technique shows promise and randomized, prospective studies to compare mechanical and excimer laser removal as well as long-term studies to ensure that progression rates are not increased by stromal tissue removal in these already biomechanically unstable eyes are indicated.
Combined CXL and limited topography-guided PRK in selected eyes with moderate ectasia and adequate corneal thicknesses has been shown to be effective with marked improvements in visual, refractive and topographic parameters and stabilization of the ectatic process in the vast majority of eyes [160–165]. Such treatments have been shown to be associated with significant improvements in quality of life scores [166]. Follow-up in these studies, however, is limited to only 3 years so that long-term biomechanical stability has not been fully elucidated [167] and progression of ectasia has been reported (T. Seiler, personal communication). In addition, significant corneal haze/scarring has been reported following these combined treatments [168, 169]. Undoubtedly, further follow-up studies, beyond 5 years in large patient series and comparative studies would be of great interest to establish this combined procedure.
CXL has also been used after intracorneal ring segment (ICRS) insertion and even in a three-step procedure with both PRK and ICRS insertion [170]. Some studies have suggested that CXL may have an additive effect with intracorneal ring segments [171], although this has not been demonstrated in all studies [172]. The sequencing of the two treatments is as yet undetermined with a single small randomized study suggesting that better results could be obtained with simultaneous treatment rather than sequential [173].
Limited high fluence CXL has also been used in conjunction with keratorefractive procedures such as PRK and LASIK in an attempt to improve long-term stability and reduce the possible occurrence of post-surgery ectasia [174, 175]. As yet, such studies are limited in terms of numbers treated and long-term follow-up. However, results are encouraging, with a contra-lateral eye study by Kanellopoulos of CXL after hyperopic LASIK in 23 eyes demonstrating less regression of correction over a mean follow-up of 23 months [176] and a comparative study by the same author of high myopic LASIK corrections combined with CXL reporting better visual outcomes [177]. Whilst such studies are of great interest, it should be noted that long-term studies of CXL have demonstrated continued flattening of the cornea and continued hyperopic refractive shift in some eyes for up to 5 years follow-up [77–79] and whilst adjunctive CXL may be useful in LASIK longer follow-up over 5 years and randomized, prospective comparative studies are indicated.
19.6 New Methodologies
Whilst Riboflavin/UVA CXL has been shown to be effective, other methodologies which are potentially more rapid and less invasive are currently under investigation. Rocha et al. reported a flash-linking process with UVA and Polyvinyl pyrrolidone may have the potential to photochemically cross-link the cornea in only 30 s [178]. Paik et al. have investigated the topical application of short-chain Aliphatic beta-nitro alcohols [179] and Cherfan et al. demonstrated an almost fourfold increase in corneal stiffness with no reduction in keratocyte viability with Rose Bengal 0.1 % administration and green light application and a less than 5 min total treatment time [180]. Undoubtedly other methodologies and applications will become available over the several next years due to the vast interest in this area of research.
19.7 Complications of Corneal Collagen Cross-Linking
To be discussed in separate chapter.
19.8 Summary
Clinical studies of CXL have shown great promise in stabilizing keratoconus and post-refractive surgery ectasia. Whilst further randomized, prospective and long-term follow up studies are necessary, it is very likely that in the future corneal ectasia can be halted at an early stage and perhaps the need for rigid contact lenses and keratoplasty avoided. Future refinement in techniques may allow for safer and more rapid procedure with less patient discomfort but require further investigation. Combined treatment with other methodologies to treat ectasia shows promise but also requires further investigative and long-term studies.
Compliance with Ethical Requirements
David P.S. O’Brart declares that he has no conflict of interest. He holds a non-commercial grant from Alcon Inc for research into Femto-second laser assisted cataract surgery. No human or animal studies were carried out by the author for this review.
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