Mali Okada

Enhanced resolution and speckle‐free three‐dimensional printing of macular optical coherence tomography angiography

V olume rendering of optical coherence tomography angiography (OCTA) is a rapidly evolving imaging tool, which has been shown to preserve the three-dimensional (3D) architecture of various retinal diseases including diabetic retinopathy, retinal vein occlusion and macular telangiectasia type 2 (Spaide 2015). This form of imaging avoids flattening of subvolumes of tissue as is done in en face imaging and does not require the use of segmentation, which often is incorrect in retinal disease. Volume rendering can illustrate the close relationship between the flow signal and structural optical coherence tomography (OCT) information from which it is derived. By extending the OCT volume rendering technology into stereolithography, the whole 3D experience can be made physically tangible by producing life-like models as well as surgical templates and implants on a larger scale for an additional conceptualization and tactile feedback. The introduction of stereolithography in medicine has already been demonstrated to be a useful tool for surgical planning in congenital heart surgery, reconstructive surgery and in simulation training for aneurysmal surgery. Such 3D models might also be important in ophthalmology for surgical training or planning of microsurgical procedures and for teaching purposes for students and patients (Choi et al. 2016). In this report, we demonstrate the first stereolithographic retinal vessel models based on standard OCTA. Two methods were developed to obtain a printable 3D model (Fig. 1). Nine repeats of tracked OCTA measurements (3 mm 9 3 mm scan area, 245 9 245 pixel), were performed on one healthy right macula of a 35-yearold emmetropic femalewithZeissCirrus HD-OCT Model 5000 with ANGIOPLEX (Review software 9.0.0.281; Carl Zeiss Meditec, Jena, Germany). The nine OCTA volumes were aligned and averaged into one final “enhanced resolution” OCTA volume (“erOCTA”), and a print model was saved in obj format. Another method for the 3D printing used single volume rendering and was tested first and freed from speckle noise using a recently developed 3D speckle denoiser. The 3D data stack was imported in open source IMAGEJ (v1.467; ref – Rasband, W.S., IMAGEJ, US National Institutes of Health, Bethesda, MD, USA, https://imagej.nih.gov/ij/, 1997–2016) and after thresholding, exported in obj format. This 3D mesh was modified with a view to seal vessel gaps and remove digital artefactswith the digital sculpting tool zBrush 4R7 (Pixologic inc., Los Angeles, CA, USA). A printable prototype was transferred to the 3D printing service company i.materialise (Materialise HQ, Leuven, Belgium) and printed in transparent resin constructed from a hardened liquid. The material is strong, hard, stiff and water-resistant and is suited for models that require a smooth, good-quality surface with a transparent look. Design specifications for 3D printing included minimum wall thickness of 1 mm, minimum details of 0.5 mm, accuracy 0.2% and a size of 200 9 200 9 15 mm, although 3D prints 300 9 300 9 28 mm have been made (Fig. 2). This corresponds to a magnification of 66.7–100 times. Finally, to accentuate the details of the retinal vessels, one stereolithographic replica was charged by conduction by submerging it in a silver bath and copper bath for 48 hr and subsequently in a gold bath, 24 karat. The 3D print depicts the typical arrangement of the superficial vascular complex vessels that lie in a linear pattern along the inner retinal surface with vertical branches into deeper retinal vascular networks. Video S1 demonstrates a 3D print of a normal 3DOCTA, especially the foveolar avascular zone (FAZ). These vessels do not necessarily look round but are thickened in the Z-axis because of decorrelation tails. The 3D rendering showed partially irregular thickening of the vessels. In addition, multiple, small, wart-like protrusions were found on the vessel surface, which appeared to be localized above and perpendicular to the vessel direction and in direction of

Biomarkers and predictors for functional and anatomic outcomes for small gauge pars plana vitrectomy and peeling of the internal limiting membrane in naïve diabetic macular edema: The VITAL Study

Purpose We aimed to investigate biomarkers and predictive factors for visual and anatomical outcome in patients with naïve diabetic macular edema (DME) who underwent small gauge pars plana vitrectomy (PPV) with internal limiting membrane (ILM) peeling as a first line treatment. Design Multicenter, retrospective, interventional study. Participants 120 eyes from 120 patients with naïve DME treated with PPV and ILM peeling with a follow up of 24 months. Methods Change in baseline best corrected visual acuity (BCVA) and central subfoveal thickness (CST) 1, 6, 12 and 24 months after surgery. Predictive value of baseline BCVA, CST, optical coherence tomography (OCT) features (presence of subretinal fluid (SRF) and photoreceptor damage), and time between DME diagnosis and surgery. Additional treatment for DME needed. Intra- and post-operative complications (cataract rate formation, increased intraocular pressure). Main outcome measures The correlation between baseline characteristics and BCVA response (mean change from baseline; categorized improvement ≥5 or ≥10; Early Treatment Diabetic Retinopathy Study (ETDRS) letters) 12 and 24 months after surgery. Results Mean BCVA was 0.66 ± 0.14 logMAR, 0.52 ± 0.21 logMAR, and 0.53 ± 0.21 logMAR (p<0.001) at baseline, 12 and 24 months, respectively. Shorter time from DME diagnosis until PPV (OR: 0.98, 95% CI: 0.97–0.99, p<0.001) was a predictor for good functional treatment response (area under the curve 0.828). For every day PPV is postponed, the patient’s chances to gain ≥5 letters at 24 months decrease by 1.8%. Presence of SRF was identified as an anatomical predictor of a better visual outcome, (OR: 6.29, 95% CI: 1.16–34.08, p = 0.033). Safety profile was acceptable. Conclusions Our results reveal a significant functional and anatomical improvement of DME 24 months after primary PPV, without the need for additional treatment. Early surgical intervention and presence of SRF predict good visual outcome. These biomarkers should be considered when treatment is chosen.

Feasibility Study of Subfoveal Choroidal Thickness Changes in Spectral-Domain Optical Coherence Tomography Measurements of Macular Telangiectasia Type 2

Macular Telangiectasia Type 2 (MacTel2) is a disease of the retina leading to a gradual deterioration of central vision. At the onset of the disease a good visual acuity is present, which declines as the disease progresses to cause reading difficulties. In this paper, we present new insights on the vascular changes in MacTel2. We investigated whether MacTel2 progression correlates to changes in the thickness of the choroid. For this purpose, we apply a recently published registration-based approach to detect deviations in the choroid on a dataset of 45 MacTel2 patients. Between 2012 and 2016 these subjects and a control group were measured twice within variable intervals of time in the Moorfields Eye Hospital in the MacTel Natural History Observation and Registry Study. Our results show that in the MacTel2 group the thickness of the choroid increased while in the control group a decrease was noted. Manual expert segmentation and an automated state-of-the-art method were used to validate the results.

Long-term visual outcome and its predictors in macular oedema secondary to retinal vein occlusion treated with dexamethasone implant

Background To evaluate the functional long-term outcome in patients with macular oedema (MO) secondary to central retinal vein occlusion (CRVO) and branch retinal vein occlusion (BRVO) treated with dexamethasone implant (DEX implant) and to identify its clinical predictors. Methods A 24-month, retrospective, multinational, real-world study. Chart review of patients with either naïve or recurrent MO secondary to CRVO/BRVO treated with DEX implant, including best-corrected visual acuity (BCVA), central subfield thickness (CST), demographic baseline characteristics and details of any additional treatment during follow-up. Results A total of 155 eyes (65 CRVO, 90 BRVO) from 155 patients were included. At 24 months, mean BCVA did not change significantly in CRVO (−2.1±24.5 letters, p=0.96) and BRVO patients (1.3±27.0 letters, p=0.07). A worse baseline BCVA (p<0.001), visual acuity (VA) gain ≥5 letters at 2 months (p=0.006) and no need for adjunctive intravitreal therapy after first DEX implant (p=0.001) were associated with a better final BCVA gain. Treatment-naïve patients (p=0.006, OR: 0.25, 95% CI 0.11 to 0.57) and those with a baseline CST≤400 µm (p=0.02, OR: 0.25, 95% CI 0.10 to 0.63) were identified as being less likely to need additional intravitreal therapy. Conclusion Clinical baseline characteristics and the early treatment response were identified as possible predictors for long-term outcome and the need of adjunctive intravitreal therapy in MO secondary to BRVO/CRVO treated by DEX implant.

ELECTROPHYSIOLOGICAL CHARACTERIZATION OF MACULAR TELANGIECTASIA TYPE 2 AND STRUCTURE–FUNCTION CORRELATION

Purpose: To investigate the electrophysiological features of macular telangiectasia Type 2 and their relationship to structure as determined by optical coherence tomography imaging. Methods: Forty-two eyes from 21 patients enrolled in the Macular Telangiectasia Natural History Observation Study were reviewed. All patients had full-field and pattern electroretinography (ERG; PERG) with some patients additionally having multifocal electroretinography (mfERG; N = 15) or electrooculography (N = 12). Multiple linear regression modeling assessed the relationship between the ellipsoid zone break size on optical coherence tomography and the central mfERG response. Results: Full-field ERG and electrooculography were normal in all eyes. Six eyes (14%) from five patients had subnormal PERG P50 amplitudes. Twenty-two of 30 eyes (73%) had reduced central or paracentral stimulus on mfERG. There was a significant correlation between ellipsoid zone break size and both the P1 amplitude (R2 = 0.37, P = 0.002) and P1:N1 ratio (R2 = 0.32, P = 0.002) of the central response on mfERG. Conclusion: The electrophysiological findings in macular telangiectasia Type 2 are those of localized central dysfunction and are consistent with the structural data available from imaging and histologic studies. The ellipsoid zone break size correlates with mfERG reduction. The reduced mfERG P1:N1 ratio is consistent with inner retinal dysfunction.

MACULAR TELANGIECTASIA TYPE 2: Quantitative Analysis of a Novel Phenotype and Implications for the Pathobiology of the Disease

Purpose: To investigate retinal microcystoid spaces in macular telangiectasia type 2 with spectral domain optical coherence tomography. Methods: Retrospective review of 135 patients enrolled in the MacTel Natural History Observation and Registry Study at Moorfields Eye Hospital, United Kingdom. One hundred seventy-two eyes from 86 patients who had a comparable scan protocol of at least 30 &mgr;m interval were included for analysis. Retinal microcystoid spaces were identified and segmented and metrics analyzed. Results: From 172 eyes of 86 patients, microcystoid spaces were found in 11 eyes (6.4%) from 8 patients (9.3%). The mean number of microcystoid spaces per eye was 12.9 ± 18.2. Most were located in the inner nuclear layer. The inferonasal quadrant of the macula was the least commonly affected region. Microcystoid spaces were distributed entirely within the assumed macular telangiectasia area on blue light reflectance in all but 2 eyes (4 of 142 microcysts). The median diameter of the microcystoid spaces was 31 &mgr;m (range 15 &mgr;m–80 &mgr;m). Conclusion: Microcystoid spaces as a phenotype of macular telangiectasia should be considered in the differentials for microcystic edema. Understanding the pathogenesis of these lesions may provide further insight into the role of Müller cell dysfunction in this disorder.

EFFECT OF DARK ADAPTATION AND BLEACHING ON BLUE LIGHT REFLECTANCE IMAGING IN MACULAR TELANGIECTASIA TYPE 2

Purpose: In patients with macular telangiectasia Type 2, blue light reflectance imaging reveals an oval, parafoveal area in the macula that has increased reflectance compared with its surrounding. Here, we examine how dark adaptation and photobleaching can affect the blue light reflectance imaging pattern. Methods: Prospective study of patients with macular telangiectasia enrolled in the MacTel Natural History Observation Study. After dark adaptation, a sequence of images was obtained with a confocal scanning laser ophthalmoscope at 488 nm. Change of reflectance patterns was analyzed over time. Results: Eighteen eyes from 16 patients were analyzed. Initially, increased reflectivity in the parafoveal area resulted in higher gray values compared with the paramacular surrounding on blue light reflectance imaging. The difference between parafoveal and paramacular reflectance intensity decreased steadily during imaging, from 17.7 gray-value units (95% confidence interval: 12.1–23.2) down to 2.8 (95% confidence interval: −0.8 to 6.5) after around 30 seconds, and recovered after 5 minutes of dark adaptation. Conclusion: A bleaching effect was evident in our study. Understanding these changes is important for both diagnosis and assessment of blue light reflectance phenotype in patients with macular telangiectasia and could also provide further insights into the pathophysiology of this disease.

Effect of glycosylated hemoglobin on response to ranibizumab therapy in diabetic macular edema: real-world outcomes in 312 patients

OBJECTIVE To investigate the effect of serum glycosylated hemoglobin (HbA1c) on the outcomes of ranibizumab therapy for diabetic macular edema (DME). DESIGN Retrospective cohort study. PARTICIPANTS Patients receiving ranibizumab injections for centre-involving DME in a National Health Service setting. METHODS The Moorfields OpenEyes database was used to study eyes with DME treated with ranibizumab from October 2013 to November 2015 at the Moorfields City Road, Ealing, Northwick Park, and St Georges Hospital sites. Only eyes receiving a minimum of 3 injections and completing 12 months of follow-up were included. If both eyes received treatment, the first eye treated was analyzed. When both eyes received initial treatment simultaneously, random number tables were used to select the eye for analysis. HbA1c was tested at the initiation of ranibizumab treatment. Multivariate regression analysis was used to identify relationships between HbA1c and the outcome measures. OUTCOMES The primary outcome was change in visual acuity (VA) Early Treatment of Diabetic Retinopathy study (ETDRS) letters. The secondary outcomes were change in central subfield thickness (CSFT) and macular volume (MV), as well as number of injections in year 1. RESULTS Three hundred and twelve eyes of 312 patients were included in the analysis. HbA1c was not related to change in VA (p = 0.577), change in CSFT (p = 0.099), change in MV (p = 0.082), or number of injections in year 1 (p = 0.859). CONCLUSIONS HbA1c is not related to functional or anatomical outcomes at 1 year in DME treated with ranibizumab.

Multimodal retinal imaging in the diagnosis of intraretinal microvascular abnormality

ABSTRACT Introduction: Retinal imaging in diabetic retinopathy has experienced significant advances since the days of the Early Treatment for Diabetic Retinopathy Studies. Differentiating intraretinal microvascular abnormalities (IRMA) from neovascular complexes remain a challenging part of disease staging but may become easier in this age of multimodal imaging. Areas covered: This review presents an overview of the available imaging modalities, their current applications and limitations as well as future developments in the pipeline. The implication of new imaging technology on the traditional definition of IRMAs and how this may translate into potential treatment outcomes for the patient will be discussed. This review is based on a literature search of all English language articles published on PubMed. Expert commentary: The characterisation of IRMA has evolved with the development of OCT to identify morphological differences. Wide field imaging may also identify IRMA outside of standard field of view of conventional imaging. The use of advanced imaging techniques is likely to play a greater role in both disease staging and management of diabetic retinopathy in the future.