Dr. Yiu is a vitreoretinal specialist and clinician-scientist involved in translational research to study the pathogenesis and develop therapies for age-related macular degeneration and other retinal diseases. His focus include advanced ocular imaging technologies, genome editing, gene therapy, and drug delivery through nanotherapeutics.
Host immune responses after suprachoroidal delivery of AAV8 in nonhuman primate eyes.
Hum Gene Ther. 2021 Jan 15;:
Authors: Chung SH, Mollhoff IN, Mishra A, Sin TN, Ngo T, Ciulla T, Sieving PA, Thomasy S, Yiu G
The suprachoroid is a potential space located between the sclera and choroid of the eye which provides a novel route for ocular drug or viral vector delivery. Suprachoroidal injection of AAV8 using transscleral microneedles enables widespread transgene expression in eyes of nonhuman primates, but may cause intraocular inflammation. We characterized the host humoral and cellular immune responses after suprachoroidal delivery of AAV8 expressing green fluorescent protein (GFP) in rhesus macaques, and found that it can induce a mild chorioretinitis that resolves after systemic corticosteroid administration, with recovery of photoreceptor morphology but persistent immune cell infiltration after 3 months, corresponding to a loss of GFP expression from retinal pigment epithelial (RPE) cells but persistent expression in scleral fibroblasts. Suprachoroidal AAV8 triggered B-cell and T-cell responses against GFP, but only mild antibody responses to the viral capsid as compared to intravitreal injections of the same vector and dose. Systemic biodistribution studies showed lower AAV8 levels in liver and spleen after suprachoroidal injection compared with intravitreal delivery. Our findings suggest that suprachoroidal AAV8 primarily triggers host immune responses to GFP, likely due to sustained transgene expression in scleral fibroblasts outside the blood-retinal barrier, but elicits less humoral immune reactivity to the viral capsid than intravitreal delivery due to lower egress into systemic circulation. As GFP is not native to primates and not a clinically-relevant transgene, suprachoroidal AAV delivery of human transgenes may have significant translational potential for retinal gene therapy.
PMID: 33446041 [PubMed - as supplied by publisher]
Anti-Retinal Antibodies in Vitamin A Deficiency.
Ophthalmic Surg Lasers Imaging Retina. 2020 Dec 01;51(12):723-726
Authors: Ellis MP, Chang MY, Yiu G
Vitamin A is an important component of the visual cycle, and its deficiency causes a retinal degeneration that may be reversed with retinol supplementation. Here, the authors present a patient with vitamin A deficiency and rod-mediated retinopathy who was found to have multiple anti-retinal antibodies that gradually dissipated after vitamin A supplementation. This interesting case suggests the possibility that the photoreceptor degeneration induced by vitamin A deficiency may lead to transient immune exposure to retinal antigens and development of anti-retinal antibodies. [Ophthalmic Surg Lasers Imaging Retina. 2020;51:723-726.].
PMID: 33339054 [PubMed - as supplied by publisher]
Visible light OCT improves imaging through a highly scattering retinal pigment epithelial wall.
Opt Lett. 2020 Nov 01;45(21):5945-5948
Authors: Zhang T, Kho AM, Zawadzki RJ, Jonnal RS, Yiu G, Srinivasan VJ
Here we provide a counter-example to the conventional wisdom in biomedical optics that longer wavelengths aid deeper imaging in tissue. Specifically, we investigate visible light optical coherence tomography of Bruch's membrane (BM) in the non-pathologic eyes of humans and two mouse strains. Surprisingly, we find that shorter visible wavelengths improve the visualization of BM in pigmented eyes, where it is located behind a highly scattering layer of melanosomes in the retinal pigment epithelium (RPE). Monte Carlo simulations of radiative transport suggest that, while absorption and scattering are higher at shorter wavelengths, detected multiply scattered light from the RPE is preferentially attenuated relative to detected backscattered light from the BM.
PMID: 33137037 [PubMed - as supplied by publisher]
Evolution of ocular defects in infant macaques following in utero zika virus infection.
JCI Insight. 2020 Nov 12;:
Authors: Yiu G, Thomasy SM, Casanova MI, Rusakevich AM, Keesler RI, Watanabe J, Usachenko J, Singapuri A, Ball EE, Bliss-Moreau E, Guo W, Webster H, Singh T, Permar SR, Ardeshir A, Coffey LL, Van Rompay KK
Congenital Zika syndrome (CZS) is associated with microcephaly and various neurological, musculoskeletal, and ocular abnormalities, but the long-term pathogenesis and postnatal progression of ocular defects in infants are not well characterized. Rhesus macaques are superior to rodents as models of CZS because they are natural hosts of the virus and share similar immune and ocular characteristics, including blood-retinal barrier characteristics and the unique presence of a macula. Using a previously-described model of CZS by infecting pregnant rhesus macaques with Zika virus (ZIKV) during the late first trimester, we characterized postnatal ocular development and evolution of ocular defects in 2 infant macaques over 2 years. We found that one of these animals exhibited colobomatous chorioretinal atrophic lesions with macular and vascular dragging, as well as retinal thinning caused by loss of retinal ganglion neuron and photoreceptor layers. Despite these congenital ocular malformations, axial elongation and retinal development in these infants progressed at normal rates compared to healthy animals. The ZIKV-exposed infants displayed a rapid loss of ZIKV-specific antibodies, suggesting the absence of viral replication after birth, and did not show any behavioral or neurological defects postnatally. Our findings suggest that ZIKV infection during early pregnancy can impact fetal retinal development and cause congenital ocular anomalies, but does not appear to affect postnatal ocular growth.
PMID: 33180748 [PubMed - as supplied by publisher]
Quantitative Fundus Autofluorescence in Rhesus Macaques in Aging and Age-Related Drusen.
Invest Ophthalmol Vis Sci. 2020 Jul 01;61(8):16
Authors: Tran TM, Kim S, Lin KH, Chung SH, Park S, Sazhnyev Y, Wang Y, Cunefare D, Farsiu S, Thomasy SM, Moshiri A, Yiu G
Purpose: To employ quantitative fundus autofluorescence (qAF) imaging in rhesus macaques to noninvasively assess retinal pigment epithelial (RPE) lipofuscin in nonhuman primates (NHPs) as a model of aging and age-related macular degeneration (AMD).
Methods: The qAF imaging was performed on eyes of 26 rhesus macaques (mean age 18.8 ± 8.2 years, range 4-27 years) with normal-appearing fundus or with age-related soft drusen using a confocal scanning laser ophthalmoscope with 488 nm excitation and an internal fluorescence reference. Eyes with soft drusen also underwent spectral-domain optical coherence tomography imaging to measure drusen volume and height of individual drusen lesions. The qAF levels were measured from the perifoveal annular ring (quantitative autofluorescence 8 [qAF8]) using the Delori grid, as well as focally over individual drusen lesions in this region. The association between qAF levels and age, sex, and drusen presence and volume were determined using multivariable regression analysis.
Results: Mean qAF levels increased with age (P < 0.001) and were higher in females (P = 0.047). Eyes with soft drusen exhibited reduced mean qAF compared with age-matched normal eyes (P = 0.003), with greater drusen volume showing a trend toward decreased qAF levels. However, qAF levels are focally increased over most individual drusen (P < 0.001), with larger drusen appearing more hyperautofluorescent (R2 = 0.391, P < 0.001).
Conclusions: In rhesus macaques, qAF levels are increased with age and female sex, but decreased in eyes with soft drusen, similar to human AMD. However, drusen lesions appear hyperautofluorescent unlike those in humans, suggesting similarities and differences in RPE lipofuscin between humans and NHPs that may provide insight into drusen biogenesis and AMD pathogenesis.
PMID: 32663290 [PubMed - as supplied by publisher]
Factors Impacting Efficacy of AAV-Mediated CRISPR-Based Genome Editing for Treatment of Choroidal Neovascularization.
Mol Ther Methods Clin Dev. 2020 Jun 12;17:409-417
Authors: Chung SH, Mollhoff IN, Nguyen U, Nguyen A, Stucka N, Tieu E, Manna S, Meleppat RK, Zhang P, Nguyen EL, Fong J, Zawadzki R, Yiu G
Frequent injections of anti-vascular endothelial growth factor (anti-VEGF) agents are a clinical burden for patients with neovascular age-related macular degeneration (AMD). Genomic disruption of VEGF-A using adeno-associated viral (AAV) delivery of clustered regularly interspaced short palindromic repeats (CRISPR)-Cas9 has the potential to permanently suppress aberrant angiogenesis, but the factors that determine the optimal efficacy are unknown. Here, we investigate two widely used Cas9 endonucleases, SpCas9 and SaCas9, and evaluate the relative contribution of AAV-delivery efficiency and genome-editing rates in vivo to determine the mechanisms that drive successful CRISPR-based suppression of VEGF-A, using a mouse model of laser-induced choroidal neovascularization (CNV). We found that SpCas9 demonstrated higher genome-editing rates, greater VEGF reduction, and more effective CNV suppression than SaCas9, despite similar AAV transduction efficiency between a dual-vector approach for SpCas9 and single-vector system for SaCas9 to deliver the Cas9 orthologs and single guide RNAs (gRNAs). Our results suggest that successful VEGF knockdown using AAV-mediated CRISPR systems may be determined more by the efficiency of genome editing rather than viral transduction and that SpCas9 may be more effective than SaCas9 as a potential therapeutic strategy for CRISPR-based treatment of CNV in neovascular AMD.
PMID: 32128346 [PubMed]
Cost Analysis of Teleophthalmology Screening for Diabetic Retinopathy Using Teleophthalmology Billing Codes.
Ophthalmic Surg Lasers Imaging Retina. 2020 May 01;51(5):S26-S34
Authors: Ellis MP, Bacorn C, Luu KY, Lee SC, Tran S, Lillis C, Lim MC, Yiu G
BACKGROUND AND OBJECTIVE: To evaluate the financial sustainability of teleophthalmology screening for diabetic retinopathy (DR) using telehealth billing codes.
PATIENTS AND METHODS: The authors performed an Institutional Review Board-approved retrospective review of medical records, billing data, and quality metrics at the University of California Davis Health System from patients screened for DR through an internal medicine-based telemedicine program using CPT codes 92227 or 92228.
RESULTS: A total of 290 patients received teleophthalmology screening over a 12-month period, resulting in an increase in the DR screening rate from 49% to 63% (P < .0001). The average payment per patient was $19.86, with an estimated cost of $41.02 per patient. The projected per-patient incentive bonus was $43.06 with a downstream referral revenue of $39.38 per patient. One hundred seventy-eight clinic visits were eliminated, providing an estimated cost savings of $42.53 per patient.
CONCLUSION: Sustainable teleophthalmology screening may be achieved by billing telehealth codes but only with health care incentive bonuses, patient referrals, and by accounting for the projected cost-savings of eliminating office visits. [Ophthalmic Surg Lasers Imaging Retina. 2020;51:S26-S34.].
PMID: 32484898 [PubMed - as supplied by publisher]
Suprachoroidal and Subretinal Injections of AAV Using Transscleral Microneedles for Retinal Gene Delivery in Nonhuman Primates.
Mol Ther Methods Clin Dev. 2020 Mar 13;16:179-191
Authors: Yiu G, Chung SH, Mollhoff IN, Nguyen UT, Thomasy SM, Yoo J, Taraborelli D, Noronha G
Retinal gene therapy using adeno-associated viruses (AAVs) is constrained by the mode of viral vector delivery. Intravitreal AAV injections are impeded by the internal limiting membrane barrier, while subretinal injections require invasive surgery and produce a limited region of therapeutic effect. In this study, we introduce a novel mode of ocular gene delivery in rhesus macaques using transscleral microneedles to inject AAV8 into the subretinal or suprachoroidal space, a potential space between the choroid and scleral wall of the eye. Using in vivo imaging, we found that suprachoroidal AAV8 produces diffuse, peripheral expression in retinal pigment epithelial (RPE) cells, but it elicited local infiltration of inflammatory cells. Transscleral subretinal injection of AAV8 using microneedles leads to focal gene expression with transduction of RPE and photoreceptors, and minimal intraocular inflammation. In comparison, intravitreal AAV8 shows minimal transduction of retinal cells, but elicits greater systemic humoral immune responses. Our study introduces a novel mode of transscleral viral delivery that can be performed without vitreoretinal surgery, with focal or diffuse transgene expression patterns suitable for different applications. The decoupling of local and systemic immune responses reveals important insights into the immunological consequences of AAV delivery to different ocular compartments surrounding the blood-retinal barrier.
PMID: 32055646 [PubMed]
Safety and Biocompatibility of Aflibercept-Loaded Microsphere Thermo-Responsive Hydrogel Drug Delivery System in a Nonhuman Primate Model.
Transl Vis Sci Technol. 2020 Feb 27;9(3):30
Authors: Kim S, Kang-Mieler JJ, Liu W, Wang Z, Yiu G, Teixeira LBC, Mieler WF, Thomasy SM
Purpose: To evaluate the safety and tolerability of a microsphere thermo-responsive hydrogel drug delivery system (DDS) loaded with aflibercept in a nonhuman primate model.
Methods: A sterile 50 µL of aflibercept-loaded microsphere thermo-responsive hydrogel-DDS (aflibercept-DDS) was injected intravitreally into the right eye of 10 healthy rhesus macaques. A complete ophthalmic examination, intraocular pressure (IOP) measurement, fundus photography, spectral-domain optical coherence tomography (SD-OCT), and electroretinogram were performed monthly for 6 months. One macaque was euthanized monthly, and the enucleated eyes were submitted for measurement of bioactive aflibercept concentrations. Four eyes were submitted for histopathology.
Results: Injected aflibercept-DDS was visualized in the vitreous until 6 months postinjection. No abnormalities were observed in the anterior segment, and IOP remained within normal range during the study period. A small number of cells were observed in the vitreous of some macaques, but otherwise the remainder of the posterior segment examination was normal. No significant changes in retinal architecture or function as assessed by SD-OCT and histology or full-field electroretinography, respectively, were observed. A mild, focal foreign body reaction around the injectate was observed with histology at 6 months postinjection. A mean of 2.1 ng/µL of aflibercept was measured in the vitreous.
Conclusions: Intravitreally injected aflibercept-DDS achieved controlled, sustained release of aflibercept with no adverse effects for up to 6 months in the eyes of healthy rhesus macaques.
Translational Relevance: Aflibercept-DDS may be a more effective method to deliver bioactive antivascular endothelial growth factor agents than current practice by reducing the frequency of intravitreal injections and providing controlled drug release.
PMID: 32742760 [PubMed]
Long-term Evolution and Remodeling of Soft Drusen in Rhesus Macaques.
Invest Ophthalmol Vis Sci. 2020 Feb 07;61(2):32
Authors: Yiu G, Chung SH, Mollhoff IN, Wang Y, Nguyen UT, Shibata B, Cunefare D, Farsiu S, Roberts J, Thomasy SM
Purpose: To characterize the evolution and structure of soft drusen in aged rhesus macaques using in vivo multimodal retinal imaging and ex vivo histologic and ultrastructural analyses as a nonhuman primate model of early age-related macular degeneration (AMD).
Methods: Multimodal imaging including fundus photography, spectral domain optical coherence tomography (SD-OCT), and fundus autofluorescence (FAF) were used to characterize and track individual drusen lesions in 20 aged rhesus macaques (mean age 23.3 ± 2.7 years) with drusenoid lesions over 2 years, followed by semithin histologic analysis and transmission electron microscopy (TEM).
Results: Although most drusen gradually increased in size, a portion spontaneously regressed or collapsed over 2 years. Histologic analyses showed that soft drusen exhibit hypertrophy and dysmorphia of overlying retinal pigment epithelium (RPE), as seen in early and intermediate AMD, but do not exhibit RPE atrophy, RPE migration, or photoreceptor degeneration characteristic of advanced AMD. Ultrastructure of soft drusen showed abundant lipid particles within Bruch's membrane and AMD-related basal linear deposits (BlinD) resembling those in human drusen.
Conclusions: The dynamic remodeling, histologic findings, and ultrastructural features of soft drusen in aged rhesus macaques support nonhuman primates as an animal model of early AMD and reveal important insights into drusen biogenesis and AMD development.
PMID: 32084273 [PubMed - as supplied by publisher]
Retinal Vessel Density in Exudative and Non-Exudative Age-Related Macular Degeneration on Optical Coherence Tomography Angiography.
Am J Ophthalmol. 2019 Dec 11;:
Authors: Lee SC, Tran S, Amin A, Morse LS, Moshiri A, Park SS, Yiu G
IMPORTANCE: Although the choroid contributes to the pathogenesis of age-related macular degeneration (AMD), the role of retinal perfusion is unclear.
PURPOSE: To compare retinal vascular measurements between eyes with non-exudative and exudative AMD using optical coherence tomography angiography (OCT-A).
DESIGN: Retrospective, cross-sectional study.
METHODS: OCT-A images were analyzed from 310 eyes of 182 patients (mean age 78.8±8.8) with non-exudative (54.2%) and exudative (45.8%) AMD to measure retinal vessel density (VD) from the superficial capillary plexus in the foveal, parafoveal, and full macular regions and foveal avascular zone (FAZ) area, perimeter, and circularity. Multivariate regressions were used to compare non-exudative and exudative AMD eyes, and the impact of anti-vascular endothelial growth factor (anti-VEGF) treatments or geographic atrophy (GA).
RESULTS: In eyes with AMD, VD decreases with age in the foveal (β=-0.211, P<0.001), parafoveal (β=-0.305, P<0.001), and full macular regions (β=-0.295, P<0.001). Eyes with exudative AMD demonstrated lower VD, especially in the parafoveal (29.8 ± 6.3% vs. 33.0 ± 5.7%, P<0.001) and full regions (27.9 ± 6.2% vs. 31.2 ± 5.5%, P<0.001) as compared to non-exudative AMD. There were no differences in FAZ area, perimeter, or circularity between the two groups (P=0.503-0.907). In eyes with exudative AMD, prior anti-VEGF treatments did not impact retinal vascular measurements (P=0.324-0.986). Nonexudative AMD severity and presence of central GA also impacted retinal VD and FAZ morphology.
CONCLUSIONS: Retinal VD is decreased in eyes with exudative AMD as compared with non-exudative AMD, but unaffected by anti-VEGF treatments, suggesting a retinal vascular contribution to the pathogenesis of AMD.
PMID: 31837316 [PubMed - as supplied by publisher]
CONVERSION AND SPONTANEOUS REVERSION OF LAMELLAR HOLE FROM FULL-THICKNESS MACULAR HOLE.
Retin Cases Brief Rep. 2019 Nov 13;:
Authors: Ellis M, Yiu G
PURPOSE: To report the conversion and spontaneous reversion of a lamellar hole from full-thickness macular hole after vitrectomy surgery for retinal detachment repair.
METHODS: Case report of a patient with a preexisting lamellar hole who underwent retinal detachment repair.
RESULTS: A patient with a history of a lamellar hole developed a fovea-sparing retinal detachment that was repaired by vitrectomy surgery with gas tamponade. Two months after the surgery, he developed a full-thickness macular hole that spontaneously reverted back to a lamellar hole configuration over several months.
CONCLUSION: Although spontaneous closure of full-thickness macular hole after retinal detachment repair has been reported, the conversion and spontaneous reversion of a lamellar hole from full-thickness macular hole after vitrectomy provide insight into the tractional forces involved in the pathophysiology of lamellar and full-thickness macular holes.
PMID: 31725596 [PubMed - as supplied by publisher]
Emerging Concepts in the Treatment of Diabetic Retinopathy.
Curr Diab Rep. 2019 Nov 20;19(11):137
Authors: Ellis MP, Lent-Schochet D, Lo T, Yiu G
PURPOSE OF REVIEW: Diabetic retinopathy (DR) is the leading cause of vision loss in working-age adults in the developed world. This review discusses the current approach to managing the disease, such as glycemic and blood pressure control, as well as laser photocoagulation, as well as emerging concepts and controversies on novel therapies.
RECENT FINDINGS: In recent years, the rise of intraocular anti-angiogenesis treatments is changing the paradigm of classic laser photocoagulation in the management of DR, but its long-term benefits remain an area of controversy. We also discuss new targets including anti-inflammation, neuroprotection, and novel laser technologies. Finally, we discuss new advances in retinal imaging that has vastly improved the diagnosis and management of DR. Diagnosis and management of diabetic retinopathy is a rapidly progressing field. Emerging concepts in ophthalmic imaging, medical treatments, and surgical approaches provide insights into how DR management will evolve in the near future.
PMID: 31748965 [PubMed - in process]
Spectral-Domain OCT Predictors of Visual Outcomes after Ranibizumab Treatment for Macular Edema Resulting from Retinal Vein Occlusion.
Ophthalmol Retina. 2019 Aug 28;:
Authors: Yiu G, Welch RJ, Wang Y, Wang Z, Wang PW, Haskova Z
PURPOSE: To evaluate spectral-domain (SD)-OCT features associated with baseline vision and visual outcomes in the prospective, multicenter Study Evaluating Dosing Regimens for Treatment with Intravitreal Ranibizumab Injections in Subjects with Macular Edema following Retinal Vein Occlusion (SHORE).
DESIGN: Post hoc analysis of prospective clinical trial data.
PARTICIPANTS: Two hundred two participants in the 15-month, phase 4 SHORE study comparing monthly versus pro re nata ranibizumab after 7 monthly doses in eyes with retinal vein occlusion (RVO) with macular edema.
METHODS: Baseline SD-OCT images were assessed for (1) central subfield thickness (CST); (2) presence of vitreomacular adhesion, vitreomacular traction, or epiretinal membrane; (3) presence, location, and amount of intraretinal fluid or subretinal fluid (SRF); (4) presence, location, and amount of hyperreflective foci (HF); (5) disorganization of retinal inner layers (DRIL); and (6) disruption of external limiting membrane (ELM), ellipsoid zone (EZ), and interdigitation zone (IZ). Univariate and multivariate regression analyses were performed to evaluate the association of these features with baseline best-corrected visual acuity (BCVA) and change in BCVA after 7 monthly ranibizumab injections.
MAIN OUTCOME MEASURES: Association of SD-OCT features with baseline BCVA and change in BCVA after 7 monthly ranibizumab injections.
RESULTS: Before therapy, worse baseline BCVA was associated with ERM presence (P = 0.0045), thicker SRF (P = 0.0006), larger intraretinal cysts (P = 0.0015), and higher percentage of DRIL (P < 0.0001), percentage of ELM disruption (P < 0.0001), percentage of EZ disruption (P = 0.0003), and percentage of IZ disruption (P = 0.0018). In multivariate models, only percentage of ELM disruption independently impacted baseline BCVA (P < 0.0001). After 7 monthly ranibizumab injections, mean BCVA improved by 18.3±12.6 Early Treatment Diabetic Retinopathy Study letters in treated eyes. The only factors independently associated with BCVA gain after 7 monthly ranibizumab treatments were younger age (P < 0.0001) and worse baseline BCVA (P < 0.0001).
CONCLUSIONS: Although SD-OCT features may be associated with presenting vision in eyes with macular edema and RVO, most eyes treated with ranibizumab achieve substantial vision gains, and only older age and better baseline BCVA limited visual improvements.
PMID: 31669329 [PubMed - as supplied by publisher]
JAMA Ophthalmol. 2019 Jun 01;137(6):e185256
Authors: Yiu G, Emami-Naeni P
PMID: 31194236 [PubMed - in process]
Long-term natural history of idiopathic epiretinal membranes with good visual acuity.
Eye (Lond). 2019 Apr 19;:
Authors: Luu KY, Koenigsaecker T, Yazdanyar A, Mukkamala L, Durbin-Johnson BP, Morse LS, Moshiri A, Park SS, Yiu G
BACKGROUND/OBJECTIVES: To evaluate the long-term progression of idiopathic epiretinal membranes (iERMs) with good baseline visual acuity, and to identify predictors of visual decline.
DESIGN: Retrospective case series SUBJECTS METHODS: We reviewed records of 145 eyes with iERM and best-corrected visual acuity (BCVA) of 20/40 or greater at presentation, including BCVA, lens status, and central macular thickness (CMT) at yearly visits; as well as anatomic biomarkers including vitreomacular adhesion, pseudohole, lamellar hole, intraretinal cysts, disorganization of the inner retinal layers (DRIL), and disruption of outer retinal layers. Linear mixed effects and mixed-effects Cox proportional hazards models were used to identify clinical and anatomic predictors of vision change and time to surgery.
RESULTS: At presentation, mean BCVA was 0.17 ± 0.10 logMAR units (Snellen 20/30) and mean CMT was 353.3 ± 75.4 μm. After a median follow-up of 3.7 years (range 1-7 years), BCVA declined slowly at 0.012 ± 0.003 logMAR units/year, with phakic eyes declining more rapidly than pseudophakic eyes (0.019 ± 0.003 vs. 0.010 ± 0.004 logMAR units/year). Metamorphopsia, phakic lens status, lamellar hole, and inner nuclear layer cysts were associated with faster visual decline. Cumulative rates of progression to surgery were 2.9, 5.6, 12.2, and 21.1% at years 1-4. Visual symptoms, metamorphopsia, greater CMT, and disruption of outer retinal layers were associated with greater hazard for surgery.
CONCLUSION: Eyes with iERM and visual acuity ≥ 20/40 experience slow visual decline, with 21% of eyes requiring surgery after 4 years. Clinical and anatomic predictors of vision loss may be distinct from factors associated with earlier surgical intervention.
PMID: 31000833 [PubMed - as supplied by publisher]
Vascular Response to Sildenafil Citrate in Aging and Age-Related Macular Degeneration.
Sci Rep. 2019 Mar 25;9(1):5049
Authors: Yiu G, Vuong VS, Tran S, Migacz J, Cunefare D, Farsiu S, Khandelwal N, Agrawal R, Cheung CMG
Age-related macular degeneration (AMD) - the leading cause of vision loss in the elderly - share many risks factors as atherosclerosis, which exhibits loss of vascular compliance resulting from aging and oxidative stress. Here, we attempt to explore choroidal and retinal vascular compliance in patients with AMD by evaluating dynamic vascular changes using live ocular imaging following treatment with oral sildenafil citrate, a phosphodiesterase type 5 (PDE5) inhibitor and potent vasodilator. Enhanced-depth imaging optical coherence tomography (EDI-OCT) and OCT angiography (OCT-A) were performed on 46 eyes of 23 subjects, including 15 patients with non-exudative AMD in one eye and exudative AMD in the fellow eye, and 8 age-matched control subjects. Choroidal thickness, choroidal vascularity, and retinal vessel density were measured across the central macula at 1 and 3 hours after a 100 mg oral dose of sildenafil citrate. Baseline choroidal thickness was 172.1 ± 60.0 μm in non-exudative AMD eyes, 196.4 ± 89.8 μm in exudative AMD eyes, and 207.4 ± 77.7 μm in control eyes, with no difference between the 3 groups (P = 0.116). After sildenafil, choroidal thickness increased by 6.0% to 9.0% at 1 and 3 hours in all groups (P = 0.001-0.014). Eyes from older subjects were associated with choroidal thinning at baseline (P = 0.005) and showed less choroidal expansion at 1 hour and 3 hours after sildenafil (P = 0.001) regardless of AMD status (P = 0.666). The choroidal thickening appeared to be primarily attributed to expansion of the stroma rather than luminal component. Retinal vascular density remained unchanged after sildenafil in all 3 groups (P = 0.281-0.587). Together, our studies suggest that vascular response of the choroid to sildenafil decreases with age, but is not affected by the presence of non-exudative or exudative AMD, providing insight into changes in vessel compliance in aging and AMD.
PMID: 30911094 [PubMed - in process]
Pneumatic Retinopexy Experience and Outcomes of Vitreoretinal Fellows in the United States: A Multicenter Study.
Ophthalmol Retina. 2019 Feb;3(2):140-145
Authors: Emami-Naeini P, Deaner J, Ali F, Gogte P, Kaplan R, Chen KC, Nudleman E, Grewal DS, Gupta M, Wolfe JD, Klufas M, Yiu G, Academic Vitreoretinal Training Centers Study Group
Objective: To evaluate the outcomes of patients undergoing pneumatic retinopexy (PR) performed by vitreoretinal fellows at 6 academic centers in the United States.
Design: Retrospective, multicenter, consecutive case series.
Participants: 483 patients with primary retinal detachments who underwent PR by 49 vitreoretinal fellows from 6 U.S. training sites between 2002 and 2016.
Methods: We reviewed medical records of patients and recorded baseline clinical characteristics (age, sex, baseline visual acuity, lens status, presence of lattice degeneration, presence of vitreous hemorrhage, location of retinal breaks, macular status, and size of detachment), visual and anatomic outcomes at 3-months after PR, as well as training level and PR experience of the fellow at the time of the procedure.
Main Outcome Measures: Single-procedure anatomic success and visual acuity at 3-months follow-up, and association with clinical and training-related factors.
Results: Vitreoretinal fellows performed a variable number of PR, with a median of 7 cases per fellow (range 1-24). Single-procedure anatomic success was 66.8%, and mean LogMAR visual outcome was 0.43 (Snellen equivalent 20/54) at 3 months. Factors that were independently associated with single-procedure success include phakic lens status (P = 0.01), smaller size of retinal detachment (P = 0.02), and the fellow's procedure experience (P = 0.01). The only factor associated with worse visual outcome was baseline visual acuity (P < 0.001).
Conclusion: Vitreoretinal fellows perform variably few pneumatic retinopexies but have outcomes comparable to reported rates by experienced specialists. Procedure experience of individual fellows may impact anatomic outcomes.
PMID: 30931417 [PubMed - in process]
Association Between the Cilioretinal Artery and Choroidal Neovascularization in Age-Related Macular Degeneration: A Secondary Analysis From the Age-Related Eye Disease Study.
JAMA Ophthalmol. 2018 Sep 01;136(9):1008-1014
Authors: Snyder K, Yazdanyar A, Mahajan A, Yiu G
Importance: A hemodynamic role in the pathogenesis of age-related macular degeneration (AMD) has been proposed, but to our knowledge, an association between retinal vasculature and late AMD has not been investigated.
Objective: To determine whether the presence and location of a cilioretinal artery may be associated with the risk of late AMD in the Age-Related Eye Disease Study (AREDS).
Design, Setting, and Participants: Retrospective analysis of prospective, randomized clinical trial data from 3647 AREDS participants. Fundus photographs of AREDS participants were reviewed by 2 masked graders for the presence or absence of a cilioretinal artery and whether any branch extended within 500 μm of the central macula. Multivariate regressions were used to determine the association of the cilioretinal artery and vessel location, adjusted for age, sex, and smoking status, with the prevalence of choroidal neovascularization (CNV) or central geographic atrophy (CGA) and AMD severity score for eyes at randomization and progression at 5 years.
Main Outcomes and Measures: Association of cilioretinal artery with prevalence and 5-year incidence of CNV or CGA.
Results: Among AREDS participants analyzed, mean (SD) age was 69.0 (5.0) years, with 56.3% female, 46.6% former smokers, and 6.9% current smokers. A total of 26.9% of patients had a cilioretinal artery in 1 eye, and 8.4% had the vessel bilaterally. At randomization, eyes with a cilioretinal artery had a lower prevalence of CNV (5.0% vs 7.6%; OR, 0.66; 95% CI, 0.51-0.85; P = .001) but no difference in CGA (1.1% vs 0.8%; OR, 1.33; 95% CI, 0.76-2.32; P = .31). In eyes without late AMD, those with a cilioretinal artery also had a lower mean (SD) AMD severity score (3.00 [2.35] vs 3.19 [2.40]; P = .02). At 5 years, eyes at risk with a cilioretinal artery had lower rates of progression to CNV (4.1% vs 5.5%; OR, 0.75; 95% CI, 0.56-1.00; P = .05) but no difference in developing CGA (2.2% vs 2.7%; OR, 0.83; 95% CI, 0.56-1.23; P = .35) or change in AMD severity score (0.65 [1.55] vs 0.73 [1.70]; P = .11). In patients with a unilateral cilioretinal artery, eyes with the vessel showed a lower prevalence of CNV than fellow eyes (4.7% vs 7.2%; P = .01).
Conclusions and Relevance: The presence of a cilioretinal artery is associated with a lower risk of developing CNV, but not CGA, suggesting a possible retinal hemodynamic contribution to the pathogenesis of neovascular AMD.
Trial Registration: ClinicalTrials.gov Identifier: NCT00000145.
PMID: 29978186 [PubMed - in process]
Subthreshold micropulse laser reduces anti-VEGF injection burden in patients with diabetic macular edema.
Eur J Ophthalmol. 2018 Jan;28(1):68-73
Authors: Moisseiev E, Abbassi S, Thinda S, Yoon J, Yiu G, Morse LS
PURPOSE: To evaluate the efficacy of micropulse laser in the early treatment of diabetic macular edema (DME) and its associated burden of anti-vascular endothelial growth factor (VEGF) injections.
METHODS: This retrospective comparative study compared a group of 19 eyes with DME treated with micropulse laser to a matched control group of 19 eyes with DME treated with ranibizumab injections without micropulse laser. Recorded parameters included previous medical and ocular history, previous and subsequent ranibizumab injections administered for DME, visual acuity (VA), central macular thickness throughout the follow-up period, and the occurrence of any complications.
RESULTS: The improvement in VA was comparable in both groups, at 12 months and at the final follow-up. Patients treated with micropulse laser required significantly fewer ranibizumab injections than their controls, both at 12 months (1.7 ± 2.3 vs 5.6 ± 2.1) and by the end of the follow-up (2.6 ± 3.3 vs 9.3 ± 5.1) (p<0.001 for both). No complications related to the micropulse laser were encountered.
CONCLUSIONS: Micropulse laser is a safe and effective treatment for DME, which may achieve comparable improvement in VA along with a significant reduction in the burden of anti-VEGF injections. We suggest a treatment approach for its inclusion in the early stages of DME.
PMID: 28731494 [PubMed - indexed for MEDLINE]
The impact of conversion to International Classification of Diseases, 10th revision (ICD-10) on an academic ophthalmology practice.
Clin Ophthalmol. 2018;12:949-956
Authors: Hellman JB, Lim MC, Leung KY, Blount CM, Yiu G
Purpose: To determine the financial and clinical impact of conversion from International Classification of Disease, 9th revision (ICD-9) to ICD-10 coding.
Design: Retrospective, database study.
Materials and methods: Monthly billing and coding data from 44,564 billable patient encounters at an academic ophthalmology practice were analyzed by subspecialty in the 1-year periods before (October 1, 2014, to September 30, 2015) and after (October 1, 2015, to September 30, 2016) conversion from ICD-9 to ICD-10.
Main outcomes and measures: Primary outcome measures were payments per visit, relative value units per visit, number of visits, and percentage of high-level visits; secondary measures were denials due to coding errors, charges denied due to coding errors, and percentage of unspecified codes used as a primary diagnosis code.
Results: Conversion to ICD-10 did not significantly impact payments per visit ($306.56±$56.50 vs $321.43±$38.12, P=0.42), relative value units per visit (7.15±0.56 vs 7.13±0.84, P=0.95), mean volume of visits (1,887.08±375.02 vs 1,863.83±189.81, P=0.71), or percentage of high-level visits (29.7%±4.9%, 548 of 1,881 vs 30.0%±1.7%, 558 of 1,864, P=0.81). For every 100 visits, the number of coding-related denials increased from 0.98±0.60 to 1.84±0.31 (P<0.001), and denied charges increased from $307.42±$443.39 to $660.86±$239.47 (P=0.002). The monthly percentage of unspecified codes used increased from 25.8%±1.1% (485 of 1,881) to 35.0%±2.3% (653 of 1,864, P<0.001).
Conclusion: The conversion to ICD-10 did not impact overall revenue or clinical volume in this practice setting, but coding-related denials, denied charges, and the use of unspecified codes increased significantly. We expect these denials to increase in the next year in the absence of Medicare's 1-year grace period.
PMID: 29849450 [PubMed]
Comparison of chorioretinal layers in rhesus macaques using spectral-domain optical coherence tomography and high-resolution histological sections.
Exp Eye Res. 2018 03;168:69-76
Authors: Yiu G, Wang Z, Munevar C, Tieu E, Shibata B, Wong B, Cunefare D, Farsiu S, Roberts J, Thomasy SM
Nonhuman primates are important preclinical models of retinal diseases because they uniquely possess a macula similar to humans. Ocular imaging technologies such as spectral-domain optical coherence tomography (SD-OCT) allow noninvasive, in vivo measurements of chorioretinal layers with near-histological resolution. However, the boundaries are based on differences in reflectivity, and detailed correlations with histological tissue layers have not been explored in rhesus macaques, which are widely used for biomedical research. Here, we compare the macular anatomy and thickness measurements of chorioretinal layers in rhesus macaque eyes using SD-OCT and high-resolution histological sections. Images were obtained from methylmethacrylate-embedded histological sections of 6 healthy adult rhesus macaques, and compared with SD-OCT images from 6 age-matched animals. Thicknesses of chorioretinal layers were measured across the central 3 mm macular region using custom semi-automated or manual software segmentation, and compared between the two modalities. We found that histological sections provide better distinction between the ganglion cell layer (GCL) and inner plexiform layer (IPL) than SD-OCT imaging. The first hyperreflective band between the external limiting membrane (ELM) and retinal pigment epithelium (RPE) appears wider on SD-OCT than the junction between photoreceptor inner and outer segments seen on histology. SD-OCT poorly distinguishes Henle nerve fibers from the outer nuclear layer (ONL), while histology correctly identifies these fibers as part of the outer plexiform layer (OPL). Overall, the GCL, inner nuclear layer (INL), and OPL are significantly thicker on histology, especially at the fovea; while the ONL, choriocapillaris (CC), and outer choroid (OC) are thicker on SD-OCT. Our results show that both SD-OCT and high-resolution histological sections allow reliable measurements of chorioretinal layers in rhesus macaques, with distinct advantages for different sublayers. These findings demonstrate the effects of tissue processing on chorioretinal anatomy, and provide normative values for chorioretinal thickness measurements on SD-OCT for future studies of disease models in these nonhuman primates.
PMID: 29352993 [PubMed - indexed for MEDLINE]
Effects of aging and environmental tobacco smoke exposure on ocular and plasma circulatory microRNAs in the Rhesus macaque.
Mol Vis. 2018;24:633-646
Authors: Smit-McBride Z, Nguyen J, Elliott GW, Wang Z, McBride RA, Nguyen AT, Oltjen SL, Yiu G, Thomasy SM, Pinkerton KE, Lee ES, Cunefare D, Farsiu S, Morse LS
Purpose: To identify changes induced by environmental tobacco smoke (ETS) in circulatory microRNA (miRNA) in plasma and ocular fluids of the Rhesus macaque and compare these changes to normal age-related changes. Tobacco smoke has been identified as the leading environmental risk factor for age-related macular degeneration (AMD).
Methods: All Rhesus macaques were housed at the California National Primate Research Center (CNPRC), University of California, Davis. Four groups of animals were used: Group 1 (1-3 years old), Group 2 (19-28 years old), Group 3 (10-16 years old), and Group 4 (middle aged, 9-14 years old). Group 4 was exposed to smoke for 1 month. Ocular fluids and plasma samples were collected, miRNAs isolated, and expression data obtained using Affymetrix miRNA GeneTitan Array Plates 4.0. Bioinformatics analysis was done on the Affymetrix Expression Console (EC), Transcriptome Analysis Software (TAS) using ANOVA for candidate miRNA selection, followed by Ingenuity Pathway Analysis (IPA).
Results: The expression of circulatory miRNAs showed statistically significant changes with age and ETS. In the plasma samples, 45 miRNAs were strongly upregulated (fold change >±1.5, p<0.05) upon ETS exposure. In the vitreous, three miRNAs were statistically significantly downregulated with ETS, and two of them (miR-6794 and miR-6790) were also statistically significantly downregulated with age. Some retinal layers exhibited a thinning trend measured with optical coherence tomography (OCT) imaging. The pathways activated were IL-17A, VEGF, and recruitment of eosinophils, Th2 lymphocytes, and macrophages.
Conclusions: ETS exposure of Rhesus macaques resulted in statistically significant changes in the expression of the circulatory miRNAs, distinct from those affected by aging. The pathways activated appear to be common for ETS and AMD pathogenesis. These data will be used to develop an animal model of early dry AMD.
PMID: 30294202 [PubMed - indexed for MEDLINE]
In Vivo Multimodal Imaging of Drusenoid Lesions in Rhesus Macaques.
Sci Rep. 2017 Nov 03;7(1):15013
Authors: Yiu G, Tieu E, Munevar C, Wong B, Cunefare D, Farsiu S, Garzel L, Roberts J, Thomasy SM
Nonhuman primates are the only mammals to possess a true macula similar to humans, and spontaneously develop drusenoid lesions which are hallmarks of age-related macular degeneration (AMD). Prior studies demonstrated similarities between human and nonhuman primate drusen based on clinical appearance and histopathology. Here, we employed fundus photography, spectral domain optical coherence tomography (SD-OCT), fundus autofluorescence (FAF), and infrared reflectance (IR) to characterize drusenoid lesions in aged rhesus macaques. Of 65 animals evaluated, we identified lesions in 20 animals (30.7%). Using the Age-Related Eye Disease Study 2 (AREDS2) grading system and multimodal imaging, we identified two distinct drusen phenotypes - 1) soft drusen that are larger and appear as hyperreflective deposits between the retinal pigment epithelium (RPE) and Bruch's membrane on SD-OCT, and 2) hard, punctate lesions that are smaller and undetectable on SD-OCT. Both exhibit variable FAF intensities and are poorly visualized on IR. Eyes with drusen exhibited a slightly thicker RPE compared with control eyes (+3.4 μm, P=0.012). Genetic polymorphisms associated with drusenoid lesions in rhesus monkeys in ARMS2 and HTRA1 were similar in frequency between the two phenotypes. These results refine our understanding of drusen development, and provide insight into the absence of advanced AMD in nonhuman primates.
PMID: 29101353 [PubMed - in process]
Optical Coherence Tomography Predictors of Risk for Progression to Non-Neovascular Atrophic Age-Related Macular Degeneration.
Ophthalmology. 2017 12;124(12):1764-1777
Authors: Sleiman K, Veerappan M, Winter KP, McCall MN, Yiu G, Farsiu S, Chew EY, Clemons T, Toth CA, Age-Related Eye Disease Study 2 Ancillary Spectral Domain Optical Coherence Tomography Study Group
PURPOSE: Appearance of geographic atrophy (GA) on color photography (CP) is preceded by specific features on spectral-domain optical coherence tomography (SD OCT). We aimed to build SD OCT-based risk assessment models for 5-year new onset of GA and central GA on CP.
DESIGN: Prospective, longitudinal study.
PARTICIPANTS: Age-Related Eye Disease Study 2 Ancillary SD OCT study participants with age-related macular degeneration (AMD) with bilateral large drusen or noncentral GA and at least 1 eye without advanced disease (n = 317).
METHODS: For 1 eye per participant, qualitative and quantitative SD OCT variables were derived from standardized grading and semiautomated segmentation, respectively, at baseline. Up to 7 years later, annual outcomes were extracted and analyzed to fit multivariate logistic regression models and build a risk calculator.
MAIN OUTCOME MEASURES: New onset of CP-visible GA and central GA.
RESULTS: Over a follow-up median of 4.0 years and among 292 AMD eyes (without advanced disease at baseline) with complete outcome data, 46 (15.8%) developed central GA. Among 265 eyes without any GA on baseline CP, 70 (26.4%) developed CP-visible GA. Final multivariate models were adjusted for age. In the model for GA, the independent predicting SD OCT factors (P < 0.001-0.03) were: hyperreflective foci and retinal pigment epithelium (RPE) layer atrophy or absence, followed by choroid thickness in absence of subretinal drusenoid deposits, photoreceptor outer segment loss, RPE drusen complex volume, and RPE drusen complex abnormal thinning volume. For central GA, the factors (P < 0.001) were RPE drusen complex abnormal thinning volume, intraretinal fluid or cystoid spaces, hyperreflective foci, and RPE layer atrophy or absence. The models yielded a calculator that computes the probabilities of CP-visible, new-onset GA and central GA after 1 to 5 years.
CONCLUSIONS: For AMD eyes with large drusen and no advanced disease, we built a novel risk assessment model-based on age and SD OCT segmentation, drusen characteristics, and retinal pathology-for progression to CP-visible GA over up to 5 years. This calculator may simplify SD OCT grading and with future validation has a promising role as a clinical prognostic tool.
PMID: 28847641 [PubMed - indexed for MEDLINE]
Effect of Syringe Design on the Accuracy and Precision of Intravitreal Injections of Anti-VEGF Agents.
Curr Eye Res. 2017 07;42(7):1059-1063
Authors: Moisseiev E, Rudell J, Tieu EV, Yiu G
PURPOSE: To evaluate the accuracy and precision of different syringe designs for intravitreal injection of anti-VEGF agents.
METHODS: Volume output was measured from three syringe designs-1) 1.0 mL tuberculin syringe, 2) 1.0 mL syringe with low dead space plunger, and 3) 0.5 mL low-volume syringe-to deliver 50 µL of bevacizumab, ranibizumab, or aflibercept, each repeated four times by three different physicians for 108 total simulated injections. Volume output was calculated from difference in syringe weight before and after expelling the drug. Accuracy was determined by mean absolute percentage error (MAPE), and precision was measured by coefficient of variation (CV).
RESULTS: Volume output from all three syringes was significantly different from 50 µL, with mean volumes of 58.0 ± 5.7 µL for the tuberculin syringe, 58.0 ± 4.0 µL for the low dead space syringe, and 55.5 ± 5.1 µL for the low-volume syringe (p < 0.00001 for all). The low-volume syringe was the most accurate (MAPE = 12.8 ± 7.8% vs. 17.3 ± 9.3% or 15.9 ± 8.1%), and the low dead space syringe was the most reproducible (CV = 0.068 vs. 0.091 or 0.097). There was no significant difference in volume output between different anti-VEGF agents.
CONCLUSIONS: Intravitreal injections of anti-VEGF agents using a 1.0 mL tuberculin syringe demonstrate poor accuracy and precision. A lower capacity syringe may improve accuracy, while a low dead space plunger may improve precision.
PMID: 28306392 [PubMed - indexed for MEDLINE]
Effect of Uveal Melanocytes on Choroidal Morphology in Rhesus Macaques and Humans on Enhanced-Depth Imaging Optical Coherence Tomography.
Invest Ophthalmol Vis Sci. 2016 Oct 01;57(13):5764-5771
Authors: Yiu G, Vuong VS, Oltjen S, Cunefare D, Farsiu S, Garzel L, Roberts J, Thomasy SM
Purpose: To compare cross-sectional choroidal morphology in rhesus macaque and human eyes using enhanced-depth imaging optical coherence tomography (EDI-OCT) and histologic analysis.
Methods: Enhanced-depth imaging-OCT images from 25 rhesus macaque and 30 human eyes were evaluated for choriocapillaris and choroidal-scleral junction (CSJ) visibility in the central macula based on OCT reflectivity profiles, and compared with age-matched histologic sections. Semiautomated segmentation of the choriocapillaris and CSJ was used to measure choriocapillary and choroidal thickness, respectively. Multivariate regression was performed to determine the association of age, refractive error, and race with choriocapillaris and CSJ visibility.
Results: Rhesus macaques exhibit a distinct hyporeflective choriocapillaris layer on EDI-OCT, while the CSJ cannot be visualized. In contrast, humans show variable reflectivities of the choriocapillaris, with a distinct CSJ seen in many subjects. Histologic sections demonstrate large, darkly pigmented melanocytes that are densely distributed in the macaque choroid, while melanocytes in humans are smaller, less pigmented, and variably distributed. Optical coherence tomography reflectivity patterns of the choroid appear to correspond to the density, size, and pigmentation of choroidal melanocytes. Mean choriocapillary thickness was similar between the two species (19.3 ± 3.4 vs. 19.8 ± 3.4 μm, P = 0.615), but choroidal thickness may be lower in macaques than in humans (191.2 ± 43.0 vs. 266.8 ± 78.0 μm, P < 0.001). Racial differences in uveal pigmentation also appear to affect the visibility of the choriocapillaris and CSJ on EDI-OCT.
Conclusions: Pigmented uveal melanocytes affect choroidal morphology on EDI-OCT in rhesus macaque and human eyes. Racial differences in pigmentation may affect choriocapillaris and CSJ visibility, and may influence the accuracy of choroidal thickness measurements.
PMID: 27792810 [PubMed - indexed for MEDLINE]
Genomic Disruption of VEGF-A Expression in Human Retinal Pigment Epithelial Cells Using CRISPR-Cas9 Endonuclease.
Invest Ophthalmol Vis Sci. 2016 Oct 01;57(13):5490-5497
Authors: Yiu G, Tieu E, Nguyen AT, Wong B, Smit-McBride Z
Purpose: To employ type II clustered regularly interspaced short palindromic repeats (CRISPR)-Cas9 endonuclease to suppress ocular angiogenesis by genomic disruption of VEGF-A in human RPE cells.
Methods: CRISPR sequences targeting exon 1 of human VEGF-A were computationally identified based on predicted Cas9 on- and off-target probabilities. Single guide RNA (gRNA) cassettes with these target sequences were cloned into lentiviral vectors encoding the Streptococcuspyogenes Cas9 endonuclease (SpCas9) gene. The lentiviral vectors were used to infect ARPE-19 cells, a human RPE cell line. Frequency of insertion or deletion (indel) mutations was assessed by T7 endonuclease 1 mismatch detection assay; mRNA levels were assessed with quantitative real-time PCR; and VEGF-A protein levels were determined by ELISA. In vitro angiogenesis was measured using an endothelial cell tube formation assay.
Results: Five gRNAs targeting VEGF-A were selected based on the highest predicted on-target probabilities, lowest off-target probabilities, or combined average of both scores. Lentiviral delivery of the top-scoring gRNAs with SpCas9 resulted in indel formation in the VEGF-A gene at frequencies up to 37.0% ± 4.0% with corresponding decreases in secreted VEGF-A protein up to 41.2% ± 7.4% (P < 0.001), and reduction of endothelial tube formation up to 39.4% ± 9.8% (P = 0.02). No significant indel formation in the top three putative off-target sites tested was detected.
Conclusions: The CRISPR-Cas9 endonuclease system may reduce VEGF-A secretion from human RPE cells and suppress angiogenesis, supporting the possibility of employing gene editing for antiangiogenesis therapy in ocular diseases.
PMID: 27768202 [PubMed - indexed for MEDLINE]
Role of Tractional Forces and Internal Limiting Membrane in Macular Hole Formation: Insights from Intraoperative Optical Coherence Tomography.
Case Rep Ophthalmol. 2016 May-Aug;7(2):372-376
Authors: Moisseiev E, Yiu G
We report the case of a 69-year-old patient who underwent vitrectomy for vitreomacular traction (VMT) and developed a postoperative macular hole that was observed 1 week after surgery. The hole did not close by in-office fluid-gas exchange alone, but was achieved after repeat surgery with internal limiting membrane (ILM) peeling. Intraoperative OCT (iOCT) images from the first surgery revealed an occult macular hole that formed after VMT release. We discuss how iOCT findings provide insight into the role of the ILM in macular hole formation and emphasize the importance of carefully inspecting iOCT images in real time to avoid missing small but important findings.
PMID: 27721786 [PubMed]
The suprachoroidal space: from potential space to a space with potential.
Clin Ophthalmol. 2016;10:173-8
Authors: Moisseiev E, Loewenstein A, Yiu G
Recent advances have made it possible to image the suprachoroidal space, and the understanding of its clinical applications is currently being greatly expanded. This opinion piece covers the advances in imaging techniques that enable the demonstration of the suprachoroidal space, and its implication in various retinal pathologies. It also reviews its potential uses as a route for drug delivery for the treatment of retinal diseases, and its use in innovative surgical techniques. Current research is leading the way for the suprachoroidal space to be an aspect of retinal disease diagnosis, monitoring, medical treatment, and surgical manipulation.
PMID: 26869750 [PubMed]
Relationship of central choroidal thickness with age-related macular degeneration status.
Am J Ophthalmol. 2015 Apr;159(4):617-26
Authors: Yiu G, Chiu SJ, Petrou PA, Stinnett S, Sarin N, Farsiu S, Chew EY, Wong WT, Toth CA
PURPOSE: To compare choroidal thickness in patients with intermediate or advanced age-related macular degeneration (AMD) and control subjects using enhanced-depth imaging optical coherence tomography (EDI-OCT).
DESIGN: Retrospective cross-sectional study of 325 eyes from 164 subjects who underwent EDI-OCT for the Age-Related Eye Disease Study (AREDS) 2 Ancillary Spectral Domain OCT study.
METHODS: Choroidal thickness was measured by semi-automated segmentation of EDI-OCT images from 1.5 mm nasal to 1.5 mm temporal to the fovea. Multivariate linear regression was used to evaluate the association of subfoveal choroidal thickness or average choroidal thickness across the central 3-mm segment with systemic and ocular variables. Choroidal thickness measurements were compared between eyes with no AMD (n = 154) (ie, controls), intermediate AMD (n = 109), and advanced AMD (n = 62).
RESULTS: Both subfoveal and average choroidal thicknesses were associated with age (P < .001) and refractive error (P < .001), but not other variables tested. Mean average choroidal thickness was significantly reduced in advanced AMD as compared with control eyes (P = .008), with no significant difference between advanced and intermediate AMD eyes (P = .152) or between intermediate AMD and control eyes (P = .098). Choroidal thinning was also noted from 1.5 mm nasal to 1.5 mm temporal to the fovea when comparing advanced AMD with control eyes (P < .05 at all 0.5 mm interval locations). After adjustment for age and refractive error, however, there was no significant difference in subfoveal (P = .675) or average choroidal thickness (P = .746) across all 3 groups.
CONCLUSIONS: When adjusted for age and refractive error, central choroidal thickness may not be significantly influenced by AMD status based on AREDS categorization.
PMID: 25526948 [PubMed - indexed for MEDLINE]
Effect of anti-vascular endothelial growth factor therapy on choroidal thickness in diabetic macular edema.
Am J Ophthalmol. 2014 Oct;158(4):745-751.e2
Authors: Yiu G, Manjunath V, Chiu SJ, Farsiu S, Mahmoud TH
PURPOSE: To determine the effect of anti-vascular endothelial growth factor (VEGF) therapy on choroidal thickness in eyes with diabetic macular edema (DME).
DESIGN: A retrospective, cohort analysis of 59 eyes from 59 patients with DME without prior anti-VEGF therapy.
METHODS: Choroidal thickness was measured using semiautomated segmentation of enhanced depth imaging optical coherence tomography images at 0.5-mm intervals from 2.5 mm nasal to 2.5 mm temporal to the fovea. Changes in choroidal thickness with and without anti-VEGF treatment over 6 months were compared. Best-corrected visual acuity and central foveal thickness were analyzed to evaluate the association of choroidal thickness with functional and anatomic outcomes.
RESULTS: Of the 59 eyes with DME, 26 eyes were observed without treatment, whereas 33 underwent intravitreal anti-VEGF therapy (mean number of injections, 2.73) over 6 months. In untreated eyes, there was no significant change in best-corrected visual acuity (P = .098), central foveal thickness (P = .472), or choroidal thickness at all measurements along the macula (P = .057 at the fovea). In eyes treated with anti-VEGF injections, choroidal thickness decreased significantly at the fovea (246.6 to 224.8 μm; P < .001) and at 0.5 mm nasal (240.9 to 221.9 μm; P = .002) and 0.5 mm temporal (249.3 to 224.8 μm; P = .011) to the fovea. The decrease in subfoveal choroidal thickness after anti-VEGF treatment was not associated with the cumulative number of anti-VEGF injections (R(2) = 0.031; P = .327) or to changes in best-corrected visual acuity (R(2) = 0.017; P = .470) or central foveal thickness (R(2) = 0.040; P = .263).
CONCLUSIONS: Central choroidal thickness decreases after anti-VEGF therapy for DME after 6 months, but may not be associated with functional or anatomic outcomes in eyes with DME.
PMID: 24952275 [PubMed - indexed for MEDLINE]
Current and investigational pharmacotherapeutic approaches for modulating retinal angiogenesis.
Expert Rev Clin Pharmacol. 2014 May;7(3):375-91
Authors: Todorich B, Yiu G, Hahn P
Retinal vascular development is a carefully orchestrated developmental process during which retinal and choroidal vasculature form to provide a dual vascular supply to the neurosensory retina and retinal pigment epithelium. The most common causes of vision loss in children and adults involve at least in part perturbation of the normal vascular physiology or development. Vascular endothelial growth factor has emerged as a key molecular regulator of retinal vascular development as well as retinal and choroidal neovascularization, which underlie the pathophysiology of many retinal diseases. Over the past decade, the advent of injectable pharmacotherapeutic agents into the vitreous cavity of the eye has revolutionized our management of neovascular age-related macular degeneration and other retinal diseases and has, for the first time, offered an opportunity to improve vision rather than just slow the progression of disease processes. The transient duration of these agents, however, requires chronic treatment with repeated intraocular injections and significant treatment burden for patients and the healthcare system. Novel treatments modulating retinal angiogenesis offer the promise of improved efficacy, decreased treatment burden and improved cost-effectiveness.
PMID: 24580084 [PubMed - indexed for MEDLINE]
Characterization of the choroid-scleral junction and suprachoroidal layer in healthy individuals on enhanced-depth imaging optical coherence tomography.
JAMA Ophthalmol. 2014 Feb;132(2):174-81
Authors: Yiu G, Pecen P, Sarin N, Chiu SJ, Farsiu S, Mruthyunjaya P, Toth CA
IMPORTANCE: Accurate measurements of choroidal thickness (CT) using enhanced-depth imaging optical coherence tomography (EDI-OCT) require a well-defined choroid-scleral junction (CSJ), which may appear in some eyes as a hyporeflective band corresponding to the suprachoroidal layer (SCL).
OBJECTIVE: To identify factors associated with the presence and thickness of the SCL in healthy participants and determine how different CSJ boundary definitions impact CT measurements.
DESIGN, SETTING, AND PARTICIPANTS: Secondary analysis of EDI-OCT images obtained prospectively from 74 eyes of 74 controls (mean age, 68.6 years) from the Age-Related Eye Disease Study 2 Ancillary SDOCT Study.
MAIN OUTCOMES AND MEASURES: The CSJ appearances were categorized as either having no visible SCL or a hyporeflective band corresponding to the SCL. Ocular parameters associated with the presence and thickness of the SCL were identified. Subfoveal CT was measured using 3 different posterior boundaries: (1) the posterior vessel border (vascular CT [VCT]), (2) inner border of the SCL (stromal CT [StCT]), and (3) inner border of the sclera (total CT [TCT]). Manual segmentation using custom software was used to compare VCT, StCT, and TCT across the macula. RESULTS The SCL was visible in 33 eyes (44.6%). Factors associated with SCL presence and thickness included hyperopic refractive error (R2 = 0.123; P = .045) and increased TCT (R2 = 0.215; P = .004), but not age, visual acuity, intraocular pressure, retinal foveal thickness, VCT, or StCT. In eyes where the SCL was not visible, mean [SD] subfoveal VCT was 222.3 [101.5] μm and StCT and TCT were 240.0 [99.0] μm, with a difference of 17.7 [16.0] μm (P < .001). In eyes where the SCL was visible, mean [SD] subfoveal VCT, StCT, and TCT were 221.9 [83.1] μm, 257.7 [97.3] μm, and 294.1 [104.8] μm, respectively, with the greatest difference of 72.2 [30.4] μm between VCT and TCT (P < .001). All 3 CT measurements were significantly different along all points up to 3.0 mm nasal and temporal to the fovea.
CONCLUSIONS AND RELEVANCE: A hyporeflective SCL is visible at the CSJ on EDI-OCT in nearly half of healthy individuals, and its presence correlates with hyperopia. Different posterior boundary definitions may result in significant differences in CT measurements and should be explicitly identified in future choroidal studies and segmentation algorithms.
PMID: 24336985 [PubMed - indexed for MEDLINE]
Choroidal metastatasis from a neuroendocrine tumor masquerading as choroidal melanoma.
Ophthalmic Surg Lasers Imaging Retina. 2014 Sep-Oct;45(5):456-8
Authors: Yiu G, Cummings TJ, Mruthyunjaya P
A mushroom-shaped choroidal mass is classically suggestive of melanoma, due to the ability of these tumors to erupt through Bruch's membrane. In contrast, choroidal metastases rarely adopt this growth pattern. The authors present an unusual case of a patient with a large choroidal metastasis from a pancreatic neuroendocrine tumor that shows a collar-button configuration. The diagnosis was confirmed by histology and immunohistochemistry following enucleation. The authors review the typical appearance of choroidal metastases from neuroendocrine tumors and discuss mechanisms by which uveal tumors may extend through Bruch's membrane.
PMID: 25153655 [PubMed - indexed for MEDLINE]
Dev Ophthalmol. 2014;54:213-22
Authors: Yiu G, Mahmoud TH
Large submacular hemorrhage (SMH) is a devastating complication of neovascular age-related macular degeneration (AMD) that cannot be effectively managed with anti-vascular endothelial growth factor injections alone. While SMH is not common, AMD patients with existing coagulopathies or taking anticoagulant medications are particularly susceptible. Today, various techniques are available for the management of SMH, including pneumatic displacement with or without intravitreal tissue plasminogen activator (tPA), pars plana vitrectomy with subretinal tPA and gas tamponade, and submacular surgery with vitrectomy and retinotomy for clot extraction. While no consensus exists, the preferred technique is often determined by the extent or duration of the hemorrhage and surgeon preference. This chapter reviews treatment options for managing SMH, as well as the current evidence for supporting their use.
PMID: 25196772 [PubMed - indexed for MEDLINE]
Surgical outcomes after epiretinal membrane peeling combined with cataract surgery.
Br J Ophthalmol. 2013 Sep;97(9):1197-201
Authors: Yiu G, Marra KV, Wagley S, Krishnan S, Sandhu H, Kovacs K, Kuperwaser M, Arroyo JG
OBJECTIVE: To compare functional and anatomical outcomes after idiopathic epiretinal membrane (ERM) peeling combined with phacoemulsification and intraocular lens implantation versus ERM peeling alone.
METHODS: A retrospective, non-randomised comparative case series study was conducted of 81 eyes from 79 patients who underwent ERM peeling at the Beth Israel Deaconess Medical Center between 2001 and 2010. Eyes that underwent combined surgery for ERM and cataracts (group 1) were compared with those that had ERM peeling alone (group 2) with respect to best-corrected visual acuity at 6 months and 1 year after surgery, postoperative central macular thickness (CMT) as measured on optical coherence tomography, and rates of complications, including elevated intraocular pressure (IOP), ERM recurrence and need for reoperation.
RESULTS: Mean logMAR visual acuity improved significantly in both groups at 6 months (p<0.001) and 1 year (p<0.001) after surgery. There was no statistical difference between the two groups in visual acuity improvement at 6 months (p=0.108) or 1 year (p=0.094). Mean CMT of both groups also significantly decreased after surgery (p=0.002), with no statistical difference in CMT reduction between the two groups, but a trend toward less CMT reduction in group 1 (p=0.061). The rates of complications, including IOP elevation, ERM recurrence and frequency of reoperation, were similar in the two groups, with non-statistical trends toward greater ERM recurrence (p=0.084) and need for reoperation (p=0.096) in those that had combined surgery.
CONCLUSIONS: Combined surgery for ERMs and cataracts may potentially be as effective as membrane peeling alone with respect to visual and anatomical outcomes. Further studies are necessary to determine if there may be greater ERM recurrence or need for reoperation after combined surgery.
PMID: 23832965 [PubMed - indexed for MEDLINE]
Progressive outer retinal necrosis presenting as cherry red spot.
Ocul Immunol Inflamm. 2012 Oct;20(5):384-6
Authors: Yiu G, Young LH
PURPOSE: To report a case of progressive outer retinal necrosis (PORN) presenting as a cherry red spot.
METHODS: Case report.
RESULTS: A 53-year-old woman with recently diagnosed HIV and varicella-zoster virus (VZV) aseptic meningitis developed rapid sequential vision loss in both eyes over 2 months. Her exam showed a "cherry red spot" in both maculae with peripheral atrophy and pigmentary changes, consistent with PORN. Due to her late presentation and the rapid progression of her condition, she quickly developed end-stage vision loss in both eyes.
CONCLUSIONS: PORN should be considered within the differential diagnosis of a "cherry red spot." Immune-deficient patients with a history of herpetic infection who present with visual loss warrant prompt ophthalmological evaluation.
PMID: 22957726 [PubMed - indexed for MEDLINE]
Dorsal midbrain syndrome from a ring-enhancing lesion.
Semin Ophthalmol. 2012 May-Jul;27(3-4):65-8
Authors: Yiu G, Lessell S
A ring-enhancing lesion is an uncommon cause of a dorsal midbrain syndrome. Here, we describe the case of a 60-year-old man with eye movement and pupillary findings consistent with dorsal midbrain syndrome, and in whom neuroimaging showed a single ring-enhancing lesion in the right midbrain and thalamus. Further investigation revealed a longstanding right groin mass which proved to be a malignant melanoma. His intracranial lesion was presumed to be a metastatic lesion, and treated with stereotactic radiosurgery. We report the patient's clinical course, and discuss the diagnosis and management of the solitary midbrain lesion.
PMID: 22784268 [PubMed - indexed for MEDLINE]