Original article
Dexamethasone implant prior to anti-VEGF therapy in pigment epithelium detachments with high-risk rupture characteristics secondary to neovascular age-related macular degeneration
Implante de dexametasona antes de tratamiento anti-VEGF en desprendimientos del epitelio pigmentario secundarios a degeneración macular asociada a la edad con características de alto riesgo de rotura
B. Burgos-Blasco
, N. Güemes-Villahoz, S. Hernández-Ruiz, J. Donate-Lopez, L. López-Guajardo
Corresponding author
Servicio de Oftalmología, Hospital Clínico San Carlos, Instituto de Investigación Sanitaria del Hospital Clínico San Carlos (IdISSC), Madrid, Spain
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Burgos-Blasco, N. Güemes-Villahoz, S. Hernández-Ruiz, J. Donate-Lopez, L. López-Guajardo" "autores" => array:5 [ 0 => array:4 [ "nombre" => "B." "apellidos" => "Burgos-Blasco" "email" => array:1 [ 0 => "Bburgos171@hotmail.com" ] "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">*</span>" "identificador" => "cor0005" ] ] ] 1 => array:2 [ "nombre" => "N." "apellidos" => "Güemes-Villahoz" ] 2 => array:2 [ "nombre" => "S." "apellidos" => "Hernández-Ruiz" ] 3 => array:2 [ "nombre" => "J." "apellidos" => "Donate-Lopez" ] 4 => array:2 [ "nombre" => "L." "apellidos" => "López-Guajardo" ] ] "afiliaciones" => array:1 [ 0 => array:2 [ "entidad" => "Servicio de Oftalmología, Hospital Clínico San Carlos, Instituto de Investigación Sanitaria del Hospital Clínico San Carlos (IdISSC), Madrid, Spain" "identificador" => "aff0005" ] ] "correspondencia" => array:1 [ 0 => array:3 [ "identificador" => "cor0005" "etiqueta" => "⁎" "correspondencia" => "<span class="elsevierStyleItalic">Corresponding author</span>." ] ] ] ] "titulosAlternativos" => array:1 [ "es" => array:1 [ "titulo" => "Implante de dexametasona antes de tratamiento anti-VEGF en desprendimientos del epitelio pigmentario secundarios a degeneración macular asociada a la edad con características de alto riesgo de rotura" ] ] "resumenGrafico" => array:2 [ "original" => 0 "multimedia" => array:8 [ "identificador" => "fig0010" "etiqueta" => "Fig. 2" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr2.jpeg" "Alto" => 977 "Ancho" => 2175 "Tamanyo" => 93708 ] ] "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at0010" "detalle" => "Fig. " "rol" => "short" ] ] "descripcion" => array:1 [ "en" => "<p id="spar0015" class="elsevierStyleSimplePara elsevierViewall">Maximum pigment epithelium detachment (PED) linear diameter in all visits.</p> <p id="spar0020" class="elsevierStyleSimplePara elsevierViewall">Measurements are shown in μm.</p>" ] ] ] "textoCompleto" => "<span class="elsevierStyleSections"><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0065">Introduction</span><p id="par0005" class="elsevierStylePara elsevierViewall">Retinal pigment epithelial tears are a well-recognized complication of neovascular age-related macular degeneration (nAMD), appearing in around 2–6% of cases. It represents a disruption in the monolayer of pigment epithelial cells responsible for the support of the overlying photoreceptors and has a severe impact in visual acuity with no effective treatment.<a class="elsevierStyleCrossRefs" href="#bib0005"><span class="elsevierStyleSup">1,2</span></a></p><p id="par0010" class="elsevierStylePara elsevierViewall">Many factors have been implicated in nAMD pathogenesis. Vascular endothelial growth factor (VEGF) is increasingly found in the neovascular membranes of AMD patients and this is the basis of pharmacologically inhibiting VEGF in order to influence the natural course of the disease.<a class="elsevierStyleCrossRef" href="#bib0015"><span class="elsevierStyleSup">3</span></a> Inflammation also plays a central role in this disease, secondary for instance to the degenerative changes in the retinal pigment epithelium cells and age-related changes in the immune system.<a class="elsevierStyleCrossRef" href="#bib0020"><span class="elsevierStyleSup">4</span></a> This adds to the hypothesis that AMD results from an altered inflammation process with inappropriate complement activation.<a class="elsevierStyleCrossRef" href="#bib0025"><span class="elsevierStyleSup">5</span></a> In this regard, steroids have antiangiogenic and anti-inflammatory properties, improving the stabilization of the blood-retinal barrier and the down-regulation of inflammation.<a class="elsevierStyleCrossRefs" href="#bib0030"><span class="elsevierStyleSup">6,7</span></a></p><p id="par0015" class="elsevierStylePara elsevierViewall">Retinal pigment epithelial tears occur in nAMD as a spontaneous complication or in relation to anti-VEGF injections. The exact incidence of each condition is unknown, although around 40% of tears occurred within two years of anti-VEGF injections the 60% may be spontaneous.<a class="elsevierStyleCrossRef" href="#bib0040"><span class="elsevierStyleSup">8</span></a> Almost all cases that develop retinal pigment epithelial tears present pigment epithelium detachment (PED) in the setting of different subtypes of nAMD.<a class="elsevierStyleCrossRef" href="#bib0045"><span class="elsevierStyleSup">9</span></a> The following specific risk factors have been identified: PED height >400 microns, PED greatest linear diameter >5 mm, diagnosis ≤4.5 months, micro-breaks, subretinal cleft, treatment with photodynamic therapy, treatment with intravitreal antiangiogenic injections, fibrovascular PED and retinal angiomatous proliferation-type neovascularization.<a class="elsevierStyleCrossRefs" href="#bib0005"><span class="elsevierStyleSup">1,10–14</span></a> Therefore, a patient diagnosed with nAMD could be identified as a "high risk" patient if, fulfilling the PED morphological criteria of higher risk (>400 microns in height and/or base >5 mm), intravitreal antiangiogenic therapy is considered.</p><p id="par0020" class="elsevierStylePara elsevierViewall">Increased hydrostatic pressure factors within the PED together with a contractile response of the neovascular membrane when it is subjected to treatment have been implicated in its pathophysiology.<a class="elsevierStyleCrossRefs" href="#bib0005"><span class="elsevierStyleSup">1,15–17</span></a> The known influence of inflammatory mediators in nAMD transforms these "high risk" PED cases, from the theoretical point of view, in possible targets for the use of intravitreal corticosteroids.<a class="elsevierStyleCrossRef" href="#bib0090"><span class="elsevierStyleSup">18</span></a> Hypothetically, the use of an anti-inflammatory drug prior to the anti-VEGF injection could reduce the tension within the PED and thus the risk of pigment epithelium tear after anti-VEGF treatment. This treatment modality has been suggested with triamcinolone (non-approved use), obtaining promising results. A similar or even better efficacy may be achieved with dexamethasone. Ozurdex (Allergan Plc, Dublin, Ireland) is a sustained-delivery biodegradable dexamethasone intravitreal implant with approved intraocular use that releases corticosteroid for up to 6 months after intravitreal injection and has proven to be safe and effective in diabetic macular edema, macular edema secondary to retinal venous obstructions, and secondary to non-infectious uveitis.</p><p id="par0025" class="elsevierStylePara elsevierViewall">This study involves an off-label use of an approved intraocular drug. It attempts to demonstrate the usefulness of the delayed-release dexamethasone implant in reducing the risk of pigment epithelial tear during the induction phase of antiangiogenic treatment of nAMD patients with “high risk PED". The main aim was to investigate if the administration of the intravitreal delayed-release dexamethasone implant causes a decrease in the size of the pigment epithelium detachment to levels considered low risk. Secondary objective was to evaluate the incidence of pigment epithelial tear after the induction phase of antiangiogenic therapy when intravitreal delayed-release dexamethasone implant is administered prior to the start of antiangiogenic treatment in nAMD patients with high-risk characteristics of presenting this complication.</p></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0070">Methods</span><p id="par0030" class="elsevierStylePara elsevierViewall">In this retrospective study, patients with nAMD who had been treated with an Ozurdex implant (off-label) prior to the usual treatment with antiangiogenic drugs from 1 July 2019 to 28 February 2021 in the Retina department of the Hospital Clínico San Carlos (Madrid, Spain) were considered. Written informed consent prior to Ozurdex off-label implant had been obtained from each participant. The study protocol was approved by the Ethics Committee of the Hospital Clínico San Carlos.</p><p id="par0035" class="elsevierStylePara elsevierViewall">This study consisted of reviewing the medical records and images of the patients. The inclusion criteria were: diagnosis of nAMD, PED height >500 microns, indication of antiangiogenic treatment (being at least 3 anti-VEGF injections prescribed) and treatment with Ozurdex implant prior to the first antiangiogenic injection, as well as acceptance of the informed consent. Many patients had indocyanine green angiography performed, but the size of the PED prevented in many cases a subtype nAMD classification. Exclusion criteria were insufficient follow-up data in the medical history or inability to measure PED dimensions in any of the optical coherence tomography (OCT) follow-up images, prior anti VEGF injection less than five weeks and contraindications for Ozurdex implant (uncontrolled glaucoma, anterior chamber intraocular lens).</p><p id="par0040" class="elsevierStylePara elsevierViewall">The main variables evaluated were PED maximum height and diameter along with the presence of pigment epithelium rupture in OCT scans/infrared images, between the time of administration of the dexamethasone implant and 30 days after the administration of the third antiangiogenic injection. The tomographic scans were independently evaluated for pigment epithelium ruptures and the maximum tomographic dimensions by a blinded ophthalmologist. In cases with RPE tear formation, the period between the last injection and RPE tear formation was also noted. In addition, age, sex, previous treatments and best-corrected visual acuity (BCVA) with Early Treatment Diabetic Retinopathy Study (ETDRS) scale were registered.</p><p id="par0045" class="elsevierStylePara elsevierViewall">All patients had OCT images with the same Spectralis device (Heidelberg Engineering, Heidelberg, Germany) before treatment and at every visit and had received Ozurdex implant between 15 and 45 days prior to the first of at least three antiangiogenic injections. The last visit was considered one month after the third anti-VEGF injection. After that, retreatment was determined by clinical examination and OCT scans.</p><p id="par0050" class="elsevierStylePara elsevierViewall">For the statistical treatment of data, the software package SPSS (Statistical Package for Social Sciences, v21.0; SPSS Inc., Chicago, Illinois) was employed. Data are provided as the mean and standard deviation for quantitative variables and frequency distributions for qualitative variables. Differences in tomographic measurements between visits were determined using a paired t-test. Significance was set at P < 0.05.</p></span><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0075">Results</span><p id="par0055" class="elsevierStylePara elsevierViewall">The study included 14 eyes of 14 patients, who met the inclusion criteria. The mean age was 77 ± 7 years (range 63–88), being 11 (79%) females and 3 (21%) males. Regarding previous treatments, 3 patients (21%) were naïve, 8 (57%) and 3 (21%) had received Ranibizumab and Aflibercept injections. In these patients, mean time since previous injection was 99 ± 75 days, no patient receiving steroid implant less than five weeks from anti -VEGF administration.</p><p id="par0060" class="elsevierStylePara elsevierViewall">All patients received an Ozurdex implant and after 25 ± 13 days, started with at least 3 anti-VEGF monthly injections. The mean BCVA at baseline was 64 ± 14 letters in the ETDRS scale and improved to 69 ± 11 after the three anti-VEGF injections (p > 0.05; <a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>).</p><elsevierMultimedia ident="tbl0005"></elsevierMultimedia><p id="par0065" class="elsevierStylePara elsevierViewall">The mean baseline PED height was 817 ± 269 µm, being 639 ± 268 µm after the Ozurdex implant and 370 ± 260 µm after the three anti-VEGF injections, these differences being statistically significant (p = 0.035 and p = 0.009; <a class="elsevierStyleCrossRef" href="#fig0005">Fig. 1</a>). As for PED maximum diameter, no differences between visits were detected (all p > 0.05; <a class="elsevierStyleCrossRef" href="#fig0010">Fig. 2</a>).</p><elsevierMultimedia ident="fig0005"></elsevierMultimedia><elsevierMultimedia ident="fig0010"></elsevierMultimedia><p id="par0070" class="elsevierStylePara elsevierViewall">In the follow-up visit after the Ozurdex implant, 5 patients (36%) now had low-risk PED (maximum height below 500 µm), which increased to 11 patients (79%) after the anti-VEGF injections. In only one patient a complete resolution of the PED was observed (<a class="elsevierStyleCrossRef" href="#fig0015">Fig. 3</a>).</p><elsevierMultimedia ident="fig0015"></elsevierMultimedia><p id="par0075" class="elsevierStylePara elsevierViewall">A retinal pigment epithelium tear occurred during the course of treatment in 1 eye (7%), which was detected 4 weeks after the Ozurdex implant, prior to the first anti-VEGF injection. The patient was an 80-year-old female with a naïve PED. In the baseline visit, PED height was 722 µm and maximum linear diameter was 3043 µm. BCVA remained stable (70 letters) with monthly Ranibizumab injections. No other adverse effects were reported.</p></span><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0080">Discussion</span><p id="par0080" class="elsevierStylePara elsevierViewall">Many risk factors have been described for pigment epithelium tears in PED, being those related to the size of the PED the only possibly modifiable issues prior to treatment with antiangiogenics. There are few bibliographic references on the possibility of reducing the size of the PED, mostly based on steroid treatment.<a class="elsevierStyleCrossRefs" href="#bib0090"><span class="elsevierStyleSup">18,19</span></a> This pilot study depicts the effect of the use of the delayed-release dexamethasone implant (Ozurdex, Allergan) in reducing the size of the PED and thus the risk of pigment epithelial tear during the induction phase of antiangiogenic treatment of nAMD patients with “high risk PED".</p><p id="par0085" class="elsevierStylePara elsevierViewall">The incidence of RPE tears in patients nAMD diagnosed with PED who receive intravitreal treatment increases to 14–20%, showing a temporal association.<a class="elsevierStyleCrossRefs" href="#bib0065"><span class="elsevierStyleSup">13,14,20–23</span></a> When considering only those cases with PED > 550 microns, the incidence doubled (31% vs 14%).<a class="elsevierStyleCrossRef" href="#bib0100"><span class="elsevierStyleSup">20</span></a> In another series, a height >580 microns in the PED presented a 68% risk of breakage compared to 32% in those that did not (p < 0.001; odds ratio = 69.4).<a class="elsevierStyleCrossRef" href="#bib0105"><span class="elsevierStyleSup">21</span></a> This data is clearly increased compared to our rate of retinal pigment epithelium tears (1/14; 7%).</p><p id="par0090" class="elsevierStylePara elsevierViewall">Moreover, two peaks have been identified in the incidence of pigment epithelial rupture. These are during the initial period of antiangiogenic treatment (induction phase; first 3 months) and later in the chronic phase of treatment.<a class="elsevierStyleCrossRef" href="#bib0120"><span class="elsevierStyleSup">24</span></a> In another study, the vast majority (92%) of the tears occurred after the first injection, being 100% within the first 4.5 months.<a class="elsevierStyleCrossRef" href="#bib0105"><span class="elsevierStyleSup">21</span></a> Therefore, the period with higher pigment epithelium tears has been extensively covered in the present series, further supporting our pigment epithelium tear incidence.</p><p id="par0095" class="elsevierStylePara elsevierViewall">Only one patient in the series presented a pigment epithelial tear, representing a 7% incidence. It remains unclear whether the tear in one eye was due to the Ozurdex or represented the natural evolution of nAMD, given that the diagnosis had been made recently and the patient had no previous anti-VEGF injections. Nevertheless, the relevant decrease in PED height in this series indicates a significant effect. After the Ozurdex implant, 5 patients (36%) developed low-risk PED (maximum height below 500 µm), which increased to 11 patients (79%) after the anti-VEGF injections. We have to point that in the first a variable period between the Ozurdex implant and the beginning of antiangiogenic therapy. We were delaying an approved treatment, and thus in the first cases, two weeks initially were considered. As no reduction in visual function was recorded with this</p><p id="par0100" class="elsevierStylePara elsevierViewall">Although half-dose or bimonthly anti-VEGF injections have been used in high-risk PED, many are resistant even to standard dose regimen.<a class="elsevierStyleCrossRefs" href="#bib0125"><span class="elsevierStyleSup">25,26</span></a> So, given that anti-VEGF therapy presents a higher pigment epithelium tear rate, an ideal approach to treat nAMD would be to reduce PED size by targeting inflammation and then using anti-VEGF drugs. With this theory, different steroids and anti-VEGF treatment combinations have been previously tested with conflicting results.</p><p id="par0105" class="elsevierStylePara elsevierViewall">Using IVTA, Sutter et al. presented a series of 20 eyes with serous PED that were treated with IVTA, observing an increasing trend for visual acuity over 3 months, PED resolution in 8/20 eyes after 3 months and only one pigment epithelium tear.<a class="elsevierStyleCrossRef" href="#bib0095"><span class="elsevierStyleSup">19</span></a> However, other comparative series have shown better visual outcomes and similar PED tomographical changes with Bevacizumab compared to IVTA.<a class="elsevierStyleCrossRef" href="#bib0135"><span class="elsevierStyleSup">27</span></a></p><p id="par0110" class="elsevierStylePara elsevierViewall">Another series reported large PED associated with nAMD (7 eyes) treated with monthly combined IVTA and intravitreal bevacizumab one week later. Average central foveal thickness reduced from 325.7 µm at baseline to 209.2 µm at the end of follow-up and in all eyes, the PED had decreased in size one week after IVTA. No retinal pigment epithelium tear appeared during follow-up and mean BCVA improved.<a class="elsevierStyleCrossRef" href="#bib0140"><span class="elsevierStyleSup">28</span></a> Therefore combined steroids and anti-VEGF seem to provide better outcomes than steroids alone.</p><p id="par0115" class="elsevierStylePara elsevierViewall">Based on previous results, similar studies with dexamethasone implant were developed. The LUCEDEX Study, a pilot randomized trial, compared ranibizumab monotherapy with ranibizumab in combination with intravitreal dexamethasone (500 µg) at 4-week intervals in 37 naïve nAMD patients. At 12 months, all parameters favored combination therapy (including BCVA, central macular quickness), although no statistically differences were detected.<a class="elsevierStyleCrossRef" href="#bib0145"><span class="elsevierStyleSup">29</span></a> The OARA Study randomized 10 patients with active nAMD in two groups: ranibizumab monotherapy and ranibizumab-dexamethasone implant, both groups receiving a previous 3-month ranibizumab load. No pigment epithelial tears were reported and BCVA improvement and central macular thickness decrease occurred in both cohorts with no statistically significant differences, although results were nondefinitive given the small sample (5 eyes per arm).<a class="elsevierStyleCrossRef" href="#bib0150"><span class="elsevierStyleSup">30</span></a> Differences with the present study lie in the different focus, inclusion criteria (active nAMD, not necessarily with PED) and outcomes measures, as central macular thickness may not be so representative of PED improvement.</p><p id="par0120" class="elsevierStylePara elsevierViewall">Similarly to our series, Limon et al. reported the case of a 72-year-old patient previously treated with intravitreal bevacizumab and aflibercept for PED secondary to nAMD, in which simultaneous bevacizumab and dexamethasone implant were injected. Baseline PED height was 910 μm and the greatest linear diameter was 5830 μm and after 3 months the PED had flattened (maximum height 168 μm). BCVA improved from 20/800 to 20/200.<a class="elsevierStyleCrossRef" href="#bib0155"><span class="elsevierStyleSup">31</span></a></p><p id="par0125" class="elsevierStylePara elsevierViewall">However, to our knowledge, this is the largest case series on the use of combined Ozurdex implant and anti-VEGF therapy specifically for high-risk RPE rupture vascular PED. Based on the effectiveness of combined Ozurdex and anti-VEGF intravitreal therapy in our case series, we hypothesize that the steroid may reduce the tension within the PED while having an antiangiogenic effect which is then maximized with anti-VEGF drugs.</p><p id="par0130" class="elsevierStylePara elsevierViewall">Several limitations of the present study must be acknowledged. Firstly, the retrospective nature of the study may have introduced unknown confounding variables and there is no control group. Secondly, the number of RPE tears may appear small, although the relatively low rate of occurrence of this pathology should be considered. However, different rates of pigment epithelium tears have been reports in typical nAMD and polypoidal choroidal vasculopathy.<a class="elsevierStyleCrossRef" href="#bib0160"><span class="elsevierStyleSup">32</span></a> Eyes with different nAMD subtypes were possibly included and it is questionable if these entities are comparable in this matter, but as we stated, imaging studies (indocyanine green, etc.) were not very useful in this setting. Finally, a variable time period between Ozurdex and anti-VEGF therapy existed, being relatively short (2 weeks) in the first cases and up to 6 weeks in the last eyes. This was due to the fact that we were delaying an approved therapy, and only after objectifying there was no functional damage in withholding treatment for two weeks in the first cases, we increased the time period in latter cases. There was a trend for decreases in PED size when a longer waiting period existed. Keeping in mind that in Geneva pivotal studies maximum steroid effect appeared around 2–3 months, this study might have not allowed enough time for maximum PED size reduction to be achieved.</p><p id="par0135" class="elsevierStylePara elsevierViewall">In summary, dexamethasone implant combined with anti-VEGF therapy may represent a promising therapeutic modality for large PED in nAMD, reducing PED dimensions and the risk of pigment epithelium tears. However, further studies are required to fully stablish its effectiveness and safety.</p></span><span id="sec0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0085">Ethical considerations</span><p id="par0140" class="elsevierStylePara elsevierViewall">This article is based on previously conducted studies and does not contain any studies with human participants or animals performed by any of the authors.</p></span><span id="sec0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0090">Funding</span><p id="par0145" class="elsevierStylePara elsevierViewall">No funding or sponsorship was received for this study or publication of this article.</p></span><span id="sec0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0095">Conflict of interest</span><p id="par0150" class="elsevierStylePara elsevierViewall">All authors declare that they have no conflict of interest.</p></span></span>" "textoCompletoSecciones" => array:1 [ "secciones" => array:12 [ 0 => array:3 [ "identificador" => "xres1813802" "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" => "xpalclavsec1583693" "titulo" => "Keywords" ] 2 => array:3 [ "identificador" => "xres1813801" "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" => "xpalclavsec1583692" "titulo" => "Palabras clave" ] 4 => array:2 [ "identificador" => "sec0005" "titulo" => "Introduction" ] 5 => array:2 [ "identificador" => "sec0010" "titulo" => "Methods" ] 6 => array:2 [ "identificador" => "sec0015" "titulo" => "Results" ] 7 => array:2 [ "identificador" => "sec0020" "titulo" => "Discussion" ] 8 => array:2 [ "identificador" => "sec0025" "titulo" => "Ethical considerations" ] 9 => array:2 [ "identificador" => "sec0030" "titulo" => "Funding" ] 10 => array:2 [ "identificador" => "sec0035" "titulo" => "Conflict of interest" ] 11 => array:1 [ "titulo" => "References" ] ] ] "pdfFichero" => "main.pdf" "tienePdf" => true "fechaRecibido" => "2022-01-28" "fechaAceptado" => "2022-03-22" "PalabrasClave" => array:2 [ "en" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Keywords" "identificador" => "xpalclavsec1583693" "palabras" => array:4 [ 0 => "Anti-VEGF therapy" 1 => "Dexamethasone implant" 2 => "Neovascular age-related macular degeneration" 3 => "Pigment epithelium detachment" ] ] ] "es" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Palabras clave" "identificador" => "xpalclavsec1583692" "palabras" => array:4 [ 0 => "Terapia anti-VEGF" 1 => "Implante de dexametasona" 2 => "Degeneración macular asociada a la edad" 3 => "Desprendimiento del epitelio pigmentario" ] ] ] ] "tieneResumen" => true "resumen" => array:2 [ "en" => array:3 [ "titulo" => "Abstract" "resumen" => "<span id="abst0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0010">Objective</span><p id="spar0045" class="elsevierStyleSimplePara elsevierViewall">Evaluate the incidence of pigment epithelial tear when intravitreal delayed-release dexamethasone implant is administered (off-label use) prior to antiangiogenic treatment in pigment epithelium detachments (PED) secondary to neovascular age-related macular degeneration (nAMD) with high-risk rupture characteristics and investigate if it causes a decrease in the PED size.</p></span> <span id="abst0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0015">Methods</span><p id="spar0050" class="elsevierStyleSimplePara elsevierViewall">Patients with nAMD, PED height >500 microns and Ozurdex implant prior to the antiangiogenic therapy were included. The presence of pigment epithelium rupture in optical coherence tomography scans, best-corrected visual acuity (BCVA) and PED measurements (maximum height and diameter) were registered.</p></span> <span id="abst0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0020">Results</span><p id="spar0055" class="elsevierStyleSimplePara elsevierViewall">The study included 14 eyes of 14 patients: mean age 77 ± 7 years, 11 (79%) females. 25 ± 13 days after the Ozurdex, patients started with at least 3 anti-VEGF monthly injections. BCVA improved from 64 ± 14–69 ± 11 letters after anti-VEGF therapy (p > 0.05). Mean baseline PED height was 817 ± 269 µm, being 639 ± 268 µm after Ozurdex and 370 ± 260 µm after anti-VEGF injections (p = 0.035 and p = 0.009). One retinal pigment epithelium tear occurred (7%). No other adverse effects were reported.</p></span> <span id="abst0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0025">Conclusions</span><p id="spar0060" class="elsevierStyleSimplePara elsevierViewall">Dexamethasone implant prior to anti-VEGF therapy may represent a promising therapeutic modality for large PED in nAMD, reducing PED dimensions and the risk of pigment epithelium tears prior to anti VEGF therapy.</p></span>" "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" => "<span id="abst0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0035">Objetivo</span><p id="spar0065" class="elsevierStyleSimplePara elsevierViewall">Evaluar la incidencia de desgarro del epitelio pigmentario cuando se administra un implante intravítreo de dexametasona de liberación retardada (uso off-label) previo al tratamiento antiangiogénico en desprendimientos del epitelio pigmentario (DEP) secundarios a degeneración macular neovascular asociada a la edad (DMAEn) con características de alto riesgo de rotura e investigar si provoca una disminución del tamaño del DEP.</p></span> <span id="abst0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0040">Métodos</span><p id="spar0070" class="elsevierStyleSimplePara elsevierViewall">Se incluyeron pacientes con DMAEn, altura del DEP > 500 micras e implante de Ozurdex previo a la terapia antiangiogénica. Se registró la presencia de rotura del epitelio pigmentario en tomografías de coherencia óptica, agudeza visual mejor corregida (AVMC) y medidas del DEP (altura y diámetro máximos).</p></span> <span id="abst0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0045">Resultados</span><p id="spar0075" class="elsevierStyleSimplePara elsevierViewall">El estudio incluyó a 14 ojos de 14 pacientes: edad media 77 ± 7 años, 11 (79%) mujeres. 25 ± 13 días después del Ozurdex, los pacientes comenzaron con al menos 3 inyecciones mensuales de anti-VEGF. La AVMC mejoró de 64 ± 14 a 69 ± 11 letras después de la terapia anti-VEGF (p > 0,05). La altura media inicial del DEP fue de 817 ± 269 µm, siendo 639 ± 268 µm después de Ozurdex y 370 ± 260 µm después de las inyecciones de anti-VEGF (p = 0,035 y p = 0,009). Se produjo un desgarro del epitelio pigmentario de la retina (7%). No se hallaron otros efectos adversos.</p></span> <span id="abst0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0050">Conclusiones</span><p id="spar0080" class="elsevierStyleSimplePara elsevierViewall">El implante de dexametasona antes de la terapia anti-VEGF puede representar una modalidad terapéutica prometedora para los DEP grandes en la DMAEn, reduciendo las dimensiones del DEP y el riesgo de desgarros del epitelio pigmentario antes de la terapia anti-VEGF.</p></span>" "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" ] ] ] ] "multimedia" => array:4 [ 0 => array:8 [ "identificador" => "fig0005" "etiqueta" => "Fig. 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr1.jpeg" "Alto" => 967 "Ancho" => 2167 "Tamanyo" => 89859 ] ] "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at0005" "detalle" => "Fig. " "rol" => "short" ] ] "descripcion" => array:1 [ "en" => "<p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">Maximum pigment epithelium detachment (PED) height in all visits.</p> <p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">Measurements are shown in μm.</p>" ] ] 1 => array:8 [ "identificador" => "fig0010" "etiqueta" => "Fig. 2" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr2.jpeg" "Alto" => 977 "Ancho" => 2175 "Tamanyo" => 93708 ] ] "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at0010" "detalle" => "Fig. " "rol" => "short" ] ] "descripcion" => array:1 [ "en" => "<p id="spar0015" class="elsevierStyleSimplePara elsevierViewall">Maximum pigment epithelium detachment (PED) linear diameter in all visits.</p> <p id="spar0020" class="elsevierStyleSimplePara elsevierViewall">Measurements are shown in μm.</p>" ] ] 2 => array:8 [ "identificador" => "fig0015" "etiqueta" => "Fig. 3" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr3.jpeg" "Alto" => 2205 "Ancho" => 1755 "Tamanyo" => 525733 ] ] "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at0015" "detalle" => "Fig. " "rol" => "short" ] ] "descripcion" => array:1 [ "en" => "<p id="spar0025" class="elsevierStyleSimplePara elsevierViewall">Example of a patient. Top row, before treatment, middle row after Ozurdex implant and just before beginning anti-VEGF therapy; bottom row one month after anti-VEGF therapy.</p>" ] ] 3 => array:8 [ "identificador" => "tbl0005" "etiqueta" => "Table 1" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at0020" "detalle" => "Table " "rol" => "short" ] ] "tabla" => array:2 [ "leyenda" => "<p id="spar0035" class="elsevierStyleSimplePara elsevierViewall">SD, standard deviation; PED, pigment epithelium detachment.</p><p id="spar0040" class="elsevierStyleSimplePara elsevierViewall">*indicates p < 0.05, while ** indicates p < 0.01.</p>" "tablatextoimagen" => array:1 [ 0 => array:1 [ "tabla" => array:1 [ 0 => """ <table border="0" frame="\n \t\t\t\t\tvoid\n \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " colspan="2" align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black"></th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="center" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Baseline \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="center" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">After Ozurdex \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="center" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Post-anti-VEGF1 \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="center" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Post-anti-VEGF2 \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="center" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Post-anti-VEGF3 \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="center" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">p (baseline vs after ozurdex) \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="center" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">p (after ozurdex vs after anti-VEGF-3) \t\t\t\t\t\t\n \t\t\t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " rowspan="2" align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Visual acuity (ETDRS)</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Mean ± SD \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">64 ± 14 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">65 ± 15 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">– \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">– \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">69 ± 11 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " rowspan="2" align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0.499</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " rowspan="2" align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0.348</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Range \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">35–80 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">31–83 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">– \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">– \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">44–90 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " rowspan="2" align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Maximum PED height (μm)</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Mean ± SD \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">817 ± 269 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">639 ± 268 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">446 ± 308 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">412 ± 295 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">370 ± 260 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " rowspan="2" align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><span class="elsevierStyleBold">0.035</span>*</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " rowspan="2" align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><span class="elsevierStyleBold">0.009</span>**</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Range \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">500 - 1402 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">229 - 1158 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0 - 860 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0 - 848 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0–812 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " rowspan="2" align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Maximum PED linear diameter (μm)</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Mean ± SD \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">4103 ± 1544 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">3892 ± 1055 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">3400 ± 1727 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">3179 ± 2005 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">3445 ± 1489 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " rowspan="2" align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0.632</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " rowspan="2" align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0.155</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Range \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">1736–7552 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">2223–6048 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0–5137 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0–5192 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0–5400 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Pigment epithelium tear \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">n (%) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">– \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">1 (7%) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">1 (7%) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">1 (7%) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">1 (7%) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">– \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">– \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] ] ] ] "descripcion" => array:1 [ "en" => "<p id="spar0030" class="elsevierStyleSimplePara elsevierViewall">Patients’ characteristics in baseline and follow-up visits.</p>" ] ] ] "bibliografia" => array:2 [ "titulo" => "References" "seccion" => array:1 [ 0 => array:2 [ "identificador" => "bibs0005" "bibliografiaReferencia" => array:32 [ 0 => array:3 [ "identificador" => "bib0005" "etiqueta" => "1" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Desgarros del epitelio pigmentario de la retina" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "M. 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