Where Are We with RPE Replacement Therapy? A Translational Review from the Ophthalmologist Perspective.

The retinal pigmented epithelium (RPE) plays a pivotal role in retinal homeostasis. It is therefore an interesting target to fill the unmet medical need of different retinal diseases, including age-related macular degeneration and Stargardt disease. RPE replacement therapy may use different cellular sources: induced pluripotent stem cells or embryonic stem cells. Cells can be transferred as suspension on a patch with different surgical approaches. Results are promising although based on very limited samples. In this review, we summarize the current progress of RPE replacement and provide a comparative assessment of different published approaches which may become standard of care in the future.

Detecting Apoptosis as a Clinical Endpoint for Proof of a Clinical Principle.

The transparent eye media represent a window through which to observe changes occurring in the retina during pathological processes. In contrast to visualising the extent of neurodegenerative damage that has already occurred, imaging an active process such as apoptosis has the potential to report on disease progression and therefore the threat of irreversible functional loss in various eye and brain diseases. Early diagnosis in these conditions is an important unmet clinical need to avoid or delay irreversible sight loss. In this setting, apoptosis detection is a promising strategy with which to diagnose, provide prognosis and monitor therapeutic response. Additionally, monitoring apoptosis in vitro and in vivo has been shown to be valuable for drug development in order to assess the efficacy of novel therapeutic strategies both in the pre-clinical and clinical setting. Detection of Apoptosing Retinal Cells (DARC) technology is to date the only tool of its kind to have been tested in clinical trials, with other new imaging techniques under investigation in the fields of neuroscience, ophthalmology and drug development. We summarise the transitioning of techniques detecting apoptosis from bench to bedside, along with the future possibilities they encase.

Vitreoretinal Surgery in the Prevention and Treatment of Toxic Tumour Syndrome in Uveal Melanoma: A Systematic Review.

Toxic tumour syndrome (TTS) is a particularly aggressive form of secondary vasculopathy occurring after radiation therapy of uveal melanoma due to the persistence of the necrotic tumour mass inside the eye. The development of TTS confers a particularly unfavourable functional and anatomical ocular prognosis, ultimately requiring enucleation in most cases if untreated. Vitreoretinal (VR) surgery has been successfully applied for treatment and prevention of TTS using both resecting and non-resecting techniques. In this systematic review, we aim to define characteristics of uveal melanomas benefiting the most from secondary VR surgery and to outline the optimal type and timing of VR intervention in such cases. Analysis of the literature reveals that endoresection should be performed within 3 months after radiotherapy to tumours thicker than 7 mm and with a largest basal diameter between 8 mm and 15 mm with post-equatorial location, especially after proton beam treatment. Alternatively, endodrainage remains a valid therapeutic option in eyes with macula-off retinal detachment, tumour diameter larger than 15 mm or ciliary body involvement. VR surgery can be successful in the management of TTS following radiotherapy for uveal melanoma when timing and indication are appropriately evaluated.

Camellin-Calossi Formula for Intraocular Lens Power Calculation in Patients With Previous Myopic Laser Vision Correction.

PURPOSE: To assess the performance of the Camellin-Calossi formula in eyes with prior myopic laser vision correction. METHODS: This was a retrospective case series. Patients included had a history of uncomplicated myopic laser vision correction and cataract surgery. The primary outcome measures were cumulative distribution of absolute refractive prediction error, absolute refractive prediction error, and refractive prediction error. These parameters were estimated post-hoc using the Camellin-Calossi, Shammas, Haigis-L, Barrett True-K with or without history, Masket, and Modified Masket formulas and their averages starting from biometric data, clinical records, postoperative refraction, and intraocular lens power implanted. RESULTS: Seventy-seven eyes from 77 patients were included. The Camellin-Calossi, Shammas, Haigis-L, Barrett True-K No History, Masket, Modified Masket, and Barrett True-K formulas showed a median absolute refractive error (interquartile range) of 0.25 (0.53), 0.51 (0.56), 0.44 (0.65), 0.45 (0.59), 0.40 (0.61), 0.60 (0.70), and 0.55 (0.76), respectively. The proportion of eyes with an absolute refractive error of ±0.25, 0.50, 0.75, 1.00, 1.50, and 2.00 diopters (D) for the Camellin-Calossi formula was 54.5%, 72.7%, 85.7%, 92.2%, 98.7%, and 100%, respectively. The cumulative distribution of the Camellin-Calossi formula showed the best qualitative performances when compared to the others. A statistically significant difference was identified with all of the others except the Haigis-L using a threshold of 0.25, with the Shammas, Modified Masket, and Barrett True-K at a threshold of 0.50 D and the Barrett True-K and Modified Masket at a threshold of 1.00 D. CONCLUSIONS: The Camellin-Calossi formula is a valid option for intraocular lens power calculation in eyes with prior myopic laser vision correction. [J Refract Surg. 2024;40(3):e156-e163.].

Endocyclophotocoagulation combined with phacoemulsification in surgically naive primary open-angle glaucoma: three-year results.

OBJECTIVE: To assess the safety and efficacy of endocyclophotocoagulation with phacoemulsification (phaco-ECP) in surgically naive, primary open-angle glaucoma (POAG). METHODS: A retrospective case series of patients undergoing phaco-ECP between 2007 and 2017 at a single centre in London, UK. The primary outcome was intraocular pressure (IOP). Secondary outcomes were visual acuity, visual field global indices, topical medications and surgical complications. Failure criteria were: (1) IOP > 21 mmHg or <20% reduction at two consecutive visits, (2) IOP <5 mmHg and (3) further IOP-lowering surgery. RESULTS: Eighty-three eyes from 83 patients were eligible. Pre-operatively, mean IOP (±SD) was 18.4 ± 5.2 mmHg. The mean number of topical agents (±SD) was 2.7 ± 0.9. Mean IOP (±SD) significantly reduced to 14.3 ± 4.7 at 1 year, 14.1 ± 4.0 at 2 years and 13.6 ± 3.7 at 3 years (p < 0.0001). Topical medications were significantly reduced to 1.3 ± 1.2 at 1 year, 1.7 ± 1.2 at 2 years and 1.8 ± 1.3 at 3 years (p < 0.0001). Annual IOP 'survival' was 70%, 54% and 45% at year 1, 2 and 3, respectively. Complications included uveitis (6%), macular oedema (2%), IOP spikes (1%) and corneal decompensation (1%) with no episodes of hypotony or retinal detachment. One patient underwent filtration surgery within 3 years (1%). CONCLUSION: Phaco-ECP facilitates significant IOP lowering and reduction of medication burden in surgically naive POAG requiring cataract extraction. The procedure is relatively safe and without the use of implants and their associated risks.

Foveal Eversion: A Possible Biomarker of Persistent Diabetic Macular Edema.

INTRODUCTION: We aimed to evaluate the impact of foveal eversion on treatment response and persistent diabetic macular edema (DME). METHODS: The study was designed as interventional and prospective. DME eyes were treated with ranibizumab and/or dexamethasone (DEX) implants, or with fluocinolone acetonide (FAc) implants. FAc-treated eyes were eventually retreated by additional ranibizumab injections. Main outcome measure was the relationship between foveal eversion and both clinical outcome and persistent DME. RESULTS: Sixty-eight DME eyes (68 patients) treated by anti-VEGF/DEX and 50 FAc-treated eyes (50 patients) were recruited. The follow-up was 16 ± 3 months. The anti-VEGF/DEX group and FAc-treated group were statistically matched for age, sex, DME duration and previous number of injections (p > 0.05). Both groups experienced statistically significant improvements of both BCVA and central macular thickness (p < 0.01) at the end of the follow-up. Persistent DME was shown by 46% of anti-VEGF/DEX eyes and 42% of FAc-treated eyes. Foveal eversion was found in 50% of anti-VEGF/DEX eyes and in 44% of FAc-treated eyes. Its presence was associated with worse anatomical and visual outcome and higher persistence of DME in both groups (p < 0.01) and with higher retreatment percentages in FAc-treated eyes (p < 0.01). CONCLUSION: Foveal eversion is associated with worse clinical and morphological outcomes in DME.

Macular Microvascular Modifications in Progressive Lamellar Macular Holes.

Lamellar macular holes (LMHs) may show morphological and functional deterioration over time, yet no definite prognostic factor for progression has been identified. Since neurovascular retinal unit impairment may take part in neurodegeneration, we compare progressive LMHs to stable ones in optical coherence tomography (OCT) angiography parameters. METHODS: OCT B scans of eyes with LMH were analyzed to detect the presence of tissue loss (TL) over time, allowing us to identify a TL group and a stable (ST) group (14 patients each). The best corrected visual acuity (BCVA) at each considered imaging time point was collected. Lastly, patients underwent macular OCT angiography. RESULTS: BCVA at last follow up was significantly reduced in the TL group compared to both the ST group and TL group baseline assessment. SCP foveal vessel density (VD), SCP and deep capillary plexus (DCP) perfusion density (PD) and parafoveal PD were lower in the TL group. Linear correlations between quantitative TL over time and parafoveal PD in SCP and between the speed of TL and BCVA variation during follow up were also detected. CONCLUSIONS: TL in LMHs is associated with both OCT angiography modifications and BCVA deterioration over time. We suggest these findings to be a manifestation of foveal Muller cell impairment in progressive LMHs.

The outcome of fluocinolone acetonide intravitreal implant is predicted by the response to dexamethasone implant in diabetic macular oedema.

BACKGROUND/OBJECTIVES: To investigate if the visual and anatomic response to the first dexamethasone implant (DEX) predicts the 12-month clinical outcome after shifting to fluocinolone acetonide (FAc) implant in patients with diabetic macular oedema (DMO). METHODS: Retrospective cohort study including pseudophakic patients with previously treated DMO, undergone one or more DEX injections before FAc. Functional and morphologic response to DEX was defined based on the best-corrected visual acuity (BCVA) and central macular thickness (CMT) changes after the first DEX, respectively. Steroid-response was defined as intraocular pressure (IOP) elevation ≥5 mmHg or IOP > 21 mmHg after any previous DEX exposure. Pairwise comparisons for BCVA, CMT, and IOP after FAc were performed with linear mixed models and a repeated-measure design. RESULTS: Forty-four eyes of 33 patients were included. Patients were shifted to FAc after a mean ± standard deviation of 4.6 ± 3.2 DEX injections. Overall, BCVA and CMT improved during the first 12 months after switching to FAc (p = 0.04 and p < 0.001, respectively). Only eyes with a good morphologic response to DEX had a significant CMT reduction after FAc (p < 0.001), while no significant relationship was found between BCVA improvement after DEX and after FAc. IOP elevation occurred in 9 eyes (20%) following DEX implant. These eyes carried a 20-fold increased risk of having an IOP rise after FAc (p < 0.001), with a non-linear relationship between the IOP increase after DEX and the one after FAc. CONCLUSION: The response to previous DEX may anticipate the morphologic response to subsequent FAc. Eyes with steroid-induced IOP elevation after DEX are at a high risk of IOP increase after FAc. The visual response after FAc was not associated with the visual response to previous steroids, indicating that FAc may have a role also in patients refractory to DEX implant.

Optical Coherence Tomography Biomarkers of Inflammation in Diabetic Macular Edema Treated by Fluocinolone Acetonide Intravitreal Drug-Delivery System Implant.

INTRODUCTION: The fluocinolone acetonide (FAc) intravitreal drug-delivery system implant is a recent, second-line, intravitreal drug for the management of diabetic macular edema (DME). FAc acts against DME with a major anti-inflammatory effect. Despite the already proved efficacy, a number of patients still show persistent DME and require anti-VEGF retreatment. The main aim of the present study was to assess the relationship between quantitative biomarkers of inflammation and both DME recovery and the need for additional anti-VEGF in eyes treated by FAc implant. METHODS: The study was designed as prospective and interventional with 1 year of follow-up. We analyzed structural optical coherence tomography (OCT) quantitative biomarkers of inflammation, namely choroidal hyperreflective foci (HF) and the choroidal vascularity index (CVI), and we assessed the relationship with other clinically relevant biomarkers and the outcome achieved after 1 year. Moreover, we stratified DME eyes in good and poor responders to FAc implant to highlight clinically relevant differences. RESULTS: Our study included 50 eyes (50 patients) treated by FAc implant. We found significant best-corrected visual acuity (BCVA) and central macular thickness (CMT) improvements after 1 year. Good responders started with worse visual acuity and higher CMT than poor responders, but gained letters significantly at the end of the follow-up, whereas poor responders showed stable BCVA values. Good responders were characterized by significantly higher choroidal HF and lower CVI than poor responders. Poor responders required significantly higher additional anti-VEGF treatments. CONCLUSIONS: Quantitative structural OCT biomarkers of inflammation allowed distinguishing different inflammatory profiles of DME. The inflammatory component helped to categorize DME eyes in good and poor responders to FAc implant.

Persistent or Recurrent Diabetic Macular Edema After Fluocinolone Acetonide 0.19 mg Implant: Risk Factors and Management.

PURPOSE: To investigate baseline characteristics of patients undergoing additional antivascular endothelial growth factor (VEGF) injections for residual or recurrent diabetic macular edema (DME) in the first year after 0.19-mg fluocinolone acetonide (FAc) implant. DESIGN: Prospective cohort study. METHODS: Ninety-four eyes of 66 patients received an FAc implant. Eyes with persistent or recurrent DME were managed with pro re nata anti-VEGF agents. Demographic data and medical history were collected at baseline. Best-corrected visual acuity and central macular thickness were measured every 2 months. The 3 outcomes explored were 1) the risk factors for administration of additional anti-VEGF agents, 2) the interval from FAc to first anti-VEGF injection; and 3) the number of anti-VEGF doses required to maintain regression of DME. RESULTS: Eighteen eyes (19.1%) of 13 patients received 1.3 ± 0.6 anti-VEGF injections. These eyes had significantly thicker central macular thickness at baseline and over the entire follow-up period (P < .001); best-corrected visual acuity was similar at every time point to eyes that were not receiving extra DME treatments. Eyes without preexistent panretinal photocoagulation (PRP) had a higher risk to undergo supplemental treatments (hazard ratio 1.5 [95% confidence interval 1.1-2.5, P = .03). The interval between FAc implant and the first anti-VEGF had a significant linear positive relationship with the number of dexamethasone implants before FAc implant (P = .002, R2 = 0.47). No association was found between baseline factors and the number of injections given. CONCLUSION: Anti-VEGF agents are efficient treatment to maintain visual acuity in residual/recurrent DME after FAc. Patients with higher baseline central macular thickness and with no previous central macular thickness are more likely to require additional treatments to control DME.