Corneal collagen cross-linking. A review of its clinical applications | Archivos de la Sociedad Española de Oftalmología (English Edition)

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A review of its clinical applications" "tieneTextoCompleto" => true "paginas" => array:1 [ 0 => array:2 [ "paginaInicial" => "166" "paginaFinal" => "174" ] ] "autores" => array:1 [ 0 => array:4 [ "autoresLista" => "K. Balparda, M.J. Maldonado" "autores" => array:2 [ 0 => array:2 [ "nombre" => "K." "apellidos" => "Balparda" ] 1 => array:4 [ "nombre" => "M.J." "apellidos" => "Maldonado" "email" => array:1 [ 0 => "maldonado@ioba.med.uva.es" ] "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "*" "identificador" => "cor0005" ] ] ] ] "afiliaciones" => array:1 [ 0 => array:2 [ "entidad" => "Instituto Universitario de Oftalmobiología Aplicada (IOBA), Universidad de Valladolid (UVa), Valladolid, Spain" "identificador" => "aff0005" ] ] "correspondencia" => array:1 [ 0 => array:3 [ "identificador" => "cor0005" "etiqueta" => "⁎" "correspondencia" => "Corresponding author." ] ] ] ] "titulosAlternativos" => array:1 [ "es" => array:1 [ "titulo" => "Entrecruzamiento del colágeno corneal. Revisión de sus aplicaciones clínicas" ] ] "textoCompleto" => "IntroductionIn less than 20 years, corneal collagen cross-linking (CXL) has evolved from an experimental technique to become a standard therapy for managing corneal ectasia.<a class="elsevierStyleCrossRef" href="#bib0380">1</a> In addition, evidence is growing to support its efficacy in other pathologies such as infectious corneal ulcers<a class="elsevierStyleCrossRef" href="#bib0385">2</a> and bullous keratopathy.<a class="elsevierStyleCrossRefs" href="#bib0390">3,4</a> In what concerns corneal ectasia, the importance of CXL lies specifically in being the only treatment that can slow down the progression of the disease, which could delay or even avoid the application of other more invasive therapies (such as keratoplasty) in a significant number of patients, particularly those with keratocone.<a class="elsevierStyleCrossRef" href="#bib0400">5</a>The objective of this review is to analyze the main evidence that have studied and demonstrated the usefulness of CXL in various pathologies and clinic situations that ophthalmologists must address.Overview of the techniqueThe use of CXL as a therapy for halting the progression of keratocone was first proposed by Wollensak et al.<a class="elsevierStyleCrossRef" href="#bib0405">6</a> in 2003. CXL includes the utilization of riboflavin (vitamin B2) as a photosensitizer coupled to irradiation with ultraviolet type A light (UVA) over the cornea.<a class="elsevierStyleCrossRef" href="#bib0410">7</a> UVA is to be understood as a segment of light that is invisible for the human eye and within the wavelength between 320 and 400nm, which comprises approximately 95% of all ultraviolet radiation reaching the surface of the earth.<a class="elsevierStyleCrossRef" href="#bib0415">8</a>The final objective of the technique is to generate an increase in the rigidity of the cornea by means of increasing the covalent links between the collagen fibers in the corneal stroma. Even though to date the action mechanism of surgery is not exactly known, it has been suggested that radiating with ultraviolet light (particularly UVA) could be related with the generation of oxygen-reactive species<a class="elsevierStyleCrossRef" href="#bib0420">9</a> and the induction of localized oxidative stress.<a class="elsevierStyleCrossRefs" href="#bib0425">10,11</a> Said oxidative reaction would produce intra-and inter-fibrillary covalent links in the corneal stroma collagen, thus increasing its strength and diminishing the tendency to the characteristic progression of corneal ectasia. Riboflavin exhibits a dual role: (1) it acts as a photosensitizer that facilitates said photo polymerization process, going from an excited form in response to UVA light stimulation, and (2) it does not allow the toxic effect of UVA radiation to cause significant damage in deeper structures. As regards the first role, it has been demonstrated that the area of the cornea that would be more hardened with said procedure are the most superficial 200μm, as this is the area with the largest diffusion of riboflavin and therefore comprising the majority of induced chemical reactions.<a class="elsevierStyleCrossRef" href="#bib0435">12</a>The standard technique has been named as “The Dresden Protocol”, and it follows the recommendations initially proposed by Wollensak et al.<a class="elsevierStyleCrossRef" href="#bib0405">6</a> The Dresden protocol includes removing the corneal epithelium and subsequently applying a 0.1% riboflavin solution during 30min, followed by UVA radiation having a wavelength of 370nm and an irradiation of 3mW/cm2 (5.4J/cm2).<a class="elsevierStyleCrossRef" href="#bib0440">13</a>However, the Dresden protocol includes some limitations inherent to the described technique, mainly related to de-epithelization. Specifically, the removal of the corneal epithelium could be related to a significant period of post-surgery pain in addition to exposing patients to re-epithelization delays and higher risk of bacterial overinfection.<a class="elsevierStyleCrossRef" href="#bib0445">14</a> For these reasons, a number of techniques have been proposed with the aim of avoiding the removal of the corneal epithelium and/or improving intra-stromal penetration and concentration of riboflavin.Some authors have suggested the use of riboflavin compounds with substances that improve penetration, i.e., enhancers, through the untouched corneal epithelium. There is a certain degree of experience with the use of 0.25% riboflavin formulations associated to benzalconium chloride (BAC), or to ethylenediaminetetraacetic acid (EDTA) associated to trometamol, among others. It has been proposed that the application thereof could temporarily modify the permeability of the corneal epithelium, allowing riboflavin to reach useful concentrations in the corneal stroma without requiring the removal of the epithelium. In animal models, Torricelli et al.<a class="elsevierStyleCrossRef" href="#bib0450">15</a> have suggested that transepithelial CXL with riboflavin enhanced with BAC and EDTA could provide sufficient corneal “hardening” that could even exceed the hardness obtained by techniques that involve withdrawing the epithelium. However, some authors have described considerably less optimistic findings. Caporossi et al.<a class="elsevierStyleCrossRef" href="#bib0455">16</a> have published that confocal analyses of corneas submitted to CXL demonstrate that the transepithelial approach with EDTA only produces one third of the apoptotic effect of the technique involving the withdrawal of epithelium. From the clinical viewpoint, it has been reported that transepithelial CXL with trometamol and EDTA could produce the stabilization of the disease in human eyes with keratocone.<a class="elsevierStyleCrossRef" href="#bib0460">17</a> To this date, the issue remains controversial as+ more studies are required to ensure the clinic effectiveness thereof.On the other hand, some authors have proposed the use of iontophoresis (local application of continuous and very low intensity electrical current) to improve the penetration of riboflavin into the corneal stroma through an intact epithelium. To date, some relatively small pre-clinic<a class="elsevierStyleCrossRef" href="#bib0465">18</a> and clinic<a class="elsevierStyleCrossRef" href="#bib0470">19</a> studies have demonstrated that this approach could be somewhat useful for managing keratocone patients. It has also been proposed that the use of iontophoresis could afford higher riboflavin penetration in the stroma than that achieved with simple transepithelial CXL, although without reaching the levels achieved by conventional CXL.<a class="elsevierStyleCrossRef" href="#bib0470">19</a> A study by Vinciguerra et al.<a class="elsevierStyleCrossRef" href="#bib0475">20</a> demonstrated that the use of CXL with iontophoresis would be effective for stabilizing keratocone patients after one year follow-up. Similar results were reported by Buzzonetti et al.<a class="elsevierStyleCrossRef" href="#bib0480">21</a> in a population of pediatric patients observed during 15months.According to the Dresden protocol, an additional variant of the conventional technique is known as “accelerated CXL”. Even though the protocols of this variant may differ for different authors, it is generally accepted that these techniques are 6 times shorter than the conventional CXL protocol, including higher intensity UVA irradiation,<a class="elsevierStyleCrossRef" href="#bib0485">22</a> between 9 and 18mW/cm2.<a class="elsevierStyleCrossRef" href="#bib0490">23</a> The logic in this type of technique is based on the Bunsen–Roscoe law, that states that a photochemical reaction would remain constant is the total energy is constant. This means that, lower irradiation times with higher intensity irradiation should induce the same degree of biostructural changes than longer exposure times at lower intensities. It has been proposed that this type of variant could be safe and yield adequate biomechanical results, even in thin corneas. However, additional studies are needed to determine the long-term effects of accelerated CXL as well as the standardization in the time and irradiation levels of the intervention.Recently it has been proposed to substitute riboflavin with Bengal rose ultraviolet irradiation coupled to 532nm green light irradiation<a class="elsevierStyleCrossRef" href="#bib0495">24</a> with apparently optimistic results suggesting higher hardening effect of corneal tissue in animal models.<a class="elsevierStyleCrossRef" href="#bib0500">25</a> For this proposal, more studies are also required.Crosslinking in keratoconeKeratocone is the most common corneal ectasia. Even though the prevalence of keratocone has been reported at approximately one case for every 1800–2000 people in the general population,<a class="elsevierStyleCrossRef" href="#bib0505">26</a> new imaging techniques (particularly tangential topography and corneal tomography) has evidenced that this pathology could be a lot more common than initially believed.One of the most important characteristics of keratocone is precisely its progressive nature, involving growing visual deterioration of patients. Despite the above, at present there is no absolute global consensus about what is understood by “progression of keratocone”, with different authors using a range of definitions. In a recent randomized study, Wittig-Silva et al.<a class="elsevierStyleCrossRef" href="#bib0510">27</a> defined progression as the appearance of at least one of the following factors in the 12 previous months: an increase of at least 1.00D in simulated keratometry plus curve (Scheimpflug technique) or in the most curved meridian measured with manual keratometry; an increase of at least 1.00D in astigmatism in manifest refraction, or a reduction of 0.1mm in the radius of contact lenses that best fitted the patient. In turn, Hersh et al.<a class="elsevierStyleCrossRef" href="#bib0515">28</a> have defined progression as the appearance of any of the following during a 24 month period: an increase of 1.00D in keratometry plus curve, an increase of 1.00D or more in subjective cylinder, or an increase of 0.50D or more in subjective spherical equivalent.Wollensak et al.<a class="elsevierStyleCrossRef" href="#bib0405">6</a> were the first to propose the use of CXL for halting keratocone progression in 2003, on the basis of their experience with animal models and humans. At present, CXL is regarded as a standard technique in keratocone management, being the only clinically available intervention that has demonstrated a potential to slow down or halt the progression of the disease.<a class="elsevierStyleCrossRef" href="#bib0380">1</a> Recently, the Global Consensus on Keratocone and Ectatic Diseases<a class="elsevierStyleCrossRef" href="#bib0380">1</a> has postulated that CXL “is extremely important in the treatment of keratocone with documented clinic progression”, as well as “important in the treatment of keratocone with a perceived risk of progression (in which said progression has not been confirmed) and in eyes with keratocone that previously underwent other forms of corneal surgery (intra-stromal ring segments or Excimer laser)”.<a class="elsevierStyleCrossRef" href="#bib0380">1</a> Several meta-analyses (such as those authored by Meiri et al.<a class="elsevierStyleCrossRef" href="#bib0520">29</a> and Craig et al.<a class="elsevierStyleCrossRef" href="#bib0525">30</a>) have provided important evidence about the usefulness of the technique in patients with keratocone in progression.Evidence on the effects produced by CXL in eyes with keratocone is relatively large. O’Brart et al.<a class="elsevierStyleCrossRef" href="#bib0530">31</a> published their experience with a 7 year follow-up of a group of 36 eyes of a like number of patients who underwent CXL due to progressive keratocone. Said group of authors found that, after 7years, the eyes submitted to CXL exhibited Kmax −0.91D when comparing it against presurgery values, and that this value had a difference of −0.74D when comparing SimK at the end of the follow-up with the presurgery numbers. Similarly, said group experienced a significant improvements in far visual acuity parameters as well as in high order aberrations. The majority of studies agreed in that CXL correlated with a significant improvement in uncorrected and corrected visual acuity parameters in keratocone patients. A recent study<a class="elsevierStyleCrossRef" href="#bib0535">32</a> has found that uncorrected visual acuity improved significantly 24months after the intervention. This could be explained by relative stabilization of corneal morphology and the improvement of its refractive characteristics, in addition to the stabilization of the disease. Obviously, these positive changes on the cornea would give rise to some visual improvements with adequate optical correction and adaptation to more user-friendly contact lenses by avoiding cone increases. Ghanem et al.<a class="elsevierStyleCrossRef" href="#bib0535">32</a> demonstrated that CXL related to a statistically significant reduction in the coma, trefoil, secondary astigmatism, quadrafoil, secondary coma and trefoil values, although these changes do not directly relate to the degree of improvement in far corrected visual acuity.It has been proposed that the effects of CXL (at least with the accelerated version of the technique) could be more marked in advanced keratocone cases (Kmax≥58.0D) when compared with patients whose pathology is not as advanced (Kmax<58.0D).<a class="elsevierStyleCrossRef" href="#bib0540">33</a>In what concerns the use of CXL in pediatric patients, published experiences are relatively few although highly encouraging.<a class="elsevierStyleCrossRef" href="#bib0545">34</a> One study<a class="elsevierStyleCrossRef" href="#bib0550">35</a> published in 2016 assessed the effect and safety of CXL with 4 years follow-up in 40 patients under 19 years of age who underwent intervention for progressive keratocone. At 48 months follow-up, the improvement in corrected and uncorrected far visual acuity was 0.2±0.2logMAR and 0.4±0.2logMAR, respectively. Thirty-two percent of patients exhibited Kmax flattening of 1.0D or more. No significant loss was found in endothelial cell counts after 48 months follow-up. In turn, Magli et al.<a class="elsevierStyleCrossRef" href="#bib0555">36</a> reported 18 months follow-up in 13 eyes of patients under 18 submitted to CXL with iontophoresis due to progressive keratocone. In this group of patients, the Kmax value at 18months after the intervention exhibited stability of the disease as well as the absence of significant changes in endothelial cell counts. Recently, McAnena and O’Keefe<a class="elsevierStyleCrossRef" href="#bib0545">34</a> and Kumar-Kodavoor et al.<a class="elsevierStyleCrossRef" href="#bib0560">37</a> described very similar results. Sabti et al.<a class="elsevierStyleCrossRef" href="#bib0565">38</a> described performing CXL in both eyes of a 4-year-old patient with progressive keratocone and trisomy,<a class="elsevierStyleCrossRef" href="#bib0480">21</a> finding stabilization of the corneal disease without evident complications. At present, the Global Consensus on Keratocone and Ectatic Diseases<a class="elsevierStyleCrossRef" href="#bib0380">1</a> recommends performing CXL in patients of any age whenever objective evidence of progression is observed.The possibility of stabilization in patients with progression of the disease is relatively high. It has been estimated that only between 8.1% and 33.3% of patients will exhibit progression of Kmax values after the intervention.<a class="elsevierStyleCrossRef" href="#bib0440">13</a>The importance of keratoplasty in ophthalmology, particularly in the management of keratocone, is beyond doubt. Until a few decades ago, cornea transplant was the only surgical therapy for this pathology. The stabilization of the disease brought about by CXL might not only delay but even avoid the need of corneal transplant in some patients with keratocone.<a class="elsevierStyleCrossRef" href="#bib0570">39</a> In this regard, an article published in 2015 by Sandvik et al.<a class="elsevierStyleCrossRef" href="#bib0400">5</a> assessed the evolution of keratoplasties in a cohort of Norwegian patients, finding that the number of corneal transplants due to keratocone carried out between 2013 and 2014 (n=26) was significantly lower than those carried out between 2005 and 2006 (n=55). The author indicates that this change is probably due to the implementation of CXL as a standard technique among surgical options in the group of 2013 and 2014, diminishing the need of performing keratoplasty techniques in said subjects.On the basis of the above described evidence, it seems clear that CXL plays a definitive role in the management and modification of the natural history of eyes with keratocone and should be performed in all patients exhibiting a demonstrated progression of the disease, regardless of age or degree of compromise. On the other hand, it is also true that the progression rate of keratocone is much higher in adolescents and young adults than as from the fourth decade of life. Accordingly, it would be logical to apply said procedure mainly in the first age group. The application of CXL in patients who have not demonstrated progression but exhibit a “perceived risk”<a class="elsevierStyleCrossRef" href="#bib0380">1</a> of progression remains at the criterion of the ophthalmologist.Crosslinking in pellucid degeneration marginalEven though keratocone is the corneal pathology in which CXL has been most widely applied, there is significant evidence about its usefulness in other noninflammatory corneal ectasia.Pellucid marginal degeneration is a relatively infrequent entity that has been classified by some authors as a phenotypical variation of classic keratocone and by others as an independent pathology.<a class="elsevierStyleCrossRef" href="#bib0575">40</a> Its main characteristic is the presence of a generally inferior corneal thinning strip together with a protrusion of the area above the thinning. In 2010, Spadea<a class="elsevierStyleCrossRef" href="#bib0580">41</a> published his experience using CXL in the eye of a patient with pellucid marginal degeneration, performing an inferior decentering of the treated area. Said author found visual acuity increase in the patients and diminished corneal cylinder, which remained stable during one year after the intervention. A similar experience was recently published by Bayraktar et al.<a class="elsevierStyleCrossRef" href="#bib0585">42</a> in 2 patients in whom bilateral CXL produced a significant improvement in corrected visual acuity and a range of topographic parameters. Three eyes described in said article did not have previous surgery, while one had received an intrastromal ring segment with 160° arc and 300μm thickness. No significant changes arose during the follow-up of said patients and the disease was not observed to evolve. When considering an inferior decentering for treating these patients, it is important to avoid irradiating over the corneal limbus, as CXL could produce permanent alterations at this level. Even so, some authors<a class="elsevierStyleCrossRef" href="#bib0590">43</a> have denied deleterious effects of CXL over corneal limbus stability.Similarly, the simultaneous utilization of CXL with surface ablation techniques in patients with said corneal ectasia has also been reported.<a class="elsevierStyleCrossRef" href="#bib0595">44</a> Kymionis et al.<a class="elsevierStyleCrossRef" href="#bib0600">45</a> have described the use of photorefractive keratectomy (PRK) and CXL in a patient with pellucid marginal degeneration which produced improvements in corrected visual acuity, which remained stable one year after the intervention. The same authors<a class="elsevierStyleCrossRef" href="#bib0605">46</a> subsequently reported their experience in 8 eyes of 6 patients with pellucid marginal degeneration who underwent conventional PRK and CXL at the same time. Said authors found significant improvements in uncorrected far visual acuity (1.05±0.33 to 0.41±0.27logMAR) with stable uncorrected far visual acuity. No evidence of complications was found in any patient. In view of the above, CXL on its own or in addition to corneal surface Excimer surgery could be an attractive therapeutic option in subjects with corneal ectasia and topographic findings compatible with pellucid marginal degeneration.Crosslinking in keratorefractive refractive surgeryNot all patients are good candidates for keratorefractive surgery with Excimer laser as they would have increased risk of secondary corneal ectasia or the presence of keratocone. A few years ago it was proposed that CXL could provide a degree of protection and stability in patients submitted to surface ablation with irregular cornea. This proposal was led by Kanellopoulos.<a class="elsevierStyleCrossRef" href="#bib0610">47</a>Patients with keratocone submitted to PRK guided by topography and CXL simultaneously have obtained significant improvements in refractive values, with keratometric stability after 12 months of observation.<a class="elsevierStyleCrossRef" href="#bib0615">48</a> Similar results have been reported by Fadlallah et al.<a class="elsevierStyleCrossRef" href="#bib0620">49</a> in patients with initial keratocone by combining unguided PRK with CXL simultaneously. Lee et al.<a class="elsevierStyleCrossRef" href="#bib0625">50</a> found greater stability in the anterior and posterior corneal surfaces of patients submitted to CXL and surface ablation simultaneously than when carrying out surface ablation on its own.Crosslinking in ectasia after keratorefractive surgeryAnother entity in which CXL has proved its usefulness to diminish the progression of the disease is ectasia after keratorefractive surgery (also known as “post-LASIK ectasia” or “iatrogenic ectasia”). A relatively large study recently published by Yildirim et al.<a class="elsevierStyleCrossRef" href="#bib0630">51</a> included 20 eyes of 14 patients who developed ectasia after keratorefractive surgery. This group found that uncorrected far visual acuity improved from 0.78±0.61 to 0.53±0.36logMAR, whereas corrected visual acuity improved from 0.27±0.23 to 0.19± 0.13logMAR. Even though keratometric values did not produce a statistically significant reduction, they did evidence stabilization of the pathology in the course of time. Li et al.<a class="elsevierStyleCrossRef" href="#bib0635">52</a> made similar findings according to which CXL related to improved visual acuity in patients with post-LASIK ectasia while providing stability to the disease at one year follow-up. In this group, uncorrected and corrected final visual acuity improved from 0.77±0.32 to 0.70±0.33 logMAR and 0.36±0.30 to 0.23±0.23 logMAR, respectively, both changes being statistically significant. Interestingly, an article<a class="elsevierStyleCrossRef" href="#bib0640">53</a> discussed the parameters that predict the response of a patient with post-LASIK ectasia with the execution of CXL. It was found that visual acuity is the most important presurgery parameter to predict which subjects will exhibit an improvement of at least one Snellen line one year after surgery (poorer presurgery visual acuity prognosticates greater improvement), in contrast with those who did not gain a single line or had stable or diminished vision. Said study also suggested that higher presurgery keratometry and thinner pachymetry equate with poorer far corrected visual acuity one year after CXL. At this time it is important to emphasize that said article was focused on visual gain after surgery and not necessarily on the stabilization of the disease, which is the final objective of CXL.Accordingly, it seems that CXL plays a stabilizing role in ectasia cases after keratorefractive surgery. However, its role in the prevention of iatrogenic ectasia when combined primarily with Excimer laser ablation procedure (known as LASIK Xtra) is not sufficiently demonstrated at this point in time.<a class="elsevierStyleCrossRef" href="#bib0585">42</a>Crosslinking in infectious keratitisThere is extensive experience and knowledge about the effect of ultraviolet radiation on the genetic material of organisms, including humans. Type B (280–320nm) and C (10–280nm) ultraviolet radiation directly produce damages in DNA by forming pyrimidine dimers that block DNA replication and RNA transcription.<a class="elsevierStyleCrossRef" href="#bib0645">54</a> In turn, UVA radiation (utilized in the CXL process) produces its biological effects through the induction of oxygen-reactive species, causing oxidative stress in lipids, proteins and DNA.<a class="elsevierStyleCrossRef" href="#bib0420">9</a>Several studies have experimentally demonstrated the aggressive effect of ultraviolet radiation of bacterial cultures. It has been described<a class="elsevierStyleCrossRef" href="#bib0650">55</a> that ultraviolet radiation in various wavelength groups is effective in vitro against methicillin-resistant Staphylococcus aureus. Similar data have been obtained for Escherichia coli strains.<a class="elsevierStyleCrossRef" href="#bib0655">56</a> Similarly, Santos et al.<a class="elsevierStyleCrossRef" href="#bib0420">9</a> have described the susceptibility of various bacterial strains (including Pseudomonas spp. and Staphylococcus spp.) to ultraviolet radiation, emphasizing that irradiation with UVA is closely related to the generation of oxygen-reactive species, mainly in Staphylococcus spp strains. This would match the expected effects of CXL in non-infected corneae, where the creation of oxygen-reactive species enhances the creation of bridges and links between different collagen fibers.The effects of ultraviolet irradiation have also been demonstrated in vitro on fungal strains. Risovic et al.<a class="elsevierStyleCrossRef" href="#bib0660">57</a> describes that various ultraviolet wavelength frequencies (254nm, 365nm, 406nm, 420nm) could be utilized for eradicating Candida albicans strains. A group from Colombia also proposed that environmental irradiation of ultraviolet lights could generate permanent changes in the genetics of Aspergillus fumigatus.<a class="elsevierStyleCrossRef" href="#bib0665">58</a>Adding up all the above data, it would seem biologically feasible to include UVA irradiation enhanced by a photosensitizer (riboflavin) among treatments for severe corneal infections. One of the first articles to propose this approach was published in 2008 by Iseli et al.,<a class="elsevierStyleCrossRef" href="#bib0670">59</a> who described their results after CXL in 5 eyes with severe keratitis associated to corneal thinning or melting (3 infections of Mycobacterium spp., one by filament fungus and another by Fusarium spp.). In the 5 cases, corneal destruction was halted by the intervention, making emergency keratoplasty unnecessary in all patients. Subsequently, the management of 7 eyes with severe infectious keratitis (including cases of Staphylococcus aureus and Haemophilus influenzae, among others) was described. These cases responded very positively to CXL with fast and complete improvement of active symptoms in all cases.<a class="elsevierStyleCrossRef" href="#bib0675">60</a> A recently published meta-analysis on the subject<a class="elsevierStyleCrossRef" href="#bib0625">50</a> found that CXL is highly effective in severe keratitis for the majority of etiologies including fungal, bacterial (both gram-positive and gram-negative) as well as Acanthamoeba spp. The only etiology with disappointing results was severe viral keratitis. It has been described<a class="elsevierStyleCrossRef" href="#bib0680">61</a> that CXL was unable to halt the progression of the disease in a patient with herpetic keratitis and corneal thinning, who required tectonic keratoplasty 15 days after CXL. The expanded corneal button was negative for other fungal or bacterial etiologies, which discards overinfection as the cause of clinical worsening. Moreover, it has been demonstrated that CXL could be a factor for viral reactivation in patients with previous although inactive herpetic keratitis, as the exposure to ultraviolet radiation could activate virus herpes.<a class="elsevierStyleCrossRef" href="#bib0685">62</a>A further recent meta-analysis by Papaioannou et al.<a class="elsevierStyleCrossRef" href="#bib0690">63</a> has explored recent evidence on the subject, finding healing rates of 85.7% in patients with bacterial infectious keratitis. In addition, patients with fungal and Acanthamoeba keratitis have also exhibited positive response rates. However, doubts still remain about the efficacy against the latter microorganism, with some authors like Berra et al.<a class="elsevierStyleCrossRef" href="#bib0695">64</a> suggesting that it could be counterproductive in these patients.According to the above, the use of CXL would seem reasonable in severe fungal or bacterial keratitis when associated to corneal thinning. CXL could also be considered in cases with demonstrated infection by multi-resistant germs. Evidence seems to indicate that this therapy is contraindicated in patients with active herpetic keratitis and should be used with extreme caution in patients with previous and currently inactive herpetic keratitis. However, in the latter case it would probably be better to administrate antiviral oral coverage (famciclovir, etc.). Its effectiveness in keratitis caused by Acanthamoeba remains controversial.<a class="elsevierStyleCrossRef" href="#bib0695">64</a>In 2013, an initiative to promote research and development of CXL technologies specifically designed for managing infectious ocular pathologies established the use of different designations for the 2 main cross-linking approaches. Accordingly, it has been proposed to use “CXL” to designate the applications focused on the management of corneal ectasia, and to use the term “photo-activated chromophore for infectious keratitis” (PACK-CXL).<a class="elsevierStyleCrossRef" href="#bib0700">65</a>Crosslinking in pseudophakic bullous keratopathyEndothelial failure is a common cause of diminished corneal transparency. Bullous keratopathy (BK) is characterized by the presence of stromal edema and epithelial bullae as a direct consequence of the loss of the pump and sweep function of the corneal endothelium that entails overhydration of corneal tissue.<a class="elsevierStyleCrossRef" href="#bib0705">66</a>It was recently suggested that CXL could be beneficial for patients with chronic BK. The formation of inter-fibrillary links between the collagen structures of the corneal stroma that takes place in CXL would increase the difficulty for water to fill in this virtual space, thus diminishing the rate of edema as a consequence of endothelial failure<a class="elsevierStyleCrossRef" href="#bib0440">13</a>. In canine eyes with BK, the installation of riboflavin during 30min followed by 3min of UVA irradiation produced improvements in apparent ocular pain symptoms as well as inducing corneal edema improvements during the first 3 months after the intervention.<a class="elsevierStyleCrossRef" href="#bib0710">67</a>In human eyes, evidence has also shown some benefits. Sharma et al.<a class="elsevierStyleCrossRef" href="#bib0715">68</a> assessed the evolution of 50 eyes with pseudophakic BK that underwent CXL, finding an important reduction in subjective pain parameters even though these are returned to presurgery values 6 months after the intervention. Even though pachymetry values diminished regularly, corrected far visual acuity values did not exhibit noteworthy improvements. Similar data were published by Arora et al.<a class="elsevierStyleCrossRef" href="#bib0720">69</a> finding that CXL in patients with pseudophakic BK produced a considerable initial improvement in visual and pain parameters, although the beneficial effect disappeared about 3 months after the intervention. A recent article did not find that CXL, even with repeated applications, was beneficial for patients with BK secondary to Fuchs-type endothelial dystrophy.In view of the above, it would seem that CXL in patients with BK could have a discreet initial effect on pain and visual symptoms, although this effect tends to disappear after a few months. In addition, there seems to be a relationship with the severity of the disease, with CXL producing better effects in less affected corneae.<a class="elsevierStyleCrossRef" href="#bib0715">68</a> It is likely that this approach is indicated only for patients with BK who are not regarded as good candidates for endothelial keratoplasty and who have important pain symptoms secondary to the pathology. Accordingly, this indication is similar to that of phototherapeutic keratectomy (PTK) for this alteration.Crosslinking in donor modification in keratoplastyOne of the main risks of corneal allograft is graft rejection. Previously, it was demonstrated that CXL generates a significant apoptotic reduction in stromal keratocytes as well as in other antigen presenting cells at that level.<a class="elsevierStyleCrossRef" href="#bib0725">70</a> On the basis of a murine model, Wang<a class="elsevierStyleCrossRef" href="#bib0730">71</a> has suggested that CXL could be utilized for pre-treating the donor corneal button in order to reduce the population of said cells, thus diminishing the risk of rejection in keratoplasty. However, as yet there is not sufficient evidence on this approach and it is likely to be relatively ineffective, particularly in penetrating keratoplasty, as the donor button endothelium that has to be preserved to enable corneal transparency is associated to a relevant proportion of rejections.Side effectsCXL is a relatively safe surgical technique with low complication rates and side effects. Even though “virtually all eyes”<a class="elsevierStyleCrossRef" href="#bib0735">72</a> had some sort of corneal haze one month after the intervention, it diminishes markedly after one year. This haze attenuation was verified with Scheimpfug images.<a class="elsevierStyleCrossRef" href="#bib0740">73</a> Overall, 7.6%<a class="elsevierStyleCrossRef" href="#bib0735">72</a> of patients developed sterile corneal infiltrates that tend to improve easily with the use of topical corticosteroids. The appearance of said infiltrates has also been reported in pediatric patients.<a class="elsevierStyleCrossRef" href="#bib0745">74</a> Abbouda et al.<a class="elsevierStyleCrossRef" href="#bib0750">75</a> recently published a review of 10 infectious keratitis cases post-CXL, the majority of which were caused by bacteria.In general, 2.9% of intervened eyes will exhibit diminished corrected far visual acuity of 2 or more Snellen lines one year after surgery.<a class="elsevierStyleCrossRef" href="#bib0735">72</a> Identified risk factors comprise age above 35 and corrected far visual acuity of 20/25 or better.ConclusionsCorneal collagen cross-linking with UVA radiation and riboflavin is an evolving surgical technique broadly supported by pre-clinic and clinic studies confirming its therapeutic usefulness for preventing the progression of corneal ectasia, particularly in keratocone although also in marginal pellucid degeneration and ectasia after keratorefractive surgery. Accordingly, even if CXL is not a cure for keratocone or other ectasia, it plays an increasingly preeminent role in the therapeutic options in addition to intrastromal ring segment implants and other treatments. However, its role in the prevention of iatrogenic ectasia when initially combined with Excimer laser ablation procedure is not sufficiently demonstrated at this date. In addition, it seems to have a considerably beneficial effect for controlling corneal infections due to fungi, bacteria or amoebas. Its usefulness in the preparation of the donor button in keratoplasty and bullous keratopathy seems less consistent. The development of the technique aims at shorter (accelerated) applications and to the preservation of the corneal epithelium. Other non-photonic cross-linking methods, including those with Bengal rose, are also emerging following the path of the currently most widely utilized technique that apply UVA radiation and riboflavin to the cornea.Conflict of interestsThe authors state that they do not have any relevant conflict of interests in relation to this article." "textoCompletoSecciones" => array:1 [ "secciones" => array:17 [ 0 => array:3 [ "identificador" => "xres818602" "titulo" => "Abstract" "secciones" => array:4 [ 0 => array:2 [ "identificador" => "abst0005" "titulo" => "Objective" ] 1 => array:2 [ "identificador" => "abst0010" "titulo" => "Methods" ] 2 => array:2 [ "identificador" => "abst0015" "titulo" => "Results" ] 3 => array:2 [ "identificador" => "abst0020" "titulo" => "Conclusions" ] ] ] 1 => array:2 [ "identificador" => "xpalclavsec815651" "titulo" => "Keywords" ] 2 => array:3 [ "identificador" => "xres818603" "titulo" => "Resumen" "secciones" => array:4 [ 0 => array:2 [ "identificador" => "abst0025" "titulo" => "Objetivo" ] 1 => array:2 [ "identificador" => "abst0030" "titulo" => "Métodos" ] 2 => array:2 [ "identificador" => "abst0035" "titulo" => "Resultados" ] 3 => array:2 [ "identificador" => "abst0040" "titulo" => "Conclusiones" ] ] ] 3 => array:2 [ "identificador" => "xpalclavsec815652" "titulo" => "Palabras clave" ] 4 => array:2 [ "identificador" => "sec0005" "titulo" => "Introduction" ] 5 => array:2 [ "identificador" => "sec0010" "titulo" => "Overview of the technique" ] 6 => array:2 [ "identificador" => "sec0015" "titulo" => "Crosslinking in keratocone" ] 7 => array:2 [ "identificador" => "sec0020" "titulo" => "Crosslinking in pellucid degeneration marginal" ] 8 => array:2 [ "identificador" => "sec0025" "titulo" => "Crosslinking in keratorefractive refractive surgery" ] 9 => array:2 [ "identificador" => "sec0030" "titulo" => "Crosslinking in ectasia after keratorefractive surgery" ] 10 => array:2 [ "identificador" => "sec0035" "titulo" => "Crosslinking in infectious keratitis" ] 11 => array:2 [ "identificador" => "sec0040" "titulo" => "Crosslinking in pseudophakic bullous keratopathy" ] 12 => array:2 [ "identificador" => "sec0045" "titulo" => "Crosslinking in donor modification in keratoplasty" ] 13 => array:2 [ "identificador" => "sec0050" "titulo" => "Side effects" ] 14 => array:2 [ "identificador" => "sec0055" "titulo" => "Conclusions" ] 15 => array:2 [ "identificador" => "sec0060" "titulo" => "Conflict of interests" ] 16 => array:1 [ "titulo" => "References" ] ] ] "pdfFichero" => "main.pdf" "tienePdf" => true "fechaRecibido" => "2016-04-02" "fechaAceptado" => "2016-10-14" "PalabrasClave" => array:2 [ "en" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Keywords" "identificador" => "xpalclavsec815651" "palabras" => array:5 [ 0 => "Cornea" 1 => "Keratoconus" 2 => "Vision disorders" 3 => "Ectasia" 4 => "Collagen" ] ] ] "es" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Palabras clave" "identificador" => "xpalclavsec815652" "palabras" => array:5 [ 0 => "Córnea" 1 => "Queratocono" 2 => "Trastornos de la visión" 3 => "Ectasia" 4 => "Colágeno" ] ] ] ] "tieneResumen" => true "resumen" => array:2 [ "en" => array:3 [ "titulo" => "Abstract" "resumen" => "ObjectiveTo perform a literature review of the current clinical applications of corneal collagen cross-linking. MethodsAn exhaustive literature search was made, including the main biomedical databases, and encompassing all years since the introduction of cross-linking in ophthalmology practice. ResultsCorneal collagen cross-linking using UVA irradiation and riboflavin is a surgical technique that is currently being optimized, and is supported by a good amount of pre-clinical and clinical studies. These papers found show the beneficial effect of the surgery on preventing the progression of corneal ectasia, especially keratoconus, but also on pellucid marginal degeneration and keratectasia after refractive surgery. The effect of cross-linking on avoiding the occurrence of iatrogenic keratectasia when combined with a photo-ablative procedure is less clear to date. Additionally, it appears that cross-linking may have a considerable beneficial effect on controlling corneal infection caused by fungi, bacteria and amoebae. However, its effect on viral keratitis can be detrimental. The benefit on bullous keratopathy seems to be rather transient. ConclusionsCorneal collagen cross-linking may be used with relative safety and efficacy in patients with progressive keratoconus. Its use could also be considered in patients with other corneal ectasias or with corneal infections of non-viral origin. Currently, there is still a need for more studies as regards its effect on preventing iatrogenic keratectasia." "secciones" => array:4 [ 0 => array:2 [ "identificador" => "abst0005" "titulo" => "Objective" ] 1 => array:2 [ "identificador" => "abst0010" "titulo" => "Methods" ] 2 => array:2 [ "identificador" => "abst0015" "titulo" => "Results" ] 3 => array:2 [ "identificador" => "abst0020" "titulo" => "Conclusions" ] ] ] "es" => array:3 [ "titulo" => "Resumen" "resumen" => "ObjetivoRealizar una revisión bibliográfica para mostrar las aplicaciones clínicas actuales de la técnica de entrecruzamiento del colágeno corneal. MétodosBúsqueda exhaustiva de la bibliografía de las principales bases de datos biomédicas desde la introducción del entrecruzamiento del colágeno corneal en el campo oftalmológico. ResultadosEl entrecruzamiento del colágeno corneal mediante radiación UVA y riboflavina es una técnica quirúrgica en estado de evolución pero ampliamente soportada por estudios preclínicos y clínicos que apoyan su utilidad terapéutica en la prevención de la progresión en las ectasias corneales, especialmente en el queratocono, aunque también en la degeneración pelúcida marginal y en las ectasias tras cirugía queratorrefractiva. Su papel en la prevención de la ectasia iatrogénica cuando se combina inicialmente con el procedimiento ablativo con láser excimer no está suficientemente probado a día de hoy. Adicionalmente, parece tener un considerable efecto beneficioso en el control de las infecciones corneales por hongos, bacterias o amebas. Sin embargo, el efecto sobre las queratitis víricas puede ser perjudicial. El beneficio en la queratopatía bullosa parece ser transitorio. ConclusionesEl entrecruzamiento del colágeno corneal puede ser usado con relativa seguridad y efectividad en pacientes con queratocono progresivo. Su uso podría considerarse en pacientes con otros tipos de ectasias y con infecciones corneales de etiología no vírica. Aún hacen falta más estudios para determinar su efectividad en la prevención de la ectasia iatrogénica." "secciones" => array:4 [ 0 => array:2 [ "identificador" => "abst0025" "titulo" => "Objetivo" ] 1 => array:2 [ "identificador" => "abst0030" "titulo" => "Métodos" ] 2 => array:2 [ "identificador" => "abst0035" "titulo" => "Resultados" ] 3 => array:2 [ "identificador" => "abst0040" "titulo" => "Conclusiones" ] ] ] ] "NotaPie" => array:1 [ 0 => array:2 [ "etiqueta" => "☆" "nota" => "Please cite this article as: Balparda K, Maldonado MJ. Entrecruzamiento del colágeno corneal. 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Corneal collagen cross-linking. A review of its clinical applications

Entrecruzamiento del colágeno corneal. Revisión de sus aplicaciones clínicas

K. Balparda, M.J. Maldonado

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maldonado@ioba.med.uva.es

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Instituto Universitario de Oftalmobiología Aplicada (IOBA), Universidad de Valladolid (UVa), Valladolid, Spain

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    "textoCompleto" => "<span class="elsevierStyleSections"><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0065">Introduction</span><p id="par0005" class="elsevierStylePara elsevierViewall">In less than 20 years&#44; corneal collagen cross-linking &#40;CXL&#41; has evolved from an experimental technique to become a standard therapy for managing corneal ectasia&#46;<a class="elsevierStyleCrossRef" href="#bib0380"><span class="elsevierStyleSup">1</span></a> In addition&#44; evidence is growing to support its efficacy in other pathologies such as infectious corneal ulcers<a class="elsevierStyleCrossRef" href="#bib0385"><span class="elsevierStyleSup">2</span></a> and bullous keratopathy&#46;<a class="elsevierStyleCrossRefs" href="#bib0390"><span class="elsevierStyleSup">3&#44;4</span></a> In what concerns corneal ectasia&#44; the importance of CXL lies specifically in being the only treatment that can slow down the progression of the disease&#44; which could delay or even avoid the application of other more invasive therapies &#40;such as keratoplasty&#41; in a significant number of patients&#44; particularly those with keratocone&#46;<a class="elsevierStyleCrossRef" href="#bib0400"><span class="elsevierStyleSup">5</span></a></p><p id="par0010" class="elsevierStylePara elsevierViewall">The objective of this review is to analyze the main evidence that have studied and demonstrated the usefulness of CXL in various pathologies and clinic situations that ophthalmologists must address&#46;</p></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0070">Overview of the technique</span><p id="par0015" class="elsevierStylePara elsevierViewall">The use of CXL as a therapy for halting the progression of keratocone was first proposed by Wollensak et al&#46;<a class="elsevierStyleCrossRef" href="#bib0405"><span class="elsevierStyleSup">6</span></a> in 2003&#46; CXL includes the utilization of riboflavin &#40;vitamin B<span class="elsevierStyleInf">2</span>&#41; as a photosensitizer coupled to irradiation with ultraviolet type A light &#40;UVA&#41; over the cornea&#46;<a class="elsevierStyleCrossRef" href="#bib0410"><span class="elsevierStyleSup">7</span></a> UVA is to be understood as a segment of light that is invisible for the human eye and within the wavelength between 320 and 400<span class="elsevierStyleHsp" style=""></span>nm&#44; which comprises approximately 95&#37; of all ultraviolet radiation reaching the surface of the earth&#46;<a class="elsevierStyleCrossRef" href="#bib0415"><span class="elsevierStyleSup">8</span></a></p><p id="par0020" class="elsevierStylePara elsevierViewall">The final objective of the technique is to generate an increase in the rigidity of the cornea by means of increasing the covalent links between the collagen fibers in the corneal stroma&#46; Even though to date the action mechanism of surgery is not exactly known&#44; it has been suggested that radiating with ultraviolet light &#40;particularly UVA&#41; could be related with the generation of oxygen-reactive species<a class="elsevierStyleCrossRef" href="#bib0420"><span class="elsevierStyleSup">9</span></a> and the induction of localized oxidative stress&#46;<a class="elsevierStyleCrossRefs" href="#bib0425"><span class="elsevierStyleSup">10&#44;11</span></a> Said oxidative reaction would produce intra-and inter-fibrillary covalent links in the corneal stroma collagen&#44; thus increasing its strength and diminishing the tendency to the characteristic progression of corneal ectasia&#46; Riboflavin exhibits a dual role&#58; &#40;1&#41; it acts as a photosensitizer that facilitates said photo polymerization process&#44; going from an excited form in response to UVA light stimulation&#44; and &#40;2&#41; it does not allow the toxic effect of UVA radiation to cause significant damage in deeper structures&#46; As regards the first role&#44; it has been demonstrated that the area of the cornea that would be more hardened with said procedure are the most superficial 200<span class="elsevierStyleHsp" style=""></span>&#956;m&#44; as this is the area with the largest diffusion of riboflavin and therefore comprising the majority of induced chemical reactions&#46;<a class="elsevierStyleCrossRef" href="#bib0435"><span class="elsevierStyleSup">12</span></a></p><p id="par0025" class="elsevierStylePara elsevierViewall">The standard technique has been named as &#8220;The Dresden Protocol&#8221;&#44; and it follows the recommendations initially proposed by Wollensak et al&#46;<a class="elsevierStyleCrossRef" href="#bib0405"><span class="elsevierStyleSup">6</span></a> The Dresden protocol includes removing the corneal epithelium and subsequently applying a 0&#46;1&#37; riboflavin solution during 30<span class="elsevierStyleHsp" style=""></span>min&#44; followed by UVA radiation having a wavelength of 370<span class="elsevierStyleHsp" style=""></span>nm and an irradiation of 3<span class="elsevierStyleHsp" style=""></span>mW&#47;cm<span class="elsevierStyleSup">2</span> &#40;5&#46;4<span class="elsevierStyleHsp" style=""></span>J&#47;cm<span class="elsevierStyleSup">2</span>&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0440"><span class="elsevierStyleSup">13</span></a></p><p id="par0030" class="elsevierStylePara elsevierViewall">However&#44; the Dresden protocol includes some limitations inherent to the described technique&#44; mainly related to de-epithelization&#46; Specifically&#44; the removal of the corneal epithelium could be related to a significant period of post-surgery pain in addition to exposing patients to re-epithelization delays and higher risk of bacterial overinfection&#46;<a class="elsevierStyleCrossRef" href="#bib0445"><span class="elsevierStyleSup">14</span></a> For these reasons&#44; a number of techniques have been proposed with the aim of avoiding the removal of the corneal epithelium and&#47;or improving intra-stromal penetration and concentration of riboflavin&#46;</p><p id="par0035" class="elsevierStylePara elsevierViewall">Some authors have suggested the use of riboflavin compounds with substances that improve penetration&#44; <span class="elsevierStyleItalic">i&#46;e&#46;</span>&#44; enhancers&#44; through the untouched corneal epithelium&#46; There is a certain degree of experience with the use of 0&#46;25&#37; riboflavin formulations associated to benzalconium chloride &#40;BAC&#41;&#44; or to ethylenediaminetetraacetic acid &#40;EDTA&#41; associated to trometamol&#44; among others&#46; It has been proposed that the application thereof could temporarily modify the permeability of the corneal epithelium&#44; allowing riboflavin to reach useful concentrations in the corneal stroma without requiring the removal of the epithelium&#46; In animal models&#44; Torricelli et al&#46;<a class="elsevierStyleCrossRef" href="#bib0450"><span class="elsevierStyleSup">15</span></a> have suggested that transepithelial CXL with riboflavin enhanced with BAC and EDTA could provide sufficient corneal &#8220;hardening&#8221; that could even exceed the hardness obtained by techniques that involve withdrawing the epithelium&#46; However&#44; some authors have described considerably less optimistic findings&#46; Caporossi et al&#46;<a class="elsevierStyleCrossRef" href="#bib0455"><span class="elsevierStyleSup">16</span></a> have published that confocal analyses of corneas submitted to CXL demonstrate that the transepithelial approach with EDTA only produces one third of the apoptotic effect of the technique involving the withdrawal of epithelium&#46; From the clinical viewpoint&#44; it has been reported that transepithelial CXL with trometamol and EDTA could produce the stabilization of the disease in human eyes with keratocone&#46;<a class="elsevierStyleCrossRef" href="#bib0460"><span class="elsevierStyleSup">17</span></a> To this date&#44; the issue remains controversial as&#43; more studies are required to ensure the clinic effectiveness thereof&#46;</p><p id="par0040" class="elsevierStylePara elsevierViewall">On the other hand&#44; some authors have proposed the use of iontophoresis &#40;local application of continuous and very low intensity electrical current&#41; to improve the penetration of riboflavin into the corneal stroma through an intact epithelium&#46; To date&#44; some relatively small pre-clinic<a class="elsevierStyleCrossRef" href="#bib0465"><span class="elsevierStyleSup">18</span></a> and clinic<a class="elsevierStyleCrossRef" href="#bib0470"><span class="elsevierStyleSup">19</span></a> studies have demonstrated that this approach could be somewhat useful for managing keratocone patients&#46; It has also been proposed that the use of iontophoresis could afford higher riboflavin penetration in the stroma than that achieved with simple transepithelial CXL&#44; although without reaching the levels achieved by conventional CXL&#46;<a class="elsevierStyleCrossRef" href="#bib0470"><span class="elsevierStyleSup">19</span></a> A study by Vinciguerra et al&#46;<a class="elsevierStyleCrossRef" href="#bib0475"><span class="elsevierStyleSup">20</span></a> demonstrated that the use of CXL with iontophoresis would be effective for stabilizing keratocone patients after one year follow-up&#46; Similar results were reported by Buzzonetti et al&#46;<a class="elsevierStyleCrossRef" href="#bib0480"><span class="elsevierStyleSup">21</span></a> in a population of pediatric patients observed during 15<span class="elsevierStyleHsp" style=""></span>months&#46;</p><p id="par0045" class="elsevierStylePara elsevierViewall">According to the Dresden protocol&#44; an additional variant of the conventional technique is known as &#8220;accelerated CXL&#8221;&#46; 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even in thin corneas&#46; However&#44; additional studies are needed to determine the long-term effects of accelerated CXL as well as the standardization in the time and irradiation levels of the intervention&#46;</p><p id="par0050" class="elsevierStylePara elsevierViewall">Recently it has been proposed to substitute riboflavin with Bengal rose ultraviolet irradiation coupled to 532<span class="elsevierStyleHsp" style=""></span>nm green light irradiation<a class="elsevierStyleCrossRef" href="#bib0495"><span class="elsevierStyleSup">24</span></a> with apparently optimistic results suggesting higher hardening effect of corneal tissue in animal models&#46;<a class="elsevierStyleCrossRef" href="#bib0500"><span class="elsevierStyleSup">25</span></a> For this proposal&#44; more studies are also required&#46;</p></span><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0075"><span class="elsevierStyleItalic">Crosslinking</span> in keratocone</span><p id="par0055" class="elsevierStylePara elsevierViewall">Keratocone is the most common corneal ectasia&#46; Even though the prevalence of keratocone has been reported at approximately one case for every 1800&#8211;2000 people in the general population&#44;<a class="elsevierStyleCrossRef" href="#bib0505"><span class="elsevierStyleSup">26</span></a> new imaging techniques &#40;particularly tangential topography and corneal tomography&#41; has evidenced that this pathology could be a lot more common than initially believed&#46;</p><p id="par0060" class="elsevierStylePara elsevierViewall">One of the most important characteristics of keratocone is precisely its progressive nature&#44; involving growing visual deterioration of patients&#46; Despite the above&#44; at present there is no absolute global consensus about what is understood by &#8220;progression of keratocone&#8221;&#44; with different authors using a range of definitions&#46; In a recent randomized study&#44; Wittig-Silva et al&#46;<a class="elsevierStyleCrossRef" href="#bib0510"><span class="elsevierStyleSup">27</span></a> defined progression as the appearance of at least one of the following factors in the 12 previous months&#58; an increase of at least 1&#46;00<span class="elsevierStyleHsp" style=""></span>D in simulated keratometry plus curve &#40;Scheimpflug technique&#41; or in the most curved meridian measured with manual keratometry&#59; an increase of at least 1&#46;00<span class="elsevierStyleHsp" style=""></span>D in astigmatism in manifest refraction&#44; or a reduction of 0&#46;1<span class="elsevierStyleHsp" style=""></span>mm in the radius of contact lenses that best fitted the patient&#46; In turn&#44; Hersh et al&#46;<a class="elsevierStyleCrossRef" href="#bib0515"><span class="elsevierStyleSup">28</span></a> have defined progression as the appearance of any of the following during a 24 month period&#58; an increase of 1&#46;00<span class="elsevierStyleHsp" style=""></span>D in keratometry plus curve&#44; an increase of 1&#46;00<span class="elsevierStyleHsp" style=""></span>D or more in subjective cylinder&#44; or an increase of 0&#46;50<span class="elsevierStyleHsp" style=""></span>D or more in subjective spherical equivalent&#46;</p><p id="par0065" class="elsevierStylePara elsevierViewall">Wollensak et al&#46;<a class="elsevierStyleCrossRef" href="#bib0405"><span class="elsevierStyleSup">6</span></a> were the first to propose the use of CXL for halting keratocone progression in 2003&#44; on the basis of their experience with animal models and humans&#46; At present&#44; CXL is regarded as a standard technique in keratocone management&#44; being the only clinically available intervention that has demonstrated a potential to slow down or halt the progression of the disease&#46;<a class="elsevierStyleCrossRef" href="#bib0380"><span class="elsevierStyleSup">1</span></a> Recently&#44; the Global Consensus on Keratocone and Ectatic Diseases<a class="elsevierStyleCrossRef" href="#bib0380"><span class="elsevierStyleSup">1</span></a> has postulated that CXL &#8220;is extremely important in the treatment of keratocone with documented clinic progression&#8221;&#44; as well as &#8220;important in the treatment of keratocone with a perceived risk of progression &#40;in which said progression has not been confirmed&#41; and in eyes with keratocone that previously underwent other forms of corneal surgery &#40;intra-stromal ring segments or Excimer laser&#41;&#8221;&#46;<a class="elsevierStyleCrossRef" href="#bib0380"><span class="elsevierStyleSup">1</span></a> Several meta-analyses &#40;such as those authored by Meiri et al&#46;<a class="elsevierStyleCrossRef" href="#bib0520"><span class="elsevierStyleSup">29</span></a> and Craig et al&#46;<a class="elsevierStyleCrossRef" href="#bib0525"><span class="elsevierStyleSup">30</span></a>&#41; have provided important evidence about the usefulness of the technique in patients with keratocone in progression&#46;</p><p id="par0070" class="elsevierStylePara elsevierViewall">Evidence on the effects produced by CXL in eyes with keratocone is relatively large&#46; O&#8217;Brart et al&#46;<a class="elsevierStyleCrossRef" href="#bib0530"><span class="elsevierStyleSup">31</span></a> published their experience with a 7 year follow-up of a group of 36 eyes of a like number of patients who underwent CXL due to progressive keratocone&#46; Said group of authors found that&#44; after 7<span class="elsevierStyleHsp" style=""></span>years&#44; the eyes submitted to CXL exhibited <span class="elsevierStyleItalic">K</span><span class="elsevierStyleInf">max</span> &#8722;0&#46;91<span class="elsevierStyleHsp" style=""></span>D when comparing it against presurgery values&#44; and that this value had a difference of &#8722;0&#46;74<span class="elsevierStyleHsp" style=""></span>D when comparing SimK at the end of the follow-up with the presurgery numbers&#46; Similarly&#44; said group experienced a significant improvements in far visual acuity parameters as well as in high order aberrations&#46; The majority of studies agreed in that CXL correlated with a significant improvement in uncorrected and corrected visual acuity parameters in keratocone patients&#46; A recent study<a class="elsevierStyleCrossRef" href="#bib0535"><span class="elsevierStyleSup">32</span></a> has found that uncorrected visual acuity improved significantly 24<span class="elsevierStyleHsp" style=""></span>months after the intervention&#46; This could be explained by relative stabilization of corneal morphology and the improvement of its refractive characteristics&#44; in addition to the stabilization of the disease&#46; Obviously&#44; these positive changes on the cornea would give rise to some visual improvements with adequate optical correction and adaptation to more user-friendly contact lenses by avoiding cone increases&#46; Ghanem et al&#46;<a class="elsevierStyleCrossRef" href="#bib0535"><span class="elsevierStyleSup">32</span></a> demonstrated that CXL related to a statistically significant reduction in the coma&#44; trefoil&#44; secondary astigmatism&#44; quadrafoil&#44; secondary coma and trefoil values&#44; although these changes do not directly relate to the degree of improvement in far corrected visual acuity&#46;</p><p id="par0075" class="elsevierStylePara elsevierViewall">It has been proposed that the effects of CXL &#40;at least with the accelerated version of the technique&#41; could be more marked in advanced keratocone cases &#40;<span class="elsevierStyleItalic">K</span><span class="elsevierStyleInf">max</span><span class="elsevierStyleHsp" style=""></span>&#8805;<span class="elsevierStyleHsp" style=""></span>58&#46;0<span class="elsevierStyleHsp" style=""></span>D&#41; when compared with patients whose pathology is not as advanced &#40;<span class="elsevierStyleItalic">K</span><span class="elsevierStyleInf">max</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>58&#46;0<span class="elsevierStyleHsp" style=""></span>D&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0540"><span class="elsevierStyleSup">33</span></a></p><p id="par0080" class="elsevierStylePara elsevierViewall">In what concerns the use of CXL in pediatric patients&#44; published experiences are relatively few although highly encouraging&#46;<a class="elsevierStyleCrossRef" href="#bib0545"><span class="elsevierStyleSup">34</span></a> One study<a class="elsevierStyleCrossRef" href="#bib0550"><span class="elsevierStyleSup">35</span></a> published in 2016 assessed the effect and safety of CXL with 4 years follow-up in 40 patients under 19 years of age who underwent intervention for progressive keratocone&#46; At 48 months follow-up&#44; the improvement in corrected and uncorrected far visual acuity was 0&#46;2<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>0&#46;2<span class="elsevierStyleHsp" style=""></span>logMAR and 0&#46;4<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>0&#46;2<span class="elsevierStyleHsp" style=""></span>logMAR&#44; respectively&#46; Thirty-two percent of patients exhibited <span class="elsevierStyleItalic">K</span><span class="elsevierStyleInf">max</span> flattening of 1&#46;0<span class="elsevierStyleHsp" style=""></span>D or more&#46; No significant loss was found in endothelial cell counts after 48 months follow-up&#46; In turn&#44; Magli et al&#46;<a class="elsevierStyleCrossRef" href="#bib0555"><span class="elsevierStyleSup">36</span></a> reported 18 months follow-up in 13 eyes of patients under 18 submitted to CXL with iontophoresis due to progressive keratocone&#46; In this group of patients&#44; the <span class="elsevierStyleItalic">K</span><span class="elsevierStyleInf">max</span> value at 18<span class="elsevierStyleHsp" style=""></span>months after the intervention exhibited stability of the disease as well as the absence of significant changes in endothelial cell counts&#46; Recently&#44; McAnena and O&#8217;Keefe<a class="elsevierStyleCrossRef" href="#bib0545"><span class="elsevierStyleSup">34</span></a> and Kumar-Kodavoor et al&#46;<a class="elsevierStyleCrossRef" href="#bib0560"><span class="elsevierStyleSup">37</span></a> described very similar results&#46; Sabti et al&#46;<a class="elsevierStyleCrossRef" href="#bib0565"><span class="elsevierStyleSup">38</span></a> described performing CXL in both eyes of a 4-year-old patient with progressive keratocone and trisomy&#44;<a class="elsevierStyleCrossRef" href="#bib0480"><span class="elsevierStyleSup">21</span></a> finding stabilization of the corneal disease without evident complications&#46; At present&#44; the Global Consensus on Keratocone and Ectatic Diseases<a class="elsevierStyleCrossRef" href="#bib0380"><span class="elsevierStyleSup">1</span></a> recommends performing CXL in patients of any age whenever objective evidence of progression is observed&#46;</p><p id="par0085" class="elsevierStylePara elsevierViewall">The possibility of stabilization in patients with progression of the disease is relatively high&#46; It has been estimated that only between 8&#46;1&#37; and 33&#46;3&#37; of patients will exhibit progression of <span class="elsevierStyleItalic">K</span><span class="elsevierStyleInf">max</span> values after the intervention&#46;<a class="elsevierStyleCrossRef" href="#bib0440"><span class="elsevierStyleSup">13</span></a></p><p id="par0090" class="elsevierStylePara elsevierViewall">The importance of keratoplasty in ophthalmology&#44; particularly in the management of keratocone&#44; is beyond doubt&#46; Until a few decades ago&#44; cornea transplant was the only surgical therapy for this pathology&#46; The stabilization of the disease brought about by CXL might not only delay but even avoid the need of corneal transplant in some patients with keratocone&#46;<a class="elsevierStyleCrossRef" href="#bib0570"><span class="elsevierStyleSup">39</span></a> In this regard&#44; an article published in 2015 by Sandvik et al&#46;<a class="elsevierStyleCrossRef" href="#bib0400"><span class="elsevierStyleSup">5</span></a> assessed the evolution of keratoplasties in a cohort of Norwegian patients&#44; finding that the number of corneal transplants due to keratocone carried out between 2013 and 2014 &#40;n<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>26&#41; was significantly lower than those carried out between 2005 and 2006 &#40;n<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>55&#41;&#46; The author indicates that this change is probably due to the implementation of CXL as a standard technique among surgical options in the group of 2013 and 2014&#44; diminishing the need of performing keratoplasty techniques in said subjects&#46;</p><p id="par0095" class="elsevierStylePara elsevierViewall">On the basis of the above described evidence&#44; it seems clear that CXL plays a definitive role in the management and modification of the natural history of eyes with keratocone and should be performed in all patients exhibiting a demonstrated progression of the disease&#44; regardless of age or degree of compromise&#46; On the other hand&#44; it is also true that the progression rate of keratocone is much higher in adolescents and young adults than as from the fourth decade of life&#46; Accordingly&#44; it would be logical to apply said procedure mainly in the first age group&#46; The application of CXL in patients who have not demonstrated progression but exhibit a &#8220;perceived risk&#8221;<a class="elsevierStyleCrossRef" href="#bib0380"><span class="elsevierStyleSup">1</span></a> of progression remains at the criterion of the ophthalmologist&#46;</p></span><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0080"><span class="elsevierStyleItalic">Crosslinking</span> in pellucid degeneration marginal</span><p id="par0100" class="elsevierStylePara elsevierViewall">Even though keratocone is the corneal pathology in which CXL has been most widely applied&#44; there is significant evidence about its usefulness in other noninflammatory corneal ectasia&#46;</p><p id="par0105" class="elsevierStylePara elsevierViewall">Pellucid marginal degeneration is a relatively infrequent entity that has been classified by some authors as a phenotypical variation of classic keratocone and by others as an independent pathology&#46;<a class="elsevierStyleCrossRef" href="#bib0575"><span class="elsevierStyleSup">40</span></a> Its main characteristic is the presence of a generally inferior corneal thinning strip together with a protrusion of the area above the thinning&#46; In 2010&#44; Spadea<a class="elsevierStyleCrossRef" href="#bib0580"><span class="elsevierStyleSup">41</span></a> published his experience using CXL in the eye of a patient with pellucid marginal degeneration&#44; performing an inferior decentering of the treated area&#46; Said author found visual acuity increase in the patients and diminished corneal cylinder&#44; which remained stable during one year after the intervention&#46; A similar experience was recently published by Bayraktar et al&#46;<a class="elsevierStyleCrossRef" href="#bib0585"><span class="elsevierStyleSup">42</span></a> in 2 patients in whom bilateral CXL produced a significant improvement in corrected visual acuity and a range of topographic parameters&#46; Three eyes described in said article did not have previous surgery&#44; while one had received an intrastromal ring segment with 160&#176; arc and 300<span class="elsevierStyleHsp" style=""></span>&#956;m thickness&#46; No significant changes arose during the follow-up of said patients and the disease was not observed to evolve&#46; When considering an inferior decentering for treating these patients&#44; it is important to avoid irradiating over the corneal limbus&#44; as CXL could produce permanent alterations at this level&#46; Even so&#44; some authors<a class="elsevierStyleCrossRef" href="#bib0590"><span class="elsevierStyleSup">43</span></a> have denied deleterious effects of CXL over corneal limbus stability&#46;</p><p id="par0110" class="elsevierStylePara elsevierViewall">Similarly&#44; the simultaneous utilization of CXL with surface ablation techniques in patients with said corneal ectasia has also been reported&#46;<a class="elsevierStyleCrossRef" href="#bib0595"><span class="elsevierStyleSup">44</span></a> Kymionis et al&#46;<a class="elsevierStyleCrossRef" href="#bib0600"><span class="elsevierStyleSup">45</span></a> have described the use of photorefractive keratectomy &#40;PRK&#41; and CXL in a patient with pellucid marginal degeneration which produced improvements in corrected visual acuity&#44; which remained stable one year after the intervention&#46; The same authors<a class="elsevierStyleCrossRef" href="#bib0605"><span class="elsevierStyleSup">46</span></a> subsequently reported their experience in 8 eyes of 6 patients with pellucid marginal degeneration who underwent conventional PRK and CXL at the same time&#46; Said authors found significant improvements in uncorrected far visual acuity &#40;1&#46;05<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>0&#46;33 to 0&#46;41<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>0&#46;27<span class="elsevierStyleHsp" style=""></span>logMAR&#41; with stable uncorrected far visual acuity&#46; No evidence of complications was found in any patient&#46; In view of the above&#44; CXL on its own or in addition to corneal surface Excimer surgery could be an attractive therapeutic option in subjects with corneal ectasia and topographic findings compatible with pellucid marginal degeneration&#46;</p></span><span id="sec0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0085"><span class="elsevierStyleItalic">Crosslinking</span> in keratorefractive refractive surgery</span><p id="par0115" class="elsevierStylePara elsevierViewall">Not all patients are good candidates for keratorefractive surgery with Excimer laser as they would have increased risk of secondary corneal ectasia or the presence of keratocone&#46; A few years ago it was proposed that CXL could provide a degree of protection and stability in patients submitted to surface ablation with irregular cornea&#46; This proposal was led by Kanellopoulos&#46;<a class="elsevierStyleCrossRef" href="#bib0610"><span class="elsevierStyleSup">47</span></a></p><p id="par0120" class="elsevierStylePara elsevierViewall">Patients with keratocone submitted to PRK guided by topography and CXL simultaneously have obtained significant improvements in refractive values&#44; with keratometric stability after 12 months of observation&#46;<a class="elsevierStyleCrossRef" href="#bib0615"><span class="elsevierStyleSup">48</span></a> Similar results have been reported by Fadlallah et al&#46;<a class="elsevierStyleCrossRef" href="#bib0620"><span class="elsevierStyleSup">49</span></a> in patients with initial keratocone by combining unguided PRK with CXL simultaneously&#46; Lee et al&#46;<a class="elsevierStyleCrossRef" href="#bib0625"><span class="elsevierStyleSup">50</span></a> found greater stability in the anterior and posterior corneal surfaces of patients submitted to CXL and surface ablation simultaneously than when carrying out surface ablation on its own&#46;</p></span><span id="sec0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0090"><span class="elsevierStyleItalic">Crosslinking</span> in ectasia after keratorefractive surgery</span><p id="par0125" class="elsevierStylePara elsevierViewall">Another entity in which CXL has proved its usefulness to diminish the progression of the disease is ectasia after keratorefractive surgery &#40;also known as &#8220;post-LASIK ectasia&#8221; or &#8220;iatrogenic ectasia&#8221;&#41;&#46; A relatively large study recently published by Yildirim et al&#46;<a class="elsevierStyleCrossRef" href="#bib0630"><span class="elsevierStyleSup">51</span></a> included 20 eyes of 14 patients who developed ectasia after keratorefractive surgery&#46; This group found that uncorrected far visual acuity improved from 0&#46;78<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>0&#46;61 to 0&#46;53<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>0&#46;36<span class="elsevierStyleHsp" style=""></span>logMAR&#44; whereas corrected visual acuity improved from 0&#46;27<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>0&#46;23 to 0&#46;19&#177; 0&#46;13<span class="elsevierStyleHsp" style=""></span>logMAR&#46; Even though keratometric values did not produce a statistically significant reduction&#44; they did evidence stabilization of the pathology in the course of time&#46; Li et al&#46;<a class="elsevierStyleCrossRef" href="#bib0635"><span class="elsevierStyleSup">52</span></a> made similar findings according to which CXL related to improved visual acuity in patients with post-LASIK ectasia while providing stability to the disease at one year follow-up&#46; In this group&#44; uncorrected and corrected final visual acuity improved from 0&#46;77<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>0&#46;32 to 0&#46;70<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>0&#46;33 logMAR and 0&#46;36<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>0&#46;30 to 0&#46;23<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>0&#46;23 logMAR&#44; respectively&#44; both changes being statistically significant&#46; Interestingly&#44; an article<a class="elsevierStyleCrossRef" href="#bib0640"><span class="elsevierStyleSup">53</span></a> discussed the parameters that predict the response of a patient with post-LASIK ectasia with the execution of CXL&#46; It was found that visual acuity is the most important presurgery parameter to predict which subjects will exhibit an improvement of at least one Snellen line one year after surgery &#40;poorer presurgery visual acuity prognosticates greater improvement&#41;&#44; in contrast with those who did not gain a single line or had stable or diminished vision&#46; Said study also suggested that higher presurgery keratometry and thinner pachymetry equate with poorer far corrected visual acuity one year after CXL&#46; At this time it is important to emphasize that said article was focused on visual gain after surgery and not necessarily on the stabilization of the disease&#44; which is the final objective of CXL&#46;</p><p id="par0130" class="elsevierStylePara elsevierViewall">Accordingly&#44; it seems that CXL plays a stabilizing role in ectasia cases after keratorefractive surgery&#46; However&#44; its role in the prevention of iatrogenic ectasia when combined primarily with Excimer laser ablation procedure &#40;known as LASIK Xtra&#41; is not sufficiently demonstrated at this point in time&#46;<a class="elsevierStyleCrossRef" href="#bib0585"><span class="elsevierStyleSup">42</span></a></p></span><span id="sec0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0095"><span class="elsevierStyleItalic">Crosslinking</span> in infectious keratitis</span><p id="par0135" class="elsevierStylePara elsevierViewall">There is extensive experience and knowledge about the effect of ultraviolet radiation on the genetic material of organisms&#44; including humans&#46; Type B &#40;280&#8211;320<span class="elsevierStyleHsp" style=""></span>nm&#41; and C &#40;10&#8211;280<span class="elsevierStyleHsp" style=""></span>nm&#41; ultraviolet radiation directly produce damages in DNA by forming pyrimidine dimers that block DNA replication and RNA transcription&#46;<a class="elsevierStyleCrossRef" href="#bib0645"><span class="elsevierStyleSup">54</span></a> In turn&#44; UVA radiation &#40;utilized in the CXL process&#41; produces its biological effects through the induction of oxygen-reactive species&#44; causing oxidative stress in lipids&#44; proteins and DNA&#46;<a class="elsevierStyleCrossRef" href="#bib0420"><span class="elsevierStyleSup">9</span></a></p><p id="par0140" class="elsevierStylePara elsevierViewall">Several studies have experimentally demonstrated the aggressive effect of ultraviolet radiation of bacterial cultures&#46; It has been described<a class="elsevierStyleCrossRef" href="#bib0650"><span class="elsevierStyleSup">55</span></a> that ultraviolet radiation in various wavelength groups is effective <span class="elsevierStyleItalic">in vitro</span> against methicillin-resistant <span class="elsevierStyleItalic">Staphylococcus aureus</span>&#46; Similar data have been obtained for <span class="elsevierStyleItalic">Escherichia coli</span> strains&#46;<a class="elsevierStyleCrossRef" href="#bib0655"><span class="elsevierStyleSup">56</span></a> Similarly&#44; Santos et al&#46;<a class="elsevierStyleCrossRef" href="#bib0420"><span class="elsevierStyleSup">9</span></a> have described the susceptibility of various bacterial strains &#40;including <span class="elsevierStyleItalic">Pseudomonas</span> spp&#46; and <span class="elsevierStyleItalic">Staphylococcus</span> spp&#46;&#41; to ultraviolet radiation&#44; emphasizing that irradiation with UVA is closely related to the generation of oxygen-reactive species&#44; mainly in <span class="elsevierStyleItalic">Staphylococcus</span> spp strains&#46; This would match the expected effects of CXL in non-infected corneae&#44; where the creation of oxygen-reactive species enhances the creation of bridges and links between different collagen fibers&#46;</p><p id="par0145" class="elsevierStylePara elsevierViewall">The effects of ultraviolet irradiation have also been demonstrated <span class="elsevierStyleItalic">in vitro</span> on fungal strains&#46; Risovic et al&#46;<a class="elsevierStyleCrossRef" href="#bib0660"><span class="elsevierStyleSup">57</span></a> describes that various ultraviolet wavelength frequencies &#40;254<span class="elsevierStyleHsp" style=""></span>nm&#44; 365<span class="elsevierStyleHsp" style=""></span>nm&#44; 406<span class="elsevierStyleHsp" style=""></span>nm&#44; 420<span class="elsevierStyleHsp" style=""></span>nm&#41; could be utilized for eradicating <span class="elsevierStyleItalic">Candida albicans</span> strains&#46; A group from Colombia also proposed that environmental irradiation of ultraviolet lights could generate permanent changes in the genetics of <span class="elsevierStyleItalic">Aspergillus fumigatus&#46;</span><a class="elsevierStyleCrossRef" href="#bib0665"><span class="elsevierStyleSup">58</span></a></p><p id="par0150" class="elsevierStylePara elsevierViewall">Adding up all the above data&#44; it would seem biologically feasible to include UVA irradiation enhanced by a photosensitizer &#40;riboflavin&#41; among treatments for severe corneal infections&#46; One of the first articles to propose this approach was published in 2008 by Iseli et al&#46;&#44;<a class="elsevierStyleCrossRef" href="#bib0670"><span class="elsevierStyleSup">59</span></a> who described their results after CXL in 5 eyes with severe keratitis associated to corneal thinning or melting &#40;3 infections of <span class="elsevierStyleItalic">Mycobacterium</span> spp&#46;&#44; one by filament fungus and another by <span class="elsevierStyleItalic">Fusarium</span> spp&#46;&#41;&#46; In the 5 cases&#44; corneal destruction was halted by the intervention&#44; making emergency keratoplasty unnecessary in all patients&#46; Subsequently&#44; the management of 7 eyes with severe infectious keratitis &#40;including cases of <span class="elsevierStyleItalic">Staphylococcus aureus</span> and <span class="elsevierStyleItalic">Haemophilus influenzae</span>&#44; among others&#41; was described&#46; These cases responded very positively to CXL with fast and complete improvement of active symptoms in all cases&#46;<a class="elsevierStyleCrossRef" href="#bib0675"><span class="elsevierStyleSup">60</span></a> A recently published meta-analysis on the subject<a class="elsevierStyleCrossRef" href="#bib0625"><span class="elsevierStyleSup">50</span></a> found that CXL is highly effective in severe keratitis for the majority of etiologies including fungal&#44; bacterial &#40;both gram-positive and gram-negative&#41; as well as <span class="elsevierStyleItalic">Acanthamoeba</span> spp&#46; The only etiology with disappointing results was severe viral keratitis&#46; It has been described<a class="elsevierStyleCrossRef" href="#bib0680"><span class="elsevierStyleSup">61</span></a> that CXL was unable to halt the progression of the disease in a patient with herpetic keratitis and corneal thinning&#44; who required tectonic keratoplasty 15 days after CXL&#46; The expanded corneal button was negative for other fungal or bacterial etiologies&#44; which discards overinfection as the cause of clinical worsening&#46; Moreover&#44; it has been demonstrated that CXL could be a factor for viral reactivation in patients with previous although inactive herpetic keratitis&#44; as the exposure to ultraviolet radiation could activate virus herpes&#46;<a class="elsevierStyleCrossRef" href="#bib0685"><span class="elsevierStyleSup">62</span></a></p><p id="par0155" class="elsevierStylePara elsevierViewall">A further recent meta-analysis by Papaioannou et al&#46;<a class="elsevierStyleCrossRef" href="#bib0690"><span class="elsevierStyleSup">63</span></a> has explored recent evidence on the subject&#44; finding healing rates of 85&#46;7&#37; in patients with bacterial infectious keratitis&#46; In addition&#44; patients with fungal and <span class="elsevierStyleItalic">Acanthamoeba</span> keratitis have also exhibited positive response rates&#46; However&#44; doubts still remain about the efficacy against the latter microorganism&#44; with some authors like Berra et al&#46;<a class="elsevierStyleCrossRef" href="#bib0695"><span class="elsevierStyleSup">64</span></a> suggesting that it could be counterproductive in these patients&#46;</p><p id="par0160" class="elsevierStylePara elsevierViewall">According to the above&#44; the use of CXL would seem reasonable in severe fungal or bacterial keratitis when associated to corneal thinning&#46; CXL could also be considered in cases with demonstrated infection by multi-resistant germs&#46; Evidence seems to indicate that this therapy is contraindicated in patients with active herpetic keratitis and should be used with extreme caution in patients with previous and currently inactive herpetic keratitis&#46; However&#44; in the latter case it would probably be better to administrate antiviral oral coverage &#40;famciclovir&#44; <span class="elsevierStyleItalic">etc&#46;</span>&#41;&#46; Its effectiveness in keratitis caused by <span class="elsevierStyleItalic">Acanthamoeba</span> remains controversial&#46;<a class="elsevierStyleCrossRef" href="#bib0695"><span class="elsevierStyleSup">64</span></a></p><p id="par0165" class="elsevierStylePara elsevierViewall">In 2013&#44; an initiative to promote research and development of CXL technologies specifically designed for managing infectious ocular pathologies established the use of different designations for the 2 main cross-linking approaches&#46; Accordingly&#44; it has been proposed to use &#8220;CXL&#8221; to designate the applications focused on the management of corneal ectasia&#44; and to use the term &#8220;photo-activated chromophore for infectious keratitis&#8221; &#40;PACK-CXL&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0700"><span class="elsevierStyleSup">65</span></a></p></span><span id="sec0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0100"><span class="elsevierStyleItalic">Crosslinking</span> in pseudophakic bullous keratopathy</span><p id="par0170" class="elsevierStylePara elsevierViewall">Endothelial failure is a common cause of diminished corneal transparency&#46; Bullous keratopathy &#40;BK&#41; is characterized by the presence of stromal edema and epithelial bullae as a direct consequence of the loss of the pump and sweep function of the corneal endothelium that entails overhydration of corneal tissue&#46;<a class="elsevierStyleCrossRef" href="#bib0705"><span class="elsevierStyleSup">66</span></a></p><p id="par0175" class="elsevierStylePara elsevierViewall">It was recently suggested that CXL could be beneficial for patients with chronic BK&#46; The formation of inter-fibrillary links between the collagen structures of the corneal stroma that takes place in CXL would increase the difficulty for water to fill in this virtual space&#44; thus diminishing the rate of edema as a consequence of endothelial failure<a class="elsevierStyleCrossRef" href="#bib0440"><span class="elsevierStyleSup">13</span></a>&#46; In canine eyes with BK&#44; the installation of riboflavin during 30<span class="elsevierStyleHsp" style=""></span>min followed by 3<span class="elsevierStyleHsp" style=""></span>min of UVA irradiation produced improvements in apparent ocular pain symptoms as well as inducing corneal edema improvements during the first 3 months after the intervention&#46;<a class="elsevierStyleCrossRef" href="#bib0710"><span class="elsevierStyleSup">67</span></a></p><p id="par0180" class="elsevierStylePara elsevierViewall">In human eyes&#44; evidence has also shown some benefits&#46; Sharma et al&#46;<a class="elsevierStyleCrossRef" href="#bib0715"><span class="elsevierStyleSup">68</span></a> assessed the evolution of 50 eyes with pseudophakic BK that underwent CXL&#44; finding an important reduction in subjective pain parameters even though these are returned to presurgery values 6 months after the intervention&#46; Even though pachymetry values diminished regularly&#44; corrected far visual acuity values did not exhibit noteworthy improvements&#46; Similar data were published by Arora et al&#46;<a class="elsevierStyleCrossRef" href="#bib0720"><span class="elsevierStyleSup">69</span></a> finding that CXL in patients with pseudophakic BK produced a considerable initial improvement in visual and pain parameters&#44; although the beneficial effect disappeared about 3 months after the intervention&#46; A recent article did not find that CXL&#44; even with repeated applications&#44; was beneficial for patients with BK secondary to Fuchs-type endothelial dystrophy&#46;</p><p id="par0185" class="elsevierStylePara elsevierViewall">In view of the above&#44; it would seem that CXL in patients with BK could have a discreet initial effect on pain and visual symptoms&#44; although this effect tends to disappear after a few months&#46; In addition&#44; there seems to be a relationship with the severity of the disease&#44; with CXL producing better effects in less affected corneae&#46;<a class="elsevierStyleCrossRef" href="#bib0715"><span class="elsevierStyleSup">68</span></a> It is likely that this approach is indicated only for patients with BK who are not regarded as good candidates for endothelial keratoplasty and who have important pain symptoms secondary to the pathology&#46; Accordingly&#44; this indication is similar to that of phototherapeutic keratectomy &#40;PTK&#41; for this alteration&#46;</p></span><span id="sec0045" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0105"><span class="elsevierStyleItalic">Crosslinking</span> in donor modification in keratoplasty</span><p id="par0190" class="elsevierStylePara elsevierViewall">One of the main risks of corneal allograft is graft rejection&#46; Previously&#44; it was demonstrated that CXL generates a significant apoptotic reduction in stromal keratocytes as well as in other antigen presenting cells at that level&#46;<a class="elsevierStyleCrossRef" href="#bib0725"><span class="elsevierStyleSup">70</span></a> On the basis of a murine model&#44; Wang<a class="elsevierStyleCrossRef" href="#bib0730"><span class="elsevierStyleSup">71</span></a> has suggested that CXL could be utilized for pre-treating the donor corneal button in order to reduce the population of said cells&#44; thus diminishing the risk of rejection in keratoplasty&#46; However&#44; as yet there is not sufficient evidence on this approach and it is likely to be relatively ineffective&#44; particularly in penetrating keratoplasty&#44; as the donor button endothelium that has to be preserved to enable corneal transparency is associated to a relevant proportion of rejections&#46;</p></span><span id="sec0050" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0110">Side effects</span><p id="par0195" class="elsevierStylePara elsevierViewall">CXL is a relatively safe surgical technique with low complication rates and side effects&#46; Even though &#8220;virtually all eyes&#8221;<a class="elsevierStyleCrossRef" href="#bib0735"><span class="elsevierStyleSup">72</span></a> had some sort of corneal haze one month after the intervention&#44; it diminishes markedly after one year&#46; This haze attenuation was verified with Scheimpfug images&#46;<a class="elsevierStyleCrossRef" href="#bib0740"><span class="elsevierStyleSup">73</span></a> Overall&#44; 7&#46;6&#37;<a class="elsevierStyleCrossRef" href="#bib0735"><span class="elsevierStyleSup">72</span></a> of patients developed sterile corneal infiltrates that tend to improve easily with the use of topical corticosteroids&#46; The appearance of said infiltrates has also been reported in pediatric patients&#46;<a class="elsevierStyleCrossRef" href="#bib0745"><span class="elsevierStyleSup">74</span></a> Abbouda et al&#46;<a class="elsevierStyleCrossRef" href="#bib0750"><span class="elsevierStyleSup">75</span></a> recently published a review of 10 infectious keratitis cases post-CXL&#44; the majority of which were caused by bacteria&#46;</p><p id="par0200" class="elsevierStylePara elsevierViewall">In general&#44; 2&#46;9&#37; of intervened eyes will exhibit diminished corrected far visual acuity of 2 or more Snellen lines one year after surgery&#46;<a class="elsevierStyleCrossRef" href="#bib0735"><span class="elsevierStyleSup">72</span></a> Identified risk factors comprise age above 35 and corrected far visual acuity of 20&#47;25 or better&#46;</p></span><span id="sec0055" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0115">Conclusions</span><p id="par0205" class="elsevierStylePara elsevierViewall">Corneal collagen cross-linking with UVA radiation and riboflavin is an evolving surgical technique broadly supported by pre-clinic and clinic studies confirming its therapeutic usefulness for preventing the progression of corneal ectasia&#44; particularly in keratocone although also in marginal pellucid degeneration and ectasia after keratorefractive surgery&#46; Accordingly&#44; even if CXL is not a cure for keratocone or other ectasia&#44; it plays an increasingly preeminent role in the therapeutic options in addition to intrastromal ring segment implants and other treatments&#46; However&#44; its role in the prevention of iatrogenic ectasia when initially combined with Excimer laser ablation procedure is not sufficiently demonstrated at this date&#46; In addition&#44; it seems to have a considerably beneficial effect for controlling corneal infections due to fungi&#44; bacteria or amoebas&#46; Its usefulness in the preparation of the donor button in keratoplasty and bullous keratopathy seems less consistent&#46; The development of the technique aims at shorter &#40;accelerated&#41; applications and to the preservation of the corneal epithelium&#46; Other non-photonic cross-linking methods&#44; including those with Bengal rose&#44; are also emerging following the path of the currently most widely utilized technique that apply UVA radiation and riboflavin to the cornea&#46;</p></span><span id="sec0060" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0120">Conflict of interests</span><p id="par0210" class="elsevierStylePara elsevierViewall">The authors state that they do not have any relevant conflict of interests in relation to this article&#46;</p></span></span>"
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          "titulo" => "Keywords"
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          "titulo" => "Resumen"
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              "titulo" => "M&#233;todos"
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          "titulo" => "Introduction"
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          "identificador" => "sec0010"
          "titulo" => "Overview of the technique"
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          "identificador" => "sec0015"
          "titulo" => "Crosslinking in keratocone"
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          "identificador" => "sec0020"
          "titulo" => "Crosslinking in pellucid degeneration marginal"
        ]
        8 => array:2 [
          "identificador" => "sec0025"
          "titulo" => "Crosslinking in keratorefractive refractive surgery"
        ]
        9 => array:2 [
          "identificador" => "sec0030"
          "titulo" => "Crosslinking in ectasia after keratorefractive surgery"
        ]
        10 => array:2 [
          "identificador" => "sec0035"
          "titulo" => "Crosslinking in infectious keratitis"
        ]
        11 => array:2 [
          "identificador" => "sec0040"
          "titulo" => "Crosslinking in pseudophakic bullous keratopathy"
        ]
        12 => array:2 [
          "identificador" => "sec0045"
          "titulo" => "Crosslinking in donor modification in keratoplasty"
        ]
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          "titulo" => "Side effects"
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          "titulo" => "Conclusions"
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          "titulo" => "Conflict of interests"
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          "titulo" => "References"
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    "fechaRecibido" => "2016-04-02"
    "fechaAceptado" => "2016-10-14"
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        0 => array:4 [
          "clase" => "keyword"
          "titulo" => "Keywords"
          "identificador" => "xpalclavsec815651"
          "palabras" => array:5 [
            0 => "Cornea"
            1 => "Keratoconus"
            2 => "Vision disorders"
            3 => "Ectasia"
            4 => "Collagen"
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        ]
      ]
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        0 => array:4 [
          "clase" => "keyword"
          "titulo" => "Palabras clave"
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          "palabras" => array:5 [
            0 => "C&#243;rnea"
            1 => "Queratocono"
            2 => "Trastornos de la visi&#243;n"
            3 => "Ectasia"
            4 => "Col&#225;geno"
          ]
        ]
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      "en" => array:3 [
        "titulo" => "Abstract"
        "resumen" => "<span id="abst0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0010">Objective</span><p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">To perform a literature review of the current clinical applications of corneal collagen cross-linking&#46;</p></span> <span id="abst0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0015">Methods</span><p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">An exhaustive literature search was made&#44; including the main biomedical databases&#44; and encompassing all years since the introduction of cross-linking in ophthalmology practice&#46;</p></span> <span id="abst0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0020">Results</span><p id="spar0015" class="elsevierStyleSimplePara elsevierViewall">Corneal collagen cross-linking using UVA irradiation and riboflavin is a surgical technique that is currently being optimized&#44; and is supported by a good amount of pre-clinical and clinical studies&#46; These papers found show the beneficial effect of the surgery on preventing the progression of corneal ectasia&#44; especially keratoconus&#44; but also on pellucid marginal degeneration and keratectasia after refractive surgery&#46; The effect of cross-linking on avoiding the occurrence of iatrogenic keratectasia when combined with a photo-ablative procedure is less clear to date&#46; Additionally&#44; it appears that cross-linking may have a considerable beneficial effect on controlling corneal infection caused by fungi&#44; bacteria and amoebae&#46; However&#44; its effect on viral keratitis can be detrimental&#46; The benefit on bullous keratopathy seems to be rather transient&#46;</p></span> <span id="abst0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0025">Conclusions</span><p id="spar0020" class="elsevierStyleSimplePara elsevierViewall">Corneal collagen cross-linking may be used with relative safety and efficacy in patients with progressive keratoconus&#46; Its use could also be considered in patients with other corneal ectasias or with corneal infections of non-viral origin&#46; Currently&#44; there is still a need for more studies as regards its effect on preventing iatrogenic keratectasia&#46;</p></span>"
        "secciones" => array:4 [
          0 => array:2 [
            "identificador" => "abst0005"
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          1 => array:2 [
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            "titulo" => "Methods"
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          2 => array:2 [
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            "titulo" => "Results"
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          3 => array:2 [
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        "titulo" => "Resumen"
        "resumen" => "<span id="abst0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0035">Objetivo</span><p id="spar0025" class="elsevierStyleSimplePara elsevierViewall">Realizar una revisi&#243;n bibliogr&#225;fica para mostrar las aplicaciones cl&#237;nicas actuales de la t&#233;cnica de entrecruzamiento del col&#225;geno corneal&#46;</p></span> <span id="abst0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0040">M&#233;todos</span><p id="spar0030" class="elsevierStyleSimplePara elsevierViewall">B&#250;squeda exhaustiva de la bibliograf&#237;a de las principales bases de datos biom&#233;dicas desde la introducci&#243;n del entrecruzamiento del col&#225;geno corneal en el campo oftalmol&#243;gico&#46;</p></span> <span id="abst0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0045">Resultados</span><p id="spar0035" class="elsevierStyleSimplePara elsevierViewall">El entrecruzamiento del col&#225;geno corneal mediante radiaci&#243;n UVA y riboflavina es una t&#233;cnica quir&#250;rgica en estado de evoluci&#243;n pero ampliamente soportada por estudios precl&#237;nicos y cl&#237;nicos que apoyan su utilidad terap&#233;utica en la prevenci&#243;n de la progresi&#243;n en las ectasias corneales&#44; especialmente en el queratocono&#44; aunque tambi&#233;n en la degeneraci&#243;n pel&#250;cida marginal y en las ectasias tras cirug&#237;a queratorrefractiva&#46; Su papel en la prevenci&#243;n de la ectasia iatrog&#233;nica cuando se combina inicialmente con el procedimiento ablativo con l&#225;ser excimer no est&#225; suficientemente probado a d&#237;a de hoy&#46; Adicionalmente&#44; parece tener un considerable efecto beneficioso en el control de las infecciones corneales por hongos&#44; bacterias o amebas&#46; Sin embargo&#44; el efecto sobre las queratitis v&#237;ricas puede ser perjudicial&#46; El beneficio en la queratopat&#237;a bullosa parece ser transitorio&#46;</p></span> <span id="abst0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0050">Conclusiones</span><p id="spar0040" class="elsevierStyleSimplePara elsevierViewall">El entrecruzamiento del col&#225;geno corneal puede ser usado con relativa seguridad y efectividad en pacientes con queratocono progresivo&#46; Su uso podr&#237;a considerarse en pacientes con otros tipos de ectasias y con infecciones corneales de etiolog&#237;a no v&#237;rica&#46; A&#250;n hacen falta m&#225;s estudios para determinar su efectividad en la prevenci&#243;n de la ectasia iatrog&#233;nica&#46;</p></span>"
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        "nota" => "<p class="elsevierStyleNotepara" id="npar0005">Please cite this article as&#58; Balparda K&#44; Maldonado MJ&#46; Entrecruzamiento del col&#225;geno corneal&#46; Revisi&#243;n de sus aplicaciones cl&#237;nicas&#46; Arch Soc Esp Oftalmol&#46; 2017&#59;92&#58;166&#8211;174&#46;</p>"
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      "titulo" => "References"
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                    ]
                  ]
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                      "titulo" => "PACK-CXL&#46; Corneal cross-linking in infectious keratitis"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
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                  ]
                  "host" => array:1 [
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                  "contribucion" => array:1 [
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                        0 => array:2 [
                          "etal" => false
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                            0 => "G&#46;F&#46; Sandvik"
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                      "doi" => "10.1097/ICO.0000000000000460"
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                        "tituloSerie" => "Cornea"
                        "fecha" => "2015"
                        "volumen" => "34"
                        "paginaInicial" => "991"
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Article information

ISSN: 21735794
Original language: English

DOI:10.1016/j.oftale.2016.10.003

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