ABSTRACT
Purpose: Surgical innovation in ophthalmology is impeded by the physiological limits of human motion, and robotic assistance may facilitate an expansion of the surgical repertoire. We conducted a systematic review to identify ophthalmic procedures in which robotic systems have been trialled, evaluate their performance, and explore future directions for research and development of robotic techniques. Methods: The Cochrane Library, Embase, MEDLINE, Scopus, and Web of Science were searched. Screening adhered to five criteria: (1) English language; (2) primary research article; (3) human patients; (4) ophthalmological surgery; and (5) robot-assisted surgery. Quality assessment was conducted with Joanna Briggs Institute Tools for Critical Appraisal. The study protocol was registered prospectively (PROSPERO ID CRD42023449793). Results: Twelve studies were included. In comparative studies, there was no difference in the occurrence of ocular harms in robot-assisted procedures and conventional surgery. However, robotic assistance did not demonstrate consistent benefits over manual surgery in terms of effectiveness or practicality, likely reflecting the learning curve associated with these systems. Single studies indicated the potential of robotic assistance to improve the consistency of subretinal drug infusion and efficiency of instrument manipulation in vitreoretinal surgery. Conclusions: Proof-of-concept studies have demonstrated the potential of robotic assistance to facilitate procedures otherwise infeasible or impractical, and may broaden access to surgery. However, robot-assisted surgery has not yet demonstrated any significant benefits over standard surgical practice. Improving the speed and reducing perioperative requirements of robot-assisted surgery are particular priorities for research and innovation to improve the practicality of these novel techniques. Translational Relevance: This systematic review summarizes the potential and limitations of robotic systems for assisting eye surgery and outlines what is required for these systems to benefit patients and surgeons.
Subject(s)
Ophthalmologic Surgical Procedures , Robotic Surgical Procedures , Humans , Robotic Surgical Procedures/methods , Robotic Surgical Procedures/adverse effects , Ophthalmologic Surgical Procedures/methods , Eye Diseases/surgeryABSTRACT
Age-related macular degeneration (AMD) is the leading cause of vision loss and visual impairment in people over 50 years of age. In the current therapeutic landscape, intravitreal anti-vascular endothelial growth factor (anti-VEGF) therapies have been central to the management of neovascular AMD (also known as wet AMD), whereas treatments for geographic atrophy have lagged behind. Several therapeutic approaches are being developed for geographic atrophy with the goal of either slowing down disease progression or reversing sight loss. Such strategies target the inflammatory pathways, complement cascade, visual cycle or neuroprotective mechanisms to slow down the degeneration. In addition, retinal implants have been tried for vision restoration and stem cell therapies for potentially a dual purpose of slowing down the degeneration and restoring visual function. In particular, therapies focusing on the complement pathway have shown promising results with the FDA approved pegcetacoplan, a complement C3 inhibitor, and avacincaptad pegol, a complement C5 inhibitor. In this review, we discuss the mechanisms of inflammation in AMD and outline the therapeutic landscapes of atrophy AMD. Improved understanding of the various pathway components and their interplay in this complex neuroinflammatory degeneration will guide the development of current and future therapeutic options, such as optogenetic therapy.
Subject(s)
Geographic Atrophy , Wet Macular Degeneration , Humans , Middle Aged , Geographic Atrophy/therapy , Angiogenesis Inhibitors , Vascular Endothelial Growth Factor A , Visual Acuity , InflammationABSTRACT
Bietti crystalline dystrophy (BCD) is an inherited retinal disease (IRD) caused by mutations in the CYP4V2 gene. It is a relatively common cause of IRD in east Asia. A number of features of this disease make it highly amenable to gene supplementation therapy. This study aims to validate a series of essential precursor in vitro experiments prior to developing a clinical gene therapy for BCD. We demonstrated that HEK293, ARPE19, and patient induced pluripotent stem cell (iPSC)-derived RPE cells transduced with AAV2 vectors encoding codon optimization of CYP4V2 (AAV2.coCYP4V2) resulted in elevated protein expression levels of CYP4V2 compared to those transduced with AAV2 vectors encoding wild type CYP4V2 (AAV2.wtCYP4V2), as assessed by immunocytochemistry and western blot. Similarly, we observed significantly increased CYP4V2 enzyme activity in cells transduced with AAV2.coCYP4V2 compared to those transduced with AAV2.wtCYP4V2. We also showed CYP4V2 expression in human RPE/choroid explants transduced with AAV2.coCYP4V2 compared to those transduced with AAV2.wtCYP4V2. These preclinical data support the further development of a gene supplementation therapy for a currently untreatable blinding condition-BCD. Codon-optimized CYP4V2 transgene was superior to wild type in terms of protein expression and enzyme activity. Ex vivo culture of human RPE cells provided an effective approach to test AAV-mediated transgene delivery.
Subject(s)
Corneal Dystrophies, Hereditary , Cytochrome P450 Family 4 , Genetic Therapy , Retinal Diseases , Corneal Dystrophies, Hereditary/genetics , Corneal Dystrophies, Hereditary/therapy , Cytochrome P450 Family 4/genetics , DNA Mutational Analysis , HEK293 Cells , Humans , Mutation , Retinal Diseases/genetics , Retinal Diseases/therapyABSTRACT
PURPOSE: To evaluate anatomic and functional intereye symmetry among individuals with Bietti crystalline dystrophy (BCD) using clinical and multimodal imaging methods, with a focus on the number, area, and distribution of the characteristic retinal crystalline deposits. DESIGN: Observational case series with prospective and retrospective data. METHODS: Setting: Multicenter. STUDY POPULATION: Thirteen Australian and New Zealand participants (26 eyes) with confirmed biallelic CYP4V2 mutations and a characteristic BCD fundus appearance. Procedures and main outcome measures: Crystals visible on color fundus photography were manually counted. Crystals were superimposed on aligned multimodal fundus images. Spearman's correlation coefficients (ρ), intraclass correlation coefficients (ICCs), and Bland-Altman plots were used to quantify symmetry between eyes. MAIN OUTCOME MEASURES: Fundus crystal area and count, and absent-autofluorescence (absent-AF) area. RESULTS: Median participant age was 48 years (interquartile range: 40-60 years). Intereye symmetry was high for fundus crystal area (ρ = 1.00, 95% confidence interval [CI]: 1.00-1.00; ICC = 0.97, 95% CI: 0.88-0.99), fundus crystal count (ρ = 0.98, 95% CI: 0.92-1.00; ICC = 0.97, 95% CI: 0.89-0.99), and absent-AF area (ρ = 0.88, 95% CI: 0.53-0.98; ICC = 0.98, 95% CI: 0.90-0.99). Average foveal volume, foveal crystal count and area, average and central foveal thickness, best corrected visual acuity, and average macular and central foveal sensitivity were not highly correlated between eyes. CONCLUSIONS: This study demonstrated strong intereye symmetry measured by fundus crystal area, fundus crystal number, and absent-AF area. This may influence the choice of outcome measures for future therapeutic trials for BCD and provides valuable clinical information for ophthalmologists involved in the care and counseling of patients with BCD.
Subject(s)
Retinal Degeneration , Tomography, Optical Coherence , Adult , Australia , Corneal Dystrophies, Hereditary , Cytochrome P450 Family 4/genetics , Fluorescein Angiography/methods , Humans , Middle Aged , Mutation , Prospective Studies , Retinal Diseases , Retrospective Studies , Tomography, Optical Coherence/methodsABSTRACT
The neutrophil-lymphocyte ratio (NLR) and platelet-lymphocyte ratio (PLR) are emerging haematological inflammatory biomarkers. However, their significance in retinal vein occlusion (RVO) and its subtypes, branch and central RVO (BRVO and CRVO, respectively), is uncertain. This systematic review and meta-analysis aimed to clarify the association of NLR and PLR with RVO. We searched MEDLINE (Ovid), EMBASE (Ovid) and the Cochrane Library for studies investigating the association of NLR and PLR with RVO from inception to 2 December 2020. We used random-effects inverse-variance modelling to generate pooled effect measures. We used bivariate Bayesian modelling to meta-analyse the ability of NLR and PLR to differ between individuals with and without RVO and performed meta-regression and sensitivity analyses to explore inter-study heterogeneity. Eight studies published encompassing 1059 patients were included for analysis. Both NLR and PLR were significantly elevated in RVO, with pooled mean differences of 0.63 (95% confidence interval (CI) 0.31-0.95) and 21.49 (95% CI 10.03-32.95), respectively. The pooled sensitivity, specificity and area under the Bayesian summary receiver operating characteristic curve were, respectively, 0.629 (95% credible interval (CrI) 0.284-0.872), 0.731 (95% CrI 0.373-0.934) and 0.688 (95% CrI 0.358-0.872) for NLR; and 0.645 (95% CrI 0.456-0.779), 0.616 (95% CrI 0.428-0.761) and 0.621 (95% CrI 0.452-0.741) for PLR. Mean and variability of age and diabetes mellitus prevalence partially explained between-study heterogeneity. NLR and PLR are significantly elevated in RVO. Future research is needed to investigate the potential prognostic value and independence of these findings.
Subject(s)
Blood Platelets/cytology , Lymphocytes/cytology , Neutrophils/cytology , Retinal Vein Occlusion/blood , Retinal Vein Occlusion/diagnosis , Bayes Theorem , Humans , Prognosis , Retrospective StudiesABSTRACT
Inherited retinal diseases (IRDs) are associated with mutations in over 250 genes and represent a major cause of irreversible blindness worldwide. While gene augmentation or gene editing therapies could address the underlying genetic mutations in a small subset of patients, their utility remains limited by the great genetic heterogeneity of IRDs and the costs of developing individualised therapies. Gene-agnostic therapeutic approaches target common pathogenic pathways that drive retinal degeneration or provide functional rescue of vision independent of the genetic cause, thus offering potential clinical benefits to all IRD patients. Here, we review the key gene-agnostic approaches, including retinal cell reprogramming and replacement, neurotrophic support, immune modulation and optogenetics. The relative benefits and limitations of these strategies and the timing of clinical interventions are discussed.
ABSTRACT
Vernier acuity measures the ability to detect a misalignment or positional offset between visual stimuli, for example between two vertical lines when reading a vernier scale. It is considered a form of visual hyperacuity due to its detectable thresholds being considerably smaller than the diameter of a foveal cone receptor, which limits the spatial resolution of classical visual acuity. Vernier acuity relies heavily on cortical processing and is minimally affected by optical media factors, making it a useful indicator of cortical visual function. Vernier acuity can be measured, usually in seconds of arc, by freely available automated online tools as well as via analysis of steady state visual-evoked potentials, which allows measurement in non- or pre-verbal subjects such as infants. Although not routinely measured in clinical practice, vernier acuity is known to be reduced in amblyopia, glaucoma and retinitis pigmentosa, and has been explored as a measure of retinal or neural visual function in the presence of optical media opacities. Current clinical utility includes a home-based vernier acuity tool, preferential hyperacuity perimetry, which is used for screening for choroidal neovascularisation in age-related macular degeneration. This review will discuss the measurement of vernier acuity, provide a current understanding of its neuro-ophthalmic mechanisms, and finally explore its utility through a clinical lens, along with our recommendations for best practice.
ABSTRACT
Age-related macular degeneration (AMD) is a multifactorial retinal disorder that is a major global cause of severe visual impairment. The development of an effective therapy to treat geographic atrophy, the predominant form of AMD, remains elusive due to the incomplete understanding of its pathogenesis. Central to AMD diagnosis and pathology are the hallmark lipid and proteinaceous deposits, drusen and reticular pseudodrusen, that accumulate in the subretinal pigment epithelium and subretinal spaces, respectively. Age-related changes and environmental stressors, such as smoking and a high-fat diet, are believed to interact with the many genetic risk variants that have been identified in several major biochemical pathways, including lipoprotein metabolism and the complement system. The APOE gene, encoding apolipoprotein E (APOE), is a major genetic risk factor for AMD, with the APOE2 allele conferring increased risk and APOE4 conferring reduced risk, in comparison to the wildtype APOE3. Paradoxically, APOE4 is the main genetic risk factor in Alzheimer's disease, a disease with features of neuroinflammation and amyloid-beta deposition in common with AMD. The potential interactions of APOE with the complement system and amyloid-beta are discussed here to shed light on their roles in AMD pathogenesis, including in drusen biogenesis, immune cell activation and recruitment, and retinal inflammation.
ABSTRACT
This review presents the phenotypic and genotypic profiles of a select group of inherited retinal diseases (IRDs) that are currently the focus of retinal gene therapy trials globally. Research progress in IRD treatment trials may soon lead to their availability in Australia and New Zealand, as either approved treatment or a clinical trial. The salient clinical characteristics of retinitis pigmentosa-the largest IRD category-are highlighted, with specific reference to RPE65-associated Leber congenital amaurosis, followed by other specific IRDs, namely choroideremia and ABCA4-associated Stargardt disease. These IRDs are selected based on their candidacy for gene therapy. Guidance on the clinical diagnostic tests that support each of these diagnoses will be presented. More broadly, the most useful structure and function measures to monitor IRD progression is discussed, along with the key assessments that offer differential diagnostic insight. This review is intended to be a clinical guide for optometrists, to assist in assessment and management of individuals who may be eligible for current and future gene therapies. A companion article in this issue will provide an overview of the basic principles of gene therapy and its development as a new treatment for inherited retinal diseases.
Subject(s)
Leber Congenital Amaurosis , Optometrists , Retinal Diseases , ATP-Binding Cassette Transporters/genetics , Genetic Therapy , Humans , Leber Congenital Amaurosis/genetics , Leber Congenital Amaurosis/therapy , RetinaABSTRACT
Inherited retinal diseases (IRDs) comprise a heterogeneous group of genetic disorders affecting the retina. Caused by mutations in over 300 genes, IRDs result in visual impairment due to dysfunction and degeneration of photoreceptors, retinal pigment epithelium, or the choroid. Important photoreceptor IRDs include retinitis pigmentosa and Leber congenital amaurosis. Macular dystrophies include Stargardt and Best disease. Currently, IRDs are largely incurable but the landscape of treatment options is rapidly changing for these diseases which, untreated, result in severe visual impairment and blindness.Advances in DNA delivery to the retina and improved genetic diagnosis of IRDs have led to a new era of research into gene therapy for these vision-threatening disorders. Gene therapy is a compelling approach due to the monogenic nature of most IRDs, with the retina being a favourable target for administering genetic vectors due to its immunoprivileged environment, direct visibility, and multiple methods to assess sensitivity and function. Generally, retinal gene therapy involves a subretinal or intravitreal injection of a viral vector, which infects target cells to deliver a therapeutic gene, or transgene. A gene augmentation strategy introduces a functioning copy of a gene to restore expression of a mutated gene, whereas a gene-editing strategy aims to directly edit and correct the mutation. Common delivery vectors include adeno-associated virus (AAV) and lentivirus.Voretigene neparvovec-rzyl (Luxturna) became the first FDA-approved direct gene therapy in December 2017, and the Australian TGA followed suit in August 2020. More are projected to follow, with clinical trials underway for many other IRDs.This review provides an overview of gene therapy for IRDs, including current progress and challenges. A companion article in this issue details target patient populations for IRD gene therapy, and how optometrists can assist in assessing individuals who may be eligible for current and future therapies.