Tjebo F. C. Heeren

Macular telangiectasia type 2

Macular telangiectasia type 2 is a bilateral disease of unknown cause with characteristic alterations of the macular capillary network and neurosensory atrophy. Its prevalence may be underestimated and has recently been shown to be as high as 0.1% in persons 40 years and older. Biomicroscopy may show reduced retinal transparency, crystalline deposits, mildly ectatic capillaries, blunted venules, retinal pigment plaques, foveal atrophy, and neovascular complexes. Fluorescein angiography shows telangiectatic capillaries predominantly temporal to the foveola in the early phase and a diffuse hyperfluorescence in the late phase. High-resolution optical coherence tomography (OCT) may reveal disruption of the photoreceptor inner segment-outer segment border, hyporeflective cavities at the level of the inner or outer retina, and atrophy of the retina in later stages. Macular telangiectasia type 2 shows a unique depletion of the macular pigment in the central retina and recent therapeutic trials showed that such depleted areas cannot re-accumulate lutein and zeaxanthin after oral supplementation. There have been various therapeutic approaches with limited or no efficacy. Recent clinical trials with compounds that block vascular endothelial growth factor (VEGF) have established the role of VEGF in the pathophysiology of the disease, but have not shown significant efficacy, at least for the non-neovascular disease stages. Recent progress in structure-function correlation may help to develop surrogate outcome measures for future clinical trials. In this review article, we summarize the current knowledge on macular telangiectasia type 2, including the epidemiology, the genetics, the clinical findings, the staging and the differential diagnosis of the disease. Findings using retinal imaging are discussed, including fluorescein angiography, OCT, adaptive optics imaging, confocal scanning laser ophthalmoscopy, and fundus autofluorescence, as are the findings using visual function testing including visual acuity and fundus-controlled microperimetry. We provide an overview of the therapeutic approaches for both non-neovascular and neovascular disease stages and provide a perspective of future directions including animal models and potential therapeutic approaches.

First symptoms and their age of onset in macular telangiectasia type 2.

Purpose: To investigate the first symptoms and their age of onset in a large cohort of patients with macular telangiectasia type 2. Methods: Patients with the characteristic findings of macular telangiectasia type 2 were interviewed. Data collection also included a chart review to determine the delay of the correct diagnosis and visual function 10 years after the onset of first symptoms. Results: Of 91 patients, 72 (79%) reported impaired reading ability as their first symptom, followed by metamorphopsia in 12%. The age of onset was most frequent (76%) in the sixth or seventh decade of life (50–69 years), and 58% of the patients were symptomatic before the age of 60 years. The median delay between first symptoms and the diagnosis of macular telangiectasia type 2 before the year 2005 was 7 years and has decreased to 1 year thereafter. Ten years after the onset of first symptoms, distance visual acuity of the better eye was ≥20/25 in 35% and ⩽20/50 in 17%. Conclusion: Impaired reading ability was the most common initial visual disturbance of patients with macular telangiectasia type 2, starting generally between the age of 50 and 70 years. Knowledge of the presenting symptoms of macular telangiectasia type 2 together with recently identified characteristic morphologic alterations on retinal imaging will likely lead to earlier accurate diagnosis of this disease entity.

Progression of Vision Loss in Macular Telangiectasia Type 2

PURPOSE To investigate progressive vision loss in patients with macular telangiectasia (MacTel) type 2 and to compare the ability to detect functional decline between microperimetry and visual acuity testing. METHODS Change of cumulative defect size (number of test points with absolute scotoma) on microperimetry testing and change in distance best-corrected visual acuity (BCVA) were evaluated in a prospective longitudinal observational study. RESULTS The mean review period was 55.3 months (SD 17.3 months). In 58% of 71 eyes (40 patients) included for analysis, microperimetry revealed spread (n = 31) or new development (n = 10) of an absolute scotoma. At the same time, BCVA decreased more than two lines in only 17% (n = 12). Twenty-five (35%) eyes showed no change in visual function. Presence of an absolute scotoma at baseline, but not baseline BCVA, was predictive for functional decline on longitudinal microperimetry testing. Eyes with an absolute scotoma at baseline (n = 33) showed further growth of the scotoma in 94% (n = 31). In contrast, only 26% (n = 10) of eyes without an absolute scotoma at baseline (n = 38) developed an absolute scotoma de novo. Scotoma growth rate (new test points with an absolute scotoma per year) was 0.62 ± 0.10 for all eyes and 1.30 ± 0.12 for the subgroup of eyes with scotoma at baseline. Scotomata always first occurred in the quadrant temporal to the foveal center. CONCLUSIONS A characteristic feature in patients with MacTel type 2 is progressive focal loss of macular sensitivity, preceding loss of visual acuity. Microperimetry is sensitive to detect such functional decline and thus may provide considerable power when being used as a functional outcome measure in future clinical trials.

VERY EARLY DISEASE MANIFESTATIONS OF MACULAR TELANGIECTASIA TYPE 2.

Background: To report very early morphologic and functional alterations in patients with macular telangiectasia type 2. Methods: Patients with asymmetric disease manifestations, in whom retinal alterations characteristic for macular telangiectasia type 2 were present in one but not in the apparently unaffected fellow eye, underwent multimodal imaging and functional testing (microperimetry, visual acuity, reading ability, Amsler test). Results: Fellow eyes not allowing the diagnosis of macular telangiectasia type 2 based on hitherto diagnostic standards consistently showed a severely reduced directional cone reflectance (Stiles–Crawford effect). Optical coherence tomography revealed an asymmetric configuration of the foveal pit with focal temporal thinning most pronounced at 1° eccentricity. Topographically related, macular pigment optical density was reduced in a small wedge-shaped temporal paracentral sector, resulting in an increased signal on fundus autofluorescence and fluorescein angiography imaging. No functional deficits were detectable in fellow eyes. Haidinger brushes were perceived in the fellow eye but not in the affected index eye with pronounced loss of macular pigment. Conclusion: Specific morphologic alterations precede vascular alterations and functional deficits in macular telangiectasia type 2. The described alterations indicate a primarily degenerative process with a secondary retinal vascular phenotype, and may be helpful for early identification of patients and affected family members.

POOR LONG-TERM OUTCOME OF ANTI-VASCULAR ENDOTHELIAL GROWTH FACTOR THERAPY IN NONPROLIFERATIVE MACULAR TELANGIECTASIA TYPE 2.

Purpose: To investigate long-term effects after intravitreal inhibition of vascular endothelial growth factor in nonproliferative macular telangiectasia type 2. Methods: Nine patients with macular telangiectasia type 2 treated with 12 monthly intravitreal ranibizumab injections in 1 eye were investigated again after a mean follow-up of 6.0 ± 0.4 years. Functional assessment included best-corrected visual acuity and microperimetry testing. Morphologic investigations included optical coherence tomography imaging and fluorescein angiography. Results: Mean visual acuity at baseline was similar in treated and control eyes (both 20/50; range: 20/32–20/125 in the treated eyes and 20/25–20/100 in the untreated eyes). None of the eyes had a neovascular membrane or a paracentral scotoma. At the last follow-up, more eyes of the treatment group had lost 2 or more lines on best-corrected visual acuity testing (4 vs. 1) and more eyes had developed an absolute paracentral scotoma (7 vs. 2). A secondary neovascular membrane had formed in four of the treated and in none of the untreated eyes. Conclusion: Vascular endothelial growth factor inhibition with monthly dosing over 1 year had no beneficial effect 5 years after cessation of therapy. The worse outcome in the treated eyes may be due to selection bias, small sample size, or a potential adverse effect of vascular endothelial growth factor inhibition in a degenerative, primarily nonvascular disease as macular telangiectasia type 2.

Treatment for Macular Telangiectasia Type 2.

Macular telangiectasia (MacTel) type 2 is a bilateral disease of unknown cause with localized retinal degeneration and characteristic changes of the retinal vasculature. Funduscopic findings include reduced retinal transparency, crystalline deposits, ectatic capillaries, blunted venules, retinal pigment plaques, foveal atrophy and neovascular complexes. Leakage of telangiectatic macular capillaries is a characteristic finding on fluorescein angiography, and neurosensory atrophy may be present on optical coherence tomography images. Furthermore, there is a specific depletion of macular pigment in the central retina. Depending on the development of neovascular membranes, a nonproliferative and a proliferative (neovascular) disease stage may be distinguished. To date, there is no evidence for an effective treatment of nonproliferative MacTel type 2. Patients with proliferative MacTel type 2 and hence decreasing visual function may benefit from intravitreal application of vascular endothelial growth factor inhibitors. Early treatment and a small size of the neovascular membrane might be predictive factors for visual function outcome.

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

CORRELATION OF CLINICAL AND STRUCTURAL PROGRESSION WITH VISUAL ACUITY LOSS IN MACULAR TELANGIECTASIA TYPE 2: MacTel Project Report No. 6-The MacTel Research Group.

Purpose: To evaluate progression of macular telangiectasia Type 2 lesions and their correlation with visual acuity. Methods: An international multicenter prospective study with annual examinations including best-corrected visual acuity (BCVA), fundus photography, fluorescein angiography, and optical coherence tomography images graded centrally. Mixed models were used to estimate progression rates, and a generalized linear model to compute the relative risk of BCVA loss, loss of ellipsoid zone (EZ) reflectivity, development of pigment plaques, or neovascularization. Results: One thousand and fourteen eyes of 507 participants were followed for 4.2 ± 1.6 years. Best-corrected visual acuity decreased 1.07 ± 0.05 letters (mean ± SE) per year. Of all eyes, 15% lost ≥15 letters after 5 years. Of the eyes without EZ loss, 76% developed a noncentral loss. Of the eyes with noncentral loss, 45% progressed to central EZ loss. The rate of BCVA loss in eyes with noncentral EZ loss at baseline was similar to eyes without EZ loss. The rate of BCVA loss was significantly higher in eyes with central EZ loss at baseline (−1.40 ± 0.14 letters, P < 0.001). Conclusion: Ellipsoid zone loss is frequently found in macular telangiectasia Type 2 and is an important structural component reflecting visual function. Its presence in the fovea significantly correlates with worse visual prognosis.

SCOTOMA CHARACTERISTICS IN MACULAR TELANGIECTASIA TYPE 2: MacTel Project Report No. 7-The MacTel Research Group.

Purpose: To characterize scotomas in macular telangiectasia Type 2 (MacTel). Methods: Five of the 27 centers performed microperimetry as part of the MacTel Natural History Observation Study. Data were analyzed in the Moorfields Eye Hospital Reading Centre. The number of stimuli under a threshold of 12, 10, 8, and <0 dB were counted (thresholding) and compared with one another. Results: A total of 565 examinations were gradable, received from 632 eyes of 322 participants (age 61.1 ± 9.1 years, 62% females). The authors found absolute scotomas in 243 eyes (43%), 98% of these affected the temporal quadrant, and 99.5% were unifocal. Growth of absolute scotomas was limited to an extent of approximately 40 deg2. Although transition from functionally unimpaired retina to absolute scotomas is generally steeply sloped, the larger a scotoma, the steeper it is. Conclusion: Scotoma features were consistent throughout a large MacTel cohort. The temporal quadrant was confirmed as predominantly affected, which might result from vascular or metabolic asymmetry. Functional loss did not exceed an area of 5° × 8° however advanced the disorder. Different MacTel phenotypes seem likely and point toward different types of progression; identifying these would improve planning for clinical trials and might lead to better understanding patient outcome.

Safety and Feasibility of a Novel Sparse Optical Coherence Tomography Device for Patient-Delivered Retina Home Monitoring

Purpose To study a novel and fast optical coherence tomography (OCT) device for home-based monitoring in age-related macular degeneration (AMD) in a small sample yielding sparse OCT (spOCT) data and to compare the device to a commercially available reference device. Methods In this prospective study, both eyes of 31 participants with AMD were included. The subjects underwent scanning with an OCT prototype and a spectral-domain OCT to compare the accuracy of the central retinal thickness (CRT) measurements. Results Sixty-two eyes in 31 participants (21 females and 10 males) were included. The mean age was 79.6 years (age range, 69–92 years). The mean difference in the CRT measurements between the devices was 4.52 μm (SD ± 20.0 μm; range, −65.6 to 41.5 μm). The inter- and intrarater reliability coefficients of the OCT prototype were both >0.95. The laser power delivered was <0.54 mW for spOCT and <1.4 mW for SDOCT. No adverse events were reported, and the visual acuity before and after the measurements was stable. Conclusion This study demonstrated the safety and feasibility of this home-based OCT monitoring under real-life conditions, and it provided evidence for the potential clinical benefit of the device. Translational Relevance The newly developed spOCT is a valid and readily available retina scanner. It could be applied as a portable self-measuring OCT system. Its use may facilitate the sustainable monitoring of chronic retinal diseases by providing easily accessible and continuous retinal monitoring.