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Background/aims: Voretigene neparvovec (VN) is the first and only subretinal gene therapy approved by the Food and Drug Administration and European Medicines Agency. Real-world application has started in 2018 in patients with vision impairment due to biallelic retinal pigment epithelium ( RPE ) 65 mutation-associated inherited retinal degenerations. Herein, we evaluated the development of retinal atrophy within in a single-centre patient cohort treated with VN., Methods: 13 eyes of eight patients treated with VN were retrospectively analysed for areas of retinal atrophy over a period of 6-24 months following surgery. Ultrawide field images were used to measure the area of atrophy. Fundus autofluorescence imaging is presented as an instrument for early detection of signs of retinal atrophy in these patients., Results: Atrophic changes beyond the retinotomy site were observed in all eyes. Areas of atrophy developed within the area of detachment (bleb) in all eight patients and outside the bleb in three patients. Changes in autofluorescence preceded the development of retinal atrophy and were already evident 2 weeks after surgery in the majority of patients. The areas of atrophy increase with time and progression continued over year 1. Functional outcomes remained stable (VA, FST, visual field)., Conclusion: Subretinal injection of VN can lead to RPE atrophy with consequent photoreceptor loss in and outside of the bleb area. Fundus autofluorescence is an important tool to monitor atrophic changes in patients after gene therapy. Interestingly, while areas of atrophy also included central areas, the functional benefits of the treatment did not appear to be affected and remained stable., Competing Interests: Competing interests: DF is on the advisory board of and/or consulting and/or receiving honoraria/grant money/travel support from following companies: Adelphi Values, Advent France Biotechnology, Alphasights, Arctos Medical, Atheneum, Axiom Healthcare Strategies, Biogen, Cambridge Consultants, Decision Resources, Dialectica, Frontera Therapeutics, Janssen Research & Development, Navigant, Novartis, Roche, RegenxBio, Sirion, System Analytic, and STZeyetrial. He is director of Fischer Consulting Limited and holds a patent (50%) on a gene therapy product for X-linked Retinitis Pigmentosa. FW reports personal fees from Novartis, outside the submitted work. KS reports personal fees from Novartis, outside the submitted work. SK reports grants from Charlotte & Tistou Kerstan Foundation, during the conduct of the study; personal fees from Novartis, outside the submitted work. No other disclosures were reported., (© Author(s) (or their employer(s)) 2023. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Voretigene neparvovec is a gene therapeutic agent for treatment of retinal dystrophies caused by bi-allelic RPE65 mutations. In this study, we report on a novel and objective evaluation of a retinotopic photoreceptor rescue., Methods: Seven eyes of five patients (14, 21, 23, 24, 36 years, 1 male, 4 females) with bi-allelic RPE65 mutations have been treated with voretigene neparvovec. The clinical examinations included visual acuity testing, dark-adapted full-field stimulus threshold (FST), dark-adapted chromatic perimeter (DAC) with a 30-degree grid, and a 30 degrees grid scotopic and photopic chromatic pupil campimetry (CPC). All evaluations and spectral domain optical coherence tomography were performed at baseline, 1 month and 3 months., Results: All except the oldest patient had a measurable improvement of the rod function assessed via FST, DAC or scotopic CPC at 1 month. The visual acuity improved slightly or remained stable in all eyes. A cone function improvement as measured by photopic CPC was observed in three eyes. The gain of the dark-adapted threshold with blue FST and the DAC stimuli (cyan) average correlated strongly with age (R 2 >0.7). The pupil response improvement in the scotopic CPC correlated with the baseline local retinal volume (R 2 =0.5)., Conclusions: The presented protocols allow evaluating the individual spatial and temporal effects of gene therapy effects. Additionally, we explored parameters that correlated with the success of the therapy. CPC and DAC present new and fast ways to assess functional changes in retinotopic maps of rod and cone function, measuring complementary aspects of retinal function., Competing Interests: Competing interests: DF is or has been on the advisory board of and/or consulting and/or receiving honoraria/grant money/travel support from following companies: Adelphi Values, Advent France Biotechnology, Alphasights, Atheneum, Axiom Healthcare Strategies, Biogen, Decision Resources, Dialectica, EyeServ, Frontera Therapeutics, Janssen Research & Development, Navigant, Novartis, Roche, RegenxBio, Sirion and STZeyetrial. DF is director of Fischer Consulting Limited and holds a patent (50%) on a gene therapy product for X-linked Retinitis Pigmentosa. DF is the lead investigator of the global (ex-US) post-authorisation, multicentre, multinational, longitudinal, observational safety registry study for patients treated with voretigene neparvovec (CLTW888A12401) and a part of the data reported here are included in that study. EZ is or has been on the advisory board of and/or consulting and/or receiving honoraria/grant money/travel support from following companies: SMERUD, Atheneum, Axiom Healthcare strategies, Biogen, Decision Resources, Janssen Research & Development, Navigant, RegenxBio, ProQR, Gyroscope, Astellas and STZ eyetrial. KaS has received grants and/or travel reimbursement from Novartis, ProQR and ORA. SK and FW received personal fees from Novartis. BaW and TP received other support from Novartis., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY. Published by BMJ.)

Background/aims: The aim of this study was to investigate a change in visual acuity and contrast sensitivity (CS) during high altitude exposure in healthy subjects due to the effects of hypobaric hypoxia. This study is related to the Tübingen High Altitude Ophthalmology study., Methods: Visual acuity and Weber CS were tested monocularly using the Freiburger Visual Acuity and Contrast Test under standardised conditions in 14 healthy subjects at high altitude at the Capanna Margherita (4559 m, Italy) and compared with baseline measurements in Tübingen (341 m, Germany). Intraindividual differences between baseline and follow-up examinations were calculated by multivariate analysis of variance for repeated measures. Clinical parameters of peripheral oxygen saturation (SpO 2 ) and heart rate (HR) as well as scores for acute mountain sickness (AMS) were correlated to psychophysical tests by Pearson's correlation coefficient., Results: A significant decrease in CS with a mean effect size of -0.13 logCS was found for Weber CS (day 1=-0.16±0.22, p=0.01; day 2=-0.10±0.2, p=0.049; day 3=-0.12±0.19, p=0.03) at high altitude compared with baseline. Visual acuity remained unchanged. Decreased CS correlated with SpO 2 (r=0.53, p=0.046) but not with HR (r=- 0.16, p=0.59) and occurred irrespective of AMS at high altitude., Conclusion: High altitude exposure leads to decreased CS. Changes occur independent of AMS. This finding is of clinical importance to trekkers and mountaineers exposed to high altitude as visual processing in particular under mesopic conditions at dusk and dawn is altered. Furthermore, it provides novel insight into hypoxia related changes in CS function., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2019. No commercial re-use. See rights and permissions. Published by BMJ.)

Background/aims: To better understand the pattern of degeneration progression in cases with choroideremia., Methods: A cohort of genotypically confirmed choroideremia cases who underwent optical coherence tomography (OCT) and fundus autofluorescence (FAF) imaging was studied. Using HEYEX review software, the foveal centre was marked on FAF images under guidance of corresponding OCT images, followed by application of an ETDRS grid. The boundaries of preserved autofluorescence (AF) were manually segmented in each individual ETDRS subfield. The regional distribution of preserved AF was assessed by comparing its area among the various subfields., Results: A total of 168 eyes from 84 choroideremia cases were enrolled. There was a statistically significant difference in the amount of preserved AF area between inner subfields as determined by one-way analysis of variance (F (3,668)=9.997, p<0.001) and also between outer subfields (F (3,668)=8.348, p<0.001). A Tukey posthoc test revealed that the preserved AF area in the nasal subfields in both the inner and outer subfields was significantly smaller compared with analogue subfields., Conclusion: The asymmetric spatial distribution of preserved AF in choroideremia (corresponding to the stellate shaped nature of these regions) suggests that the progression of degeneration has directional preference., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2019. No commercial re-use. See rights and permissions. Published by BMJ.)

Background/aims: The study aims to investigate changes in the optic nerve sheath diameter (ONSD) at high altitude and to assess correlation to optic disc oedema (ODE) and acute mountain sickness (AMS). This investigation is part of the Tübingen High Altitude Ophthalmology study., Methods: Fourteen volunteers ascended to 4559 m for 4 days before returning to low altitude. Ultrasonography of ONSD, quantification of optic disc parameters using a scanning laser ophthalmoscope and fluorescein angiography were performed at 341 m and at high altitude. Pearson's coefficient was used to correlate changes in ONSD with the optic disc and AMS. Assessment of AMS was performed using the Lake Louise (LL) and AMS-cerebral (AMS-C) scores of the Environmental Symptom Questionnaire-III. All volunteers were clinically monitored for heart rate (HR) and oxygen saturation (SpO 2 )., Results: The mean ONSD at high altitude (4.6±0.3 mm, p<0.05) was significantly increased compared with baseline (3.8±0.4 mm) and remained enlarged throughout high-altitude exposure. This change in ONSD did not correlate with AMS (AMS-C, r=0.26, p=0.37; LL, r=0.21, p=0.48) and high-altitude headache (r=0.54, p=0.046), or clinical parameters of SpO 2 (r=0.11, p=0.72) and HR (r=0.22, p=0.44). Increased ONSD did not correlate with altered key stereometric parameters of the optic disc describing ODE at high altitude (r<0.1, p>0.5)., Conclusion: High-altitude exposure leads to marked oedema formation of the optic nerve independent of AMS. Increased ONSD and ODE reflect hypoxia-driven oedema formation of the optic nerve at high altitude, providing important pathophysiological insight into high-altitude illness development and for future research., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2018. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Competing Interests: Competing interests: None declared.

Aim: To investigate changes in colour discrimination as a result of chronic hypoxic exposure induced by extreme altitudes (above 8000 m) during an expedition to Mt Everest., Methods: Colour discrimination thresholds for tritan, protan and deutan axes were measured extensively in two male participants (four eyes) during an expedition to Mt Everest, using a quantitative, computer controlled psychophysical colour vision test (modified version of the Cambridge Colour Test). The tests were carried out over a period of 54 days at altitudes of 1300 m, 3450 m, 4410 m, 5060 m, 5300 m, 6450 m, 7200 m and 8000 m., Results: Colour vision tests 1 week before and 6 months after the expedition indicated normal colour discrimination in both participants. With increasing altitude, colour discrimination thresholds were found to rise, predominantly for the tritan (blue) axes in both observers. Deutan (green) thresholds were minimally elevated at high altitude, whereas protan (red) was altered in one observer. Tritan colour discrimination thresholds decreased as a function of time spent at a given altitude and normalised upon return to low altitude., Conclusions: Chronic hypoxia induced by high altitude exposure transiently affects colour discrimination, in particular tritan axis discrimination. Decreased tritan discrimination is partly reversible upon physiological adaptation to high altitude and completely normalised upon return to low altitude.