See clearer: survey on the subjective and objective information levels as well as perception and information transfer using virtual reality headsets in patients with diabetic macular edema receiving anti-VEGF treatment.

PURPOSE: The purpose of this study is to investigate the use of a VR Headset in routine clinical practice as an additional source of information for patients with diabetic macular edema (DME) and their companions. METHODS: Survey including 121 patients with DME, 22 companions, and 14 healthcare professionals from 8 ophthalmology centers in Germany. Patients' and their companions' health literacy was assessed by questionnaires including knowledge statements before and after watching a VR-based 3-D educational video. HCPs' perspectives on the usability of a VR Headset were also assessed. RESULTS: Patients' mean age was 63.4 ± 12.2 years, 64.5% were men, and 76% (92/121) had previous anti-VEGF (VEGF, vascular endothelial growth factor) injections. After using the VR Headset, over 85% of patients and companions felt better informed about DME and its treatment. Patients' mean (± SD) number of correct answers to knowledge statements increased from 13.2 ± 3.7 before to 15.5 ± 2.3 after using the VR Headset. Over 95% of patients and companions rated content and ease of understanding of the video as "very good" or "good." Most patients and all companions considered the use of a VR Headset as a positive experience, most wishing to obtain information via VR Headset in the future. Most physicians and all medical assistants rated the effect of the VR Headset on patient satisfaction as positive and suggested further VR modules. CONCLUSION: After using the VR Headset, patients with DME and their companions demonstrated knowledge gains that may be meaningful individually and contribute to better adherence. This may offer an additional opportunity for knowledge transfer.

Open doors by fair means: Study protocol for a 3-year prospective controlled study with a quasi-experimental design towards (or to implement) an open Ward policy in acute care units.

BACKGROUND: Acute psychiatric wards in Germany are often locked due to the assumption that opening could endanger patients and society. On the contrary, some findings suggest that aversive events such as absconding and attempted suicides do not occur more often on wards with an open-door policy. However, these data are probably biased with regard to differing patient populations on open and locked wards. To our best knowledge, the present study is the first prospective controlled study with a quasi-experimental design dealing with this issue. METHODS: This study investigates whether indicators of an open-door policy, as measured by a priori determined outcomes, can be improved by a defined complex intervention on two intervention wards in two psychiatric hospitals, compared to two control wards with otherwise very similar conditions. Both hospitals contain two wards identical in structure and patient admittance policies, so that a similar study protocol can be followed with similar patient populations. Both hospitals have a defined catchment area and receive voluntary and involuntary admissions. In a baseline phase, wards will be opened facultatively (i.e., if it seems possible to staff). In the following intervention period, one ward per hospital will establish an enhanced open-door policy by applying additional strategic and personnel support. As a control group, the control ward will continue to be opened facultatively. After one year, control wards will be opened according to the open-door policy as well. Interventions will include the continuous identification of patients at risk as well as the development of individual care concepts and additional staffing. For this purpose, nursing and medical staff will be methodically supported on an ongoing basis by study staff. Outcomes variables will be the percentage of door opening on each ward between 8 a.m. and 8 p.m., the percentage of all treatment days with the door opened and the number of involuntary treatment days with open doors. Data on frequencies of aggressive incidents, absconding, police searches, and seclusion or restraint will be used as control variables. Additional costs will be calculated. DISCUSSION: Treating mentally ill patients on locked wards is a highly relevant and critically discussed topic. In particular, it is controversially discussed whether changes in door policy can be established without increasing risks to patients and others. This study aims to gain robust data on this issue, going beyond beliefs and questionable retrospective observational studies. TRIAL REGISTRATION: Our trial "Open Doors By Fair Means" is retrospectively registered with DRKS (DRKS00015154) on Sept. 10th 2018 and displayed on the public web site. It is searchable via its Meta-registry ( http://apps.who.int/trialsearch/ ).

ACUTE ZONAL OCCULT OUTER RETINOPATHY: Structural and Functional Analysis Across the Transition Zone Between Healthy and Diseased Retina.

PURPOSE: To assess structure and function across the transition zone (TZ) between relatively healthy and diseased retina in acute zonal occult outer retinopathy. METHODS: Six patients (6 eyes; age 22-71 years) with acute zonal occult outer retinopathy were studied. Spectral-domain optical coherence tomography, fundus autofluorescence, near-infrared reflectance, color fundus photography, and fundus perimetry were performed and images were registered to each other. The retinal layers of the spectral-domain optical coherence tomography scans were segmented and the thicknesses of two outer retinal layers, that is, the total receptor and outer segment plus layers, and the retinal nerve fiber layer were measured. RESULTS: All eyes showed a TZ on multimodal imaging. On spectral-domain optical coherence tomography, the TZ was in the nasal retina at varying distances from the fovea. For all eyes, it was associated with loss of the ellipsoid zone band, significant thinning of the two outer retinal layers, and in three eyes with thickening of the retinal nerve fiber layer. On fundus autofluorescence, all eyes had a clearly demarcated peripapillary area of abnormal fundus autofluorescence delimited by a border of high autofluorescence; the latter was associated with loss of the ellipsoid zone band and with a change from relatively normal to markedly decreased or nonrecordable visual sensitivity on fundus perimetry. CONCLUSION: The results of multimodal imaging clarified the TZ in acute zonal occult outer retinopathy. The TZ was outlined by a distinct high autofluorescence border that correlated with loss of the ellipsoid zone band on spectral-domain optical coherence tomography. However, in fundus areas that seemed healthy on fundus autofluorescence, thinning of the outer retinal layers and thickening of the retinal nerve fiber layer were observed near the TZ. The TZ was also characterized by a decrease in visual sensitivity.

Anti-VEGF therapy in symptomatic peripheral exudative hemorrhagic chorioretinopathy (PEHCR) involving the macula.

INTRODUCTION: The purpose of this study was to describe the anatomical and functional outcome of vascular endothelial growth factor inhibitor (anti-VEGF) treatment in symptomatic peripheral exudative hemorrhagic chorioretinopathy (PEHCR) involving the macula. METHODS: Clinical records from patients seen between 2012 and 2013 at a single academic center were reviewed to identify PEHCR patients receiving anti-VEGF therapy due to disease-associated changes involving the macula. Affected eyes were either treated with consecutive intravitreal injections of anti-VEGF or vitrectomy combined with anti-VEGF followed by pro re nata injections. RESULTS: The mean age of the patients was 76 years (range 70-89 years). In all nine eyes, visual acuity was reduced due to central subretinal fluid. On average, three anti-VEGF injections (range 2-5 injections) were required initially to achieve complete resolution of macular subretinal fluid. In three eyes, subretinal fluid reappeared after an average of 10 months (range 5-16 months), and an average of 2.5 anti-VEGF injections (range 2-3 injections) were necessary to attain complete resolution of macular subretinal fluid a second time. Median visual acuity at the visit before the first injection was 1.0 logMAR (range 2.1-0.4 logMAR) and increased to 0.8 logMAR (range 2-0.1 logMAR) at the last visit. CONCLUSION: Results of this study show that for cases in which PEHCR becomes symptomatic due to macular involvement, anti-VEGF treatment may have drying potential. Although vision was improved in some patients, it remained limited in cases with long-term macular involvement, precluding any definitive functional conclusion. However, we believe that the use of anti-VEGF agents should be recommended in PEHCR that threatens the macula. Due to its often self-limiting course, peripheral lesions should be closely observed. Larger studies are needed in order to provide clear evidence of the efficacy of anti-VEGF therapy in PEHCR.

Quantitative Fundus Autofluorescence in Best Vitelliform Macular Dystrophy: RPE Lipofuscin is not Increased in Non-Lesion Areas of Retina.

Since the lipofuscin of retinal pigment epithelial (RPE) cells has been implicated in the pathogenesis of Best vitelliform macular dystrophy, we quantified fundus autofluorescence (quantitative fundus autofluorescence, qAF) as an indirect measure of RPE lipofuscin levels. Mean non-lesion qAF was found to be within normal limits for age. By spectral domain optical coherence tomography (SD-OCT) vitelliform lesions presented as fluid-filled subretinal detachments containing reflective material. We discuss photoreceptor outer segment debris as the source of the intense fluorescence of these lesions and loss of anion channel functioning as an explanation for the bullous photoreceptor-RPE detachment. Unexplained is the propensity of the disease for central retina.

Quantitative fundus autofluorescence distinguishes ABCA4-associated and non-ABCA4-associated bull's-eye maculopathy.

PURPOSE: Quantitative fundus autofluorescence (qAF) and spectral-domain optical coherence tomography (SD OCT) were performed in patients with bull's-eye maculopathy (BEM) to identify phenotypic markers that can aid in the differentiation of ABCA4-associated and non-ABCA4-associated disease. DESIGN: Prospective cross-sectional study at an academic referral center. SUBJECTS: Thirty-seven BEM patients (age range, 8-60 years) were studied. All patients exhibited a localized macular lesion exhibiting a smooth contour and qualitatively normal-appearing surrounding retina without flecks. Control values consisted of previously published data from 277 healthy subjects (374 eyes; age range, 5-60 years) without a family history of retinal dystrophy. METHODS: Autofluorescence (AF) images (30°, 488-nm excitation) were acquired with a confocal scanning laser ophthalmoscope equipped with an internal fluorescent reference to account for variable laser power and detector sensitivity. The grey levels (GLs) from 8 circularly arranged segments positioned at an eccentricity of approximately 7° to 9° in each image were calibrated to the reference (0 GL), magnification, and normative optical media density to yield qAF. In addition, horizontal SD OCT images through the fovea were obtained. All patients were screened for ABCA4 mutations using the ABCR600 microarray, next-generation sequencing, or both. MAIN OUTCOME MEASURES: Quantitative AF, correlations between AF and SD OCT, and genotyping for ABCA4 variants. RESULTS: ABCA4 mutations were identified in 22 patients, who tended to be younger (mean age, 21.9±8.3 years) than patients without ABCA4 mutations (mean age, 42.1±14.9 years). Whereas phenotypic differences were not obvious on the basis of qualitative fundus AF and SD OCT imaging, with qAF, the 2 groups of patients were clearly distinguishable. In the ABCA4-positive group, 37 of 41 eyes (19 of 22 patients) had qAF8 of more than the 95% confidence interval for age. Conversely, in the ABCA4-negative group, 22 of 26 eyes (13 of 15 patients) had qAF8 within the normal range. CONCLUSIONS: The qAF method can differentiate between ABCA4-associated and non-ABCA4-associated BEM and may guide clinical diagnosis and genetic testing.

Structural and functional changes associated with normal and abnormal fundus autofluorescence in patients with retinitis pigmentosa.

PURPOSE: To analyze the structure and visual function of regions bordering the hyperautofluorescent ring/arcs in retinitis pigmentosa. METHODS: Twenty-one retinitis pigmentosa patients (21 eyes) with rings/arcs and 21 normal individuals (21 eyes) were studied. Visual sensitivity in the central 10° was measured with microperimetry. Retinal structure was evaluated with spectral-domain optical coherence tomography. The distance from the fovea to disruption/loss of the inner outer segment (IS/OS) junction and thicknesses of the total receptor plus retinal pigment epithelial complex and outer segment plus retinal pigment epithelial complex layers were measured. Results were compared with measurements of the distance from the fovea to the inner and outer borders of the ring/arc seen on fundus autofluorescence. RESULTS: Disruption/loss of the inner outer segment junction occurred closer to the inner border of the ring/arc and it was closer to the fovea in eight eyes. For 19 eyes, outer segment plus and receptor plus RPE complex thicknesses were significantly decreased at locations closer to the fovea than the appearance of the inner border of hyperautofluorescence. Mean visual sensitivity was decreased inside, across, and outside the ring/arc by 3.5 ± 3.8, 8.9 ± 4.8, and 17.0 ± 2.4 dB, respectively. CONCLUSION: Structural and functional changes can occur inside the hyperfluorescent ring/arc in retinitis pigmentosa.

The impact of vitrectomy on outcomes achieved with 0.19 mg fluocinolone acetonide implant in patients with diabetic macular edema.

BACKGROUND: There is a lack of consensus on the use of intravitreal corticosteroid therapies in patients with diabetic macular edema (DME) and prior vitrectomized eyes in clinical practice. METHODS: Retro-IDEAL was a 3-year retrospective, multicenter study in patients with chronic DME (i.e. DME that persists or recurs despite treatment) treated with ILUVIEN® (0.2 µg daily fluocinolone acetonide intravitreal implant), who had suboptimal outcomes with first-line vascular endothelial growth-factor inhibitors and other DME therapies. RESULTS: A total of 81 eyes (63 patients) were included of which 39 eyes had undergone prior vitrectomy (PV group) while 42 eyes had not undergone prior vitrectomy (NPV). Baseline characteristics were balanced; however, more patients had proliferative diabetic retinopathy in the PV group vs. the NPV group (21.62% vs 9.38%, respectively). Over 36 months, mean visual acuity (VA) increased in both groups with a tendency for more ETDRS letters being gained in the NPV group (+5.33) vs. the PV group (+2.42). By month 36, central retinal thickness was reduced to ⩽300 µm in two-thirds of the eyes in both groups and the mean change from baseline in intraocular pressure was similar in both groups (+0.50 mmHg -0.75 mmHg; NPV and PV group). CONCLUSIONS: These long-term data suggest that the 0.2 µg/day FAc implant is effective in both vitrectomized and non-vitrectomized patients, with a manageable safety profile, and improved VA and reduced supplemental therapies for patients with a suboptimal response to first-line DME therapies. Clinicians may consider utilizing the FAc implant earlier in the DME disease process.

Lessons learned from quantitative fundus autofluorescence.

Quantitative fundus autofluorescence (qAF) is an approach that is built on a confocal scanning laser platform and used to measure the intensity of the inherent autofluorescence of retina elicited by short-wavelength (488 nm) excitation. Being non-invasive, qAF does not interrupt tissue architecture, thus allowing for structural correlations. The spectral features, cellular origin and topographic distribution of the natural autofluorescence of the fundus indicate that it is emitted from retinaldehyde-adducts that form in photoreceptor cells and accumulate, under most conditions, in retinal pigment epithelial cells. The distributions and intensities of fundus autofluorescence deviate from normal in many retinal disorders and it is widely recognized that these changing patterns can aid in the diagnosis and monitoring of retinal disease. The standardized protocol employed by qAF involves the normalization of fundus grey levels to a fluorescent reference installed in the imaging instrument. Together with corrections for magnification and anterior media absorption, this approach facilitates comparisons with serial images and images acquired within groups of patients. Here we provide a comprehensive summary of the principles and practice of qAF and we highlight recent efforts to elucidate retinal disease processes by combining qAF with multi-modal imaging.

Spontaneous closure of small full-thickness macular holes: Presumed role of Müller cells.

PURPOSE: To document with spectral domain optical coherence tomography the formation and spontaneous closure of small full-thickness macular holes and to propose the active role of Müller cells in macular hole closure. METHODS: A retrospective case series of five patients with spontaneous closure of macular holes is reviewed. In one patient, foveal images were recorded over a period of 18 months. RESULTS: In a 66-year-old man, vitreofoveal traction caused a detachment of the inner Müller cell layer of the foveola from the outer nuclear layer (ONL) which was associated with a large pseudocyst and a horizontal gap in the central ONL. The traction caused an elongation and subsequent disruption of the stalk of the Müller cell cone in the foveola. A small full-thickness macular hole developed when a portion of the inner Müller cell layer of the foveola was pulled out. After phacoemulsification and shortly before the subsequent spontaneous closure of the hole, there were rapid increases in the number and size of the cystic cavities in the foveal walls resulting in a narrowing of the hole. The hole closed by bridging the gap in the inner part of the central ONL; a new inner Müller cell layer of the foveola was formed, and the gap of the external limiting membrane (ELM) was closed. The cystic cavities in the foveal walls rapidly disappeared within 2 weeks after the closure of the hole. One to 2.5 months after hole closure, the thickness of the central ONL increased which decreased the distance between the central ELM and retinal pigment epithelium. In three of the four other patients, the hole also closed by bridging the gap in the inner part of the ONL. CONCLUSION: It is suggested that the spontaneous closure of small macular holes and the subsequent reconstruction of the normal foveal structure are mediated by active mechanisms of Müller cells which resemble those involved in ontogenetic foveal development.

How to Implement Adherence-Promoting Programs in Clinical Practice? A Discrete Choice Experiment on Physicians' Preferences.

INTRODUCTION: The aim of this study was to examine physicians' preferences regarding adherence-promoting programs (APPs), and to investigate which APP characteristics influence the willingness of physicians to implement these in daily practice. MATERIALS AND METHODS: A discrete choice experiment was conducted among general practitioners, cardiologists, neurologists and ophthalmologists in Germany. The design considered five attributes with two or three attribute levels each: validation status of the APP; possibility for physicians to receive a certificate; type of intervention; time commitment per patient and quarter of the year to carry out the APP; reimbursement for APP participation, per included patient and quarter of the year.A multinomial logit model was run to estimate physicians' utility for each attribute and to evaluate the influence of different levels on the probability of choosing a specific APP. The relative importance of the attributes was compared between different pre-defined subgroups. RESULTS: In total, 222 physicians were included in the analysis. The most important characteristics of APPs were time commitment to carry out the program (34.8% importance), reimbursement (33.3%), and validation status of the program (23.7%). The remaining attributes (type of intervention: 3.6%; possibility to receive a certificate: 4.7%) were proven to be less important for a physician's decision to participate in an APP. Physicians on average preferred APP alternatives characterized by little time commitment (ß=1.456, p<0.001), high reimbursement for work (ß=1.392, p<0.001), "positive validation status" (ß=0.990, p<0.001), the "possibility to get a certificate" (ß=0.197, p<0.001), and the provision of "tools for both physicians and patients" (ß=0.150, p<0.001). CONCLUSION: For the majority of the physicians participating in this survey, the willingness to implement an APP is determined by the associated time commitment and reimbursement. Considering physicians' preferences regarding different APP features in the promoting process of these programs may enhance physicians' participation and engagement.

Three-year results from the Retro-IDEAL study: Real-world data from diabetic macular edema (DME) patients treated with ILUVIEN® (0.19 mg fluocinolone acetonide implant).

INTRODUCTION: The Retro-IDEAL (ILUVIEN Implant for chronic DiabEtic MAcuLar edema) study is a retrospective study designed to assess real-world outcomes achieved with the ILUVIEN® (0.19 mg fluocinolone acetonide (FAc)) in patients with chronic diabetic macular edema (DME) in clinical practices in Germany. METHODS: This study was conducted across 16 sites in Germany and involved 81 eyes (63 patients) with persistent or recurrent DME and a prior suboptimal response to a first-line intravitreal therapy (primarily anti-VEGF intravitreal therapies). RESULTS: Patients were followed-up for 30.8 ± 11.3 months (mean ± standard deviation) and had a mean age of 68.0 ± 10.4 years. Best-recorded visual acuity (BRVA) improved by +5.5 letters at month 9 (P ⩽ 0.005, n=56; from a baseline of 49 letters) and this was maintained through to month 30 (P ⩽ 0.05, n = 42). There was a concurrent improvement in central macular thickness with a reduction from 502 µm at baseline to 338 µm at year 1 (P ⩽ 0.0001, n = 43). This effect was sustained to year 3 (i.e. 318 µm; P ⩽ 0.0001, n = 29). Mean intraocular pressure (IOP) remained constant between baseline and year 3 with a peak change of 1.9 mm Hg occurring at year 1. Elevated IOP was observed in a similar percentage of patients prior to (22.2% of cases) and following (27.2%) treatment with the FAc implant. In the majority of cases, these elevations were managed effectively with IOP medications. CONCLUSIONS: Despite substantial amounts of prior intravitreal treatments - primarily with anti-vascular endothelial growth factor (VEGF) drugs - this real-world study showed that sustained structural and functional improvements can last for up to 3 years with a single FAc implant.

A prospective pilot study using a low power piggy-back toric implantable Collamer lens to correct residual refractive error after multifocal IOL implantation.

PURPOSE: To assess whether residual refractive error after in-the-bag multifocal intraocular lens (mIOL) implantation can efficaciously and safely be corrected with a piggy-back low power Visian Toric Implantable Collamer Lens® (VTICL, STAAR Surgical) placed in the ciliary sulcus. PATIENTS AND METHODS: Twenty-four eyes of 23 patients (mean age: 57.5 years) with diminished uncorrected distance visual acuity (UDVA) of ≥2 lines due to residual refractive error after mIOL implantation were included in the study. VTICL size was calculated using the standard STAAR Visian ICL calculation software for phakic eyes. Postoperative study visits (1 day, 1 week, 3 months and 6 months after VTICL implantation) included UDVA, corrected distance visual acuity (CDVA), VTICL axis alignment, vault (space between mIOL and VTICL), IOP and documentation of adverse events. RESULTS: At 6 months, mean UDVA (logMAR) increased from 0.26 preoperatively to -0.01 (P<0.001) while mean CDVA remained unchanged. Mean VTICL misalignment from the preoperative target axis was 5.3° and mean vault was 1385 µm. In the initial phase of the study, 2 VTICL had to be exchanged due to oversizing. CONCLUSION: Piggy-back low power VTICL can efficaciously correct residual refractive error after mIOL implantation and significantly increase UDVA. Advantages of this novel surgical approach include: VTICL availability in small diopter steps, no significant surgical-induced astigmatism, atraumatic and reversible procedure.

Quantifying Fundus Autofluorescence in Patients With Retinitis Pigmentosa.

Purpose: Using quantitative fundus autofluorescence (qAF), we analyzed short-wavelength autofluorescent (SW-AF) rings in RP. Methods: Short-wavelength autofluorescent images (486 nm excitation) of 40 patients with RP (69 eyes) were acquired with a confocal scanning laser ophthalmoscope equipped with an internal fluorescent reference. Mean qAF was measured in eight preset segments (qAF8) and in region of interest (ROI)-qAF (200-700 µm) within and external to the borders of the rings at superior, temporal, and inferior sites relative to the ring. For both groups, qAF in patients with RP was compared to age-similar and race/ethnicity-matched healthy eyes at equivalent retinal locations. Results: In 71% of eyes of RP patients, qAF8 acquired internal to the inner border of the ring, was within the 95% confidence interval (CI) for healthy eyes, while in the remaining RP eyes qAF8 was either higher or lower than the CI. Measured external to the ring, qAF8 values were within the CI in 47% of RP eyes with the other eyes being higher or lower. In 28% of sites measured by ROI-qAF within the SW-AF ring, values were above the 95% CI of healthy controls. Region of interest-qAF measured just external to the ring was within the CI of healthy eyes in 74% of locations. The average local elevation in qAF within the ring was approximately 15%. In SD-OCT scans, photoreceptor-attributable reflectivity bands were thinned within and external to the ring. Conclusions: Increased fluorophore production may be a factor in the formation of the SW-AF rings in RP.

Flecks in Recessive Stargardt Disease: Short-Wavelength Autofluorescence, Near-Infrared Autofluorescence, and Optical Coherence Tomography.

PURPOSE: We evaluated the incongruous observation whereby flecks in recessive Stargardt disease (STGD1) can exhibit increased short-wavelength autofluorescence (SW-AF) that originates from retinal pigment epithelium (RPE) lipofuscin, while near-infrared AF (NIR-AF), emitted primarily from RPE melanin, is usually reduced or absent at fleck positions. METHODS: Flecks in SW- and NIR-AF images and spectral-domain optical coherence tomography (SD-OCT) scans were studied in 19 STGD1 patients carrying disease-causing ABCA4 mutations. Fleck spatial distribution and progression were recorded in serial AF images. RESULTS: Flecks observed in SW-AF images typically colocalized with darkened foci in NIR-AF images; the NIR-AF profiles were larger. The decreased NIR-AF signal from flecks preceded apparent changes in SW-AF. Spatiotemporal changes in fleck distribution usually progressed centrifugally, but in one case centripetal expansion was observed. Flecks in SW-AF images corresponded to hyperreflective deposits that progressively traversed photoreceptor-attributable bands in SD-OCT images. Outer nuclear layer (ONL) thickness negatively correlated with expansion of flecks from outer to inner retina. CONCLUSIONS: In the healthy retina, RPE lipofuscin fluorophores form in photoreceptor cells but are transferred to RPE; thus the SW-AF signal from photoreceptor cells is negligible. In STGD1, NIR-AF imaging reveals that flecks are predominantly hypofluorescent and larger and that NIR-AF darkening occurs prior to heightened SW-AF signal. These observations indicate that RPE cells associated with flecks in STGD1 are considerably changed or lost. Spectral-domain OCT findings are indicative of ongoing photoreceptor cell degeneration. The bright SW-AF signal of flecks likely originates from augmented lipofuscin formation in degenerating photoreceptor cells impaired by the failure of RPE.

Quantitative Fundus Autofluorescence and Optical Coherence Tomography in PRPH2/RDS- and ABCA4-Associated Disease Exhibiting Phenotypic Overlap.

PURPOSE: To assess whether quantitative fundus autofluorescence (qAF), a measure of RPE lipofuscin, and spectral-domain optical coherence tomography (SD-OCT) can aid in the differentiation of patients with fundus features that could either be related to ABCA4 mutations or be part of the phenotypic spectrum of pattern dystrophies. METHODS: Autofluorescence images (30°, 488-nm excitation) from 39 patients (67 eyes) were acquired with a confocal scanning laser ophthalmoscope equipped with an internal fluorescent reference and were quantified as previously described. In addition, horizontal SD-OCT images through the fovea were obtained. Patients were screened for ABCA4 and PRPH2/RDS mutations. RESULTS: ABCA4 mutations were identified in 19 patients (mean age, 37 ± 12 years) and PRPH2/RDS mutations in 8 patients (mean age, 48 ± 13 years); no known ABCA4 or PRPH2/RDS mutations were found in 12 patients (mean age, 48 ± 9 years). Differentiation of the groups using phenotypic SD-OCT and AF features (e.g., peripapillary sparing, foveal sparing) was not reliable. However, patients with ABCA4 mutations could be discriminated reasonably well from other patients when qAF values were corrected for age and race. In general, ABCA4 patients had higher qAF values than PRPH2/RDS patients, while most patients without mutations in PRPH2/RDS or ABCA4 had qAF levels within the normal range. CONCLUSIONS: The high qAF levels of ABCA4-positive patients are a hallmark of ABCA4-related disease. The reason for high qAF among many PRPH2/RDS-positive patients is not known; higher RPE lipofuscin accumulation may be a primary or secondary effect of the PRPH2/RDS mutation.

Near-infrared autofluorescence: its relationship to short-wavelength autofluorescence and optical coherence tomography in recessive stargardt disease.

PURPOSE: We compared hypoautofluorescent (hypoAF) areas detected with near-infrared (NIR-AF) and short-wavelength autofluorescence (SW-AF) in patients with recessive Stargardt disease (STGD1) to retinal structure using spectral domain optical coherence tomography (SD-OCT). METHODS: The SD-OCT volume scans, and SW-AF and NIR-AF images were obtained from 15 eyes of 15 patients with STGD1 and registered to each other. Thickness maps of the total retina, receptor-plus layer (R+, from distal border of the RPE to outer plexiform/inner nuclear layer boundary), and outer segment-plus layer (OS+, from distal border of the RPE to ellipsoid zone [EZ] band) were created from SD-OCT scans. These were compared qualitatively and quantitatively to the hypoAF areas in SW-AF and NIR-AF images. RESULTS: All eyes showed a hypoAF area in the central macula and loss of the EZ band in SD-OCT scans. The hypoAF area was larger in NIR than SW-AF images and it exceeded the area of EZ band loss for 12 eyes. The thickness maps showed progressive thinning towards the central macula, with the OS+ layer showing the most extensive and severe thinning. The central hypoAF areas on NIR corresponded to the OS+ thinned areas, while the hypoAF areas on SW-AF corresponded to the R+ thinned areas. CONCLUSIONS: Since the larger hypoAF area on NIR-AF exceeded the region of EZ band loss, and corresponded to the OS+ thinned area, RPE cell loss occurred before photoreceptor cell loss. The NIR-AF imaging may be an effective tool for following progression and predicting loss of photoreceptors in STGD1.

Quantitative Fundus Autofluorescence and Optical Coherence Tomography in ABCA4 Carriers.

PURPOSE: To assess whether carriers of ABCA4 mutations have increased RPE lipofuscin levels based on quantitative fundus autofluorescence (qAF) and whether spectral-domain optical coherence tomography (SD-OCT) reveals structural abnormalities in this cohort. METHODS: Seventy-five individuals who are heterozygous for ABCA4 mutations (mean age, 47.3 years; range, 9-82 years) were recruited as family members of affected patients from 46 unrelated families. For comparison, 57 affected family members with biallelic ABCA4 mutations (mean age, 23.4 years; range, 6-67 years) and two noncarrier siblings were also enrolled. Autofluorescence images (30°, 488-nm excitation) were acquired with a confocal scanning laser ophthalmoscope equipped with an internal fluorescent reference. The gray levels (GLs) of each image were calibrated to the reference, zero GL, magnification, and normative optical media density to yield qAF. Horizontal SD-OCT scans through the fovea were obtained and the thicknesses of the outer retinal layers were measured. RESULTS: In 60 of 65 carriers of ABCA4 mutations (age range, 9-60), qAF levels were within normal limits (95% confidence level) observed for healthy noncarrier subjects, while qAF levels of affected family members were significantly increased. Perifoveal fleck-like abnormalities were observed in fundus AF images in four carriers, and corresponding changes were detected in the outer retinal layers in SD-OCT scans. Thicknesses of the outer retinal layers were within the normal range. CONCLUSIONS: With few exceptions, individuals heterozygous for ABCA4 mutations and between the ages of 9 and 60 years do not present with elevated qAF. In a small number of carriers, perifoveal fleck-like changes were visible.

Fundus Autofluorescence and RPE Lipofuscin in Age-Related Macular Degeneration.

Genes that increase susceptibility to age-related macular degeneration (AMD) have been identified; however, since many individuals carrying these risk alleles do not develop disease, other contributors are involved. One additional factor, long implicated in the pathogenesis of AMD, is the lipofuscin of retinal pigment epithelium (RPE). The fluorophores that constitute RPE lipofuscin also serve as a source of autofluorescence (AF) that can be imaged by confocal laser ophthalmoscopy. The AF originating from lipofuscin is excited by the delivery of short wavelength (SW) light. A second autofluorescence is emitted from the melanin of RPE (and choroid) upon near-infrared (NIR-AF) excitation. SW-AF imaging is currently used in the clinical management of retinal disorders and the advantages of NIR-AF are increasingly recognized. Here we visit the damaging properties of RPE lipofuscin that could be significant when expressed on a background of genetic susceptibility. To advance interpretations of disease-related patterns of fundus AF in AMD, we also consider the photochemical and spectrophotometric features of the lipofuscin compounds responsible for generating the fluorescence emission.

Hyperautofluorescent macular ring in a series of patients with enhanced S-cone syndrome.

The authors describe fundus autofluorescence (AF) and spectral-domain optical coherence tomography (SD-OCT) findings in three patients with enhanced S-cone syndrome and their correlation around the hyperautofluorescent ring border. Patients had AF imaging in combination with SD-OCT line-scans through the fovea, at the posterior pole, and at a temporal locus centered on the ring border. All eyes demonstrated a macular ring of high-intensity AF. The inner segment ellipsoid band showed thinning and disorganization toward the ring border, where it was lost.