Comparative analysis of in-silico tools in identifying pathogenic variants in dominant inherited retinal diseases.

Inherited retinal diseases (IRDs) are a group of rare genetic eye conditions that cause blindness. Despite progress in identifying genes associated with IRDs, improvements are necessary for classifying rare autosomal dominant (AD) disorders. AD diseases are highly heterogenous, with causal variants being restricted to specific amino acid changes within certain protein domains, making AD conditions difficult to classify. Here, we aim to determine the top-performing in-silico tools for predicting the pathogenicity of AD IRD variants. We annotated variants from ClinVar and benchmarked 39 variant classifier tools on IRD genes, split by inheritance pattern. Using area-under-the-curve (AUC) analysis, we determined the top-performing tools and defined thresholds for variant pathogenicity. Top-performing tools were assessed using genome sequencing on a cohort of participants with IRDs of unknown etiology. MutScore achieved the highest accuracy within AD genes, yielding an AUC of 0.969. When filtering for AD gain-of-function and dominant negative variants, BayesDel had the highest accuracy with an AUC of 0.997. Five participants with variants in NR2E3, RHO, GUCA1A, and GUCY2D were confirmed to have dominantly inherited disease based on pedigree, phenotype, and segregation analysis. We identified two uncharacterized variants in GUCA1A (c.428T>A, p.Ile143Thr) and RHO (c.631C>G, p.His211Asp) in three participants. Our findings support using a multi-classifier approach comprised of new missense classifier tools to identify pathogenic variants in participants with AD IRDs. Our results provide a foundation for improved genetic diagnosis for people with IRDs.

Treatment of serpiginous choroiditis with sub-tenon triamcinolone in conjunction with systemic steroids case report.

PURPOSE: To report two cases of serpiginous choroiditis which were treated with sub-Tenon's triamcinolone in conjunction with systemic steroids to control acute and chronic disease progression. Increased success of disease remission has been postulated for sub-Tenon's triamcinolone therapy in conjunct with systemic steroids. METHODS: Retrospective chart review of two serpiginous choroiditis patients who presented at an eye center. Both patients received sub-Tenon's triamcinolone and systemic steroids. Visual acuity and disease course are reported. RESULTS: Both cases of serpiginous choroiditis received sub-Tenon's triamcinolone on presentation and were hospitalized for intravenous corticosteroids and systemic work up. The first patient had been on oral corticosteroids before presentation. Both patients reported same day visual improvement after sub-Tenon's triamcinolone was administered. CONCLUSIONS: These two case reports describe unique clinical scenarios in which sub-Tenon's triamcinolone was used in both the acute and chronic phases of serpiginous choroiditis. Local steroid therapy can be a useful adjunctive therapy when systemic steroids are delayed, contraindicated or intolerable.

Optic inversion of scleral-fixated intraocular lens after vitrectomy with fluid-air exchange: case series and review of the literature.

Lens dislocation is a significant complication after cataract surgery. Scleral fixation of 3-piece intraocular lens provides favorable visual outcome and can spare patients the need for lens exchange. Two patients presented with dislocated 3-piece lenses implanted over 10 years earlier. Both patients underwent pars plana vitrectomy and dropped lens rescue with scleral fixation. Postoperatively, the lens optic was found flipped nearly 90° at the optic-haptic junctions secondary to fluid-air exchange performed during vitrectomy. Both patients underwent intraocular lens exchange with a four point sclera fixated lens. Our study found that air tamponade is better avoided during rescue of old dislocated 3-piece lens implants. Intraocular lens exchange is preferred, when possible, to avoid complications associated with old dislocated lenses. Larger studies are needed to determine the effect of time on dislocated lens implants materials.

Endoscopy-assisted pars plana vitrectomy in retinal detachments associated with anterior proliferative vitreoretinopathy and epiciliary membranes.

BACKGROUND: Proliferative vitreoretinopathy (PVR) is the leading cause of recurrent retinal detachment. Anterior PVR can contribute to recurrent retinal detachment and is often difficult to remove during conventional pars plana vitrectomy. The purpose of this study is to report surgical outcomes of single endoscopy-assisted pars plana vitrectomy (E-PPV) in patients with tractional retinal detachments associated with anterior proliferative vitreoretinopathy and epiciliary membranes. METHODS: Retrospective review of E-PPV between 2017 and 2021 at a tertiary referral center. Inclusion criteria involved adult patients who underwent E-PPV for tractional retinal detachment with anterior PVR and epiciliary membranes. Data collection included patients' demographics, ophthalmic exam findings, and surgical outcomes. A series of independent sample tests of proportion were conducted using a p-value of 0.05 as the threshold for statistical significance. RESULTS: Eighteen out of 55 patients who underwent E-PPV met the inclusion criteria. There were six females (33%) and 12 males (p-value = 0.096). Age ranged between 27 and 82 years old (mean age 52.1 ± 17.3 years). Nine patients (50%) had a history of ipsilateral retinal detachment repair. Single E-PPV success rate was 100% after three months, and 94.4% at the latest follow up visit. Recurrent retinal detachment with posterior PVR occurred in one patient four months after surgery. Cataract progressed in 57% (8/14) of phakic patients, with 63% (5/8) undergoing cataract extraction surgery within the first postoperative year. CONCLUSION: E-PPV enabled epiciliary membrane and anterior PVR visualization and removal. The single E-PPV success rate remained high at the latest follow up visit. E-PPV enabled the preservation of the phakic lens in all study patients. Larger prospective studies are needed on the role of E-PPV in retina surgeries.

Prophylactic Laser Treatment Posterior to Pars Plana Vitrectomy Sclerotomy Wounds During Macular Surgery.

Introduction: Sclerotomy related retinal breaks (SRRBs) are a risk factor for postoperative retinal detachment (RD). Endolaser posterior to sclerotomy wounds decreased the risk of SRRBs after 20G pars plana vitrectomy (PPV) for macular disease. However, similar data do not exist for 25G and 23G wounds. Methods: A retrospective cohort study of patients after 23G and 25G PPV for macular pathology was conducted between August 2017 and August 2020. The primary outcome was the postoperative rate of SRRBs or RDs. The secondary outcome was the postoperative rate of pupillary dysfunction and neurotrophic keratopathy. All participants had a minimum postoperative follow-up of one year. Results: One hundred seventeen patients were included in the study (62 in the laser group and 55 in the control group). Mean age was 65.4 ± 11.3 years (56.4% female and 43.6% male). Most of the laser group underwent 23G PPV (90%) while most of the control group underwent 25G PPV (96%). One patient in the control group developed RD secondary to a SRRB. No SRRBs or RDs developed in the laser group. None of the secondary outcomes developed in either group after one year. Conclusions: To the best of the authors' knowledge, this is the first report in the literature on prophylactic laser posterior to small gauge sclerotomies (25G and 23G) during macular surgery. Laser treatment posterior to small gauge sclerotomies (25G and 23G) had a similar incidence of SRRBs as with 20G sclerotomies. Larger prospective studies are needed to further understand the role of laser in lowering SRRB risk.

Bilateral Exudative Retinal Detachments Associated with Nivolumab Immunotherapy.

A 58-year-old Caucasian female presented to the retina service with a 2-week history of bilateral decrease in vision. She had stage 4 renal cell carcinoma with osseous metastasis and choroidal metastasis for which she has been treated with Nivolumab immunotherapy. Her exudative retinal detachments resolved after cessation of Nivolumab in association with subtenon steroids (STK) and intravitreal bevacizumab injections. To the best of our knowledge, this is the first report in the literature describing the resolution of Nivolumab-related exudative retinal detachment after early local therapy using STK injections (10 mg), bevacizumab intravitreal injections, and cessation of Nivolumab. We hope by sharing this report to provide new insight into the management of similar patients.

Seronegative ocular toxoplasma panuveitis in an immunocompetent patient.

PURPOSE: Toxoplasma gondii is the most common cause of infectious posterior uveitis worldwide in immunocompetent patients. Despite its prevalence, diagnosis can still be challenging and vision-threatening in cases with atypical presentations. This case exemplifies the importance of clinical exam and additional workup when required despite negative initial serology results. OBSERVATIONS: A 73-year-old immunocompetent woman presented with a 2-year history of recurrent panuveitis and retinal necrosis not responsive to systemic antiviral therapy. Toxoplasma serum antibodies (IgG and IgM) were not detected on systemic workup one year prior. The slit-lamp exam revealed mutton fat keratic precipitates, panuveitis, and necrotic retinal lesions adjacent to a retinal scar. Repeated Toxoplasma serum antibodies (IgG and IgM) were again negative. However, aqueous fluid testing by polymerase chain reaction (PCR) was highly positive for Toxoplasma gondii. The patient improved after starting systemic anti-toxoplasma therapy. CONCLUSION/IMPORTANCE: To our knowledge, this is the first report in the literature of an immunocompetent patient with ocular toxoplasmosis and undetectable serum IgG and IgM. Aqueous fluid PCR testing is useful in suspected ocular toxoplasmosis in patients with vision-threatening lesions despite negative serology.

NONCONFOCAL ULTRA-WIDEFIELD SCANNING LASER OPHTHALMOSCOPY: Polarization Artifacts and Diabetic Macular Edema.

PURPOSE: Bowtie-shaped polarization artifacts are often present in nonconfocal ultra-widefield scanning laser ophthalmoscope (SLO) images. We studied these artifacts and evaluated their potential value as clinical biomarkers in screening for center-involving diabetic macular edema (DME). METHODS: We performed a retrospective, observational, cohort study on 78 diabetic adult patients (143 eyes) who had spectral domain optical coherence tomography and nonmydriatic nonconfocal ultra-widefield SLO testing on the same day. Scanning laser ophthalmoscope green-only (532 nm), red-only (635 nm), and composite pseudocolor (532 plus 635 nm) images were examined for the presence of a foveal bowtie polarization artifact. RESULTS: Polarization artifacts were absent in all but one eye with center-involving DME (32 of 33 eyes). Polarization artifacts were also absent in many eyes without center-involving DME (49 of 110 eyes in pseudocolor images). As clinical biomarkers of center-involving DME, artifact absence has high specificity (99, 100, and 98% for green, red, and pseudocolor images, respectively) but poor sensitivity (49, 31, and 40% for green, red, and pseudocolor images, respectively). CONCLUSION: Foveal bowtie-shaped polarization artifacts occur routinely in nonconfocal ultra-widefield SLO images. Their presence indicates preserved foveal Henle fiber layer structure. Contemporary nonconfocal ultra-widefield SLO images lack the sensitivity for their bowtie artifacts to serve as reliable biomarkers in screening for center-involving DME.

Anterior hyaloid membrane dissection using the conventional surgical microscope: a novel surgical approach in 2 patients.

BACKGROUND: To describe the dissection and removal of the anterior hyaloid membrane using the conventional surgical microscope. CASE PRESENTATION: This microscopic surgical approach involves dissecting the anterior hyaloid at the natural anatomical plane. A 30-gauge needle mounted on a 3.0 cc syringe is used to inject filtered air anterior to the anterior hyaloid membrane. Two patients needed this procedure; the first patient was pseudophakic with proliferative diabetic retinopathy, tractional retinal detachment, and vitreous hemorrhage. The second patient was phakic with proliferative diabetic retinopathy, anterior proliferative vitreoretinopathy, and recurrent vitreous hemorrhage. Both patients tolerated the procedure well with no complications. CONCLUSION: Pneumatic dissection of the anterior hyaloid membrane is previously thought to be only possible with the aid of ophthalmic endoscopy. This novel surgical approach provides surgeons with the option to perform pneumatic dissection of the anterior hyaloid when ophthalmic endoscopy is not available. Prospective studies are needed to reveal possible additional benefits or risks associated with this approach.

Endoscopic vitreoretinal surgery: principles, applications and new directions.

PURPOSE: To analyze endoscopic vitreoretinal surgery principles, applications, challenges and potential technological advances. BACKGROUND: Microendoscopic imaging permits vitreoretinal surgery for tissues that are not visible using operating microscopy ophthalmoscopy. Evolving instrumentation may overcome some limitations of current endoscopic technology. ANALYSIS: Transfer of the fine detail in endoscopic vitreoretinal images to extraocular video cameras is constrained currently by the caliber limitations of intraocular probes in ophthalmic surgery. Gradient index and Hopkins rod lenses provide high resolution ophthalmoscopy but restrict surgical manipulation. Fiberoptic coherent image guides offer surgical maneuverability but reduce imaging resolution. Coaxial endoscopic illumination can highlight delicate vitreoretinal structures difficult to image in chandelier or endoilluminator diffuse, side-scattered lighting. Microendoscopy's ultra-high magnification video monitor images can reveal microscopic tissue details blurred partly by ocular media aberrations in contemporary surgical microscope ophthalmoscopy, thereby providing a lower resolution, invasive alternative to confocal fundus imaging. Endoscopic surgery is particularly useful when ocular media opacities or small pupils restrict or prevent transpupillary ophthalmoscopy. It has a growing spectrum of surgical uses that include the management of proliferative vitreoretinopathy and epiretinal membranes as well as the implantation of posterior chamber intraocular lenses and electrode arrays for intraretinal stimulation in retinitis pigmentosa. Microendoscopy's range of applications will continue to grow with technological developments that include video microchip sensors, stereoscopic visualization, chromovitrectomy, digital image enhancement and operating room heads-up displays. CONCLUSION: Microendoscopy is a robust platform for vitreoretinal surgery. Continuing clinical and technological innovation will help integrate it into the modern ophthalmic operating room of interconnected surgical microscopy, microendoscopy, vitrectomy machine and heads-up display instrumentation.

Bisphosphonate-induced orbital inflammation in a patient on chronic immunosuppressive therapy.

BACKGROUND: To report a case of orbital inflammation after bisphosphonate infusion in a patient who was already receiving immunosuppressive therapy. CASE PRESENTATION: A 56-year-old woman presented to the ophthalmology clinic with acute onset of right eye pain 24 h after receiving her first Zolendronic acid infusion. She has a past medical history of chronic inflammatory demyelinating polyneuropathy, Sjogren's syndrome, and systemic lupus erythematosus that have been controlled with immunosuppressive therapy for three years. Clinical ophthalmic exam and MRI studies were significant for right orbital inflammation. The patient was started on oral prednisone with rapid resolution of symptoms. CONCLUSIONS: This is the first case report of a patient receiving chronic immunosuppressive therapy to develop orbital inflammation after Zoledronic acid infusion. In addition, it demonstrates that corticosteroids can be an effective first line therapy in treating orbital inflammation in similar patients. Physicians should be aware of this rare but serious potential side effect of bisphosphonates, and have bisphosphonate-related orbital inflammation on their differential for proper initiation of treatment.

STELLATE NONHEREDITARY IDIOPATHIC FOVEOMACULAR RETINOSCHISIS: RESPONSE TO TOPICAL DORZOLAMIDE THERAPY.

PURPOSE: To report the clinical course of a patient presenting with stellate nonhereditary idiopathic foveomacular retinoschisis (SNIFR) in response to topical Dorzolamide treatment. METHODS: Case report, with multimodal imaging findings, including spectral domain optical coherence tomography and fluorescein angiography. Topical Dorzolamide Hydrochloride 2% drops were used three times per day in the affected eye. RESULTS: We identified a 27-years-old male patient who presented with 1-week history of decreased vision in his left eye. Spectral domain optical coherence tomography of the affected eye showed macular splitting of the inner plexiform layer and outer plexiform layer involving the fovea with no other evidence of a hereditary or acquired predisposing condition. The patient was started on the topical treatment for 6 months with visual improvement from 20/40 to 20/30 in the left eye, after which the decision to stop topical dorzolamide therapy was made. On 3 months of follow-up, visual acuity decreased back to 20/40 in the left eye with an increase in retinal thickening on spectral domain optical coherence tomography. Topical dorzolamide was restarted three times per day in the left eye. At 1-year point after restarting treatment, visual acuity was 20/20 in the left eye, with resolved inner plexiform layer and outer plexiform layer splitting on spectral domain optical coherence tomography in the left eye. CONCLUSION: Stellate nonhereditary idiopathic foveomacular retinoschisis can be a devastating problem causing decrease in vision. To the best of our knowledge, this is the first case in the literature to report the complete resolution of SNIFR in response to topical dorzolamide hydrochloride 2% therapy. Further prospective studies are vital to better elucidate our understanding of this new disease identity.

Ultrawide field scanning laser ophthalmoscopy imaging of lipemia retinalis.

OBJECTIVE: To describe the characteristic retinal features of lipemia retinalis when using ultrawide field scanning laser ophthalmoscopy. MAIN POINTS: We report a case series of three subjects with ultrawide field retinal images showing cream discoloration of the fundus, light salmon-coloured posterior retinal vessels and greyish pink peripheral vasculature. On green-only imaging, many of the vessels appear light rather than typically dark. CONCLUSION: Lipemia retinalis is readily apparent on ultrawide field imaging and illustrates the alterations that systemic diseases may induce in the posterior and peripheral retinal vasculature. Ultrawide field imaging highlights the disparate vascular appearance of the posterior pole and retinal periphery in this condition.

Vascular Endothelial Growth Factor and Diabetic Retinal Disease.

Diabetic retinal disease remains a leading cause of blindness among working-aged adults around the world. Until this decade, laser photocoagulation for both proliferative diabetic retinopathy and diabetic macular edema had been the standard of care for millions of patients. The introduction of vascular endothelial growth factor inhibitors (anti-VEGF) and subsequent clinical trials demonstrating their efficacy for treatment of diabetic eye disease have established a new standard in treatment of center-involved diabetic macular edema that is highly specific to the pathologic process and highly effective in preserving and improving vision. This review focuses on clinically relevant developments that led to the shift from focal/grid laser photocoagulation to anti-VEGF injections in the treatment of center-involved diabetic macular edema (DME), with an overview of the disease pathophysiology, clinical disease course, and available anti-VEGF agents. This article also reviews the scientific evidence exploring the use of anti-VEGF agents in nonproliferative and proliferative diabetic retinopathy.