[Clinical Decision Making for Treatment of Diabetic Macular Oedema with DEX Implant: a Consensus Paper]. / Klinische Entscheidungsfindung bei der Behandlung des diabetischen Makulaödems mit DEX-Implantat: ein Konsenspapier.

BACKGROUND: Currently two intravitreally applied corticosteroids (dexamethasone and fluocinolone) are licensed in Germany for treatment of diabetic macular oedema (DME). The use of DEX implant for DME in daily clinical practice has not been defined in detail. Following a Delphi panel survey, a group of retina experts set out to come up with a consensus for use of the DEX implant in DME. MATERIAL AND METHODS: International and national treatment recommendations were identified from the literature. A steering group generated a catalogue of 72 statements on the aetiology and pathogenesis of DME, therapy with DEX implant, use of DEX implant in patients previously treated with VEGF-inhibitors, use of DEX implant in combination therapy, safety of DME therapies as well as patients' burden of treatment. Twenty-two ophthalmologists from private practice and 6 hospital ophthalmologists participated in the Delphi panel via Survey Monkey. Consensus was reached if at least 75% of participants agreed or disagreed with a statement. Statements for which consensus was not reached were discussed once more during the expert consensus meeting and a vote was taken. Based on these results a treatment algorithm for foveal DME was proposed. RESULTS: If a patient does not show sufficient response after 3 - 6 months of anti-VEGF treatment (visual acuity gain of < 5 ETDRS letters or reduction of central retinal thickness ≤ 20%), a switch to DEX implant should take place. DEX implant is also suitable in eyes with longer presentation of DME, showing e.g. massive lipid exudates. DEX implant is suitable as first-line therapy especially in pseudophakic patients, patients unwilling or able to comply with tight anti-VEGF injection intervals or patients with known vascular diseases. With fixed control visits every 4 - 8 weeks, use of DEX implant is flexible and individual. Decision parameters for repeated use should be visual acuity, retinal thickness and intraocular pressure. Treatment of both eyes on the same day should not take place. CONCLUSION: The algorithm presented reflects survey as well as expert discussion results and may differ from recommendations issued by the German professional society. The consensus recommendations for the treatment of DME generated during the survey and meeting of retina experts are intended to guide use of DEX implant in daily practice.

Application of subretinal fluid to close refractory full thickness macular holes: treatment strategies and primary outcome: APOSTEL study.

INTRODUCTION: Persisting macular holes (PMH) after surgical release of any epiretinal traction of the vitreous and adjacent membrane may rely on secondary firm adhesions between the retracted retina and adjacent retinal pigment epithelium. Secondary application of subretinal (SR)-fluid may release these adhesions followed by an anatomical closure. METHODS: Twelve surgeons applied in a consecutive case series SR-fluid in 41 eyes with PMH and reported retrospectively their initial surgical, anatomical and functional experience with this approach. RESULTS: The mean duration of the MH prior to SR-fluid application was 17 months (6-96 months). The mean age of the patients at the time of surgery was 72 years (54-88). The mean preoperative aperture diameter of the opening was 1212 µm (239-4344 µm), base diameter 649 µm (SD 320 µm). The mean preoperative BCVA prior to surgery was 0.1 (0.01-0.3). All patients (41/41) complained about reduced BCVA and a significant central scotoma (negative scotoma) in their central field of vision. The secondary closure rate for our PMH was 85.36% (35 out of 41 eyes) at 6 weeks after surgery. The postoperative BCVA improved to 0.22 (0.02-0.5). The application of SR-fluid was not associated with major intraoperative adverse effects. CONCLUSION: Remaining SR-adhesions may inhibit PMH closure. Their release by application of SR-fluid will lead to a fast and immediate anatomical closure in many cases without serious adverse events.

[Vitreomacular Traction Following Anti-VEGF Therapy - Two Cases]. / Vitreomakuläres Traktionssyndrom im Rahmen der Anti-VEGF-Therapie ­ 2 Kasuistiken.

Vitreomacular traction syndrome (VMTS) is defined as an incomplete or anomalous posterior vitreous detachment resulting in tractional forces at the macular region. In the context of anti-VEGF therapy, the formation of vitreoretinal traction has mainly been reported as a potential complication of VEGF inhibition in ischemic proliferative retinal disease, such as proliferative diabetic retinopathy. In this report, we present two patients who developed VMTS during anti-VEGF therapy for exudative age-related macular degeneration and diabetic macular edema. VMTS following anti-VEGF therapy of exudative macular diseases is rare. The exact pathomechanism remains unclear. However, there is a hypothesis that in eyes with adherent vitreous cortex, the induction of fibrosis as a result of the VEGF inhibition may lead to vitreomacular traction.

[Cost Comparison of Licensed Intravitreal Therapies for Insufficiently Anti-VEGF Responding Fovea Involving Diabetic Macular Edema in Germany]. / Kostenvergleich zugelassener intravitrealer Therapien bei nicht ausreichend auf primäre Therapie ansprechendem diabetischem Makulaödem mit fovealer Beteiligung in Deutschland.

BACKGROUND: In the treatment of center-involving diabetic macular edema, despite initial therapy with an anti-VEGF compound, an insufficient response may occur. Further therapy options include a switch of anti-VEGF products or to corticosteroid implants, such as Fluocinolone acetonide or Dexamethasone. OBJECTIVES: Firstly, to investigate systematically which evidence-based study data are available describing the efficacy of in-label treatments after primary anti-VEGF treatment, secondly, to investigate which costs go along for the healthcare provider. METHODS: A systematic literature review (SLR) for randomized controlled trials (RCT) was performed in Medline and Embase. A short-term cost-cost model was built in MS Excel with a 3 year time horizon to compare in-label intravitreal options Ranibizumab (Lucentis®), Aflibercept (Eylea®), Fluocinolone acetonide implant (Iluvien®), and Dexamethasone implant (Ozurdex®). Cost components comprised of drug and injection costs, optical coherence tomography (OCT) procedures, and adverse events such as endophthalmitis, IOP-lowering drugs and surgery and cataract surgery. RESULTS: A total of 42 publications of 20 RCTs were identified. No study had a clearly defined population after first line anti-VEGF treatment, thus no direct efficacy comparison was possible. In the short-term cost-cost model total costs were 17,542 € for Ranibizumab, 15,896 € for Aflibercept, 10,826 € for Fluocinolone acetonide implant and 12,365 € for Dexamethasone implant. For all treatment regimens, drug costs were the predominant cost component, followed by injection costs (with variations dependent on the specific drug) and OCT costs. In the uni- and multivariate sensitivity analyses, the results obtained were robust to changes of model inputs. CONCLUSIONS: In summary, the short-term cost-cost comparison demonstrates that steroid implants can provide significant cost savings versus in-label anti-VEGF treatment for center-involving diabetic macular edema. Single application of the long-lasting Fluocinolone acetonide implant is the most cost-efficient in-label treatment option.

Impact of Preinjection Spectral Domain Optical Coherence Tomography Findings in the Use of Intravitreal Ocriplasmin in a Clinical Setting.

PURPOSE: To investigate the impact of spectral domain optical coherence tomography (SD-OCT) morphological predictive markers on visual acuity and outcome using ocriplasmin for macular hole and vitreomacular traction syndrome. METHODS: A series of 40 patients in a retrospective study received intravitreal ocriplasmin. The primary endpoint was defined as morphological resolution of vitreomacular traction or closure of a macular hole. We analyzed the impact of pre- and postinjection SD-OCT findings on the outcome and visual acuity. RESULTS: Thirteen of the 40 patients benefited from treatment. Statistical correlation between baseline characteristics and outcome revealed that higher foveal thickness (p = 0.018) and nontractional epiretinal membranes (p = 0.05) resulted in a worse outcome. In treatment success best corrected visual acuity gained was 9 (SD 12) letters and in failure 1 (SD 9) letter. We could not observe an influence of preinjection SD-OCT findings and other factors on visual outcome. CONCLUSION: We could confirm the therapeutic effect of ocriplasmin injections. SD-OCT morphological factors that influence treatment success and visual acuity were determined.

Propiedades biomecánicas de la membrana limitante interna tras recibir tratamiento intravítreo con ocriplasmina.

Objetivo: Evaluar la rigidez de la membrana limitante interna (MLI) humana y evaluar los posibles cambios de las propiedades mecánicas tras administrar una inyección intravítrea de ocriplasmina para tratar la tracción vitreomacular. Métodos: Este estudio se compone de una serie de casos intervencionales y comparativos de 12 muestras de MLI extraídas mediante cirugía y obtenidas de forma consecutiva de 9 ojos de 9 pacientes después de someterse sin éxito a vitreólisis farmacológica con ocriplasmina. Durante el mismo periodo de tiempo, 16 muestras de otros 13 ojos sin tratamiento con ocriplasmina se obtuvieron mediante vitrectomía y sirvieron como controles. Todos los pacientes presentaron agujeros maculares o tracción vitreomacular y se sometieron a vitrectomía con disección de la MLI tanto con tinción con azul brillante (AB) como sin ella. Todas las muestras se analizaron con un microscopio de fuerza atómica con imágenes de las regiones de 25 × 25 µm. En todas las muestras, se analizaron tanto la parte de la retina como la del vítreo de la MLI. Resultados: La microscopia de fuerza atómica no reveló diferencias significativas en cuanto a elasticidad de las muestras de MLI extraídas de ojos con o sin tratamiento con ocriplasmina. Las áreas onduladas de la parte de la retina presentaron una mayor rigidez que la parte del vítreo de la MLI. La cartografía topográfica tanto de la parte del vítreo como de la retina de la MLI no mostró ninguna alteración aparente de la morfología en ojos tratados con ocriplasmina en comparación con los ojos no tratados. La tinción con azul brillante conllevó un aumento de la rigidez tisular. Conclusiones: Las inyecciones intravítreas de ocriplasmina no varían las propiedades biomecánicas de la MLI humana. No existen pruebas de un posible efecto enzimático que interfiera con la rigidez de esta membrana basal.

Viability of Primary Human Pigment Epithelium Cells and Muller-Glia Cells after Intravitreal Ziv-Aflibercept and Aflibercept.

PURPOSE: The aim of this study was to access the safety profiles of 2 fusion proteins with anti-vascular endothelial growth factor action (ziv-aflibercept and aflibercept) on retinal pigment epithelium cells and Muller-Glia cells in culture by assessing cell viability post drug exposure. METHODS: Primary human retinal pigment epithelium cells (pRPE) and Muller-Glia cells (Mio-M1) were exposed to the clinical standardized concentrations of ziv-aflibercept (25 mg/mL) and aflibercept (40 mg/mL). Progressively higher concentrations of NaCl (300, 500, 1,000, 1,500, 2,000, 5,000, and 10,000 mosm/kg) were also applied to cells to assess the possibility of potentiating hyperosmotic cytotoxity effect. The study was applied to measure pRPE and Mio-M1 viability by a tetrazolium dye-reduction assay (XTT). RESULTS: Cell viability of both pRPE and Mio-M1 presented no significant changes after exposure of ziv-aflibercept and aflibercept. Progressive NaCl concentrations did not significantly alter cell viability. The exposure to the negative control of 75 µL/mL of dimethyl sulfoxide showed significant reduction in cell viability. CONCLUSIONS: At clinical doses, neither ziv-aflibercept nor aflibercept caused any significant reduction in cell viability in vitro. Furthermore, injection solutions of NaCl with higher osmolality caused no significant reduction in cell viability.

Biomechanical Properties of the Internal Limiting Membrane after Intravitreal Ocriplasmin Treatment.

PURPOSE: To assess the stiffness of the human internal limiting membrane (ILM) and evaluate potential changes of mechanical properties following intravitreal ocriplasmin injection for vitreomacular traction. METHODS: This is an interventional comparative case series of 12 surgically excised ILM specimens consecutively obtained from 9 eyes of 9 patients after unsuccessful pharmacologic vitreolysis with ocriplasmin. During the same time period, 16 specimens from 13 other eyes without ocriplasmin treatment were harvested during vitrectomy and served as controls. All patients presented with macular holes or vitreomacular traction and underwent vitrectomy with ILM peeling either with or without brilliant blue (BB) staining. All specimens were analyzed using atomic force microscopy with scan regions of 25 × 25 µm. In all specimens, both the retinal side and vitreal side of the ILM were analyzed. RESULTS: Atomic force microscopy revealed no significant differences in elasticity of ILM specimens removed from eyes with or without ocriplasmin treatment. Undulated areas of the retinal side presented stiffer than the vitreal side of the ILM. Topographical mapping of both the vitreal and retinal side of the ILM showed no apparent alteration of the morphology in ocriplasmin-treated eyes compared to untreated eyes. Staining with BB resulted in an increase of tissue stiffness. CONCLUSIONS: Intravitreal injection of ocriplasmin does not change biomechanical properties of the human ILM. There is no evidence of a potential enzymatic effect of ocriplasmin interfering with the stiffness of this basement membrane.

Cells at the vitreoretinal interface in small full-thickness macular holes.

PURPOSE: To report on total number, distribution, and type of cells at the vitreomacular interface in small full-thickness macular holes. METHODS: Internal limiting membrane specimens were removed from 20 consecutive patients with macular holes <250 µm at times when pharmacologic vitreolysis was not available. Specimens were flat mounted and investigated by phase contrast and interference microscopy and immunocytochemistry. Clinical data were documented including optical coherence tomography analysis using the caliper function. Thirteen antibodies were used for glial cells, hyalocytes, macrophages, retinal pigment epithelial cells, different types of collagen, alpha-smooth muscle actin, and proliferating cells. RESULTS: There was a positive correlation between macular hole size and cell density at the internal limiting membrane (Spearman's Rho: r = 0.519, P = 0.019). Mostly, single glial cells were found on the internal limiting membrane. In five patients, cell clusters were present. There was a strong immunoreactivity for glial cell markers. Immunoreactivity of hyalocyte markers, alpha-smooth muscle actin, and Ki-67 was found in cell clusters but otherwise sparse. CONCLUSION: Single cells of glial origin without signs of proliferation or contraction are present in eyes with small full-thickness macular holes. In some eyes, however, clusters of cells can be seen, capable of proliferation and exerting tangential traction. Our findings emphasize the need for better visualization of the vitreoretinal pathology by optical coherence tomography, especially to distinguish between single cells and cell clusters.

Epiretinal membrane characteristics correlate with photoreceptor layer defects in lamellar macular holes and macular pseudoholes.

PURPOSE: To report on epiretinal membrane (ERM) characteristics and photoreceptor layer integrity of lamellar macular holes (LMHs) and macular pseudoholes (MPHs), and to compare with clinical course in operated and untreated eyes. METHODS: We consecutively reviewed the charts of patients with LMH and MPH between 2003 and 2013. For clinical analysis, we included 87 eyes (48 with LMH, 39 with MPH) with a minimum follow-up of 6 months. Of these, we included 64 eyes (37 with LMH, 27 with MPH) for high-resolution spectral domain optical coherence tomography analysis with examinations fulfilling the required resolution and quality of optical coherence tomography images. Epiretinal membranes were termed "typical tractional ERM" if presenting with contractive properties, or "atypical epiretinal tissue" if presenting as epiretinal material of homogeneous medium reflectivity without contractive properties. Integrity or discontinuity of the inner and outer segment (IS/OS) and the external limiting membrane (ELM) was evaluated by differentiating between "defect present" and "defect absent." RESULTS: In eyes with LMH, atypical epiretinal tissue presented in 29%, typical tractional ERMs were seen in 57%, and a combination of both in 14%. In contrast, eyes with MPH rarely presented atypical epiretinal tissue, and typical tractional ERMs were found in 89%. Comparing cases with LMH, eyes with atypical epiretinal tissue showed significantly more defects of the IS/OS and the ELM than eyes with typical tractional ERM. Both IS/OS and ELM defects correlated with a significant lower best-corrected visual acuity. Defects of the IS/OS were seen in 41% of LMH and 11% of MPH. Defects of the ELM revealed in 27% of LMH and in 11% of MPH. Operated eyes with disrupted IS/OS but intact ELM had significant better best-corrected visual acuity than eyes with defects in both layers. CONCLUSION: Atypical epiretinal tissue is related to the presence of photoreceptor layer defects and to poor visual acuity. It seems that integrity of the ELM is most important for functional recovery after surgery in both LMH and MPH. The presence of atypical epiretinal tissue in eyes with LMH may represent differences in the pathogenesis compared with MPH, and might have therapeutic implications for the proceeding with macular surgery in selected cases.

Retrospective, observational study in patients receiving a dexamethasone intravitreal implant 0.7 mg for macular oedema secondary to retinal vein occlusion.

PURPOSE: To retrospectively evaluate the re-injection interval, efficacy and safety of dexamethasone (DEX) intravitreal implant 0.7 mg in the treatment of macular oedema (ME) due to retinal vein occlusion (RVO) in Germany in 2009-2012. METHODS: Retrospective, multicentre, anonymised observational study of data collected from the first DEX implant 0.7 mg injection through 3-6 months following the last injection. Data were included if the patient was >18 years old, had a diagnosis of ME secondary to branch or central RVO, and received at least 2 DEX implant 0.7 mg injections during routine practice. RESULTS: Data from 87 patients were analysed. Mean time to re-injection between first and second treatments was 5.03 months in the total RVO population, and 5.46 and 4.52 months for the branch and central RVO subpopulations, respectively. An intraocular pressure increase of >25 mm Hg was recorded in 20% of patients, and 34% of patients began treatment with anti-glaucoma medication, but surgery was not needed for this condition. CONCLUSIONS: DEX implant 0.7 mg was found to be well tolerated and effective with repeat treatments in clinical practice.

Testing the effects of the dye acid violet-17 on retinal function for an intraocular application in vitreo-retinal surgery.

PURPOSE: To facilitate epiretinal or inner limiting membrane peeling, dyes like Indocyanine Green (ICG) as well as Trypan Blue (TB) were used so far. However, toxic effects on the retina were described for both dyes. The aim of our study was to investigate the effects of a novel vital dye Acid violet-17 (AV-17) on retinal histology and function to assess a possible application in vitreo-retinal surgery. METHODS: AV-17 was dissolved in a solvent with heavy water. An electroretinogram was recorded on perfused bovine retina. After reaching stable b-wave amplitudes, AV-17 (0.125-0.5 mg/ml) or the solvent was applied epiretinally for 30-300 seconds. The b-wave amplitudes were recorded before, during, and after treatment. Cultures of bovine retina were incubated for 30 or 300 seconds with the dye or solvent and processed for live/dead staining, immunohistochemistry, and immunoblotting. RESULTS: Reductions of the b-wave amplitudes were observed directly after the exposure to AV-17, which were rapidly and completely reversible within the recovery period for all exposure times at the concentrations of 0.125 and 0.25 mg/ml as opposed to the partial recovery after exposure to 0.5 mg/ml. A high degree of damage in the ganglion cell layer (GCL) and glial reactivity were detected at the concentrations of 0.25 and 0.5 mg/ml but not after exposure to lower concentrations or the solvent. CONCLUSION: Application of AV-17 at a concentration of up to 0.125 mg/ml was well tolerated in terms of retinal function, survival in the GCL, and glial reactivity whereas higher concentrations are not recommended.

Megahertz ultra-wide-field swept-source retina optical coherence tomography compared to current existing imaging devices.

BACKGROUND: To investigate the image quality of wide-angle cross-sectional and reconstructed fundus images based on ultra-megahertz swept-source Fourier domain mode locking (FDML) OCT compared to current generation diagnostic devices. METHODS: A 1,050 nm swept-source FDML OCT system was constructed running at 1.68 MHz A-scan rate covering approximately 70° field of view. Twelve normal eyes were imaged with the device applying an isotropically dense sampling protocol (1,900 × 1,900 A-scans) with a fill factor of 100 %. Obtained OCT scan image quality was compared with two commercial OCT systems (Heidelberg Spectralis and Stratus OCT) of the same 12 eyes. Reconstructed en-face fundus images from the same FDML-OCT data set were compared to color fundus, infrared and ultra-wide-field scanning laser images (SLO). RESULTS: Comparison of cross-sectional scans showed a high overall image quality of the 15× averaged FDML images at 1.68 MHz [overall quality grading score: 8.42 ± 0.52, range 0 (bad)-10 (excellent)] comparable to current spectral-domain OCTs (overall quality grading score: 8.83 ± 0.39, p = 0.731). On FDML OCT, a dense 3D data set was obtained covering also the central and mid-peripheral retina. The reconstructed FDML OCT en-face fundus images had high image quality comparable to scanning laser ophthalmoscope (SLO) as judged from retinal structures such as vessels and optic disc. Overall grading score was 8.36 ± 0.51 for FDML OCT vs 8.27 ± 0.65 for SLO (p = 0.717). CONCLUSIONS: Ultra-wide-field megahertz 3D FDML OCT at 1.68 MHz is feasible, and provides cross-sectional image quality comparable to current spectral-domain OCT devices. In addition, reconstructed en-face visualization of fundus images result in a wide-field view with high image quality as compared to currently available fundus imaging devices. The improvement of >30× in imaging speed over commercial spectral-domain OCT technology enables high-density scan protocols leading to a data set for high quality cross-sectional and en-face images of the posterior segment.

Hyalocytes in idiopathic epiretinal membranes: a correlative light and electron microscopic study.

PURPOSE: To describe characteristics of epiretinal cells at the vitreoretinal interface by correlative light and electron microscopy (CLEM). METHODS: Epiretinal membrane (ERM) specimens and internal limiting membrane (ILM) specimens were harvested by sequential peeling during vitrectomy from 27 eyes with idiopathic epiretinal gliosis, and processed for CLEM. Intraoperatively, the presence of posterior vitreous detachment (PVD) was documented. We used anti-vimentin, anti-α-smooth muscle actin (α-SMA), and anti-CD45 as primary antibodies. A fluorescein-tagged immunonanogold cluster was used as secondary antibody and visualized under the fluorescence and transmission electron microscope. RESULTS: We demonstrated CD45-positive cells specifically labelled at their plasma membranes with ultrastructural features known for hyalocytes, such as oval nucleus with marginal chromatin, vacuoles, dense granules, and thin cytoplasmic protrusions. CD45-positive cells were mostly located on a thick layer of native vitreous collagen. They were covered by newly formed collagen strands with multilayered proliferation of myofibroblasts. We also demonstrated immunoreactivity for vimentin and alpha-SMA. Cell fragments with positive labelling for α-SMA and vimentin were not only found on the vitreal side of the ILM, but also on the retinal side. CONCLUSIONS: By CLEM, the majority of CD45-positive cells in epiretinal cell proliferation were characterized as hyalocytes. In the context of anomalous PVD and vitreoschisis, ultrastructural features and topographic localization of hyalocytes suggest that these cells play a significant role in ERM formation. CLEM enables a more accurate characterization of epiretinal cell proliferation, and therefore, contributes to a better understanding of the pathogenesis of diseases at the vitreoretinal interface.

Microaneurysm formation rate as a predictive marker for progression to clinically significant macular edema in nonproliferative diabetic retinopathy.

PURPOSE: To evaluate the predictive value of microaneurysm (MA) formation rate concerning the development of clinically significant macular edema (CSME) in patients with mild-to-moderate nonproliferative diabetic retinopathy as evaluated by an automated analysis of central field fundus 30° photographs. METHODS: Two hundred and eighty-seven eyes were included in the study. Photographs obtained at Day 0, at 6, and 12 months were analyzed using the RetmarkerDR software (Critical Health SA) in a masked manner, and the MA formation rate was documented. A threshold of a calculated MA formation rate of 2 or more was chosen to consider a patient "positive." The ability to predict CSME development was then calculated for a period of up to 5 years. HbA1c values, blood pressure, or duration of diabetes were also evaluated. RESULTS: The study population consisted of 89 male and 59 female patients with a mean age of 57.6 years, a mean HbA1c of 7.8, and a mean duration of diabetes of 12.3 years. Forty-seven of 287 eyes (16.4%) developed CSME during follow-up. An increased MA formation rate of >2 MA was clearly associated with development of CSME. Using the automated analysis and a threshold of 2 or more new MA, the authors were able to identify 70.2% of the eyes that developed CSME during follow-up ("true positive") and using a threshold of up to 2 new MA, 71.7% of the patients that did not develop CSME ("true negative"). No significant differences concerning baseline and 1-year HbA1c levels within patient eyes that developed CSME compared with patient eyes below or over the calculated threshold of 2 MA (P = 0.554 and P = 0.890, respectively) were seen. The positive and negative predictive value was calculated to be 33% versus 92.5%, sensitivity was 70%, and specificity was 72%. CONCLUSION: Using the RetmarkerDR software, the authors were able to identify patients with higher risk to develop CSME during follow-up using a threshold of 2 or more MA formation rate. Together with the high negative predictive value, the automated analysis may help to determine the individual risk of a patient to develop sight-threatening complications related to diabetic retinopathy and schedule individual screening intervals.

Microaneurysm turnover in diabetic retinopathy assessed by automated RetmarkerDR image analysis--potential role as biomarker of response to ranibizumab treatment.

PURPOSE: To evaluate the influence of a ranibizumab treatment on microaneurysm (MA) turnover in diabetic retinopathy. METHODS: Sixty-nine eyes were included in this retrospective study. We compared a group of 33 eyes with ranibizumab treatment for diabetic macular edema to 36 eyes with nonproliferative diabetic retinopathy only. Nonmydriatic ultra-widefield scanning laser ophthalmoscopy (Optomap) images were obtained at a mean 4.76 ± 1.69 days prior to the first ranibizumab injection (baseline) and again 35.94 ± 2.44 days after the third consecutive injection in a 4-week interval. In untreated controls, images were obtained at baseline and 97.81 ± 3.16 days thereafter. Images were analyzed using the RetmarkerDR software (Critical Health SA, Coimbra, Portugal), and the turnover of MAs was documented and analyzed. Thereafter, MA turnover was correlated with central retinal thickness (CRT) as assessed by OCT. RESULTS: At baseline, patients in the treatment group had 5.64 ± 0.75 MAs. One month after 3 ranibizumab injections, measured MAs decreased to 4.03 ± 0.66. In the untreated control group, the initial number of 3.36 ± 0.6 MAs remained almost unchanged over 3-4 months (2.89 ± 0.57 MAs). Dynamic analysis showed that after ranibizumab treatment 3.06 ± 0.5 new MAs appeared, while 5.09 ± 0.79 disappeared. In the control group, 2.11 ± 0.4 new MAs appeared and 2.61 ± 0.48 disappeared. MA turnover was significantly higher with ranibizumab compared to the control group (8.15 ± 1.14 vs. 4.72 ± 0.81, p < 0.001). Consistently, CRT decreased from 444 to 330 µm in the ranibizumab group, while there was no change in the control group (291 vs. 288 µm). CONCLUSION: The treatment of macular edema using ranibizumab does not only reduce macular thickness, but also has an impact on the turnover of MAs in diabetic retinopathy. RetmarkerDR analysis showed that more pre-existent MAs disappeared than new MAs developed, and the absolute number of MAs also decreased.

Nonmydriatic ultra-wide-field scanning laser ophthalmoscopy (Optomap) versus two-field fundus photography in diabetic retinopathy.

The purpose of this study was to investigate the diagnostic properties of a 2-laser wavelength nonmydriatic 200° ultra-wide-field scanning laser ophthalmoscope (SLO) versus mydriatic 2-field 45° color fundus photography (EURODIAB standard) for assessing diabetic retinopathy (DR). A total of 143 consecutive eyes of patients with different levels of DR were graded regarding DR level and macular edema based on 2-field color photographs or 1 Optomap Panoramic 200 SLO image. All SLO images were nonmydriatic and all photographs mydriatic. Grading was performed masked to patient and clinical data. Based on photography, 20 eyes had no DR, 44 had mild, 18 moderate and 42 severe nonproliferative DR, and 19 eyes had proliferative DR. Overall correlation for grading DR level compared to Optomap SLO was moderate with kappa 0.54 (p < 0.001), fair-to-moderate in macular edema grading with kappa 0.39 (p < 0.001), and substantial for grading clinically significant macular edema (kappa 0.77). The wide-field SLO offers a wider field of view and can potentially better differentiate lesions by applying the 2 laser wavelengths. However, these advantages over 2-field fundus photography need to be confirmed in further studies.

Advances in management strategies for large and persistent macular hole: An update.

The standard of care to treat small- and medium-sized macular holes (<400 µm diameter) consists of a conventional transconjunctival sutureless pars plana vitrectomy followed by ILM peeling and endotamponade, mainly with gas or in some cases with silicone oil, resulting in closure rates of over 90% and good functional results. Large (>400 µm diameter), chronic and persistent macular holes remain a surgical challenge since closure rates and functional results decrease with larger macular hole diameters. Various modifications of the conventional surgical technique were introduced to improve anatomic and functional success in refractory cases not suitable for conventional macular hole surgery. These techniques comprise the positioning of tissue at the top of the hole to improve closure as performed by an inner limiting membrane flap and free flap preparation or the transplantation of autologous retinal tissue, lens capsule or amniotic membrane. For the treatment of very large and persistent macular holes, the induction of a localized retinal detachment at the posterior pole by subretinal injection of balanced salt solution and a subsequent attenuation of the rim of the hole during fluid-air exchange has been suggested as a promising surgical technique. In particular, accurate patient education about the expected surgical outcome in this specific group of patients appears important.

Natural History and Surgical Outcomes of Lamellar Macular Holes.

PURPOSE: To assess the natural history and surgical outcomes of lamellar macular holes (LMHs). DESIGN: Retrospective and consecutive case series. SUBJECTS: Patients with LMHs from multiple tertiary care centers. METHODS: Clinical charts and OCT scans were reviewed. MAIN OUTCOME MEASURES: The visual acuity (VA) changes and the occurrence rate of full-thickness macular hole (FTMH) were studied in both groups. Within the operated group, factors associated with 6-month VA and development of FTMH were explored. RESULTS: One hundred seventy-eight eyes were included, of which 89 were monitored and 89 underwent surgery. In the observation group, the mean VA decreased from 0.25 ± 0.18 to 0.28 ± 0.18 logarithm of the minimum angle of resolution (logMAR; P = 0.13), with 14 eyes (15.7%) that lost ≥ 0.2 logMAR VA, after 45.7 ± 33.3 months. Nine eyes (10.1%) spontaneously developed an FTMH. In the operated group, the mean VA increased from 0.47 ± 0.23 to 0.35 ± 0.25 logMAR at 6 months (P < 0.001) and 0.36 ± 0.28 logMAR (P = 0.001) after 24.1 ± 30.1 months. By multivariate analysis, better baseline VA (P < 0.001), the presence of an epiretinal membrane (P = 0.03), and the peeling of the internal limiting membrane (ILM; P = 0.02), with a greater effect of ILM perihole sparing, were associated with a greater 6-month VA. Perihole epiretinal proliferation sparing was associated with a better postoperative VA by univariate analysis (P = 0.03), but this was not significant by multivariate analysis. Eight eyes (9.0%) developed a postoperative FTMH. Using Cox proportional hazard ratios [HRs], pseudophakia at baseline (HR, 0.06; 95% confidence interval [CI], 0.00-0.75; P = 0.03) and peeling of the ILM (HR, 0.05; 95% CI, 0.01-0.39; P = 0.004) were protective factors, while ellipsoid zone disruption (HR, 10.5; 95% CI, 1.04-105; P = 0.05) was associated with an increased risk of FTMH. CONCLUSION: Observed eyes with LMH experienced, on average, progressive VA loss. Patients with LMH and altered vision may benefit from surgery. Internal limiting membrane peeling, with perihole ILM sparing, represents a crucial step of the surgery associated with a greater VA and a lower risk of postoperative FTMH. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

Epiretinal cell proliferation in macular pucker and vitreomacular traction syndrome: analysis of flat-mounted internal limiting membrane specimens.

PURPOSE: To describe new details of epiretinal cell proliferation in flat-mounted internal limiting membrane specimens. METHODS: One hundred nineteen internal limiting membrane specimens were removed en bloc with epiretinal membranes from 79 eyes with macular pucker (MP) and 40 eyes with vitreomacular traction syndrome. Intraoperatively, posterior vitreous detachment was assessed as complete or incomplete. Whole specimens were flat-mounted on glass slides and processed for interference and phase-contrast microscopy, cell viability assay, and immunocytochemistry. RESULTS: Mean cell viability percentage was higher in MP than in vitreomacular traction syndrome. Two cell distribution patterns were found. Anti-CD163 labeling presented predominantly in MP with complete posterior vitreous detachment. CD45 expression was similar in all groups of diagnosis. Anti-glial fibrillary acidic protein (GFAP) labeling was found in MP irrespective of the extent of posterior vitreous detachment. Alpha-SMA (α-smooth muscle actin) labeling was mainly presented in MP with incomplete posterior vitreous detachment and in vitreomacular traction syndrome. Simultaneous antibody labeling included GFAP/CD45, GFAP/CD163, CD163/CD45, and CD163/α-SMA. CONCLUSION: Hyalocytes constitute a major cell type of epiretinal cell proliferation in eyes with MP and vitreomacular traction syndrome. Glial cells, notably retinal Muller cells, are involved as well. It appears that transdifferentiation of cells in vitreomacular traction might be more frequent than previously thought and that those cells possess a greater variability of immunocytochemical properties than expected.