Crystalline Hepatopathy Associated With Bietti Crystalline Dystrophy: A Striking Manifestation of Disordered Fatty Acid Metabolism.

Bietti crystalline dystrophy (BCD) is a rare heritable retinal disease characterized by crystal deposition primarily in the retina. It is associated with atrophy of the retinal pigment epithelium (RPE) and is caused by variants in CYP4V2, which encodes a cytochrome P450 hemethiolate protein superfamily member. CYP4V2 is involved in the selective hydrolysis of saturated medium chain fatty acids, and patients with BCD demonstrate abnormalities in fatty acid metabolism, including abnormal lipid profiles and the accumulation of the pathogenic crystals within the RPE, which leads to the visual pathologies characteristic of BCD. However, the precise identity of the crystals is currently unknown, and BCD has no established extraocular manifestations. Here, we report granulomatous hepatitis associated with abundant diffuse crystalline clefts in the hepatic parenchyma in 3 patients with retinal dystrophy and dyslipidemia: 2 with pathogenic CYP4V2 variants and 1 patient with clinical ophthalmologic findings suggestive of BCD but without available genetic testing. The unique and striking histologic features unifying the liver biopsies in all 3 patients strongly support a process related to abnormal fatty acid metabolism underlying the genetic disease of BCD, expanding the spectrum of BCD and shedding light on the importance of CYP4V2 in systemic fatty acid metabolism.

METformin for the MINimization of Geographic Atrophy Progression (METforMIN): A Randomized Trial.

Purpose: Metformin use has been associated with a decreased risk of age-related macular degeneration (AMD) progression in observational studies. We aimed to evaluate the efficacy of oral metformin for slowing geographic atrophy (GA) progression. Design: Parallel-group, multicenter, randomized phase II clinical trial. Participants: Participants aged ≥ 55 years without diabetes who had GA from atrophic AMD in ≥ 1 eye. Methods: We enrolled participants across 12 clinical centers and randomized participants in a 1:1 ratio to receive oral metformin (2000 mg daily) or observation for 18 months. Fundus autofluorescence imaging was obtained at baseline and every 6 months. Main Outcome Measures: The primary efficacy endpoint was the annualized enlargement rate of the square root-transformed GA area. Secondary endpoints included best-corrected visual acuity (BCVA) and low luminance visual acuity (LLVA) at each visit. Results: Of 66 enrolled participants, 34 (57 eyes) were randomized to the observation group and 32 (53 eyes) were randomized to the treatment group. The median follow-up duration was 13.9 and 12.6 months in the observation and metformin groups, respectively. The mean ± standard error annualized enlargement rate of square root transformed GA area was 0.35 ± 0.04 mm/year in the observation group and 0.42 ± 0.04 mm/year in the treatment group (risk difference = 0.07 mm/year, 95% confidence interval = -0.05 to 0.18 mm/year; P = 0.26). The mean ± standard error decline in BCVA was 4.8 ± 1.7 letters/year in the observation group and 3.4 ± 1.1 letters/year in the treatment group (P = 0.56). The mean ± standard error decline in LLVA was 7.3 ± 2.5 letters/year in the observation group and 0.8 ± 2.2 letters/year in the treatment group (P = 0.06). Fourteen participants in the metformin group experienced nonserious adverse events related to metformin, with gastrointestinal side effects as the most common. No serious adverse events were attributed to metformin. Conclusions: The results of this trial as conducted do not support oral metformin having effects on reducing the progression of GA. Additional placebo-controlled trials are needed to explore the role of metformin for AMD, especially for earlier stages of the disease. Financial Disclosures: Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

Electroretinographic findings in retinal vasculitis.

AIM: To describe and correlate electroretinographic responses with clinical and angiographic findings in retinal vasculitis (RV). METHODS: Medical records of patients with diagnosis of RV at a tertiary eye centre from December 2017 to May 2021 were reviewed. Cases in which fluorescein angiography (FFA) and full field electroretinography (ffERG) were done within 1 month were included. FFAs were graded according to the Angiography Scoring for Uveitis Working Group from 0 to 40, where 0 is normal. A novel ffERG grading system was implemented where individual waves were graded for timing and amplitude and general ffERG score was determined with 6 being a perfect score. RESULTS: 20 patients (34 eyes) were included. Mean age was 43.9±19.8 years; 70% were female. Median best-corrected visual acuity was 0.8 (0.08-1). Mean FFA score was 12.6±6.5. Median general ffERG score was 5 (0-6). 68% and 91% of eyes had responses with general ffERG scores ≥5 and 4, respectively. Flicker timing was most commonly affected.FFA scores weakly correlated with delayed photopic cone b-wave and flicker timing (p=0.03 and 0.016, respectively). Vitreous haze moderately correlated with delayed cone b-wave timing (p<0.001), delayed flicker timing (p=0.002) and weakly correlated with lower flicker amplitude (p=0.03). Underlying systemic disease was associated with poor ffERG responses. CONCLUSION: In this study, RV was not frequently associated with severe global retinal dysfunction Higher FFA scores, and vitreous haze grading were weakly, but significantly, correlated with cone-generated ffERG responses.

C3 glomerulopathy associated with both hypertensive retinopathy and purtscher-like retinopathy.

Purpose: This article reports the case of a 21-year-old woman with both hypertensive retinopathy and Purtscher-like retinopathy in association with C3 glomerulopathy. Observations: The patient was referred for bilateral painless vision loss with posterior pole cotton wool spots, optic disc edema, and confluent retinal whitening suggesting a mixed picture of hypertensive retinopathy, with initial blood pressure 236/152, and Purtscher-like retinopathy. She was subsequently diagnosed with C3 glomerulopathy which likely caused her severe hypertension and which likely occurred alongside Purtscher-like retinopathy due to a shared pathogenesis of complement dysregulation. Follow up examination and imaging revealed gradual improvement in visual acuity, almost complete resolution of fundus exam abnormalities, improvement in macular nonperfusion, resolution of disc leakage and choroidal leakage, resolution of macular edema, and residual outer retinal hyperreflective foci in both eyes. Conclusion and importance: This case represents the first report of both Purtscher-like retinopathy and hypertensive retinopathy occurring in association with C3 glomerulopathy. It supports investigation of anti-complement therapy as a potential treatment for Purtscher-like retinopathy.

Immunotherapy-induced retinopathy mimicking cancer associated retinopathy.

Purpose: To report a patient who developed a cancer associated retinopathy (CAR) like syndrome in the setting of pembrolizumab and lenvatinib combination therapy for metastatic endometrial carcinoma. Symptoms resolved with normalization of objective functional tests following cessation of medications. Observations: A 52-year-old female with history of endometrial carcinoma, managed with pembrolizumab infusions and daily oral lenvatinib treatment for 18 months, presented to a tertiary eye center with complaints of nyctalopia, photosensitivity and photopsia. Further investigations revealed a reduction in b-wave amplitude on full field ERG (ffERG), a mild color vision deficit, and positive antiretinal antibodies against carbonic anhydrase II, enolase and arrestin. A preliminary diagnosis of CAR was made. One month following diagnosis, the patient discontinued both lenvatinib and pembrolizumab and subsequently reported significant improvement in her eye symptoms and vision. Repeat ffERG had normalized with a robust b-wave, with an improvement noted on repeat color vision testing. A presumed diagnosis of immunotherapy-induced retinopathy was made, with clinical findings mimicking CAR. Conclusions and importance: Pembrolizumab and lenvatinib treatment may be associated with a reversible retinopathy, with presentation very similar to CAR.

Macular Edema and Serous Macular Detachment after a Standard Dose of Intracameral Cefuroxime.

Intracameral cefuroxime has been associated with postoperative macular edema and sub-retinal fluid. To date, nearly all published cases are attributed to errors in antibiotic dilution, leading to administration of supratherapeutic doses. We report three cases of postoperative macular edema and subretinal fluid following a standard dose of 1 mg/0.1 mL of cefuroxime at the end of cataract surgery. Distinguishing features of these cases were intraoperative zonular instability and history of vitrectomy. We hypothesize that certain factors may increase the risk of cefuroxime-associated retinal toxicity, including history of vitrectomy, zonular compromise, posterior capsular break, surgery for a secondary intraocular lens, and unicameral state. [Ophthalmic Surg Lasers Imaging Retina. 2021;52:615-618.].

Comparison of Telemedicine Screening of Diabetic Retinopathy by Mydriatic Smartphone-Based vs Nonmydriatic Tabletop Camera-Based Fundus Imaging.

PURPOSE: To compare dilated smartphone-based imaging with a nonmydriatic, tabletop fundus camera as a teleophthalmology screening tool for diabetic retinopathy (DR). METHODS: This was a single-institutional, cross-sectional, comparative-instrument study. Fifty-six patients at a safety-net hospital underwent teleophthalmology screening for DR using standard, nonmydriatic fundus photography with a tabletop camera (Nidek NM-1000) and dilated fundus photography using a smartphone camera with lens adapter (Paxos Scope, Verana Health). Masked graders performed standardized photo grading. Quantitative comparisons were performed employing descriptive, κ, Bland-Altman, and receiver operating characteristic analyses. RESULTS: Posterior segment photography was of sufficient quality to grade in 89% of mydriatic smartphone-imaged eyes and in 86% of nonmydriatic tabletop camera-imaged eyes (P = .03). Using the tabletop camera as the reference to detect moderate nonproliferative DR or worse (referral-warranted DR), mydriatic smartphone-acquired photographs were found to be 82% sensitive and 96% specific. Dilated smartphone imaging detected referral-warranted DR in 3 eyes whose tabletop camera imaging did not demonstrate referral-warranted DR. Secondary masked review of medical records for the discordances in referral-warranted status from the two imaging modalities was performed, and it revealed revised sensitivity and specificity values of 95% and 98%, respectively. Overall, there was good agreement between tabletop camera and smartphone-acquired photo grades (κ = 0.91 ± 0.1, P < .001; area under the receiver operating characteristic curve = 0.99, 95% CI, 0.98-1.00). CONCLUSIONS: Mydriatic smartphone-based imaging resulted in fewer ungradable photos compared to nonmydriatic table-top camera imaging and detected more patients with referral-warranted DR. Our study supports the use of mydriatic smartphone teleophthalmology as an alternative method to screen for DR.

Retinal Diseases that Can Masquerade as Neurological Causes of Vision Loss.

PURPOSE OF REVIEW: This review aims to discuss retinal diseases that may masquerade as neurological causes of vision loss and highlights modern ophthalmic ancillary testing that can help to establish these diagnoses. RECENT FINDINGS: Retinal diseases with signs and symptoms overlapping with neurological causes of vision loss include central serous chorioretinopathy, retinal ischemia, acute macular neuroretinopathy, Acute zonal occult outer retinopathy (AZOOR) complex diseases, paraneoplastic retinopathy, retinal dystrophy, and toxic retinopathy. Diagnosis is facilitated by electrophysiologic studies and multimodal ophthalmic imaging including optical coherence tomography and fundus autofluorescence imaging. Looking into the future, translation of adaptive optics ophthalmoscopy into clinical practice may facilitate early detection of microscopic retinal abnormalities that characterize these conditions. With conventional methods of physical examination, diagnosis of retinal diseases that may masquerade as neurological causes of vision loss can be challenging. Current advance in multimodal ophthalmic imaging along with electrophysiologic studies enhances the provider's ability to make early diagnosis and monitor progression of these conditions.

Assessment of Eye Disease and Visual Impairment in the Nursing Home Population Using Mobile Health Technology.

BACKGROUND AND OBJECTIVE: To characterize the burden of eye disease and the utility of teleophthalmology in nursing home patients, a population with ophthalmic needs not commensurate with care received. PATIENTS AND METHODS: Informed consent was obtained from 78 California Bay Area skilled nursing facility patients. Near visual acuity (VA) and anterior/posterior segment photographs were taken with a smartphone-based VA app and ophthalmic camera system. The Nursing Home Vision-Targeted Health-Related Quality of Life questionnaire was also administered. Risk factors for visual impairment were assessed. Institutional review board approval was obtained from Stanford University. RESULTS: Cataracts (51%), diabetic retinopathy (DR) (12%), optic neuropathy (12%), and age-related macular degeneration (AMD) (10%) were common findings; 11.7% had other referral-warranted findings. AMD and DR correlated with a higher risk of poor VA, with adjusted odds ratios of 22 (P = .01) and 43 (P = .004). CONCLUSIONS: This study demonstrated a high prevalence of poor VA and ophthalmic disease in the nursing home population impacting quality of life. Smartphone-based teleophthalmology platforms have the potential to increase access to eye care for nursing home patients. [Ophthalmic Surg Lasers Imaging Retina. 2020;51:262-270.].

Reductions in final visual acuity occur even within the first 3 days after a macula-off retinal detachment.

PURPOSE: To determine if final visual acuity (VA) is affected by duration of macular detachment (DMD) within the first week of macula-off retinal detachment (RD). METHODS: This is a retrospective study of eyes that underwent repair within 7 days with vitrectomy or vitrectomy with scleral buckle for macula-off RD at Stanford University Hospital between 1 May 2007 and 1 May 2017. A generalised linear model was constructed using DMD, postoperative lens status, preoperative VA, patient age and surgeon as the independent variables and the final VA as the dependent variable. The main outcome measure was the final VA. RESULTS: Seventy-nine eyes met the entry criteria. Group 1 included 52 eyes with RD repaired within 3 days of DMD, and group 2 included 27 eyes repaired between 4 and 7 days of DMD. The average final VA in group 1 eyes was logarithm of the minimum angle of resolution (logMAR) 0.21 (Snellen 20/33) and in group 2 eyes was logMAR 0.54 (Snellen 20/69). In group 1 and group 2 eyes, preoperative VA (p=0.017and p=0.007), DMD (p=0.004 and p=0.041) and final lens status (p<0.0001 and p<0.001) predicted postoperative VA. Post-hoc analysis showed significant differences in final VA between detachments of 1day vs 3 days (p=0.0009). CONCLUSION: DMD affects the final VA even among patients whose DMD is <3 days. Based on these results, interventions that shorten DMD, including those occurring within the first 3days, may result in improved long-term VA outcomes.

Photodynamic Therapy-Induced Macular Hole.

A 72-year-old female with neovascular macular degeneration refractory to anti-vascular endothelial growth factor injections underwent photodynamic therapy and subsequently developed a macular hole (MH) associated with vitreomacular traction. After a period of observation, the MH enlarged. Pars plana vitrectomy was performed, and the MH was closed successfully. [Ophthalmic Surg Lasers Imaging Retina. 2018;49:270-272.].

Comparison of Pneumatic Retinopexy and Scleral Buckle for Primary Rhegmatogenous Retinal Detachment Repair.

BACKGROUND AND OBJECTIVE: To compare pneumatic retinopexy (PR) and scleral buckle for the repair of primary rhegmatogenous retinal detachment. PATIENTS AND METHODS: Retrospective analysis of 90 patients undergoing surgery for primary rhegmatogenous retinal detachment, with 46 patients undergoing PR compared with 44 patients undergoing scleral buckle procedure (SBP). RESULTS: Both groups had similar baseline characteristics. Single surgery reattachment rate was 95.5% with SBP and 67% with PR (P = .00057). Final reattachment rate was 100% with SBP and 97.8% with PR. A final visual acuity (VA) of 20/40 or better occurred in 89% of patients with SBP and 72% of patients with PR (P = .04). PR and SBP had a similar mean VA if the primary procedures were successful, whereas those patients with unsuccessful PR had lower mean final acuities. CONCLUSIONS: This study demonstrates that SBP has a significantly higher rate of single surgery reattachment than PR, along with improved final VA. Initial success of PR may be an important predictor of final visual outcome. [Ophthalmic Surg Lasers Imaging Retina. 2017;48:887-893.].

Rapid Onset of Retinal Toxicity From High-Dose Hydroxychloroquine Given for Cancer Therapy.

PURPOSE: To report rapid onset of retinal toxicity in a series of patients followed on high-dose (1000 mg daily) hydroxychloroquine during an oncologic clinical trial studying hydroxychloroquine with erlotinib for non-small cell lung cancer. DESIGN: Retrospective observational case series. METHODS: Ophthalmic surveillance was performed on patients in a multicenter clinical trial testing high-dose (1000 mg daily) hydroxychloroquine for advanced non-small cell lung cancer. The US Food & Drug Administration-recommended screening protocol included only visual acuity testing, dilated fundus examination, Amsler grid testing, and color vision testing. In patients seen at Stanford, additional sensitive screening procedures were added at the discretion of the retinal physician: high-resolution spectral-domain optical coherence tomography (OCT), fundus autofluorescence (FAF) imaging, Humphrey visual field (HVF) testing, and multifocal electroretinography (mfERG). RESULTS: Out of the 7 patients having exposure of at least 6 months, 2 developed retinal toxicity (at 11 and 17 months of exposure). Damage was identified by OCT imaging, mfERG testing, and, in 1 case, visual field testing. Fundus autofluorescence imaging remained normal. Neither patient had symptomatic visual acuity loss. CONCLUSIONS: These cases show that high doses of hydroxychloroquine can initiate the development of retinal toxicity within 1-2 years. Although synergy with erlotinib is theoretically possible, there are no prior reports of erlotinib-associated retinal toxicity despite over a decade of use in oncology. These results also suggest that sensitive retinal screening tests should be added to ongoing and future clinical trials involving high-dose hydroxychloroquine to improve safety monitoring and preservation of vision.

Restoration of retinal structure and function after selective photocoagulation.

CNS neurons change their connectivity to accommodate a changing environment, form memories, or respond to injury. Plasticity in the adult mammalian retina after injury or disease was thought to be limited to restructuring resulting in abnormal retinal anatomy and function. Here we report that neurons in the mammalian retina change their connectivity and restore normal retinal anatomy and function after injury. Patches of photoreceptors in the rabbit retina were destroyed by selective laser photocoagulation, leaving retinal inner neurons (bipolar, amacrine, horizontal, ganglion cells) intact. Photoreceptors located outside of the damaged zone migrated to make new functional connections with deafferented bipolar cells located inside the lesion. The new connections restored ON and OFF responses in deafferented ganglion cells. This finding extends the previously perceived limits of restorative plasticity in the adult retina and allows for new approaches to retinal laser therapy free of current detrimental side effects such as scotomata and scarring.

Effect of intravitreal triamcinolone acetonide on healing of retinal photocoagulation lesions.

PURPOSE: To evaluate the effect of intravitreal triamcinolone acetonide (TA) on healing of retinal photocoagulation lesions using drug and laser dosing typically employed in clinical practice. METHODS: Laser burns with a 267-µm retinal beam size at 532-nm wavelength were applied to 40 eyes of Dutch belted rabbits. Barely visible to intense lesions were produced with pulses of 5, 10, 20, and 50 milliseconds and power of 175 mW. Eyes received intravitreal injections of either 2 mg TA/50 µL or balanced salt solution administered either 1 week before or immediately after laser treatment. Lesion grades were assessed acutely ophthalmoscopically and by a masked observer histologically at 1, 3, 7, 30, and 60 days. RESULTS: Both TA groups demonstrated significant reduction in retinal thickness throughout follow-up compared with balanced salt solution groups (P < 0.001). The width of the lesions at 1 day after injection was not significantly different between groups. However, by 7 days, the lesions in balanced salt solution groups contracted much more than in the TA groups, especially the more intense burns, and this difference persisted to 2 months. The healing rate of the barely visible burns was not significantly affected by TA compared with the balanced salt solution control eyes. CONCLUSION: Triamcinolone acetonide injection previously or concurrently with photocoagulation significantly decreases laser-induced edema but interferes with lesions healing, thereby leaving wider residual scarring, especially persistent in more intense burns.

Macular infarction following intravitreal bevacizumab for treatment of central retinal vein occlusion.

Bevacizumab, a monoclonal antibody against vascular endothelial growth factor (VEGF), is widely used for the treatment of macular edema associated with central retinal vein occlusion (CRVO). The authors present a series of three patients with CRVO who suffered apparent macular infarction within weeks of intravitreal administration of bevacizumab. Of the nearly 200 patients undergoing intravitreal injections of bevacizumab for this indication over a surveillance period of 3 years, this event occurred in three patients. This has not been described in the natural history of the disease and is associated with poor visual outcomes.

Therapeutic window of retinal photocoagulation with green (532-nm) and yellow (577-nm) lasers.

BACKGROUND AND OBJECTIVE: The 577-nm (yellow) laser provides an alternative to the 532-nm (green) laser in retinal photocoagulation, with potential benefits in macular treatment and through ocular opacities. To assess relative risk of thermomechanical rupture of Bruch's membrane with yellow laser in photocoagulation, the therapeutic window, the ratio of threshold powers for mild coagulation and rupture, was measured. MATERIALS AND METHODS: Retinal coagulation and rupture thresholds, visualized ophthalmoscopically, were measured with 577- and 532-nm lasers using 10- to 100-ms pulses in 34 rabbit eyes. Lesions at 1 and 7 days were assessed histologically. RESULTS: Coagulation threshold with yellow laser was 26% lower than with green laser. The therapeutic window increased linearly with log-duration for both wavelengths with a difference in parallel-slope intercept of 0.36 ± 0.20, corresponding to 8% to 15% wider therapeutic window for yellow wavelength. CONCLUSION: The therapeutic window of retinal photocoagulation in rabbits at 577 nm is slightly wider than at 532 nm, whereas histologically the lesions are similar.

Critical appraisal of the clinical utility of the dexamethasone intravitreal implant (Ozurdex) for the treatment of macular edema related to branch retinal vein occlusion or central retinal vein occlusion.

Macular edema is a common cause of visual loss in patients with retinal vein occlusions. Ozurdex(®), a dexamethasone intravitreal implant, has been shown in randomized controlled trials to reduce macular edema and improve visual acuity in patients with either branch retinal vein occlusions or central retinal vein occlusions. It was approved in the United States in 2009. Since then, new therapeutic agents and clinical data have emerged. The purpose of this review is to critically evaluate the clinical utility of Ozurdex(®) in the current treatment strategy of macular edema related to retinal vein occlusion.