Understanding and preventing visual loss in commotio retinae

Commotio retinae describes retinal opacification following trauma and affected 16% of British soldiers suffering major trauma. The macula was affected in 55% of soldiers and 31% of civilian cases, permanently reducing vision to less than 6/9 in 26% of cases, associated with photoreceptor degeneration. In an experimental rat model, commotio retinae was more readily induced by high velocity ballistic injury (20m/s) than low velocity weight drop (2-7m/s). In rats, after experimentally induced commotio retinae, photoreceptors died by a combination of necrosis (central to the impact site) and apoptosis (peripheral to it), demonstrated by morphological changes on electron micrographs and TUNEL staining. Photoreceptor death after commotio retinae was associated with reduced ERG a-wave amplitude. Apoptosis occurred through the intrinsic pathway, mediated by caspase 9 but not involving any of the classical executioner caspases (3, 6 and 7). Inhibition of caspase 9 reduced photoreceptor death and improved retinal function, assessed by a-wave amplitude. Clinical studies suggested a protective effect of female gender after commotio retinae, but progesterone treatment increased photoreceptor death after ballistic injury in the experimental model

The UK paediatric ocular trauma study 2 (POTS2):Demographics and mechanisms of injuries

Freda Sii,1,2 Robert J Barry,1 Joseph Abbott,3 Richard J Blanch,1,4 Caroline J MacEwen,5 Peter Shah1,2,6,7 1Department of Ophthalmology, Queen Elizabeth Hospital Birmingham, University Hospitals Birmingham NHS Foundation Trust, Birmingham, 2Birmingham Institute for Glaucoma Research, Institute of Translational Medicine, University Hospitals Birmingham NHS Foundation Trust, Birmingham, 3Department of Ophthalmology, Birmingham Children’s Hospital NHS Foundation Trust, Birmingham, 4Academic Department of Military Surgery and Trauma, Royal Centre for Defence Medicine, Birmingham, 5Department of Ophthalmology, Ninewells Hospital and Medical School, Dundee, 6National Institute of Health Research Biomedical Research Centre, Moorfields Eye Hospital NHS Foundation Trust and UCL Institute of Ophthalmology, London, 7Centre for Health and Social Care Improvement, School of Health and Wellbeing, University of Wolverhampton, Wolverhampton, UK Purpose: Pediatric ocular trauma is an important cause of visual morbidity worldwide, accounting for up to one-third of all ocular trauma admissions. It has long-term implications for those affected and significant economic consequences for healthcare providers. It has been estimated that 90% of all ocular trauma is preventable. Targeted strategies are required to reduce the incidence and the severity of pediatric ocular trauma; this requires an understanding of the epidemiology and characteristics of these injuries and the children involved. Methods: Prospective, observational study of pediatric ocular trauma cases presenting to UK-based ophthalmologists over a 1-year period; reporting cards were distributed by the British Ophthalmological Surveillance Unit, and clinicians were asked to report incidents of acute orbital and ocular trauma in children aged ≤16 years requiring inpatient or day-case admission. A validated, standardized questionnaire was sent to reporting ophthalmologists to collect data on the demographics and circumstances of injury. Results: Median age at presentation was 7.7 years, with boys more than twice as likely to be affected than girls (M:F =2.1:1.0). Almost 50% of injuries occurred at home, with 25% occurring in school or nursery. A total of 67% of injuries occurred during play, and 31% involved a sharp implement. Conclusion: Pediatric ocular trauma remains an important public health problem. At least three-quarters of all injuries are preventable through measures, including education of children and responsible adults, restricting access to sharp implements, improving adult supervision, and appropriate use of eye protection. Keywords: etiology, childhood eye injury, epidemiology, penetrating eye injury, perforating eye injury, preventio

The UK Paediatric Ocular Trauma Study 1 (POTS1):development of a global standardized protocol for prospective data collection in pediatric ocular trauma

Freda Sii,1,2 Robert J Barry,1 Richard J Blanch,1 Joseph Abbott,3 Caroline J MacEwen,4 Peter Shah1,2,5,6 1Department of Ophthalmology, Queen Elizabeth Hospital Birmingham, 2Birmingham Institute for Glaucoma Research, Institute of Translational Medicine, University Hospitals Birmingham NHS Foundation Trust, 3Department of Ophthalmology, Birmingham Children’s Hospital NHS Foundation Trust, Birmingham, 4Department of Ophthalmology, Ninewells Hospital and Medical School, Dundee, 5National Institute of Health Research Biomedical Research Centre, Moorfields Eye Hospital NHS Foundation Trust and UCL Institute of Ophthalmology, London, 6Centre for Health and Social Care Improvement, School of Health and Wellbeing, University of Wolverhampton, Wolverhampton, UK Background: Ocular trauma is an important cause of visual morbidity in children worldwide. Pediatric ocular trauma accounts for up to one third of all ocular trauma admissions, with significant economic implications for health care providers. It is estimated that 90% of all ocular trauma is preventable. Development of strategies to reduce the incidence and severity of pediatric ocular trauma requires an understanding of the epidemiology of these injuries and their characteristics. This will enable appropriate targeting of resources toward prevention and allow effective service planning. At present, there is no standardized methodology for the collection of global cross-sectional data in pediatric ocular trauma, and the ability to undertake detailed epidemiological and health-economic analyses is limited. Furthermore, it is difficult to draw international comparisons in incidence, etiology, and outcomes of pediatric ocular trauma due to the range of published reporting criteria. This study describes two novel questionnaires for standardized data collection in pediatric ocular trauma, which can be adopted across a range of health care settings internationally.Methods: Two standardized data collection questionnaires have been developed from previously reported templates. The first enables collection of demographic and incident data on serious pediatric ocular trauma requiring hospitalization, and the second enables follow-up outcome data collection. Both the questionnaires are designed to collect primarily categorical data in order to increase ease of completion and facilitate quantitative analysis. These questionnaires enable acquisition of standardized data on the incidence, etiology, and outcomes of pediatric ocular trauma.Discussion: These questionnaires enable collection of standardized data and are designed for global use across all health care settings. Through prospective data collection, epidemiological trends can be determined, allowing health care providers to develop collaborative global preventive strategies. Furthermore, the same questionnaires may be used in future studies to draw comparisons with baseline data, allowing assessment of the efficacy of targeted preventative interventions. Keywords: childhood eye injury, epidemiology, health economic analyses, international standardization, penetrating eye injury, perforating eye injury, preventio

Window into the mind:Advanced handheld spectroscopic eye-safe technology for point-of-care neurodiagnostic

Traumatic brain injury (TBI), a major cause of morbidity and mortality worldwide, is hard to diagnose at the point of care with patients often exhibiting no clinical symptoms. There is an urgent need for rapid point-of-care diagnostics to enable timely intervention. We have developed a technology for rapid acquisition of molecular fingerprints of TBI biochemistry to safely measure proxies for cerebral injury through the eye, providing a path toward noninvasive point-of-care neurodiagnostics using simultaneous Raman spectroscopy and fundus imaging of the neuroretina. Detection of endogenous neuromarkers in porcine eyes' posterior revealed enhancement of high-wave number bands, clearly distinguishing TBI and healthy cohorts, classified via artificial neural network algorithm for automated data interpretation. Clinically, translating into reduced specialist support, this markedly improves the speed of diagnosis. Designed as a hand-held cost-effective technology, it can allow clinicians to rapidly assess TBI at the point of care and identify long-term changes in brain biochemistry in acute or chronic neurodiseases.</p

A systematic review of optical coherence tomography findings in adults with mild traumatic brain injury

Mild traumatic brain injury (mTBI) is common with many patients suffering disabling long-term sequelae, with visual symptoms frequently reported. There are no objective biomarkers of mTBI that are routinely used in clinical practice. Optical coherence tomography (OCT) has been used in mTBI research, as it enables visualisation of the neuroretina, allowing measurement of the retinal nerve fibre layer and ganglion cell layer. This systematic review aims to appraise the available literature and assess whether there are significant changes within the retinal nerve fibre layer and ganglion cell layer in subjects after mTBI. A systematic review was carried out in accordance with PRISMA guidelines and registered with PROSPERO (Number: CRD42022360498). Four databases were searched for relevant literature published from inception until 1 September 2022. Abstracts and full texts were screened by three independent reviewers. Initial screening of databases yielded 341 publications, of these, three fulfilled all the criteria for inclusion. All three studies showed thinning of the retinal nerve fibre layer, whereas there were no significant changes in the ganglion cell layer. This systematic review demonstrated that thinning of the retinal nerve fibre layer (but not of the ganglion cell layer) is associated with mTBI. It provides preliminary evidence for the use of the retinal nerve fibre layer as a potential biomarker of damage to the visual system in mTBI. Further prospective longitudinal studies ensuring uniform diagnosis and accurate phenotyping of mTBI are needed to understand the effects on the visual system and potential of OCT as a prognostic biomarker

Improving corneal permeability of dexamethasone using penetration enhancing agents:First step towards achieving topical drug delivery to the retina

With an ever-increasing burden of vision loss caused by diseases of the posterior ocular segment, there is an unmet clinical need for non-invasive treatment strategies. Topical drug application using eye drops suffers from low to negligible bioavailability to the posterior segment as a result of static and dynamic defensive ocular barriers to penetration, while invasive delivery systems are expensive to administer and suffer potentially severe complications. As the cornea is the main anatomical barrier to uptake of topically applied drugs from the ocular surface, we present an approach to increase corneal permeability of a corticosteroid, dexamethasone sodium-phosphate (DSP), using a novel penetration enhancing agent (PEA). We synthesised a novel polyacetylene (pAc) polymer and compared its activity to two previously described cell penetrating peptide (CPP) based PEAs, TAT and penetratin, with respect to increasing transcorneal permeability of DSP in a rapid ex-vivo porcine corneal assay over 60 min. The transcorneal apparent permeability coefficients (Papp) for diffusion of pAc, and fluorescein isothiocyanate (FITC) conjugated TAT and penetratin were up to 5 times higher (p &lt; 0.001), when compared to controls. When pAc was used in formulation with DSP, an almost 5-fold significant increase was observed in Papp of DSP across the cornea (p = 0.0130), a significant 6-fold increase with TAT (p = 0.0377), and almost 7-fold mean increase with penetratin (p = 0.9540). Furthermore, we investigated whether the PEAs caused any irreversible damage to the barrier integrity of the corneal epithelium by measuring transepithelial electrical resistance (TEER) and immunostaining of tight junction proteins using zonula occludens-1 (ZO-1) and occludin antibodies. There was no damage or structural toxicity, and the barrier integrity was preserved after PEA application. Finally, an in-vitro cytotoxicity assessment of all PEAs in human retinal pigment epithelium cells (ARPE-19) demonstrated that all PEAs were very well-tolerated, with IC50 values of 64.79 mM for pAc and 1335.45 µM and 87.26 µM for TAT and penetratin, respectively. Our results suggest that this drug delivery technology could potentially be used to achieve a significantly higher intraocular therapeutic bioavailability after topical eye drop administration, than currently afforded

Mesenchymal stromal cell-mediated neuroprotection and functional preservation of retinal ganglion cells in a rodent model of glaucoma

Background aims: Glaucoma is a leading cause of irreversible blindness involving loss of retinal ganglion cells (RGC). Mesenchymal stromal cells (MSC) have shown promise as a paracrine-mediated therapy for compromised neurons. It is, however, unknown whether dental pulp stem cells (DPSC) are effective as a cellular therapy in glaucoma and how their hypothesized influence compares with other more widely researched MSC sources. The present study aimed to compare the efficacy of adipose-derived stem cells, bone marrow-derived MSC (BMSC) and DPSC in preventing the loss of RGC and visual function when transplanted into the vitreous of glaucomatous rodent eyes. Methods: Thirty-five days after raised intraocular pressure (IOP) and intravitreal stem cell transplantation, Brn3a+ RGC numbers, retinal nerve fibre layer thickness (RNFL) and RGC function were evaluated by immunohistochemistry, optical coherence tomography and electroretinography, respectively. Results: Control glaucomatous eyes that were sham-treated with heat-killed DPSC had a significant loss of RGC numbers, RNFL thickness and function compared with intact eyes. BMSC and, to a greater extent, DPSC provided significant protection from RGC loss and RNFL thinning and preserved RGC function. Discussion: The study supports the use of DPSC as a neuroprotective cellular therapy in retinal degenerative disease such as glaucoma

Improving corneal permeability of dexamethasone using penetration enhancing agents:First step towards achieving topical drug delivery to the retina

With an ever-increasing burden of vision loss caused by diseases of the posterior ocular segment, there is an unmet clinical need for non-invasive treatment strategies. Topical drug application using eye drops suffers from low to negligible bioavailability to the posterior segment as a result of static and dynamic defensive ocular barriers to penetration, while invasive delivery systems are expensive to administer and suffer potentially severe complications. As the cornea is the main anatomical barrier to uptake of topically applied drugs from the ocular surface, we present an approach to increase corneal permeability of a corticosteroid, dexamethasone sodium-phosphate (DSP), using a novel penetration enhancing agent (PEA). We synthesised a novel polyacetylene (pAc) polymer and compared its activity to two previously described cell penetrating peptide (CPP) based PEAs, TAT and penetratin, with respect to increasing transcorneal permeability of DSP in a rapid ex-vivo porcine corneal assay over 60 min. The transcorneal apparent permeability coefficients (Papp) for diffusion of pAc, and fluorescein isothiocyanate (FITC) conjugated TAT and penetratin were up to 5 times higher (p &lt; 0.001), when compared to controls. When pAc was used in formulation with DSP, an almost 5-fold significant increase was observed in Papp of DSP across the cornea (p = 0.0130), a significant 6-fold increase with TAT (p = 0.0377), and almost 7-fold mean increase with penetratin (p = 0.9540). Furthermore, we investigated whether the PEAs caused any irreversible damage to the barrier integrity of the corneal epithelium by measuring transepithelial electrical resistance (TEER) and immunostaining of tight junction proteins using zonula occludens-1 (ZO-1) and occludin antibodies. There was no damage or structural toxicity, and the barrier integrity was preserved after PEA application. Finally, an in-vitro cytotoxicity assessment of all PEAs in human retinal pigment epithelium cells (ARPE-19) demonstrated that all PEAs were very well-tolerated, with IC50 values of 64.79 mM for pAc and 1335.45 µM and 87.26 µM for TAT and penetratin, respectively. Our results suggest that this drug delivery technology could potentially be used to achieve a significantly higher intraocular therapeutic bioavailability after topical eye drop administration, than currently afforded