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Plasma rich in growth factors as treatment for a full-thickness macular hole due to macular telangiectasia type 2
Plasma rico en factores de crecimiento como tratamiento para agujero macular de espesor total secundario a telangiectasia macular tipo 2
C.M. Rangela, N.A. Blancob, A. Pedraza-Conchab,
, M.A. Gomezc, M.M. Parrad, J.D. Ariasd
Corresponding author
a Fundación Oftalmológica de Santander, Centro Oftalmológico Virgilio Galvis, Universidad Industrial de Santander, Universidad Autónoma de Bucaramanga, Santander, Colombia
b Universidad Industrial de Santander, Fundación Oftalmológica de Santander, Santander, Colombia
c Universidad Autónoma de Bucaramanga, Fundación Oftalmológica de Santander, Santander, Colombia
d FOSCAL Internacional, Centro Oftalmológico Virgilio Galvis, Santander, Colombia
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OCT B-scan que muestra cierre del agujero macular con regeneración incompleta de las capas externas de la retina. B. Fotografía a color muestra migración del EPR temporal a la fóvea y agujero macular cerrado. C. OCT-Angiografía revela resolución de la lesión hiperreflectiva vista en el preoperatorio y solo se ven las telangiectasias en el plexo vascular superficial y profundo. D. Imagen <span class="elsevierStyleItalic">En-face</span> muestra lesiones hiperreflectivas las cuales corresponden a telangiectasias maculares, sin embargo, sin la lesión hiperreflectiva vista en el preoperatorio.</p>" ] ] ] "autores" => array:1 [ 0 => array:2 [ "autoresLista" => "C.M. Rangel, N.A. Blanco, A. Pedraza-Concha, M.A. Gomez, M.M. Parra, J.D. Arias" "autores" => array:6 [ 0 => array:2 [ "nombre" => "C.M." "apellidos" => "Rangel" ] 1 => array:2 [ "nombre" => "N.A." "apellidos" => "Blanco" ] 2 => array:2 [ "nombre" => "A." 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"apellidos" => "Arias" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">d</span>" "identificador" => "aff0020" ] ] ] ] "afiliaciones" => array:4 [ 0 => array:3 [ "entidad" => "Fundación Oftalmológica de Santander, Centro Oftalmológico Virgilio Galvis, Universidad Industrial de Santander, Universidad Autónoma de Bucaramanga, Santander, Colombia" "etiqueta" => "a" "identificador" => "aff0005" ] 1 => array:3 [ "entidad" => "Universidad Industrial de Santander, Fundación Oftalmológica de Santander, Santander, Colombia" "etiqueta" => "b" "identificador" => "aff0010" ] 2 => array:3 [ "entidad" => "Universidad Autónoma de Bucaramanga, Fundación Oftalmológica de Santander, Santander, Colombia" "etiqueta" => "c" "identificador" => "aff0015" ] 3 => array:3 [ "entidad" => "FOSCAL Internacional, Centro Oftalmológico Virgilio Galvis, Santander, Colombia" "etiqueta" => "d" "identificador" => "aff0020" ] ] "correspondencia" => array:1 [ 0 => array:3 [ "identificador" => "cor0005" "etiqueta" => "⁎" "correspondencia" => "<span class="elsevierStyleItalic">Corresponding author</span>." ] ] ] ] "titulosAlternativos" => array:1 [ "es" => array:1 [ "titulo" => "Plasma rico en factores de crecimiento como tratamiento para agujero macular de espesor total secundario a telangiectasia macular tipo 2" ] ] "resumenGrafico" => array:2 [ "original" => 0 "multimedia" => array:8 [ "identificador" => "fig0005" "etiqueta" => "Fig. 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr1.jpeg" "Alto" => 4263 "Ancho" => 2500 "Tamanyo" => 763277 ] ] "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at0005" "detalle" => "Fig. " "rol" => "short" ] ] "descripcion" => array:1 [ "en" => "<p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">Multimodal BE image.</p> <p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">A. Macular OCT of RE showing full-thickness macular hole with measurements of the hole (inner diameter 624 μm, and basal diameter 920 μm) without vitreous traction at the edges of the hole. B. Color fundus photograph shows artifact in foveal area, migration of temporal RPE to fovea. C. OCT angiography shows circular hyperreflective lesion corresponding to the macular hole (yellow arrow), nasal to telangiectatic vessels. D. <span class="elsevierStyleItalic">En-face</span> image shows the same hyperreflective lesion nasal to the macular telangiectasias (yellow arrow). E. OCT of the LE shows alteration of the foveal architecture, hyperreflective lesions in intermediate layers, loss of the outer segments of the temporal photoreceptors to the fovea, foveal hyperreflective lesions corresponding to cavitations and thickened choroid. F. Color fundus photograph shows artifact in foveal area, migration of temporal RPE to fovea. G. OCT. Angiography shows temporal telangiectasias to the fovea in the superficial and deep plexuses. H. <span class="elsevierStyleItalic">En-face</span> image shows temporal hyperreflective lesions to the fovea.</p>" ] ] ] "textoCompleto" => "<span class="elsevierStyleSections"><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0025">Introduction</span><p id="par0005" class="elsevierStylePara elsevierViewall">Macular telangiectasia type 2 (Mac Tel 2) is a bilateral disease of unknown cause, with characteristic alteration of the macular capillary network and neurosensory atrophy<a class="elsevierStyleCrossRef" href="#bib0005"><span class="elsevierStyleSup">1</span></a>. Full-thickness macular hole (FTMH) secondary to Mac Tel 2 is a rare complication initially described in 2006, the pathogenesis of which is uncertain<a class="elsevierStyleCrossRef" href="#bib0010"><span class="elsevierStyleSup">2</span></a>. It is thought to be due to alteration of the endothelial wall and its metabolism, leading to increased permeability and chronic deficits in metabolism and degeneration of Müller cells. This nutritional deficit in addition to atrophy is what has been proposed to lead to weakness and consequent formation of the hole, and it is still debated whether vitreomacular traction may contribute to its development<a class="elsevierStyleCrossRef" href="#bib0015"><span class="elsevierStyleSup">3</span></a>. A recent study of patients treated with pars plana vitrectomy (PPV) had moderately successful results in the management of this pathology<a class="elsevierStyleCrossRef" href="#bib0020"><span class="elsevierStyleSup">4</span></a>.</p><p id="par0010" class="elsevierStylePara elsevierViewall">Plasma rich in growth factors (PRGF) is a substance with biological properties for tissue regeneration and modulation of inflammation. Its effectiveness depends on platelet concentration, platelet activation and the absence of leukocytes<a class="elsevierStyleCrossRef" href="#bib0025"><span class="elsevierStyleSup">5</span></a>.</p><p id="par0015" class="elsevierStylePara elsevierViewall">The case of a patient with FTMH secondary to Mac Tel 2 is presented, who was successfully treated with the innovative PRGF membrane technique.</p></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0030">Case report</span><p id="par0020" class="elsevierStylePara elsevierViewall">Female, 70, with a history of systemic arterial hypertension and refractive surgery performed 20 years ago, who consulted for blurred vision in both eyes (BE) of 9 months of evolution. Corrected visual acuity (CVA) of the right eye (RE) was 20/200 and left eye (LE) 20/70 with Snellen chart. Examination revealed incipient cataract BE, rest of biomicroscopy without alterations. Fundus BE: normal disc, hyperplasia of the retinal pigment epithelium (RPE) parafoveal temporal retina, adherent retina. RE: FTMH, LE: macular pseudohole.</p><p id="par0025" class="elsevierStylePara elsevierViewall">Optical coherence tomography angiography (OCT-A) (DRI OCT-1 Triton, Topcon, USA) showed Mac Tel in BE, FTMH in RE and cavitations in LE (<a class="elsevierStyleCrossRef" href="#fig0005">Fig. 1</a>). Due to the characteristics of the case, the visual and anatomical prognosis with conventional treatment was lower, so the new surgical technique was proposed.</p><elsevierMultimedia ident="fig0005"></elsevierMultimedia><p id="par0030" class="elsevierStylePara elsevierViewall">The PRGF membrane was prepared according to the Endoret® system (BTI Biotechnology Institute, Alava, Spain). Blood was collected from the patient in tubes, then centrifuged, obtaining 3 components: fraction 1 (F1) with platelet number similar to peripheral blood, fraction 2 (F2) with 3 times higher concentration of platelets and lower concentration of erythrocytes, fraction 3 (F3) whole blood. To obtain the PRGF membrane shape, 2 mm of F2 was obtained and activated with 10% calcium chloride, then incubated at 37 °C for 30 min until a clot was achieved, which was flattened with a mold.</p><p id="par0035" class="elsevierStylePara elsevierViewall">In the same procedure, after cataract extraction and intraocular lens implantation, PPV with internal limiting membrane peeling was performed, the PRGF membrane was introduced through a trocar and placed as a plug inside the FTMH. Subsequently, endocular silicone was left as a buffering agent, because the patient had to travel by plane to her city of residence.</p><p id="par0040" class="elsevierStylePara elsevierViewall">On the first postoperative day, the PRGF membrane was properly positioned (<a class="elsevierStyleCrossRef" href="#fig0010">Fig. 2</a>). The silicone oil was removed 4 months after surgery. At the sixth month of follow-up, anatomical closure of the MH was achieved, with visual acuity with RE correction of 20/100 (<a class="elsevierStyleCrossRef" href="#fig0015">Fig. 3</a>), with no evidence of FTMH recurrence or associated adverse events.</p><elsevierMultimedia ident="fig0010"></elsevierMultimedia><elsevierMultimedia ident="fig0015"></elsevierMultimedia></span><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0035">Discussion</span><p id="par0045" class="elsevierStylePara elsevierViewall">Mac Tel 2 is a disease of unknown etiology with characteristic macular capillary disorders and neurosensory atrophy; it has recently been described as an autosomal dominant inherited disease with reduced penetrance. The prevalence is 0.1% in people over 40 years of age1.</p><p id="par0050" class="elsevierStylePara elsevierViewall">Currently, treatment for Mac Tel 2 in the absence of retinal neovascularization is merely supportive. Studies have been published with no demonstrable effectiveness in controlling the disease with macular grid laser photocoagulation, photodynamic therapy or intravitreal injections of anti-VEGF<a class="elsevierStyleCrossRef" href="#bib0005"><span class="elsevierStyleSup">1</span></a>. Similarly, a recent retrospective study by Miller et al. confirmed that in patients with TMA due to Mac Tel 2 and despite improved OCT findings no statistical difference was observed in visual acuity in patients who underwent conventional PPV compared to those who did not undergo surgery<a class="elsevierStyleCrossRef" href="#bib0020"><span class="elsevierStyleSup">4</span></a>.</p><p id="par0055" class="elsevierStylePara elsevierViewall">In 2010, Gregori and Flynn reported 2 cases, one of which reopened during follow-up<a class="elsevierStyleCrossRef" href="#bib0030"><span class="elsevierStyleSup">6</span></a>. Charbel Issa et al. established the differences in the success rate of FTMH closure related to Mac Tel and suggest the coexistence of factors other than traction that may influence it<a class="elsevierStyleCrossRef" href="#bib0005"><span class="elsevierStyleSup">1</span></a>.</p><p id="par0060" class="elsevierStylePara elsevierViewall">The PRGF preparation is characterized by a moderate concentration of platelets, activated platelets and lack of leukocytes<a class="elsevierStyleCrossRef" href="#bib0025"><span class="elsevierStyleSup">5</span></a>. The absence of leukocytes is because they synthesize matrix metalloproteinases, free radicals and proinflammatory cytokines that hinder the process of tissue regeneration<a class="elsevierStyleCrossRef" href="#bib0035"><span class="elsevierStyleSup">7</span></a>. This PRGF technology is an alternative treatment of autologous origin in ophthalmology with active biological properties that promote tissue regeneration, modulate healing response and anti-inflammatory properties.</p><p id="par0065" class="elsevierStylePara elsevierViewall">PRGF has been successfully used in ophthalmology in patients with sequelae of dry eye and complex FTMH<a class="elsevierStyleCrossRefs" href="#bib0025"><span class="elsevierStyleSup">5,7</span></a>. On the other hand, in 2015 Figueroa et al. report a prospective case series of 7 patients with myopic FTMH who underwent PPV with removal of the internal limiting membrane and application of PRGF liquid glue over the foramen, showing anatomical improvement in 100% of cases. However, no statistically significant difference was found in the improvement of CVA<a class="elsevierStyleCrossRef" href="#bib0040"><span class="elsevierStyleSup">8</span></a>. Sánchez-Ávila et al., reported a patient with high myopia who underwent a conventional surgical procedure without PRGF and presented with recurring FTMH 3 months later. A second surgery with PRGF membrane showed a successful complete closure of the MH, without recurrence, and VA was stable during the 6 months of follow-up<a class="elsevierStyleCrossRef" href="#bib0025"><span class="elsevierStyleSup">5</span></a>. Although few articles use PRGF membrane, those that do show good results<a class="elsevierStyleCrossRefs" href="#bib0025"><span class="elsevierStyleSup">5,7</span></a>.</p><p id="par0070" class="elsevierStylePara elsevierViewall">The proposed mechanism by which the PRGF membrane achieves TMA closure is due to the trophic actions exerted by growth factors, in addition to promoting the activation of Müller cells, serving as a bed for cell growth, regeneration of the affected tissue that modulates the healing response and decreases the inflammatory process<a class="elsevierStyleCrossRefs" href="#bib0025"><span class="elsevierStyleSup">5,7,8</span></a>.</p><p id="par0075" class="elsevierStylePara elsevierViewall">Tha authors consider the use of PRGF membrane is promising when looking for a stable improvement of VA, despite having only isolated case reports. Some advantages of PRGF membrane in contrast to its liquid form is that it remains longer in the area of interest, thus not only filling the area of the hole, but also maintaining a continuous release of growth factors, which stimulate not only the hole closure but also the reconstitution of the inner and outer retinal layers. On the other hand, in liquid form, it does not remain for a long time and loses its effect within a few hours. A disadvantage with the technique may be the difficulty in handling the membrane intraoperatively to place it in the hole and that in the early postoperative period it comes out of the hole. If we compare the liquid form of PRGF vs. inverted internal limiting membrane no significant differences can be observed, although the few studies that exist do find superiority with the PRGF membrane<a class="elsevierStyleCrossRefs" href="#bib0025"><span class="elsevierStyleSup">5,7</span></a>.</p><p id="par0080" class="elsevierStylePara elsevierViewall">Figueroa et al. found adequate anatomic closure with PRGF glue although with no impact on the final VA. Meanwhile, with PRGF membrane presentation, successful results were observed in both VA and anatomical closure of FTMH. Concordantly, Arias et al. reported 2 cases of persistent FTMH in which complete closure was achieved with stable visual improvement during a 12-month follow-up<a class="elsevierStyleCrossRef" href="#bib0035"><span class="elsevierStyleSup">7</span></a>, a result consistent with the present case.</p><p id="par0085" class="elsevierStylePara elsevierViewall">In conclusion, in the knowledge of the authors, this is the first case report of FTMH secondary to Mac Tel 2 treated with the PRGF membrane technique. Since this is a challenging foramen both for size and concurrent disease such as Mac Tel 2, the main objective was to achieve anatomical and functional success in the first intervention. These results indicate that this is a valid, safe and effective alternative to manage this type of disease. However, the literature search evidenced the lack of clinical trials evaluating the PRGF membrane as an alternative treatment for FTMH of difficult cases such as those greater than 600 μm, traumatic, persistent and myopic, among others, and their long-term results.</p></span><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0040">Conflict of interest</span><p id="par0090" class="elsevierStylePara elsevierViewall">No conflicts of interests were declared by the authors.</p></span></span>" "textoCompletoSecciones" => array:1 [ "secciones" => array:9 [ 0 => array:3 [ "identificador" => "xres1700679" "titulo" => "Abstract" "secciones" => array:1 [ 0 => array:1 [ "identificador" => "abst0005" ] ] ] 1 => array:2 [ "identificador" => "xpalclavsec1505107" "titulo" => "Keywords" ] 2 => array:3 [ "identificador" => "xres1700678" "titulo" => "Resumen" "secciones" => array:1 [ 0 => array:1 [ "identificador" => "abst0010" ] ] ] 3 => array:2 [ "identificador" => "xpalclavsec1505106" "titulo" => "Palabras clave" ] 4 => array:2 [ "identificador" => "sec0005" "titulo" => "Introduction" ] 5 => array:2 [ "identificador" => "sec0010" "titulo" => "Case report" ] 6 => array:2 [ "identificador" => "sec0015" "titulo" => "Discussion" ] 7 => array:2 [ "identificador" => "sec0020" "titulo" => "Conflict of interest" ] 8 => array:1 [ "titulo" => "References" ] ] ] "pdfFichero" => "main.pdf" "tienePdf" => true "fechaRecibido" => "2020-08-12" "fechaAceptado" => "2020-11-21" "PalabrasClave" => array:2 [ "en" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Keywords" "identificador" => "xpalclavsec1505107" "palabras" => array:5 [ 0 => "Platelet-rich plasma" 1 => "Platelet-derived growth factor" 2 => "Macular telangiectasia" 3 => "Macular hole" 4 => "Retina" ] ] ] "es" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Palabras clave" "identificador" => "xpalclavsec1505106" "palabras" => array:5 [ 0 => "Plasma rico en plaquetas" 1 => "Factor de crecimiento derivado de plaquetas" 2 => "Telangiectasia macular" 3 => "Agujero macular" 4 => "Retina" ] ] ] ] "tieneResumen" => true "resumen" => array:2 [ "en" => array:2 [ "titulo" => "Abstract" "resumen" => "<span id="abst0005" class="elsevierStyleSection elsevierViewall"><p id="spar0035" class="elsevierStyleSimplePara elsevierViewall">Full-thickness macular hole is a rare complication of macular telangiectasia type 2, and its treatment is still controversial. A patient with a full-thickness macular hole secondary to macular telangiectasia type 2 underwent vitreoretinal surgery with a plasma rich in growth factors membrane in the macular hole. At the sixth month of follow-up, anatomical and functional improvements were achieved, with no adverse effects. Plasma rich in growth factors is a new option, with advantages due to its biological properties that achieves good results in terms of safety and effectiveness in the surgical treatment of macular hole.</p></span>" ] "es" => array:2 [ "titulo" => "Resumen" "resumen" => "<span id="abst0010" class="elsevierStyleSection elsevierViewall"><p id="spar0040" class="elsevierStyleSimplePara elsevierViewall">El agujero macular de espesor total es una complicación rara de la telangiectasia macular tipo 2, y su tratamiento es aún controvertido. Una paciente con esta entidad fue llevada a cirugía vitreorretiniana con aplicación de membrana de plasma rico en factores de crecimiento sobre el agujero macular. Al sexto mes de cirugía se logró mejoría anatómica y funcional, sin efectos adversos asociados. El plasma rico en factores de crecimiento es una alternativa nueva en el tratamiento quirúrgico del agujero macular atípico y/o persistente, que logra buenos resultados en términos de seguridad y efectividad, debido a sus propiedades biológicas.</p></span>" ] ] "NotaPie" => array:1 [ 0 => array:2 [ "etiqueta" => "☆" "nota" => "<p class="elsevierStyleNotepara" id="npar0005">Please cite this article as: Rangel CM, Blanco NA, Pedraza-Concha A, Gomez MA, Parra MM, Arias JD. Plasma rico en factores de crecimiento como tratamiento para agujero macular de espesor total secundario a telangiectasia macular tipo 2. Arch Soc Esp Oftalmol. 2022;97:219–223.</p>" ] ] "multimedia" => array:3 [ 0 => array:8 [ "identificador" => "fig0005" "etiqueta" => "Fig. 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr1.jpeg" "Alto" => 4263 "Ancho" => 2500 "Tamanyo" => 763277 ] ] "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at0005" "detalle" => "Fig. " "rol" => "short" ] ] "descripcion" => array:1 [ "en" => "<p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">Multimodal BE image.</p> <p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">A. Macular OCT of RE showing full-thickness macular hole with measurements of the hole (inner diameter 624 μm, and basal diameter 920 μm) without vitreous traction at the edges of the hole. B. Color fundus photograph shows artifact in foveal area, migration of temporal RPE to fovea. C. OCT angiography shows circular hyperreflective lesion corresponding to the macular hole (yellow arrow), nasal to telangiectatic vessels. D. <span class="elsevierStyleItalic">En-face</span> image shows the same hyperreflective lesion nasal to the macular telangiectasias (yellow arrow). E. OCT of the LE shows alteration of the foveal architecture, hyperreflective lesions in intermediate layers, loss of the outer segments of the temporal photoreceptors to the fovea, foveal hyperreflective lesions corresponding to cavitations and thickened choroid. F. Color fundus photograph shows artifact in foveal area, migration of temporal RPE to fovea. G. OCT. Angiography shows temporal telangiectasias to the fovea in the superficial and deep plexuses. H. <span class="elsevierStyleItalic">En-face</span> image shows temporal hyperreflective lesions to the fovea.</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" => 1301 "Ancho" => 2476 "Tamanyo" => 318916 ] ] "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at0010" "detalle" => "Fig. " "rol" => "short" ] ] "descripcion" => array:1 [ "en" => "<p id="spar0015" class="elsevierStyleSimplePara elsevierViewall">OCT postoperative RE findings.</p> <p id="spar0020" class="elsevierStyleSimplePara elsevierViewall">A. OCT of the first postoperative day showing hyperreflective band covering the macular hole. B. Color fundus photograph shows silicone in vitreous cavity and PRFG membrane (yellow arrow) covering the macular hole. C. 10-day postoperative OCT shows smaller hyperreflective area and closure of the macular hole. D. Color fundus photograph shows silicone in vitreous cavity and macular hole closure.</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" => 2116 "Ancho" => 2896 "Tamanyo" => 609841 ] ] "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at0015" "detalle" => "Fig. " "rol" => "short" ] ] "descripcion" => array:1 [ "en" => "<p id="spar0025" class="elsevierStyleSimplePara elsevierViewall">Multimodal image of postoperative RE findings.</p> <p id="spar0030" class="elsevierStyleSimplePara elsevierViewall">A. OCT B-scan showing macular hole closure with incomplete regeneration of the outer retinal layers. B. Color photograph shows migration of the temporal RPE to the fovea and closed macular hole. C. OCT-Angiography reveals resolution of the hyperreflective lesion seen preoperatively and only telangiectasias are seen in the superficial and deep vascular plexus. D. <span class="elsevierStyleItalic">En-face</span> image shows hyperreflective lesions which correspond to macular telangiectasias, however, without the hyperreflective lesion seen preoperatively.</p>" ] ] ] "bibliografia" => array:2 [ "titulo" => "References" "seccion" => array:1 [ 0 => array:2 [ "identificador" => "bibs0005" "bibliografiaReferencia" => array:8 [ 0 => array:3 [ "identificador" => "bib0005" "etiqueta" => "1" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Macular telangiectasia type 2" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "P. Charbel Issa" 1 => "M.C. Gillies" 2 => "E.Y. Chew" 3 => "A.C. Bird" 4 => "T.F.C. Heeren" 5 => "T. 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