THE WAY PATIENTS SEE FLOATERS: Widefield Dynamic Scanning Laser Ophthalmoscopy Imaging of Vitreous Abnormalities.

PURPOSE: To investigate the use of dynamic widefield scanning laser ophthalmoscopy (SLO) and B-scan ultrasonography in imaging vitreous abnormalities in patients with complaints of floaters. METHODS: Twenty-one patients underwent both dynamic SLO and B-scan ultrasonography to image their vitreous abnormalities. After reviewing these videos, patients graded each imaging technique on a scale of 1 to 10, based on how closely it represented their visual perception of floaters. RESULTS: The mean age of the patients (12 women and nine men) was 47.7 ± 18.5 years. The patients graded a median score of nine for SLO imaging (mean = 8.43) compared with a median score of 5 (mean = 4.95) for ultrasound ( P = 0.001). Widefield SLO imaging demonstrated three-dimensional interconnectivity within the condensations of the formed vitreous that exhibited translational and rotational movements with eye saccades. CONCLUSION: Floaters are a common complaint, but it is difficult to know whether imaging findings of the vitreous correlate to what patients perceive. Widefield SLO seems to image vitreous abnormalities related to how patients perceive their own floaters better than B-scan ultrasonography. Despite the term "floaters", the vitreous abnormalities in the videos seemed to be manifestations of a complex three-dimensional degeneration of the vitreous framework.

Effects of medications on hypoxia-inducible factor in the retina: A review.

Hypoxia-inducible factor (HIF) plays a critical role in the mechanisms that allow cells to adapt to various oxygen levels in the environment. Specifically, HIF-1⍺ has shown to be widely involved in cellular repair, survival, and energy metabolism. HIF-1⍺ has also been found in increased levels in cancer cells, highlighting the importance of balance in the hypoxic response. Promoting HIF-1⍺ activity as a potential therapy for degenerative diseases and inhibiting HIF-1⍺ as a therapy for pathologies with overactive cell proliferation are actively being explored. Digoxin and metformin, HIF-1⍺ inhibitors, and deferoxamine and ⍺-ketoglutarate analogues, HIF-1⍺ activators, are being studied for application in age-related macular degeneration, diabetic retinopathy, and retinitis pigmentosa. However, these same medications have retinal toxicities that must be assessed before implementation of therapeutic care. Herein, we highlight the duality of therapeutic and toxic potential of HIF-1⍺ that must be carefully assessed prior to its clinical application in retinal disorders.

SAUSAGING AND BULBOSITIES OF THE CHOROIDAL VEINS IN CENTRAL SEROUS CHORIORETINOPATHY.

PURPOSE: To evaluate the caliber of the choroidal veins in central serous chorioretinopathy, a disease proposed to be associated with overloading of choroidal venous outflow. METHODS: Widefield indocyanine green angiograms of eyes with central serous chorioretinopathy were graded for sausaging defined as three or more contiguous fusiform dilations that vary by at least 50% from the narrowest to largest diameters. A bulbosity was defined as a focal 2X dilation of a blood vessel as compared with the diameter of the surrounding host vessel. The data underwent statistical analysis including the use of generalized estimating equations. RESULTS: There were 73 eyes of 41 patients with a mean age of 53.5 years. Sausaging of vessels was seen in a mean and median of three quadrants per eye. Using generalized estimating equations, the only significant risk factor for sausaging was the use of corticosteroids. The two significant predictors of subfoveal choroidal thickness using generalized estimating equations were age ( P = 0.021) and proportion of quadrants involved by sausaging ( P < 0.001). The decrease in choroidal thickness per year of age was estimated to be 3.7 µ m, while the increase with four quadrant involvement with sausaging was estimated to be 236 µ m. There were a total of 39 bulbosities in 26 eyes (35.6%), preferentially involving intervortex venous anastomoses. CONCLUSION: Variations in the venous caliber are very common in eyes with central serous chorioretinopathy and seems to be associated with pathophysiologic alterations related to increased pressure within and remodeling of the larger choroidal veins. This may lead to overloading of the choriocapillaris with leakage as one manifestation.

REGIONAL SCLERAL THICKNESS AS A RISK FACTOR FOR CENTRAL SEROUS CHORIORETINOPATHY.

PURPOSE: To evaluate regional sclera thicknesses as possible risk factors for central serous chorioretinopathy (CSC). METHODS: Patients with CSC and controls were evaluated with contact B-scan ultrasonography using a 20 Mhz concentric phased array ultrasound unit and enhanced depth imaging optical coherence tomography to measure the scleral thickness at the equator and posterior pole. The resultant data were evaluated using univariate analysis and generalized estimating equations. RESULTS: There were 40 patients with CSC with a mean age of 58 years and 23 controls with a mean age of 60.7 years (P = 0.31). The mean subfoveal scleral thicknesses were 1.3 mm in the CSC group and 0.86 mm in the control group (P < 0.001). The mean equatorial scleral thickness was 0.61 mm in the CSC group and 0.42 mm in the control group (P < 0.001). Using generalized estimating equations, the equatorial scleral thickness (P = 0.001), posterior scleral thickness (P < 0.001), and subfoveal choroidal thickness (P = 0.032) were independent predictors of CSC. Once these variables were entered into the equation, neither sex nor age were significant predictors. Generalized estimating equation analysis showed that equatorial, but not posterior, scleral thickness was a significant predictor of subfoveal choroidal thickness. CONCLUSION: Scleral thicknesses of the posterior and equatorial portions of the eye were found to be significant predictors of CSC, consistent with what was proposed in the theory of venous overload choroidopathy. Direct measurement by high resolution ultrasonography provides independent information about specific regions of the sclera and also avoids making speculative assumptions derived from anterior segment measurements.

Comparing efficacy of reduced-fluence and standard-fluence photodynamic therapy in the treatment of polypoidal choroidal vasculopathy.

BACKGROUND: The EVEREST II study reported superior polyp closure rates and visual outcomes using combination standard photodynamic therapy (PDT) with intravitreal ranibizumab in the treatment of polypoidal choroidal vasculopathy (PCV). The optimal PDT protocol remains controversial and it is postulated that less intensive PDT strategies may reduce complications. We aimed to compare the efficacy of reduced and standard-fluence PDT. METHODS: Case-control review of 38 consecutive PDT-naïve macular PCV patients who underwent verteporfin PDT using one of two PDT regimens at a tertiary referral centre in an Asian population. Comparison of outcomes between standard-fluence PDT (light dose, 50 J/cm2; dose rate, 600 mW/cm2; wavelength, 689 nm PDT applied to the treatment eye for 83 s) and reduced-fluence PDT (light dose, 25 J/cm2; dose rate, 600 mW/cm2; wavelength, 689 nm PDT applied to the treatment eye for 42 s). Primary outcome measure was best corrected LogMAR visual acuity (VA). Secondary outcome measures included OCT measurements such as central retinal thickness (CRT), height of subfoveal sub-retinal fluid (SRF), central choroid thickness (CCT), mean number of PDT treatments needed, mean number of anti-VEGF injections needed, polyp closure and recurrence rates. RESULTS: Of these 38 eyes of 38 patients, an equal number of eyes (19 in each arm) were treated with standard-fluence and reduced-fluence PDT. Mean letter gain at 12 months for the standard-fluence group was 6.0 compared to 4.3 letters for the reduced-fluence group (p = 0.61). Similar results were observed at all time points. There was no statistically significant difference between the retinal and choroidal anatomical OCT outcomes, rates of polyp closure and recurrences between the two PDT regimens. CONCLUSIONS: Reduced-fluence PDT was comparable to standard-fluence PDT in the treatment of PCV in terms of visual gains, clinical and anatomical OCT outcomes.

Predictors of persistent disease activity following anti-VEGF loading dose for nAMD patients in Singapore: the DIALS study.

BACKGROUND: To determine the frequency of persistent disease activity following 3 loading doses of anti- vascular endothelial growth factor (VEGF) agents, and the anatomic and demographic predictors of early persistent disease activity among patients with neovascular age-related macular degeneration (nAMD). METHODS: In a retrospective real-world cohort study, 281 consecutive patients with nAMD were reviewed at baseline and after 3 anti-VEGF injections for pre-defined indicators of disease activity. Optical coherence tomography (OCT) features such as subretinal fluid, intraretinal cysts and intraretinal fluid were assessed by reading-center certified graders. Multiple logistic regression was performed on demographic and anatomic factors. RESULTS: At month 3, 66.1% of patients had persistent disease activity. The best-corrected visual acuity (BCVA) improvement was 0.16 LogMAR for those with no disease activity compared to 0 for patients with persistent activity (p < 0.001). The significant risk factors for persistent activity at 3 months were male gender (odds ratio [OR] 0.54, 95% confidence interval [CI] 0.32-0.93, p = 0.025), intraretinal cysts at baseline (OR 2.95, 95% CI 1.67-5.20, p < 0.001) and subretinal fluid at baseline (OR 3.17, 95% CI 1.62-6.18, p = 0.002). At 3 months, 58% of patients had features of activity on OCT. Patients with intraretinal cysts and intraretinal fluid at baseline had worse BCVA at month 3 compared to patients without these OCT features (0.69 vs. 0.43, p < 0.001, and 0.62 vs. 0.43, p < 0.001, respectively). CONCLUSIONS: In a real-world study, 66.1% of nAMD patients have persistent disease activity after the initial loading dose, with poorer BCVA compared to those without. Baseline OCT features (intraretinal cysts and subretinal fluid) are useful predictors of persistent disease activity at month 3.

EVEREST study report 3: diagnostic challenges of polypoidal choroidal vasculopathy. Lessons learnt from screening failures in the EVEREST study.

PURPOSE: To describe screening failures in the EVEREST study by examining the imaging characteristics that enabled differentiation of polypoidal choroidal vasculopathy (PCV) from cases that were subsequently diagnosed not to be PCV. METHODS: Post-hoc analysis of 34 patients with PCV reported as screening failures from EVEREST study. Standardised confocal scanning laser indocyanine green angiography (ICGA) images were graded by the Central Reading Centre to confirm PCV diagnosis based on the presence of early focal sub-retinal hyperfluorescence on ICGA and at least one of the following six diagnostic criteria: (1) nodular appearance of polyp(s) on stereoscopic examination, (2) hypofluorescent halo around nodule(s), (3) presence of a branching vascular network, (4) pulsation of polyp(s) on dynamic ICGA, (5) orange sub-retinal nodules on colour fundus photography, or (6) massive sub-macular haemorrhage (≥4 disc areas in size). Additional detailed image grading was performed with stereo-imaging and dynamic early-phase ICGA. RESULTS: Of the 95 screened PCV cases, 34 were excluded: (1) cases not suitable for recruitment as per the study protocol (n = 14), (2) equivocal lesions on ICGA characterised by small hyperfluorescent dots (n = 9), and (3) cases that were definitely not PCV (non-PCV, n = 11), identified by definitive diagnoses which included one case each of micro-aneurysm, retinal angiomatous proliferation, retino-choroidal anastomosis, small type-2 choroidal neovascularisation, retinal pigment epithelial (RPE) window defect and disciform scar; two cases of lesions where the choroidal vessel changed its course; and three cases of late-onset RPE staining. CONCLUSIONS: Standardised image grading techniques used in EVEREST study enabled effective differentiation of non-PCV from actual PCV.

PRIMARY OCCLUSIVE PANVASCULITIS WITH SEGMENTAL PERIARTERIAL PLAQUES.

PURPOSE: The purpose of this study was to describe a new clinical entity of bilateral occlusive panvasculitis with segmental periarterial plaques and its clinical course in two patients. METHODS: This was a retrospective chart review. RESULTS: Two patients with no medical history of any systemic inflammatory diseases presented with bilateral segmental periarterial plaques (Kyrieleis plaques), cotton wool spots, and microaneurysms. Segmental leakage, staining, and vascular occlusions involved the arterioles, venules, and capillaries. Leakage from the superficial capillary plexus in some areas bordering deep capillary plexus nonperfusion was observed. Both had recurrent episodes of vascular occlusions, normal brain MRI, and audiology tests. Complete workup including serology for infections, inflammatory markers, and antibody titers was unremarkable. They were started on with corticosteroids and immunosuppressant, and there were no further vascular occlusions. Both developed neovascularization adjacent to the areas of capillary nonperfusion. The second patient also developed vitreomacular traction and cystoid macular edema. He required intravitreal anti-VEGF injection, sector laser photocoagulation, and underwent a vitrectomy with membrane peeling. At the last visit, the visual acuity was 20/30 in both eyes for the first patient and 20/20 in the right eye and 20/40 in the left eye for the second patient, 12 and 6.5 years after initial presentation, respectively. CONCLUSION: Both patients presented with findings of bilateral panvasculitis with prominent segmental periarterial plaques and had repeated episodes of vascular occlusions before corticosteroid and immunosuppressants treatment, after which no additional occlusions were observed. We propose that the constellation of findings constitutes a novel clinical entity, occlusive panvasculitis with segmental periarterial plaques.

Rationale and protocol paper for the Asia Pacific Network for inherited eye diseases.

PURPOSE: There are major gaps in our knowledge of hereditary ocular conditions in the Asia-Pacific population, which comprises approximately 60% of the world's population. Therefore, a concerted regional effort is urgently needed to close this critical knowledge gap and apply precision medicine technology to improve the quality of lives of these patients in the Asia-Pacific region. DESIGN: Multi-national, multi-center collaborative network. METHODS: The Research Standing Committee of the Asia-Pacific Academy of Ophthalmology and the Asia-Pacific Society of Eye Genetics fostered this research collaboration, which brings together renowned institutions and experts for inherited eye diseases in the Asia-Pacific region. The immediate priority of the network will be inherited retinal diseases (IRDs), where there is a lack of detailed characterization of these conditions and in the number of established registries. RESULTS: The network comprises 55 members from 35 centers, spanning 12 countries and regions, including Australia, China, India, Indonesia, Japan, South Korea, Malaysia, Nepal, Philippines, Singapore, Taiwan, and Thailand. The steering committee comprises ophthalmologists with experience in consortia for eye diseases in the Asia-Pacific region, leading ophthalmologists and vision scientists in the field of IRDs internationally, and ophthalmic geneticists. CONCLUSIONS: The Asia Pacific Inherited Eye Disease (APIED) network aims to (1) improve genotyping capabilities and expertise to increase early and accurate genetic diagnosis of IRDs, (2) harmonise deep phenotyping practices and utilization of ontological terms, and (3) establish high-quality, multi-user, federated disease registries that will facilitate patient care, genetic counseling, and research of IRDs regionally and internationally.

Heat profiling of phacoemulsification tip using a thermal scanning camera.

An experimental study to measure the heat profile of the phacoemulsification (phaco) tip using standard continuous phaco and hyperpulse phaco with and without waveform power modulation in the Millennium Microsurgical System with Custom Control Software (CCS). The phaco tip was imaged in air using a thermal camera. The highest temperature was measured 15 s after application of phaco power. Continuous, hyperpulse and waveform power modulations of the Millennium Microsurgical System were used with different power settings (20, 50 and 100 %) and duty cycles (40, 60 and 90 %), with the irrigation turned on and off. Using continuous phaco with the irrigation on, the phaco tip temperature remains <28.0 °C. With irrigation off, the temperature is higher compared to irrigation on but still remains <45.0 °C. Comparing the temperatures for all three power modulations when irrigation is on, at each phaco power and duty cycle setting, the temperature of the phaco tip is highest with continuous phaco, followed by hyperpulse with rise time 1, then hyperpulse with rise time 2. When irrigation is off, the highest temperatures are recorded using the hyperpulse with rise time 2, followed by continuous phaco, then hyperpulse with rise time 1. Hyperpulse and waveform modulations reduce heat generation compared to the continuous mode when irrigation is turned on. Lower duty cycles and lower ultrasound power produce less heat at the phaco tip.

Optical Coherence Tomography Angiography (OCTA) Findings in Retinitis Pigmentosa.

Optical coherence tomography angiography (OCTA) is a noninvasive new imaging modality that can be used to diagnose and monitor progression of retinitis pigmentosa (RP). Cohorts and case series have shown correlation between OCTA findings and visual function and disease severity. Although an early use of the technology is promising, there are concerns about segmentation errors and artifacts. There is also a paucity of data on genotype and how that correlates with OCTA findings. Despite its limitations, OCTA remains a useful tool for clinicians managing retinitis pigmentosa patients.

Bulbosities and Intervortex Venous Anastomosis in Venous Overload Choroidopathy Masquerading as Polypoidal Choroidal Vasculopathy.

PURPOSE: To describe a patient with venous overload choroidopathy in whom venous bulbosities masqueraded as polyps and intervortex venous anastomosis mimicked a branching vascular network, giving the appearance of polypoidal choroidal vasculopathy (PCV). METHODS: The patient had complete ophthalmic examination including indocyanine green angiography (ICGA) and optical coherence tomography (OCT). Venous bulbosities were defined on ICGA as focal dilations in which the diameter of the dilation is 2 times that of the host vessel. RESULTS: A 75-year-old female presented with combined subretinal and sub-retinal pigment epithelium (RPE) hemorrhages in the right eye. During ICGA, focal nodular hyperfluorescent lesions connected to a network of vessels were observed, which looked like polyps and branching vascular network in PCV. In both eyes, the mid-phase angiogram had multifocal choroidal vascular hyperpermeability. There was late-phase placoid staining nasal to the nerve in the right eye. During EDI-OCT evaluation, there were no RPE elevations that would be expected with polyps or branching vascular network in the right eye. A double layer sign was seen corresponding to the placoid area of staining. Diagnosis of venous overload choroidopathy and choroidal neovascularization membrane was made. She was treated with intravitreal anti-vascular endothelial growth factor injections for the choroidal neovascularization membrane. CONCLUSION: ICGA findings in venous overload choroidopathy may mimic PCV, but differentiation is essential as it has implications for treatment. Similar findings may have been misinterpreted in the past and may have previously contributed to conflicting clinical and histopathologic descriptions of PCV.

Ophthalmic Fluorescein Angiography.

Following its implementation in the 1960s, fluorescein angiography (FA) has become a widely used and reliable tool in the diagnosis of retinal and choroidal disorders. FA is an imaging modality utilized to examine the circulation of the retina and choroid. Here, we describe the process of obtaining fundus images with sodium fluorescein dye as a contrast agent. Using this methodology, ophthalmologists may examine the retinal and choroidal vasculature to diagnose a wide scope of retinal and choroidal diseases.

Protocol for Indocyanine Green Angiography.

Indocyanine green (ICG) angiography was first approved by the Food and Drug Administration for human use in the 1956. Prior to its use in chorioretinal angiograms, ICG was used to measure blood flow and track cardiac output. It was only in 1969 when two researchers, Kyuga Kogure and Earl Choromokos from the University of Miami, first used ICG to create more accurate angiograms. In the following years, researchers were able to hone the underlying science of this new form of angiography. As time passed and technology advanced, the application of ICG in clinical practice became widespread. Today ICG is used to diagnose and monitor the progression of retinal and choroidal diseases affecting millions of individuals across the globe. ICG utilizes the injection of indocyanine green dye into a patient's bloodstream to visualize abnormalities of the choroid and retina by evaluating choroidal circulation. ICG angiography is useful in the diagnosis and management of occult choroidal neovascularization in age-related macular degeneration and may be used in other inflammatory conditions with central serous chorioretinopathy. ICG angiography offers advanced imaging for improved monitoring and treatment of a wide variety of choroidal and retinal diseases.

Scleral Thickness in Autosomal Dominant Best Vitelliform Macular Dystrophy.

PURPOSE: To investigate the posterior and equatorial scleral thickness in patients with autosomal dominant Best disease, a condition that has chronic subretinal fluid. METHODS: Retrospective study involving patients with Best disease and age-matched controls. Participants were evaluated with contact B-scan ultrasonography and enhanced depth imaging optical coherence tomography to evaluate scleral thickness in the posterior pole and equator. Univariate analysis and generalized estimating equations were used. RESULTS: Of 9 patients with genetically proven Best disease and 23 age-matched controls, there was no significant difference in the age or the gender proportion between groups. Subfoveal choroidal thickness and axial length were not significantly different between groups. Both posterior scleral (OD; 1.38mm vs. 0.89mm, P<.001 and OS; 1.39mm vs. 0.83mm, P<.001) and equatorial scleral (OD; 0.61mm vs. 0.42mm, P=.003, and OS; 0.55mm vs. 0.41mm, P=.017) thicknesses were much greater in cases as compared with controls. Multivariate analysis showed male sex and having Best disease were each significant predictors of posterior scleral thickness and Best disease was the sole significant predictor for equatorial scleral thickness. CONCLUSION: BEST1 gene may have a developmental role leading to having a thicker sclera, influencing disease manifestation, and contributing to the accumulation of subretinal fluid in Best disease.

Correlations of Full-Field Stimulus Threshold With Functional and Anatomical Outcome Measurements in Advanced Retinitis Pigmentosa.

PURPOSE: To compare full-field stimulus (FST) threshold values to conventional functional and anatomical measures commonly used in clinical practice. DESIGN: Cross-sectional study. METHODS: Patients with retinitis pigmentosa with nondetectable electroretinogram rod-mediated responses and light-adapted 3.0 cd·s·m2 30-Hz flicker (LA 3.0 flicker) amplitudes of 15 mV or less were included in this study. The threshold values for blue, white, and red stimuli on FST were correlated with best-corrected visual acuity, LA 3.0 flicker amplitude and implicit times, length of the ellipsoid zone (EZ) band and thickness of outer nuclear layer measurements on optical coherence tomography, and the vertical and horizontal diameters of the autofluorescent ring on autofluorescence imaging. RESULTS: Forty-two eyes of 21 patients were included in the study. The mean FST thresholds were -22.5 ± 15.5 dB, -17.6 ± 11.5 dB, and -12.7 ± 6.0 dB for the blue, white, and red stimuli, respectively. The threshold values for the 3 FST stimuli were significantly correlated with selected functional and anatomical outcome measures. Specifically, they were strongly correlated with LA 3.0 flicker amplitude and EZ band length measured on optical coherence tomography. Using linear regression, blue and white stimulus values on FST were found to be predictive of EZ band length (R2 = 0.579 and 0.491, respectively), and the vertical (R2 = 0.694 and 0.532, respectively) and horizontal (R2 = 0.626 and 0.400, respectively) diameters of the hyperautofluorescent ring. CONCLUSIONS: The significant correlations between FST and other clinical outcome measures highlight its potential as an adjunct outcome measure.

Neovascular Age-Related Macular Degeneration (nAMD): A Review of Emerging Treatment Options.

Neovascular age-related macular degeneration (nAMD) is a common world-wide cause of visual loss. Intravitreal anti-vascular endothelial growth factor (anti-VEGF) agents are an effective means to treat nAMD and reduce its impact on vision compared to either sham treatment or photodynamic therapy. Currently, the approved anti-VEGF drugs include ranibizumab, aflibercept and brolucizumab. In addition, bevacizumab, used as an off-label drug, and has been shown to be effective in treating nAMD. While anti-VEGF agents are effective, its limitations include the requirement for frequent, often monthly injections, and the need for long-term treatment of nAMD. These present significant burdens on the healthcare system and on the patients. In addition, reviews of patients with nAMD treated with anti-VEGF have reported deterioration of vision over time with progression of geographic atrophy. These limitations are partly addressed by exploring different treatment regimens that reduce the frequency of treatments. Newer anti-VEGF drugs have been shown in Phase III clinical trials to have injection intervals as long as 12 or even 16 weeks for a proportion of patients. There is research on newer drugs that affect other pathways, such as the angiopoietin pathway, which may impact nAMD by extending the treatment interval and reducing the burden of treatment. Other measures include the use of sustained-release implants that release the drug regularly over a period of time, and can be refilled periodically, as well as hydrogel platforms that serve to release the drug. The use of biosimilars will also serve to reduce the cost of treatment for nAMD. A new frontier of gene therapy, primarily targeting genes involved in the transduction of retinal cells to produce anti-VEGF proteins intraocularly, also opens a new avenue of therapeutic approaches that can be used for treatment. This review paper will discuss both current treatment options and the newer treatments under development.