Comparison of Different Doses of Oral and Ocular Propranolol for Retinopathy of Prematurity: A Network Meta-Analysis.

OBJECTIVE: The efficacy and safety of propranolol for retinopathy of prematurity (ROP) remain under debate. This network meta-analysis (NMA) focuses on whether a ranking may be established for different dose levels of propranolol as treatment of ROP in terms of stage progression as the primary outcome, with appearance of plus disease and need for anti-vascular endothelial growth factors (anti-VEGFs) or laser therapy as secondary endpoints. METHODS: Fourteen studies (10 randomised controlled trials, three single-arm trials and one retrospective observational study) of 474 patients treated with oral or ocular propranolol were retrieved from databases up to April 2024. Meta-insight and model-based NMA were undertaken to evaluate the propranolol dose-response relationship. Studies were evaluated for model fit, risk of bias and Confidence of evidence In Network Meta-Analysis (CINeMA). Effect sizes were determined as odds ratio (OR) with 95% credible interval (CrI). RESULTS: Bayesian analysis showed a trend towards improved effects for propranolol given at late stages (stages 2-3; S23) of ROP progression compared with its administration at earlier stages (stages 0-1; S01). OR values for oral propranolol 1.5 and 2 mg/kg/day given at S23 were 0.13 (95% CrI 0.04-0.37) and 0.16 (95% CrI 0.04-0.61), respectively, while given at S01 were 0.28 (95% CrI 0.02-2.96) and 0.78 (95% CrI 0.14-4.43), respectively. Similarly, OR of eye propranolol 0.2% at S23 was 0.37 (95% CrI 0.09-1.00) versus an S01 OR of 0.64 (95% CrI 0.21-2.04). Surface under the cumulative ranking curve (SUCRA) analyses confirmed best probability values for oral propranolol 1.5-2 mg/kg followed by eye propranolol 0.2%, all at S23. Model-based NMA showed nonlinearity in the dose-response for oral propranolol with a trend to greater maximal effect for its administration at late versus early stages. For secondary endpoints, lower risk values were found with oral propranolol 1.5 mg/kg/day at S23 for progression to plus disease (OR 0.14; 95% CrI 0.02-0.84) and need for anti-VEGFs (OR 0.23; 95% CrI 0.05-0.93) and laser (OR 0.16; 95% CrI 0.02-1.10) therapies also followed by eye propranolol 0.2%, and a similar profile was obtained with SUCRA analysis. Lower doses (0.5-1.0 mg/kg/day) of oral propranolol retained efficacy. Threat of adverse events was estimated as risk difference versus control with no difference for eye propranolol 0.2% and oral propranolol 0.5 mg/kg/day, modest increases of risk for oral propranolol 1.0 and 1.5 mg/kg/day and the highest risk difference for oral propranolol 2.0 mg/kg/day (0.06; 95% CI -0.01 to 0.13). CONCLUSION: A diminished risk of disease progression and need for additional treatment was obtained with propranolol in ROP, but safety is a potential concern. Propranolol eye micro-drops (0.2%) can be as efficacious as oral propranolol. Nonetheless, the evidence is limited due to the paucity and quality of the available studies.

Comparison of different agents and doses of anti-vascular endothelial growth factors (aflibercept, bevacizumab, conbercept, ranibizumab) versus laser for retinopathy of prematurity: A network meta-analysis.

Laser photocoagulation (LPC) and/or intravitreal anti-vascular endothelial growth factor (anti-VEGF) injections constitute the current standard treatment for retinopathy of prematurity (ROP). This network meta-analysis focus on whether a ranking of interventions may be established for different dose levels of intravitreal injection of anti-VEGF agents (aflibercept, bevacizumab, conbercept, ranibizumab) as primary treatments for ROP versus laser in terms of retreatment rate as primary outcome, and time to retreatment and refractive error as secondary endpoints, since best anti-VEGF dosage remains under debate. Sixty-eight studies (15 randomized control trials and 53 nonrandomized studies) of 12,356 eyes of 6445 infants were retrieved from databases (2005 Jan. - 2023 June). Studies were evaluated for model fit, risk of bias and confidence of evidence in Network Meta-Analysis (CINeMA). Bayesian NMA showed that anti-VEGF drugs were not inferior to laser in terms of retreatment rate. For intravitreal bevacizumab (IVB), doses half of the conventional infant dose showed a low risk of retreatment rate (risk ratio (RR) of 1.43; 95% credible interval (CrI): 0.508, 4.03). On probability ranking as surface under the cumulative ranking curve (SUCRA) plot, half dose of bevacizumab had a better position than conventional and augmented (1.2-2 times the regular dose) doses. A similar probability trend was observed for half vs. conventional doses of aflibercept and ranibizumab. Conventional infant dose of conbercept showed the lowest risk for retreatment (RR 0.846; 95% CrI: 0.245, 2.91). For secondary endpoints, lower doses of anti-VEGF agents were associated with shorter times to retreatment. The largest changes were noted for the augmented doses of bevacizumab and ranibizumab (0.3 mg) with means of 14.1 weeks (95% CrI: 6.65, 21.6) and 12.8 weeks (95% CrI: 3.19, 20.9), respectively. Finally, NMA demonstrated better refractive profile for anti-VEGF than laser therapy, especially for the conventional infant doses of bevacizumab and ranibizumab which exhibited a significantly better refractive profile than LPC, with mean differences of 1.67 (spherical equivalent - diopters) (95% CrI: 0.705, 2.67) and 2.19 (95% CrI: 0.782, 3.59), respectively. In the SUCRA plots, LPC had a markedly different position with a higher probability for myopia. Further clinical trials comparing different intravitreal doses of anti-VEGF agents are needed, but our findings suggest that low doses of these drugs retain efficacy and may reduce ocular and systemic undesired events.

An association between bilateral keratoconus in a patient with spondyloocular syndrome and xylosyltransferase II gene mutation.

Spondyloocular syndrome (SOS) is a rare autosomal-recessive disorder. Since 2015, SOS has been linked to mutations in xylosyltransferase II (XYLT2) locus. Phenotypic features could affect multiple systems, such as sight, hearing, or bones. Herein, we report a case of SOS with multiple bone fractures without trauma, bilateral cataracts, and sensorineural hearing loss. Mutations in XYLT2 gene were detected, and the diagnosis of SOS was made. At the age of 8, the patient presented with progressive vision loss. Slit-lamp examination revealed inferior steepening, apical scarring, and thinning of the cornea. Due to keratoconus suspicion, a corneal tomography was done, confirming the diagnosis of keratoconus. We present the first case of bilateral keratoconus in a patient with SOS.

Ciliary body medulloepithelioma treated with intra-operative brachytherapy after fine needle aspiration biopsy.

Medulloepithelioma is the second most common type of pediatric intra-ocular tumors. It commonly arises from ciliary body, and it is generally diagnosed in the first decade of life. Management options for medulloepithelioma include enucleation, resection, or radiotherapy, but further investigation is still needed. Herein, we report a case of a 1-year-old girl with a ciliary body mass highly suggestive of medulloepithelioma, which caused recurrent acute episodes of intense pain. Fine needle aspiration biopsy (FNAB) of ciliary body mass was performed with trans-scleral approach, and treatment with a iodine-125 brachytherapy COMS10 plaque was undertaken during the same interventional procedure. Lesion was treated using a plaque brachytherapy, with total radioactivity of 13.5 mCi distributed in 5 seeds with immediate disappearance of pain episodes and decrease of tumor size. This is the first case of medulloepithelioma treated with brachytherapy plaque after an extemporaneous anatomo-pathological examination in children with favorable response. We consider that intra-operative brachytherapy therapy after FNAB in selected ocular tumors may be safe and effective therapeutic option, but longer follow-up is needed to confirm safety and applicability of this approach in a larger group of patients.

Severe Cocaine-Induced Midline Destructive Lesions (CIMDL) Leading to Orbital Apex Syndrome and Peripheral Ulcerative Keratitis.

PURPOSE: To describe a case of cocaine-induced midline destructive lesions (CIMDL) associated with ocular autoimmune disease.Methods: Observational case report. RESULTS: A 45-year-old man with history of chronic osteolytic sinusitis due to cocaine abuse presented with sudden vision loss in right eye. Ophthalmic examination revealed fixed right mydriasis with extraocular movements limitation and optic disc swelling. Computed tomography showed an orbital infiltrating mass. The diagnosis of orbital-apex syndrome secondary to CIMDL was established. Steroids and antibiotics therapy were started without vision improvement. At 6-months follow-up, a corneal ulcer with characteristics of peripheral ulcerative keratitis (PUK) was evidenced, coinciding with an upper respiratory bacterial infection. CONCLUSIONS: CIMDL and PUK share common pathogenic pathways, with implication of autoimmune factors and exposure to infective antigens. We hypothesized that chronic cocaine use, along with persistent bacterial infection, could have triggered an inflammatory reaction, which contributed to CIMDL development and the appearance of PUK.

Fungal Necrotizing Scleritis After Intravitreal Injection Therapy.

PURPOSE: To report a case of infectious necrotizing scleritis secondary to Aspergillus terreus after intravitreal injection therapy. METHODS: This is a case report with literature review. RESULTS: A 98-year-old woman receiving intravitreal aflibercept injections for neovascular age-related macular degeneration in the left eye presented with severe pain, redness, and purulent discharge at the injection site. She was initially treated with topical fortified antibiotics, and clinical improvement was achieved, although microbial cultures showed negative results. Two months later, she presented with severe ocular pain and was diagnosed with anterior necrotizing scleritis. Scleral scrapings were collected for cultures, and intensive topical antibiotic therapy was reintroduced. Evaluation for autoimmune etiology and microbiological testing showed negative results. Because of the progression of the scleral necrotic area, empirical therapy with topical voriconazole was initiated, and surgical debridement was performed. Finally, the culture was positive for A. terreus. The modified therapy consisted of topical voriconazole and oral voriconazole for 3 months with an excellent clinical outcome. CONCLUSIONS: To our knowledge, this is the first case of fungal necrotizing scleritis secondary to intravitreal injection. Diagnosis was delayed due to its chronic clinical course and the slow fungal growth in culture media, but the combined medical and surgical approach resulted in a satisfactory outcome.

Ophthalmic and Neuro-ophthalmic Manifestations of Coronavirus Disease 2019 (COVID-19).

PURPOSE: To describe a case of inflammatory chorioretinopathy and Adie's syndrome possibly associated with COVID-19. METHODS: Observational case report. RESULTS: A 51-year-old woman developed fever, cough, and headache followed by retro-ocular pain and reading impairment. She tested positive for SARS-COV-2 infection by qualitative real-time reverse-transcriptase-polymerase-chain-reaction. The slit-lamp and funduscopic exam revealed abnormal pupillary response and yellowish creamy deep chorioretinal lesions, which were not present in previous examinations. Instillation of pilocarpine demonstrated denervation supersensitivity, and it was suggestive of bilateral Adie tonic pupil. A comprehensive work-up ruled out other systemic, autoimmune, or infectious diseases. CONCLUSIONS: This case illustrates the possible association between multifocal chorioretinitis and Adie's syndrome, and the SARS-COV-2 infection in humans. Further investigation of virus infectivity specifically within ocular tissues has to be conducted.