Microbial keratitis in Southern Malawi: a microbiological pilot study.

OBJECTIVE: Microbial keratitis (MK) is a significant cause of blindness in sub-Saharan Africa. We investigated the feasibility of using a novel corneal impression membrane (CIM) for obtaining and processing samples by culture, PCR and whole-genome sequencing (WGS) in patients presenting with suspected MK in Malawi. METHODS AND ANALYSIS: Samples were collected from patients presenting with suspected MK using a 12 mm diameter polytetrafluoroethylene CIM disc. Samples were processed using culture and PCR for Acanthamoeba, herpes simplex virus type 1 (HSV-1) and the bacterial 16S rRNA gene. Minimum inhibitory concentrations of isolates to eight antimicrobials were measured using susceptibility strips. WGS was used to characterise Staphylococcus aureus isolates. RESULTS: 71 eyes of 71 patients were included. The overall CIM isolation rate was 81.7% (58 positive samples from 71 participants). 69 (81.2%) of isolates were Gram-positive cocci. Coagulase-negative Staphylococcus 31.8% and Streptococcus species 14.1% were the most isolated bacteria. Seven (9.9%) participants were positive for HSV-1. Fungi and Acanthamoeba were not detected. Moxifloxacin and chloramphenicol offered the best coverage for both Gram-positive and Gram-negative isolates when susceptibility was determined using known antimicrobial first quartile concentrations and European Committee on Antimicrobial Susceptibility Testing breakpoints, respectively. WGS identified known virulence genes associated with S. aureus keratitis. CONCLUSIONS: In a resource-poor setting, a CIM can be used to safely sample the cornea in patients presenting with suspected MK, enabling identification of causative microorganisms by culture and PCR. Although the microbiological spectrum found was limited to the dry season, these preliminary results could be used to guide empirical treatment.

Adalimumab vs placebo as add-on to Standard Therapy for autoimmune Uveitis: Tolerability, Effectiveness and cost-effectiveness-a protocol for a randomised controlled trial (ASTUTE trial).

INTRODUCTION: Adalimumab is an effective treatment for autoimmune non-infectious uveitis (ANIU), but it is currently only funded for a minority of patients with ANIU in the UK as it is restricted by the National Institute for Health and Care Excellence guidance. Ophthalmologists believe that adalimumab may be effective in a wider range of patients. The Adalimumab vs placebo as add-on to Standard Therapy for autoimmune Uveitis: Tolerability, Effectiveness and cost-effectiveness (ASTUTE) trial will recruit patients with ANIU who do and do not meet funding criteria and will evaluate the effectiveness and cost-effectiveness of adalimumab versus placebo as an add-on therapy to standard care. METHODS AND ANALYSIS: The ASTUTE trial is a multicentre, parallel-group, placebo-controlled, pragmatic randomised controlled trial with a 16-week treatment run-in (TRI). At the end of the TRI, only responders will be randomised (1:1) to 40 mg adalimumab or placebo (both are the study investigational medicinal product) self-administered fortnightly by subcutaneous injection. The target sample size is 174 randomised participants. The primary outcome is time to treatment failure (TF), a composite of signs indicative of active ANIU. Secondary outcomes include individual TF components, retinal morphology, adverse events, health-related quality of life, patient-reported side effects and visual function, best-corrected visual acuity, employment status and resource use. In the event of TF, open-label drug treatment will be restarted as per TRI for 16 weeks, and if a participant responds again, allocation will be switched without unmasking and treatment with investigational medicinal product restarted. ETHICS AND DISSEMINATION: The trial received Research Ethics Committee (REC) approval from South Central - Oxford B REC in June 2020. The findings will be presented at international meetings, by peer-reviewed publications and through patient organisations and newsletters to patients, where available. TRIAL REGISTRATION: ISRCTN31474800. Registered 14 April 2020.

Using Deep Learning to Segment Retinal Vascular Leakage and Occlusion in Retinal Vasculitis.

PURPOSE: Retinal vasculitis (RV) is characterised by retinal vascular leakage, occlusion or both on fluorescein angiography (FA). There is no standard scheme available to segment RV features. We aimed to develop a deep learning model to segment both vascular leakage and occlusion in RV. METHODS: Four hundred and sixty-three FA images from 82 patients with retinal vasculitis were used to develop a deep learning model, in 60:20:20 ratio for training:validation:testing. Parameters, including deep learning architectures (DeeplabV3+, UNet++ and UNet), were altered to find the best binary segmentation model separately for retinal vascular leakage and occlusion, using a Dice score to determine the reliability of each model. RESULTS: Our best model for vascular leakage had a Dice score of 0.6279 (95% confidence interval (CI) 0.5584-0.6974). For occlusion, the best model achieved a Dice score of 0.6992 (95% CI 0.6109-0.7874). CONCLUSION: Our RV segmentation models could perform reliable segmentation for retinal vascular leakage and occlusion in FAs of RV patients.

Clinical Outcomes of Observed and Treated Acute Posterior Multifocal Placoid Pigment Epitheliopathy and Relentless Placoid Chorioretinitis.

PURPOSE: To assess the efficacy of treatment on acute posterior multifocal placoid pigment epitheliopathy (APMPPE) and relentless placoid chorioretinopathy (RPC). METHODS: Cases were identified from three UK uveitis centers. Retrospective analysis of visual acuity recovery; OCT structural outcomes; and retinal lesion quantification in observed and treated cases of APMPPE/RPC. RESULTS: There were nine APMPPE and three RPC cases. Out of 12 patients, six were female. Median age: 26.5 years (range, 20-57 years). Four cases (six eyes) were observed, and eight cases (15 eyes) received corticosteroids ± immunosuppression. 4/4 observed and 6/10 treated foveal involving eyes regained 0.00 LogMAR vision. Observed lesions achieved more favorable anatomical outcomes. New lesions post-presentation developed in 1/6 (16%) observed eye versus 10/15 (66%) treated eyes. In three cases, a delayed, rebound lesion occurrence was observed post-high-dose corticosteroids. CONCLUSIONS: While subject to potential treatment bias, in this small case series, natural history alone appears non-inferior to corticosteroid treatment.

RETINAL VASCULITIS SEVERITY ASSESSMENT: Intraobserver and Interobserver Reliability of a New Scheme for Grading Wide-Field Fluorescein Angiograms in Retinal Vasculitis.

PURPOSE: Wide-field fluorescein angiography is commonly used to assess retinal vasculitis (RV), which manifests as vascular leakage and occlusion. Currently, there is no standard grading scheme for RV severity. The authors propose a novel RV grading scheme and assess its reliability and reproducibility. METHODS: A grading scheme was developed to assess both leakage and occlusion in RV. Wide-field fluorescein angiography images from 50 patients with RV were graded by four graders, and one grader graded them twice. An intraclass correlation coefficient (ICC) was used to determine intraobserver-interobserver reliability. Generalized linear models were calculated to associate the scoring with visual acuity. RESULTS: Repeated grading by the same grader showed good intraobserver reliability for both leakage (ICC = 0.85, 95% CI 0.78-0.89) and occlusion (ICC = 0.82, 95% CI 0.75-0.88) scores. Interobserver reliability among four independent graders showed good agreement for both leakage (ICC = 0.66, 95% CI 0.49-0.77) and occlusion (ICC = 0.75, 95% CI 0.68-0.81) scores. An increasing leakage score was significantly associated with worse concurrent visual acuity (generalized linear models, ß = 0.090, P < 0.01) and at 1-year follow-up (generalized linear models, ß = 0.063, P < 0.01). CONCLUSION: The proposed grading scheme for RV has good to excellent intraobserver and interobserver reliability across a range of graders. The leakage score related to present and future visual acuity.

Retinal imaging technologies in cerebral malaria: a systematic review.

BACKGROUND: Cerebral malaria (CM) continues to present a major health challenge, particularly in sub-Saharan Africa. CM is associated with a characteristic malarial retinopathy (MR) with diagnostic and prognostic significance. Advances in retinal imaging have allowed researchers to better characterize the changes seen in MR and to make inferences about the pathophysiology of the disease. The study aimed to explore the role of retinal imaging in diagnosis and prognostication in CM; establish insights into pathophysiology of CM from retinal imaging; establish future research directions. METHODS: The literature was systematically reviewed using the African Index Medicus, MEDLINE, Scopus and Web of Science databases. A total of 35 full texts were included in the final analysis. The descriptive nature of the included studies and heterogeneity precluded meta-analysis. RESULTS: Available research clearly shows retinal imaging is useful both as a clinical tool for the assessment of CM and as a scientific instrument to aid the understanding of the condition. Modalities which can be performed at the bedside, such as fundus photography and optical coherence tomography, are best positioned to take advantage of artificial intelligence-assisted image analysis, unlocking the clinical potential of retinal imaging for real-time diagnosis in low-resource environments where extensively trained clinicians may be few in number, and for guiding adjunctive therapies as they develop. CONCLUSIONS: Further research into retinal imaging technologies in CM is justified. In particular, co-ordinated interdisciplinary work shows promise in unpicking the pathophysiology of a complex disease.

Cerebral malaria-using the retina to study the brain.

Cerebral malaria (CM) remains a common cause of death of children in Africa with annual mortality of 400 000. Malarial retinopathy is a unique set of fundus signs which has diagnostic and prognostic value in CM. Assessment of malarial retinopathy is now widely utilised in clinical care, and routinely incorporated into clinical studies to refine entry criteria. As a visible part of the central nervous system, the retina provides insights into the pathophysiology of this infectious small-vessel vasculitis with adherent parasitised red blood cells. Fluorescein angiography and optical coherence tomography (OCT) have shown that patchy capillary non-perfusion is common and causes ischaemic changes in the retina in CM. It is likely this is mirrored in the brain and may cause global neurological impairments evident on developmental follow up. Three types of blood-retina barrier breakdown are evident: large focal, punctate, and vessel leak. Punctate and large focal leak (haemorrhage in formation) are associated with severe brain swelling and fatal outcome. Vessel leak and capillary non-perfusion are associated with moderate brain swelling and neurological sequelae. These findings imply that death and neurological sequelae have separate mechanisms and are not a continuum of severity. Each haemorrhage causes a temporary uncontrolled outflow of fluid into the tissue. The rapid accumulation of haemorrhages, as evidenced by multiple focal leaks, is a proposed mechanism of severe brain swelling, and death. Current studies aim to use optic nerve head OCT to identify patients with severe brain swelling, and macula OCT to identify those at risk of neurological sequelae.

A systematic review of OCT and OCT angiography in retinal vasculitis.

BACKGROUND: Retinal vasculitis is a component of uveitis for which the Standardisation of Uveitis Nomenclature (SUN) working group has no standard diagnostic criteria or severity grading. Fluorescein angiography is the gold standard test to assess retinal vasculitis, but is invasive and time-consuming. Optical coherence tomography (OCT) provides non-invasive detailed imaging of retinal structures and abnormalities, including blood vessel architecture and flow with OCT angiography (OCT-A). However, use of OCT in retinal vasculitis beyond assessing macular oedema, is not well established. We conducted a systematic review to understand the features of retinal vasculitis in OCT, Enhanced-depth imaging OCT (OCT-EDI) and OCT-A imaging. METHODS: The systematic search was done in March 2022 and updated in January 2023, through PubMed, EMBASE and the Web of Science database for studies related to OCT, OCT-EDI and OCT-A findings and retinal vasculitis. Bias assessment was assessed using JBI Critical Appraisal Checklist, and any findings associated with retinal vasculitis were extracted by qualitative analysis. RESULTS: We identified 20 studies, including 8 articles on OCT, 6 on OCT-EDI and 6 on OCT-A. The studies included analytical retrospective studies, case-series, and a case-control study. Five OCT studies reported secondary complications could be detected, and four reported retinal thickness alteration in retinal vasculitis. Five studies explored choroidal thickness alteration in OCT-EDI, and four explored capillary density alterations in retinal vasculitis using OCT-A. The heterogeneity in the studies' analysis and design precluded a meta-analysis. DISCUSSION: There were no clear OCT, OCT-EDI or OCT-A findings that demonstrated potential to supersede fluorescein angiography for assessing retinal vasculitis. Some signs of macular structural effects secondary to retinal vasculitis may help prognostication for vision. The OCT signs of inflamed retinal vessels and perivascular tissue is an unexplored area.

OCT Assisted Quantification of Vitreous Inflammation in Uveitis.

Purpose: Vitreous haze (VH) is a key marker of inflammation in uveitis but limited by its subjectivity. Optical coherence tomography (OCT) has potential as an objective, noninvasive method for quantifying VH. We test the hypotheses that OCT can reliably quantify VH and the measurement is associated with slit-lamp based grading of VH. Methods: In this prospective study, participants underwent three repeated OCT macular scans to evaluate the within-eye reliability of the OCT vitreous intensity (VI). Association between OCT VI and clinical findings (including VH grade, phakic status, visual acuity [VA], anterior chamber cells, and macular thickness) were assessed. Results: One hundred nineteen participants were included (41 healthy participants, 32 patients with uveitis without VH, and 46 patients with uveitis with VH). Within-eye test reliability of OCT VI was high in healthy eyes and in all grades of VH (intraclass correlation coefficient [ICC] > 0.79). Average OCT VI was significantly different between healthy eyes and uveitic eyes without and uveitic eyes with VH, and was associated with increasing clinical VH grade (P < 0.05). OCT VI was significantly associated with VA, whereas clinical VH grading was not. Cataract was also associated with higher OCT VI (P = 0.03). Conclusions: OCT VI is a fast, noninvasive, objective, and automated method for measuring vitreous inflammation. It is associated with clinician grading of vitreous inflammation and VA, however, it can be affected by media opacities. Translational Relevance: OCT imaging for quantifying vitreous inflammation shows high within-eye repeatability and is associated with clinical grading of vitreous haze. OCT measurements are also associated with visual acuity but may be affected by structures anterior to the acquisition window, such as lens opacity and other anterior segment changes.

How Does Blood-Retinal Barrier Breakdown Relate to Death and Disability in Pediatric Cerebral Malaria?

BACKGROUND: In cerebral malaria, the retina can be used to understand disease pathogenesis. The mechanisms linking sequestration, brain swelling, and death remain poorly understood. We hypothesized that retinal vascular leakage would be associated with brain swelling. METHODS: We used retinal angiography to study blood-retinal barrier integrity. We analyzed retinal leakage, histopathology, brain magnatic resonance imaging (MRI), and associations with death and neurological disability in prospective cohorts of Malawian children with cerebral malaria. RESULTS: Three types of retinal leakage were seen: large focal leak (LFL), punctate leak (PL), and vessel leak. The LFL and PL were associated with death (odds ratio [OR] = 13.20, 95% confidence interval [CI] = 5.21-33.78 and OR = 8.58, 95% CI = 2.56-29.08, respectively) and brain swelling (P < .05). Vessel leak and macular nonperfusion were associated with neurological disability (OR = 3.71, 95% CI = 1.26-11.02 and OR = 9.06, 95% CI = 1.79-45.90). Large focal leak was observed as an evolving retinal hemorrhage. A core of fibrinogen and monocytes was found in 39 (93%) white-centered hemorrhages. CONCLUSIONS: Blood-retina barrier breakdown occurs in 3 patterns in cerebral malaria. Associations between LFL, brain swelling, and death suggest that the rapid accumulation of cerebral hemorrhages, with accompanying fluid egress, may cause fatal brain swelling. Vessel leak, from barrier dysfunction, and nonperfusion were not associated with severe brain swelling but with neurological deficits, suggesting hypoxic injury in survivors.

Metformin, A Potential Role in Age-Related Macular Degeneration: A Systematic Review and Meta-Analysis.

BACKGROUND: Currently, no generally approved medical treatment can delay the onset of age-related macular degeneration (AMD) or slow the progression of degenerative changes. Repurposing drugs with beneficial effects on AMD pathophysiology offers a route to new treatments which is faster, cost-effective, and safer for patients. Recent studies indicate a potential role for metformin in delaying AMD development and progression. In this context, we conducted a systematic review and meta-analysis to look for beneficial associations between metformin and AMD. METHODS: We systematically searched Medline and Embase (via Ovid), Web of Science, and ClinicalTrials.gov databases for clinical studies in humans that examined the associations between metformin treatment and AMD published from inception to February 2021. We calculated pooled odds ratio (OR) with 95% confidence interval (CI) considering a random effect model in the meta-analysis. RESULTS: Five retrospective studies met the inclusion criteria. There are no prospective studies that have reported the effect of metformin in AMD. The meta-analysis showed that people taking metformin were less likely to have AMD although statistical significance was not met (pooled adjusted OR = 0.80, 95% CI 0.54-1.05, I2 = 98.8%). Subgroup analysis of the association between metformin and early and late AMD could not be performed since the data was not available from the included studies. CONCLUSIONS: Analysis of retrospective data suggests a signal that metformin may be associated with decreased risk of any AMD. It should be interpreted with caution because of the failure to meet statistical significance, the small number of studies, and the limitation of routine record data. However prospective studies are warranted in generalizable populations without diabetes, of varied ethnicities, and AMD stages. Clinical trials are needed to determine if metformin has efficacy in treating early and late-stage AMD.

Evolving Longitudinal Retinal Observations in a Cohort of Survivors of Ebola Virus Disease.

Importance: The 2-year ophthalmic sequelae of Ebola virus disease (EVD) in survivors of the 2013 to 2016 epidemic is unknown and may have public health implications for future outbreaks. Objective: To assess the potential for uveitis recurrence, the behavior of dark without pressure, and visual outcomes in a cohort of Sierra Leonean survivors of EVD 2 years following the 2013 to 2016 Ebola epidemic. Design, Setting, and Participants: Prospective, 1-year observational cohort study performed between 2016 and 2017 at 34 Military Hospital, Freetown, Sierra Leone. Participants included survivors of EVD who reported ocular symptoms since Ebola treatment unit discharge and were participants of a previous case-control study. Participants were invited for ophthalmic reexamination and finger-prick blood sampling for immunoglobulin G (IgG) to Toxoplasma gondii and HIV. Exposures: Ebola virus disease. Main Outcomes and Measures: Primary outcome measure: comparative ultra-widefield retinal imaging. Secondary outcome measures: visual acuity and detection of IgG to T gondii and HIV. Results: Of 57 survivors of EVD who underwent repeated ophthalmic evaluation, 37 were women (64.9%). Mean (SD) age was 31.9 (11.1) years. Median interval between first and last examination was 370 days (interquartile range [IQR], 365-397.5 days), and median time from discharge to last examination was 779 days (IQR, 732-821 days). Fifteen eyes of 10 survivors (17.5%) had retinal lesions secondary to EVD. No new EVD-associated retinal lesions were observed. Two survivors (3.5%) developed new posterior uveitis resembling toxoplasmosis chorioretinitis and 41 (73%) were seropositive for T gondii IgG. Areas of dark without pressure were observed either confined to the perimeter of Ebola retinal lesions (n = 7) and non-Ebola lesions (n = 2), involving extensive retinal areas adjacent to Ebola retinal lesions (n = 4) and non-Ebola lesions (n = 2) or in isolation (n = 6). Both expansion and regression of areas of dark without pressure were observed over the study period. Best eye-presenting visual acuity had mild or no visual impairment in 55 survivors (96.4%) 2 years following discharge. Conclusions and Relevance: Vision was maintained in survivors of EVD 2 years following discharge. Evolving regions of dark without pressure may be associated with EVD retinal lesions and might suggest the presence of an ongoing intraretinal stimulus, which may be associated with infective etiology. Treatment strategies should account for the possibility of toxoplasmosis chorioretinitis recurrence within survivors of EVD.

Case Series of Severe Neurologic Sequelae of Ebola Virus Disease during Epidemic, Sierra Leone.

We describe a case series of 35 Ebola virus disease (EVD) survivors during the epidemic in West Africa who had neurologic and accompanying psychiatric sequelae. Survivors meeting neurologic criteria were invited from a cohort of 361 EVD survivors to attend a preliminary clinic. Those whose severe neurologic features were documented in the preliminary clinic were referred for specialist neurologic evaluation, ophthalmologic examination, and psychiatric assessment. Of 35 survivors with neurologic sequelae, 13 had migraine headache, 2 stroke, 2 peripheral sensory neuropathy, and 2 peripheral nerve lesions. Of brain computed tomography scans of 17 patients, 3 showed cerebral and/or cerebellar atrophy and 2 confirmed strokes. Sixteen patients required mental health followup; psychiatric disorders were diagnosed in 5. The 10 patients who experienced greatest disability had co-existing physical and mental health conditions. EVD survivors may have ongoing central and peripheral nervous system disorders, including previously unrecognized migraine headaches and stroke.

Clinical outcomes in Caucasian patients with polypoidal choroidal vasculopathy.

PURPOSE: To describe treatment outcomes in a cohort of Caucasian patients with polypoidal choroidal vasculopathy (PCV). METHODS: Clinical charts from 48 eyes of 45 Caucasian patients with PCV were retrospectively reviewed. All cases were diagnosed with indocyanine green angiography. Best corrected visual acuity (BCVA) and optical coherence tomography (OCT) imaging were analyzed at baseline and final follow-up. RESULTS: Eyes were treated with a combination of verteporfin photodynamic therapy (PDT) and anti-vascular endothelial growth factor (VEGF) (n = 24), or PDT monotherapy (n = 9), or anti-VEGF monotherapy (n = 8), or no treatment (n = 7). Aflibercept was the anti-VEGF agent in 30 out of 32 eyes. Sixteen out of 24 eyes in the combination treatment group received initial PDT at diagnosis. All treatments led to stabilization of BCVA at final visit with a trend for better visual acuity in the anti-VEGF monotherapy group. There was a substantial reduction in central retinal thickness associated with resolution of subfoveal fluid and improvement in retinal pigment epithelial detachment in all treatment groups. BCVA and OCT findings remained stable in eyes which received no treatment. The use of PDT was associated with 0.5 fewer intravitreal injections per annum, which was not statistically significant. CONCLUSIONS: In the largest series of Caucasian patients with PCV presented to date, anti-VEGF monotherapy, PDT, or their combination preserved visual acuity and improved subfoveal exudative changes. Combination treatment was not superior to anti-VEGF monotherapy.

Multimodal Imaging and Spatial Analysis of Ebola Retinal Lesions in 14 Survivors of Ebola Virus Disease.

Importance: Differentiation between Ebola retinal lesions and other retinal pathologies in West Africa is important, and the pathogenesis of Ebola retinal disease remains poorly understood. Objective: To describe the appearance of Ebola virus disease (EVD) retinal lesions using multimodal imaging to enable inferences on potential pathogenesis. Design, Setting, and Participants: This prospective case series study was carried out at 34 Military Hospital in Freetown, Sierra Leone. Ophthalmological images were analyzed from 14 consecutively identified survivors of EVD of Sierra Leonean origin who had identified Ebola retinal lesions. Main Outcomes and Measures: Multimodal imaging findings including ultra-widefield scanning laser ophthalmoscopy, fundus autofluorescence, swept-source optical coherence tomography (OCT), Humphrey visual field analysis, and spatial analysis. Results: The 14 study participants had a mean (SD) age of 37.1 (8.8) years; 6 (43%) were women. A total of 141 Ebola retinal lesions were observed in 22 of 27 eyes (81%) of these 14 survivors on ultra-widefield imaging. Of these, 41 lesions (29.1%) were accessible to OCT imaging. Retinal lesions were predominantly nonpigmented with a pale-gray appearance. Peripapillary lesions exhibited variable curvatures in keeping with the retinal nerve fiber layer projections. All lesions respected the horizontal raphe and spared the fovea. The OCT imaging demonstrated a V-shaped hyperreflectivity of the outer nuclear layer overlying discontinuities of the ellipsoid zone and interdigitation zone in the smaller lesions. Larger lesions caused a collapse of the retinal layers and loss of retinal thickness. Lesion shapes were variable, but sharp angulations were characteristic. Perilesional areas of dark without pressure (thinned ellipsoid zone hyporeflectivity) accompanied 125 of the 141 lesions (88.7%) to varying extents. Conclusions and Relevance: We demonstrate OCT evidence of localized pathological changes at the level of the photoreceptors in small lesions among survivors of EVD with retinal lesions. The relevance of associated areas of dark without pressure remains undetermined.