Ophthalmology research in the UK’s National Health Service: the structure and performance of the NIHR’s Ophthalmology research portfolio

Purpose- To report on the composition and performance of the portfolio of Ophthalmology research studies in the United Kingdom’s National Institute for Health Research (NIHR) Clinical Research Network (UK CRN). Methods- Ophthalmology studies open to recruitment between 1 April 2010 and 31 March 2018 were classified by: sub-specialty, participant age, gender of Chief Investigator, involvement of genetic investigations, commercial/ non-commercial, interventional/observational design. Frequency distributions for each covariate and temporal variation in recruitment to time and target were analysed. Results- Over 8 years, 137,377 participants were recruited (average of 15,457 participants/year; range: 5485–32,573) with growth by year in proportion of commercial studies and hospital participation in England (76% in 2017/18). Fourteen percent of studies had a genetic component and most studies (82%) included only adults. The majority of studies (41%) enrolled patients with retinal diseases, followed by glaucoma (17%), anterior segment and cataract (13%), and ocular inflammation (6%). Overall, 68% of non-commercial studies and 55% of commercial studies recruited within the anticipated time set by the study and also recruited to or exceeded the target number of participants. Conclusions- High levels of clinical research activity, growth and improved performance have been observed in Ophthalmology in UK over the past 8 years. Some sub-specialties that carry substantial morbidity and a very high burden on NHS services are underrepresented and deserve more patient-centred research. Yet the NIHR and its CRN Ophthalmology National Specialty Group has enabled key steps in achieving the goal of embedding research into every day clinical care

Dimethyl fumarate in patients admitted to hospital with COVID-19 (RECOVERY): a randomised, controlled, open-label, platform trial

Dimethyl fumarate (DMF) inhibits inflammasome-mediated inflammation and has been proposed as a treatment for patients hospitalised with COVID-19. This randomised, controlled, open-label platform trial (Randomised Evaluation of COVID-19 Therapy [RECOVERY]), is assessing multiple treatments in patients hospitalised for COVID-19 (NCT04381936, ISRCTN50189673). In this assessment of DMF performed at 27 UK hospitals, adults were randomly allocated (1:1) to either usual standard of care alone or usual standard of care plus DMF. The primary outcome was clinical status on day 5 measured on a seven-point ordinal scale. Secondary outcomes were time to sustained improvement in clinical status, time to discharge, day 5 peripheral blood oxygenation, day 5 C-reactive protein, and improvement in day 10 clinical status. Between 2 March 2021 and 18 November 2021, 713 patients were enroled in the DMF evaluation, of whom 356 were randomly allocated to receive usual care plus DMF, and 357 to usual care alone. 95% of patients received corticosteroids as part of routine care. There was no evidence of a beneficial effect of DMF on clinical status at day 5 (common odds ratio of unfavourable outcome 1.12; 95% CI 0.86-1.47; p = 0.40). There was no significant effect of DMF on any secondary outcome

Dimethyl fumarate in patients admitted to hospital with COVID-19 (RECOVERY): a randomised, controlled, open-label, platform trial

Dimethyl fumarate (DMF) inhibits inflammasome-mediated inflammation and has been proposed as a treatment for patients hospitalised with COVID-19. This randomised, controlled, open-label platform trial (Randomised Evaluation of COVID-19 Therapy [RECOVERY]), is assessing multiple treatments in patients hospitalised for COVID-19 (NCT04381936, ISRCTN50189673). In this assessment of DMF performed at 27 UK hospitals, adults were randomly allocated (1:1) to either usual standard of care alone or usual standard of care plus DMF. The primary outcome was clinical status on day 5 measured on a seven-point ordinal scale. Secondary outcomes were time to sustained improvement in clinical status, time to discharge, day 5 peripheral blood oxygenation, day 5 C-reactive protein, and improvement in day 10 clinical status. Between 2 March 2021 and 18 November 2021, 713 patients were enroled in the DMF evaluation, of whom 356 were randomly allocated to receive usual care plus DMF, and 357 to usual care alone. 95% of patients received corticosteroids as part of routine care. There was no evidence of a beneficial effect of DMF on clinical status at day 5 (common odds ratio of unfavourable outcome 1.12; 95% CI 0.86-1.47; p = 0.40). There was no significant effect of DMF on any secondary outcome

Glaucoma surgery with or without adjunctive antiproliferatives in normal tension glaucoma: 1 Intraocular pressure control and complications

BACKGROUND—Reduction of intraocular pressure (IOP) by 20-30% with glaucoma drainage surgery slows disease progression in normal tension glaucoma (NTG). It is not clear whether adjunctive antiproliferative agents are necessary or safe in eyes at low risk for scarring.
METHOD—86 eyes of 73 white NTG patients who had undergone a primary guarded fistulising procedure were reviewed. 25 eyes had no antiproliferatives, 36 had peroperative 5-fluorouracil (5-FU) and 25 had peroperative mitomycin C (MMC). Their postoperative IOPs, complications, and changes in visual acuity were recorded.
RESULTS—Eyes that had no adjunctive antiproliferative less commonly maintained a 20-30% reduction in IOP (47.4% at 2 years) compared with either the 5-FU group (69.4%at 2 years, p=0.01) or the MMC group (64.9% at 2 years, p=0.04). Eyes that had adjunctive MMC more often had late hypotony (28%, p=0.02) and late bleb leak (12%, p<0.001). Eyes that had adjunctive MMC also more often had a two lines loss of Snellen visual acuity (39.8% by 2 years) compared with those that had adjunctive 5-FU (14.7% by 2 years), p=0.06.
CONCLUSION—For NTG patients at low risk of scarring trabeculectomy with adjunctive peroperative 5-FU should maintain a suitable target IOP without the additional sight threatening complications seen with adjunctive MMC.


Screening for age-related macular degeneration using nonstereo digital fundus photographs.

Age-related macular degeneration (AMD) is a disease with significant visual morbidity and accounts for the majority of blind registrations in the developed world including the UK. Certain forms of neovascular AMD are amenable to treatment but require expeditious referral to a retinal specialist. AIM: To evaluate the possibility of using nonstereo fundus photographs as a low-cost screening tool for neovascular AMD. DESIGN: Retrospective review of patients referred to the macular clinic of a teaching hospital in London. METHODS: A total of 198 randomised digital fundus photographs, without any other clinical information, were presented to two independent ophthalmic interns who graded them into one of the three categories: normal, age-related maculopathy (ARM), or neovascular age-related macular degeneration (AMD) to determine the urgency of referral to clinic. The results were compared with the known diagnosis for each patient and sensitivities and specificities for each diagnostic category calculated. RESULTS: The intraobserver Kappa statistic was 0.75 and 0.91 for grader 1 and 2, respectively. The interobserver Kappa was 0.54. The mean sensitivity and specificity for the identification of ARM was 60.5 and 76.3%, respectively The mean sensitivity and specificity for the identification of AMD was 85.7 and 78.8%, respectively. CONCLUSION: Nonstereo digital fundus photograph is a reasonable screening tool for CNV and may aid in decreasing the visual morbidity it causes by enabling timely referrals and treatment

Comparison of visual field progression in patients with normal pressure glaucoma between eyes with and without visual field loss that threatens fixation

AIM—To compare the frequency and site of visual field progression and changes in visual acuity in patients with normal pressure glaucoma (NPG) with and without pre-existing visual field loss.
METHOD—Patients with normal tension glaucoma were selected who had at least 10 visual fields over 5 or more years of follow up and no other condition that might influence the visual field or visual acuity. Alternate left and right eyes were selected from patients in random order. These eyes were then subdivided according to visual field defect threatening fixation, visual field defect not threatening fixation, and no visual field defect (fellow eyes). Eyes were defined as showing a threat to fixation according to the presence of a visual field defect involving one of more of four paracentral visual field locations. Pointwise linear regression analysis was applied to each visual field series using PROGRESSOR software. Progression of visual field loss was defined as the appearance of a regression slope 1 dB per year or more with a significance of p<0.01, which remained consistent with the addition of two of three successive visual fields to the series. The number of patients showing progression and the number where progression occurred in one of the four paracentral visual field locations was noted. The number of eyes losing two or more lines of Snellen visual acuity over the follow up period was also noted.
RESULTS—174 eyes of 174 patients were selected. 106 eyes had visual field loss threatening fixation, 46 eyes had visual field loss that did not threaten fixation, and 22 were fellow eyes with normal visual fields. The median follow up was 7.2 years. Eight eyes (36.4%) in the "normal visual fields" group, 31 eyes (67.4%) in the "visual field loss away from fixation" group, and 87 eyes (82.1%) in the "threat to fixation" group showed progression in any part of the visual field. Two eyes (9.1%) in the "normal visual fields" group, nine eyes (19.6%) in the "visual field loss away from fixation" group, and 45 eyes (42.5%) in the "threat to fixation" group showed progression at "threat to fixation". The Cox proportional hazards regression model showed an increased risk of progression at any part of the visual field for female sex and a decreased risk for eyes with normal visual fields. For progression at threat to fixation this model showed an increased risk with pre-existing threat to fixation. Eyes from older patients and those that went on to have progressive visual field loss at fixation were more likely to lose two lines of Snellen visual acuity over the follow up period.
CONCLUSION—Since 20-30% of previously field damaged eyes and over 60% without prior field loss fail to demonstrate progressive visual field damage over a long follow up it is recommended that normal pressure glaucoma patients be monitored for progression and that potentially harmful therapy be withheld until progression is demonstrated. Although the presence of visual field loss that threatens fixation does not constitute an increased risk of visual field progression it does indicate an increased risk of further loss of visual field close to fixation which is in turn associated with loss of central acuity. In the light of this finding, patients with visual field loss that threatens fixation should be managed more aggressively.


Longitudinal nerve fibre layer thickness change in normal-pressure glaucoma

PURPOSE: To investigate longitudinal retinal nerve fibre layer (RNFL) thickness change in patients with normal-pressure glaucoma (NPG) and to assess how this may be related to visual fields. METHODS: NPG patients and normal subjects who had had serial GDx nerve fibre layer Analyzer II imaging and Humphrey visual fields performed at least 18 months apart were selected for study. These measurements were compared between groups at baseline and at subsequent follow-up, for change over time. RESULTS: Seventy-five NPG patients and 35 normal subjects were studied. Significant differences in RNFL thickness were found between NPG patients and normal controls at baseline (P < or = 0.001). Over the same time, there was greater RNFL thinning in NPG patients than in normal subjects (P < or = 0.0001). RNFL thinning in NPG was negatively correlated with visual field log MD at baseline (P < 0.001) and change in MD over time (P < 0.001). CONCLUSION: Reduction of RNFL thickness over time was significantly greater in NPG patients than in normal subjects, indicating that NPG patients' RNFL had thinned at a faster rate. NPG patients with initially better visual fields had a greater reduction in RNFL thickness than did those with initially more advanced visual field defects, suggesting that more RNFL change may be observed when glaucoma is at an earlier stage. There was a direct relationship between RNFL thinning and visual field deterioration

Pilot randomised controlled trial of face-down positioning following macular hole surgery.

OBJECTIVE: This was a pilot randomised controlled trial (RCT) to investigate the effect of post-operative face-down positioning on the outcome of macular hole surgery and to inform the design of a larger definitive study. METHODS: In all, 30 phakic eyes of 30 subjects with idiopathic full-thickness macular holes underwent vitrectomy with dye-assisted peeling of the ILM and 14% perfluoropropane gas. Subjects were randomly allocated to posture face down for 10 days (posturing group) or to avoid a face-up position only (non-posturing group). The primary outcome was anatomical hole closure. RESULTS: Macular holes closed in 14 of 15 eyes (93.3%; 95% confidence interval (CI) 68-100%) in the posturing group and in 9 of 15 (60%; 95% CI 32-84%) in the non-posturing group. In a subgroup analysis of outcome according to macular hole size, all holes smaller than 400 μm closed regardless of posturing (100%). In contrast, holes larger than 400 μm closed in 10 of 11 eyes (91%; 95% CI 58-99%) in the posturing group and in only 4 of 10 eyes (40%; 95% CI 12-74%) in the non-posturing group (Fisher's exact test P=0.02). CONCLUSION: Post-operative face-down positioning may improve the likelihood of macular hole closure, particularly for holes larger than 400 μm. These results support the case for a RCT