Adeno-Associated Virus Serotype 2-hCHM Subretinal Delivery to the Macula in Choroideremia: Two-Year Interim Results of an Ongoing Phase I/II Gene Therapy Trial.

PURPOSE: To assess the safety of the subretinal delivery of a recombinant adeno-associated virus serotype 2 (AAV2) vector carrying a human choroideremia (CHM)-encoding cDNA in CHM. DESIGN: Prospective, open-label, nonrandomized, dose-escalation, phase I/II clinical trial. PARTICIPANTS: Fifteen CHM patients (ages 20-57 years at dosing). METHODS: Patients received uniocular subfoveal injections of low-dose (up to 5 × 1010 vector genome [vg] per eye, n = 5) or high-dose (up to 1 × 1011 vg per eye, n = 10) of a recombinant adeno-associated virus serotype 2 (AAV2) vector carrying a human CHM-encoding cDNA (AAV2-hCHM). Patients were evaluated preoperatively and postoperatively for 2 years with ophthalmic examinations, multimodal retinal imaging, and psychophysical testing. MAIN OUTCOME MEASURES: Visual acuity, perimetry (10-2 protocol), spectral-domain OCT (SD-OCT), and short-wavelength fundus autofluorescence (SW-FAF). RESULTS: We detected no vector-related or systemic toxicities. Visual acuity returned to within 15 letters of baseline in all but 2 patients (1 developed acute foveal thinning, and 1 developed a macular hole); the rest showed no gross changes in foveal structure at 2 years. There were no significant differences between intervention and control eyes in mean light-adapted sensitivity by perimetry or in the lateral extent of retinal pigment epithelium relative preservation by SD-OCT and SW-FAF. Microperimetry showed nonsignificant (< 3 standard deviations of the intervisit variability) gains in sensitivity in some locations and participants in the intervention eye. There were no obvious dose-dependent relationships. CONCLUSIONS: Visual acuity was within 15 letters of baseline after the subfoveal AAV2-hCHM injections in 13 of 15 patients. Acute foveal thinning with unchanged perifoveal function in 1 patient and macular hole in 1 patient suggest foveal vulnerability to the subretinal injections. Longer observation intervals will help establish the significance of the minor differences in sensitivities and rate of disease progression observed between intervention and control eyes.

OPTICAL COHERENCE TOMOGRAPHY FINDINGS IN CHOROIDAL MELANOMA-ASSOCIATED SUBRETINAL FLUID.

PURPOSE: To report optical coherence tomography findings of choroidal melanoma with subretinal fluid (SRF). METHODS: Single-center, retrospective review of spectral-domain optical coherence tomography in treatment-naive choroidal melanoma with associated SRF presenting between July 2009 and August 2021. RESULTS: Of 236 included patients, choroidal melanoma was small (n = 98, 41.5%), medium (n = 99, 41.9%), or large (n = 39, 16.5%). The most common optical coherence tomography feature was ellipsoid zone loss/disruption (n = 174, 73.7%), with unique features of bacillary layer detachment (n = 67, 28.4%), and heterogenous (n = 72, 30.5%) or homogenous (n = 48, 20.3%) subretinal hyperreflective material. Comparison (small vs. medium vs. large) revealed greater SRF extent with increasing tumor size (SRF ≥2 quadrants: 6.1% vs. 27.2% vs. 67.7%, P < 0.001). Ellipsoid zone disruption was less common in small tumors (52.0% vs. 86.9% vs. 94.9%, P < 0.001). Bacillary layer detachment was more common in medium tumors (16.3% vs. 40.4% vs. 28.2%, P < 0.001) and, compared with eyes without bacillary layer detachment, was associated with more SRF (minimal SRF vs. SRF ≥1 quadrant: likelihood ratio 18.8, P < 0.001) and more frequent heterogenous subretinal hyperreflective material (58.2% vs. 19.5%, P < 0.001). CONCLUSION: Optical coherence tomography features of choroidal melanoma-associated SRF vary by tumor size, with greater SRF extent in larger tumors, less ellipsoid zone disruption in small tumors, and more bacillary layer detachment in medium tumors.

Intravitreal bevacizumab for postoperative recurrent vitreous hemorrhage after vitrectomy for proliferative diabetic retinopathy.

PURPOSE: To describe the experience of authors using intravitreal bevacizumab (IVB) for eyes with recurrent vitreous hemorrhage (VH) after vitrectomy for proliferative diabetic retinopathy. METHODS: Chart review was performed on eligible eyes from the Illinois Retina Associates' patient database that had at least 6 months of follow-up after receiving IVB in the operative eye for recurrent VH after vitrectomy for proliferative diabetic retinopathy. RESULTS: Twelve eyes of nine patients were included in the study and none required repeat vitrectomy for recurrent VH. Mean follow-up was 22 months (range, 8-42). A mean of 8.1 IVB (range, 1-18) were given. The mean number of recurrent VH was 4 (range, 2-8), and a mean of 3.5 of these VHs (range, 1-8) were clear at the appointment after an injection, typically in 4 to 6 weeks. Patients with history of multiple recurrent VH received prophylactic IVB, and repeated injections at regular intervals were associated with increased time period without recurrent VH. CONCLUSION: Intravitreal bevacizumab was a safe and effective adjunct in this series for the management of recurrent VH after vitrectomy for proliferative diabetic retinopathy. No patients required repeat vitrectomy for recurrent VH, and prophylactic IVB was associated with longer periods of clear vitreous in the late postoperative period.

Gore-Tex Suture-Associated Endophthalmitis in a Scleral-Sutured Intraocular Lens.

PURPOSE: To describe a unique case of Gore-Tex (Gore Medical, Arizona, USA), suture-associated delayed-onset endophthalmitis in a patient with a history of scleromalacia, pathologic myopia, multiple prior vitrectomies in the setting of an scleral sutured intraocular lens. METHODS: Retrospective case report. PATIENT: A 69-year-old man complained of blurry vision and eye pain 21 months after implantation of a scleral-sutured intraocular lens and was found to have an exposed Gore-Tex suture with scleromalacia, vision loss to hand motion, a hypopyon and vitritis. He was diagnosed with culture-positive endophthalmitis. He had a previous history of a rhegmatogenous retinal detachment repair and subsequent dislocated intraocular lens in this eye treated with a scleral sutured intraocular lens. A vitreous tap and injection of broad-spectrum antibiotics and suture removal at the slit lamp were performed at the time of presentation. One week later he later underwent pars plana vitrectomy and removal of the intraocular lens. RESULTS: Following the tap and inject and subsequent lens removal, his vision has returned to his pre-operative vision of 20/100 with refraction. DISCUSSION: Gore-Tex suture is a non-absorbable and flexible option with great tensile strength that has emerged as a favored alternative to polypropylene for the use in transscleral fixated intraocular lenses. While endophthalmitis and suture erosion are known complications of this procedure, this report describes one of the first cases of Gore-Tex associated-endophthalmitis.

Scleral sutured toric intraocular lens with pars plana vitrectomy for the correction of corneal astigmatism without capsular support.

PURPOSE: To describe the repair of a patient with bilateral subluxed cataract and corneal astigmatism in the setting of a coloboma of the iris, zonules, lens, and retina. Pre-operatively his best corrected acuity was 20/500 OD and 20/200 OS. His pre-operative refraction was -7.25 +1.00 at 080 OD and -7.75 +3.00 at 040 OS. On corneal topography, he had 1.95D and 1.45D of regular astigmatism in the right and left eye respectively. METHODS: This technique involves pars plana vitrectomy in combination with the placement of a MX60 toric intraocular lens fixated to the sclera using 8-0 Gore-Tex in line with the axis of steep corneal astigmatism. The lens is affixed through two pair of nasal and temporal sclerotomies, with each pair located 3 mm posterior to the limbus and 5 mm apart, centered along the axis of steep astigmatism. RESULTS: Post-operatively the patient was 20/25 uncorrected OD and 20/20 uncorrected OS with a refraction of -0.75 +0.50 at 180 in the OD and -0.75 +1.00 at 180 in the OS. CONCLUSION: Scleral sutured toric intraocular lens placement and pars plana vitrectomy is a viable solution for patients with regular corneal astigmatism and cataract repair in the absence of zonular support.

VITREORETINAL INVOLVEMENT BY INDOLENT T-CELL LYMPHOPROLIFERATIVE DISORDER OF THE GASTROINTESTINAL TRACT DIAGNOSED BY FLUORESCENCE IN SITU HYBRIDIZATION.

PURPOSE: The purpose of this study was to describe an exceedingly rare presentation of secondary vitreoretinal involvement by the uncommon entity "indolent T-cell lymphoproliferative disorder of the gastrointestinal tract" and illustrate the utility of fluorescence in situ hybridization for diagnosis. METHODS: This is a case report. RESULTS: A 57-year-old woman with presumed iritis on chronic topical prednisolone acetate presented with increased vitreous opacities in the right eye. She had a history of biopsy-confirmed indolent T-cell lymphoproliferative disorder of the gastrointestinal tract involving the stomach and duodenum, JAK2 -rearrangement positive, controlled on maintenance oral methotrexate. Vitreous biopsy was unremarkable with small CD3-positive and CD4-positive and CD20-negative lymphocytes, along with histiocytes and fibroblasts. Immunostains showed CD4 positivity, and fluorescence in situ hybridization revealed a JAK2 gene rearrangement, consistent with the patient's previously diagnosed indolent T-cell lymphoproliferative disorder of the gastrointestinal tract. Intravitreal methotrexate injections were started in the right eye. MRI of the brain and lumbar puncture with cytology, MYD88 , IL10, and flow cytometry performed at the time of right eye vitreoretinal lymphoma diagnosis revealed no evidence of central nervous system lymphoma, but subsequent bone marrow biopsy demonstrated 5% involvement by indolent T-cell lymphoproliferative disorder of the gastrointestinal tract, JAK2 -rearrangement positive, with a lung nodule on PET computed tomography. She returned 4 months later with fatigue, night sweats, and blurry vision in the left eye with vitreous and anterior chamber cellular infiltration and retinal vasculitis. CONCLUSION: T-cell vitreoretinal lymphoma is rare, and diagnosis can be challenging. Despite inconclusive cytology in this case, interphase fluorescence in situ hybridization detected a JAK2 gene rearrangement, which confirmed the involvement by indolent T-cell lymphoproliferative disorder of the gastrointestinal tract and prompted appropriate treatment and workup for recurrent systemic or central nervous system lymphoma.

Diurnal variation of optical coherence tomography-based macular fluid in exudative age-related macular degeneration.

BACKGROUND: Significant diurnal fluctuation of optical coherence tomography (OCT)-based macular fluid occurs in patients with several macular conditions including diabetic macular edema (DME) and cystoid macular edema due to retinal venous occlusion (RVO). OCT imaging and analysis of macular fluid status plays a central role in clinical management of exudative age-related macular degeneration (eAMD), however diurnal variation of eAMD OCT findings has not yet been formally studied. Herein, we investigate whether clinically meaningful fluctuation of OCT-based macular fluid occurs in patients with eAMD. METHODS: Prospective observational study. Patients with eAMD and intra- and/or sub-retinal fluid on early AM OCT were enrolled to receive two consecutive OCT scans at least four hours later. Retinal layers were manually segmented on all OCT rasters and AM-to-PM and PM-to-PM image pairs were analyzed for total retinal and neurosensory retinal volume changes within the central 1 and 3 mm ETDRS subfields. Finally, two masked retinal specialists analyzed all OCT image pairs for qualitative differences that may impact clinical management. RESULTS: 21 patients with eAMD and fluid on OCT were recruited between January 2020 and November 2021. There was no mean difference between AM and PM central 3 mm total retinal volume (p = 0.56), central 3 mm neurosensory retinal volume (p = 0.25), central 1 mm total retinal mean thickness (p = 0.96), or central 1 mm neurosensory retinal mean thickness (p = 0.63), nor were any differences identified in PM-to-PM control comparisons. Qualitative analysis by two masked experts identified no clinically significant differences between any AM-to-PM OCT image pairs. CONCLUSIONS: No significant diurnal variation in OCT-based macular fluid or thickness was identified in patients with eAMD, either quantitatively or qualitatively.

Antisense Oligonucleotide Therapy for Ophthalmic Conditions.

Antisense oligonucleotides (AON) are synthetic single-stranded fragments of nucleic acids that bind to a specific complementary messenger RNA (mRNA) sequence and change the final gene product. AON were initially approved for treating cytomegalovirus retinitis and have shown promise in treating Mendelian systemic disease. AON are currently being investigated as a treatment modality for many ophthalmic diseases, including inherited retinal disorders (IRD), inflammatory response and wound healing after glaucoma surgery, and macular degeneration. They provide a possible solution to gene therapy for IRD that are not candidates for adeno-associated virus (AAV) delivery. This chapter outlines the historical background of AON and reviews clinical applications and ongoing clinical trials.

Quantitative autofluorescence: Review of Current Technical Aspects and Applications in Chorioretinal Disease.

Purpose: In this review we discuss the broad clinical application of qAF and provide a descriptive summary of the phenotypic findings of different chorioretinal pathologies.Background: Quantitative Fundus autofluorescence (qAF) is a novel developing technology that can aid in diagnosis and longitudinal disease monitoring by measuring and comparing autofluorescence intensities. Fundus autofluorescence (FAF) is a noninvasive imaging method that creates a density map of the fluorophores of the ocular fundus and provides both functional and topographic anatomic information about retinal cells. Fluorophores are molecules that have the ability to temporarily absorb irradiated light, and emit a small amount of light of a different wavelength. Different endogenous fluorophores can be found in the ocular fundus. Changes in accumulation of retinal fluorophores usually indicate retinal pathology and create characteristic patterns of hyper-autofluorescence and hypo-autofluorescence that help establish a diagnosis.Conclusion: qAF allows a safe non-invasive visualization of the retina, enables a standard for AF intensities comparison and aids to the understanding of the genotype-phenotype correlations.

Expanding the phenotypic spectrum in RDH12-associated retinal disease.

Retinol dehydrogenase 12, RDH12, plays a pivotal role in the visual cycle to ensure the maintenance of normal vision. Alterations in activity of this protein result in photoreceptor death and decreased vision beginning at an early age and progressing to substantial vision loss later in life. Here we describe 11 patients with retinal degeneration that underwent next-generation sequencing (NGS) with a targeted panel of all currently known inherited retinal degeneration (IRD) genes and whole-exome sequencing to identify the genetic causality of their retinal disease. These patients display a range of phenotypic severity prompting clinical diagnoses of macular dystrophy, cone-rod dystrophy, retinitis pigmentosa, and early-onset severe retinal dystrophy all attributed to biallelic recessive mutations in RDH12 We report 15 causal alleles and expand the repertoire of known RDH12 mutations with four novel variants: c.215A > G (p.Asp72Gly); c.362T > C (p.Ile121Thr); c.440A > C (p.Asn147Thr); and c.697G > A (p.Val233Ille). The broad phenotypic spectrum observed with biallelic RDH12 mutations has been observed in other genetic forms of IRDs, but the diversity is particularly notable here given the prior association of RDH12 primarily with severe early-onset disease. This breadth emphasizes the importance of broad genetic testing for inherited retinal disorders and extends the pool of individuals who may benefit from imminent gene-targeted therapies.

Differential requirements of the C terminus of Nbs1 in suppressing adenovirus DNA replication and promoting concatemer formation.

Adenoviruses (Ad) with the early region E4 deleted (E4-deleted virus) are defective for DNA replication and late protein synthesis. Infection with E4-deleted viruses results in activation of a DNA damage response, accumulation of cellular repair factors in foci at viral replication centers, and joining together of viral genomes into concatemers. The cellular DNA repair complex composed of Mre11, Rad50, and Nbs1 (MRN) is required for concatemer formation and full activation of damage signaling through the protein kinases Ataxia-telangiectasia mutated (ATM) and ATM-Rad3-related (ATR). The E4orf3 and E4orf6 proteins expressed from the E4 region of Ad type 5 (Ad5) inactivate the MRN complex by degradation and mislocalization, and prevent the DNA damage response. Here we investigated individual contributions of the MRN complex, concatemer formation, and damage signaling to viral DNA replication during infection with E4-deleted virus. Using virus mutants, short hairpin RNA knockdown and hypomorphic cell lines, we show that inactivation of MRN results in increased viral replication. We demonstrate that defective replication in the absence of E4 is not due to concatemer formation or DNA damage signaling. The C terminus of Nbs1 is required for the inhibition of Ad DNA replication and recruitment of MRN to viral replication centers. We identified regions of Nbs1 that are differentially required for concatemer formation and inhibition of Ad DNA replication. These results demonstrate that targeting of the MRN complex explains the redundant functions of E4orf3 and E4orf6 in promoting Ad DNA replication. Understanding how MRN impacts the adenoviral life cycle will provide insights into the functions of this DNA damage sensor.

Outcomes of vitrectomy for diabetic tractional retinal detachment in Chicago's county health system.

PURPOSE: To examine outcomes of 23-gauge (23G) pars plana vitrectomy (PPV) for complex diabetic tractional retinal detachment (TRD) in Chicago's Cook County Health and Hospitals System (CCHHS). MATERIALS AND METHODS: This is a retrospective noncomparative study of diabetic TRD cases that underwent PPV at CCHHS. Primary retinal reattachment rate, visual function, and postoperative complications were analyzed. RESULTS: Sixty nine consecutive cases were included. Primary reattachment and final attachment were achieved in 68/69 eyes (98.6%). Secondary retinal detachment was noted in 1 eye (1.4%). Vitreous hemorrhage requiring repeat PPV developed in 5 eyes (7.2%) and reoperation due to other complications was required in 4/69 eyes (5.8%). Perfluoropropane (C3F8) gas tamponade was used in 91.3% of eyes and silicone oil in 8.7% of eyes. Mean LogMAR visual acuity significantly improved from 1.84 ± 0.61 to 0.93 ± 0.66, (P<0.0001). Vision was stabilized or improved in 66 eyes (95.7%). Visual acuity of 20/200 or better was achieved in 49/69 eyes (71.0%) and 20/50 or better in 16/69 eyes (23.2%). CONCLUSIONS: Even in patients with severe and advanced diabetic TRD pathology and unique demographics as seen in CCHHS, modern vitrectomy techniques can provide excellent anatomical and visual outcomes.

Macular Hole Formation After Pars Plana Vitrectomy for Diabetic Tractional Retinal Detachment.

BACKGROUND AND OBJECTIVE: To investigate the incidence, clinical features, and outcomes of patients with macular hole (MH) formation after pars plana vitrectomy (PPV) for diabetic tractional retinal detachment (TRD). PATIENTS AND METHODS: We conducted a retrospective review of all cases of PPV for diabetic TRD performed by a surgeon (DS) at a large county hospital between November 2013 and August 2016. RESULTS: Ninety consecutive eyes of 79 patients were included in this case series, of which four eyes developed MH, yielding an incidence of 4.4% (95% confidence interval [CI], 1.2%-11.0%). The mean interval between PPV for TRD and MH formation was 7.0 ± 5.5 (mean ± 1 standard deviation) months, and mean follow-up time was 29.6 months ± 6.9 months. Three of the four eyes that developed MH underwent intervention, and of the three that underwent intervention, all had successful hole closure. CONCLUSION: In this case series, the incidence of MH after PPV for TRD is 4.4% (95% CI, 1.2%-11.0%). The mechanism of MH formation after diabetic TRD repair is not certain but may be related to a taut internal limiting membrane, epiretinal membrane formation, macular edema, or residual vitreous contraction. [Ophthalmic Surg Lasers Imaging Retina. 2018;49:e256-e262.].

Optical coherence tomography findings and successful repair of retina detachment in Knobloch syndrome.

A 7-year-old Afghani girl was referred to the retina clinic of Massachusetts Eye and Ear for a chronic-appearing, macula-off retinal detachment in the left eye. On examination, best-corrected visual acuity was 20/400 in the right eye and 20/800 in the left eye. She had bilateral horizontal nystagmus. Ophthalmoscopy revealed prominent choroidal vessels, chorioretinal atrophy in the macular area, attenuated retinal vasculature, and pale optic discs bilaterally. Spectral domain optical coherence tomography demonstrated atrophy of the choriocapillaris and the retinal pigment epithelium, retinal thinning, and abnormal foveal contour. In the right eye, findings were reminiscent of dome shape maculopathy with an adjacent lesion suspicious for inactive choroidal neovascularization. A suspected diagnosis of Knobloch syndrome was confirmed by genetic testing, which showed a homozygous variant in exon 33 of the COL18A1 gene defined as c.3213dupC. She underwent cryotherapy and scleral buckling surgery in the left eye and remained attached bilaterally at 3 years' follow-up, with progressive myopia and best-corrected visual acuity of 20/100 in the right eye and 20/125 in the left eye.

Role of the Infectious Disease Consultant in Management of Patients With Tuberculosis-Associated Ocular Inflammation.

Background. Tuberculosis is a disease with continued worldwide prevalence, morbidity, and mortality. Tuberculosis-associated ocular inflammation (TB-AOI) is a manifestation that can occur with pulmonary or extrapulmonary TB. Evaluation of these ocular presentations and treatment in the United States are limited. Our objective was to describe cases in an urban area and assess the role of the infectious diseases specialist in managing these complex patients. Methods. We performed a retrospective case series of all patients referred to our infectious disease clinic for presumed TB-AOI from 2005 through 2013. Patients with ocular inflammation were determined to have presumed TB-AOI based on clinical presentation with correlative positive tuberculin skin test and/or QuantiFERON-TB Gold. Attempts were made to exclude other diagnoses. Data were collected and analyzed with respect to demographics, ocular manifestations, and treatment. Results. Sixty eyes of 42 patients were included in the study; anterior uveitis was the most common site of involvement. The median age was 46 years, and 33 patients (79%) were foreign born. Forty patients (95%) received a course of antituberculous therapy with 38% experiencing treatment-related side effects. A 6-month duration was recommended in 78% cases. There was improvement or stability of the vision in 42 eyes (74%) of those treated. Conclusions. Ocular involvement is an uncommon but important manifestation of TB. Our data further characterize TB-AOI cases in the United States. Treatment provides significant benefit to properly selected patients. A multidisciplinary approach, with care provided by ophthalmology and infectious disease providers, should be used to allow for the most efficacious treatment.