Fifteen years follow-up of photorefractive keratectomy up to 10 D of myopia: outcomes and analysis of the refractive regression

PURPOSE: To evaluate outcomes of photorefractive keratectomy up to -10.00 D of myopia and -4.50 of astigmatism and to develop a predictive model for the refractive changes in the long term. SETTING: Vissum Corporation and Miguel Hernandez University (Alicante, Spain). DESIGN: Retrospective-prospective observational series of cases. METHODS: This study included 33 eyes of 33 patients aged 46.79±7.04 years (range 40-57) operated with the VISX 20/20 excimer laser with optical zones of 6 mm. No mitomycin C was used in any of these cases. The minimum follow-up was 15 years. The main outcome measures were: uncorrected and corrected distance visual acuity, manifest refraction and corneal topography. Linear regression models were developed from the observed refractive changes over time. RESULTS: Safety and efficacy indexes at 15 years were 1.18 and 0.83, respectively. No statistically significant differences were detected for any keratometric variable during the follow-up (p≥0.103). 15 years after the surgery 54.55% of the eyes were within ±1.00 D of spherical equivalent and 84.85% within ±2.00 D. The uncorrected distance visual acuity at 15 years was 20/25 or better in 60.6% of the eyes and 20/40 or better in 72.73% of the eyes. The correlation between the attempted and the achieved refractions was r=0.948 (p<0.001) at 1 year, and r=0.821 (p<0.001) at 15 years. No corneal ectasia was detected in any case during the follow-up. CONCLUSIONS: Photorefractive keratectomy is a safe refractive procedure in the long term within the range of myopia currently considered suitable for its use, although its efficacy decreases with time, especially, in high myopia. The model developed predicts a myopic regression of 2.00 D at 15 years for an ablation depth of 130 µm

Update on Gene Therapy Clinical Trials for Choroideremia and Potential Experimental Therapies

Background and objectives: Choroideremia (CHM) is an X-linked recessive chorioretinal dystrophy caused by mutations involving the CHM gene. Gene therapy has entered late-phase clinical trials, although there have been variable results. This review gives a summary on the outcomes of phase I/II CHM gene therapy trials and describes other potential experimental therapies. Materials and Methods: A Medline (National Library of Medicine, Bethesda, MD, USA) search was performed to identify all articles describing gene therapy treatments available for CHM. Results: Five phase I/II clinical trials that reported subretinal injection of adeno-associated virus Rab escort protein 1 (AAV2.REP1) vector in CHM patients were included. The Oxford study (NCT01461213) included 14 patients; a median gain of 5.5 ± 6.8 SD (-6 min, 18 max) early treatment diabetic retinopathy study (ETDRS) letters was reported. The Tubingen study (NCT02671539) included six patients; only one patient had an improvement of 17 ETDRS letters. The Alberta study (NCT02077361) enrolled six patients, and it reported a minimal vision change, except for one patient who gained 15 ETDRS letters. Six patients were enrolled in the Miami trial (NCT02553135), which reported a median gain of 2 ± 4 SD (-1 min, 10 max) ETDRS letters. The Philadelphia study (NCT02341807) included 10 patients; best corrected visual acuity (BCVA) returned to baseline in all by one-year follow-up, but one patient had -17 ETDRS letters from baseline. Overall, 40 patients were enrolled in trials, and 34 had 2 years of follow-up, with a median gain of 1.5 ± 7.2 SD (-14 min, 18 max) in ETDRS letters. Conclusions: The primary endpoint, BCVA following gene therapy in CHM, showed a marginal improvement with variability between trials. Optimizing surgical technique and pre-, peri-, and post-operative management with immunosuppressants to minimize any adverse ocular inflammatory events could lead to reduced incidence of complications. The ideal therapeutic window needs to be addressed to ensure that the necessary cell types are adequately transduced, minimizing viral toxicity, to prolong long-term transgenic potential. Long-term efficacy will be addressed by ongoing studies

Update on gene therapy clinical trials for choroideremia and potential experimental therapies

Background and objectives: Choroideremia (CHM) is an X-linked recessive chorioretinal dystrophy caused by mutations involving the CHM gene. Gene therapy has entered late-phase clinical trials, although there have been variable results. This review gives a summary on the outcomes of phase I/II CHM gene therapy trials and describes other potential experimental therapies. Materials and Methods: A Medline (National Library of Medicine, Bethesda, MD, USA) search was performed to identify all articles describing gene therapy treatments available for CHM. Results: Five phase I/II clinical trials that reported subretinal injection of adeno-associated virus Rab escort protein 1 (AAV2.REP1) vector in CHM patients were included. The Oxford study (NCT01461213) included 14 patients; a median gain of 5.5 ± 6.8 SD (−6 min, 18 max) early treatment diabetic retinopathy study (ETDRS) letters was reported. The Tubingen study (NCT02671539) included six patients; only one patient had an improvement of 17 ETDRS letters. The Alberta study (NCT02077361) enrolled six patients, and it reported a minimal vision change, except for one patient who gained 15 ETDRS letters. Six patients were enrolled in the Miami trial (NCT02553135), which reported a median gain of 2 ± 4 SD (−1 min, 10 max) ETDRS letters. The Philadelphia study (NCT02341807) included 10 patients; best corrected visual acuity (BCVA) returned to baseline in all by one-year follow-up, but one patient had −17 ETDRS letters from baseline. Overall, 40 patients were enrolled in trials, and 34 had 2 years of follow-up, with a median gain of 1.5 ± 7.2 SD (−14 min, 18 max) in ETDRS letters. Conclusions: The primary endpoint, BCVA following gene therapy in CHM, showed a marginal improvement with variability between trials. Optimizing surgical technique and pre-, peri-, and post-operative management with immunosuppressants to minimize any adverse ocular inflammatory events could lead to reduced incidence of complications. The ideal therapeutic window needs to be addressed to ensure that the necessary cell types are adequately transduced, minimizing viral toxicity, to prolong long-term transgenic potential. Long-term efficacy will be addressed by ongoing studies

Active surveillance of choroidal neovascularisation in children: incidence, aetiology and management findings from a national study in the UK

BACKGROUND/AIMS: To determine the UK incidence, demographics, aetiology, management and visual outcome for children developing choroidal neovascularisation (CNV). METHODS: A prospective population-based observational study of routine practice via the British Ophthalmological Surveillance Unit between January 2012 and December 2013 with subsequent 1-year follow-up in children under 16 years old with newly diagnosed CNV. RESULTS: Twenty-seven children with CNV were reported. The UK estimated annual incidence for those aged 16 and under was 0.21 per 100 000 (95% CI 0.133 to 0.299). The mean age was 11.1 years (SD 3.9, range 4-16). Fourteen were female. Seventy-seven per cent (22 patients) were Caucasian British. Twenty-three children (85%) had unilateral disease. The most common aetiology included inflammatory retinochoroidopathy (n=9), optic disc abnormalities (n=9) and idiopathic (n=5). Optical coherence tomography was performed in all cases and fundus fluorescein angiography in 61%. Management included observation only (n=10), anti-vascular endothelial growth factor (anti-VEGF) injection of bevacizumab (n=14) or ranibizumab (n=2), or both (n=1), and additional use of oral (n=1) and local (periocular n=2 and intravitreal n=2) steroids in five children with inflammatory retinochoroidopathy. The mean number of anti-VEGF injections was 2±1, with eight patients receiving only one injection. The mean (SD) best corrected visual acuity in LogMAR was 0.91 (0.53) at presentation and 0.74 (0.53) at 1-year follow-up (p=0.09). CONCLUSION: This is the first population-based prospective study of CNV in children. This is a rare disorder with a poor visual prognosis irrespective of CNV location and the use of anti-VEGF therapy

REP1 deficiency causes systemic dysfunction of lipid metabolism and oxidative stress in choroideremia

Choroideremia (CHM) is an X-linked recessive chorioretinal dystrophy caused by mutations in CHM, encoding for Rab escort protein 1 (REP1). Loss of functional REP1 leads to the accumulation of unprenylated Rab proteins and defective intracellular protein trafficking, the putative cause for photoreceptor, retinal pigment epithelium (RPE), and choroidal degeneration. CHM is ubiquitously expressed, but adequate prenylation is considered to be achieved, outside the retina, through the isoform REP2. Recently, the possibility of systemic features in CHM has been debated; therefore, in this study, whole metabolomic analysis of plasma samples from 25 CHM patients versus age- and sex-matched controls was performed. Results showed plasma alterations in oxidative stress-related metabolites, coupled with alterations in tryptophan metabolism, leading to significantly raised serotonin levels. Lipid metabolism was disrupted with decreased branched fatty acids and acylcarnitines, suggestive of dysfunctional lipid oxidation, as well as imbalances of several sphingolipids and glycerophospholipids. Targeted lipidomics of the chmru848 zebrafish provided further evidence for dysfunction, with the use of fenofibrate over simvastatin circumventing the prenylation pathway to improve the lipid profile and increase survival. This study provides strong evidence for systemic manifestations of CHM and proposes potentially novel pathomechanisms and targets for therapeutic consideration

Identifying characteristic features of the retinal and choroidal vasculature in choroideremia using optical coherence tomography angiography

PURPOSE: Using optical coherence tomography angiography (OCTA) to investigate the area with flow in the superficial retinal vessel network (SVRN) and choriocapillaris (CC) layer among male subjects with choroideremia (CHM), female carriers, and normal controls to identify vascular changes. PATIENTS AND METHODS: Images of SRVN and CC layer were acquired in 9 affected males, 5 female carriers, and 14 age- and gender-matched controls using the Angiovue software of the RTVue XR Avanti. RESULTS: The mean age was 33 years for affected male CHM patients (median 30 years), 46 years for female carriers (median 53 years), and 39 years for controls (median 38.5). Mean SRVN area±SD in subjects with CHM was 12.93±2.06 mm², in carrier subjects 15.36±0.60 mm², and in controls 15.30±1.35 mm² (P<0.01). The mean CC area±SD with flow was 6.97±5.26 mm² in CHM subjects, 21.65±0.17 mm² in carriers and 21.36±0.76 mm² in controls (P<0.01). SRVN and CC area with flow showed a negative correlation in CHM subjects with the age (r=−0.86; P<0.003 and r=−0.77; P<0.01, respectively). CC area with flow had a positive correlation with SRVN (r=0.83, P<0.001). Overall, visual acuity had a negative correlation with SRVN and CC area with flow (r=−0.67, P<0.001 and r=−0.57, P<0.002, respectively). CONCLUSIONS: This is the first study to highlight changes in the SRVN in CHM subjects. OCTA detected a reduced area with flow in both retinal and choroidal circulations, and may be a useful tool for monitoring natural history and disease progression in forthcoming clinical trials

A mild Grave's ophthalmopathy during pregnancy

Introduction: Thyroid ophthalmopathy is a complication most commonly associated with Grave’s disease. The disease course ranges from mild to severe, with severe cases resulting in major visual impairment. Methods: A complete ophthalmic examination in a 35-year-old secundigravida to 14 weeks of gestation presented to the hospital for a routine ophthalmological examination with eyelid retraction in the right eye was made. We studied the course of ocular disease through the gestation with orbit ecography and a 3T MRI. Results: A diagnosis of Grave’s Ophthalmopathy was made. Conclusion: This case presents an unusual course of the GD during pregnancy and a normal post-partum relapse, according to the Th1/Th2 balance. The frequent follow-up and the use of MRI allowed a prompt identification and complete control of the disease