Because the retina has high energy demands, the loss of a mitochondrial ATP transporter was predicted to impact retinal function. The authors examined retinal function and morphology in mice without ANT1, a key ATP transporter associated with myopathy.

The quality of ocular fundus photographs can affect the accuracy of the morphologic assessment of the optic nerve head (ONH), either by humans or by deep learning systems (DLS). In order to automatically identify ONH photographs of optimal quality, we have developed, trained, and tested a DLS, using an international, multicentre, multi-ethnic dataset of 5015 ocular fundus photographs from 31 centres in 20 countries participating to the Brain and Optic Nerve Study with Artificial Intelligence (BONSAI). The reference standard in image quality was established by three experts who independently classified photographs as of “good”, “borderline”, or “poor” quality. The DLS was trained on 4208 fundus photographs and tested on an independent external dataset of 807 photographs, using a multi-class model, evaluated with a one-vs-rest classification strategy. In the external-testing dataset, the DLS could identify with excellent performance “good” quality photographs (AUC = 0.93 (95% CI, 0.91–0.95), accuracy = 91.4% (95% CI, 90.0–92.9%), sensitivity = 93.8% (95% CI, 92.5–95.2%), specificity = 75.9% (95% CI, 69.7–82.1%) and “poor” quality photographs (AUC = 1.00 (95% CI, 0.99–1.00), accuracy = 99.1% (95% CI, 98.6–99.6%), sensitivity = 81.5% (95% CI, 70.6–93.8%), specificity = 99.7% (95% CI, 99.6–100.0%). “Borderline” quality images were also accurately classified (AUC = 0.90 (95% CI, 0.88–0.93), accuracy = 90.6% (95% CI, 89.1–92.2%), sensitivity = 65.4% (95% CI, 56.6–72.9%), specificity = 93.4% (95% CI, 92.1–94.8%). The overall accuracy to distinguish among the three classes was 90.6% (95% CI, 89.1–92.1%), suggesting that this DLS could select optimal quality fundus photographs in patients with neuro-ophthalmic and neurological disorders affecting the ONH.

Ischemic optic neuropathy (ION) is the term ascribed to optic nerve disease that is the result of a transient or permanent interruption of the blood supply to any portion of the optic nerve. Anterior ischemic optic neuropathy (AION) refers to ischemia of the optic nerve head, whereas posterior ischemic optic neuropathy (PION) indicates ischemia of the posterior optic nerve. IONs are primarily classified as arteritic ION and non-Arteritic ION. A subset of ION that occurs around the time of surgery is termed peri-operative ION. These phenomena will be discussed as distinct entities.

Purposeof Review: To outline the current landscape of treatments for Leber hereditary optic neuropathy (LHON) along the therapeutic delivery pipeline, exploring the mechanisms of action and evidence for these therapeutic approaches. Recent Findings: Treatments for LHON can be broadly classified as either mutation-specific or mutation-independent. Mutation-specific therapies aim to correct the underlying mutation through the use of a gene-editing platform or replace the faulty mitochondrial DNA-encoded protein by delivering the wild-type gene using a suitable vector. Recent gene therapy clinical trials assessing the efficacy of allotopically expressed MT-ND4 for the treatment of LHON due to the m.11778G > A mutation in MT-ND4 have shown positive results when treated within 12 months of symptom onset. Mutation-independent therapies can have various downstream targets that aim to improve mitochondrial respiration, reduce mitochondrial stress, inhibit or delay retinal ganglion cell apoptosis, and/or promote retinal ganglion cell survival. Idebenone, a synthetic hydrosoluble analogue of co-enzyme Q10 (ubiquinone), is the only approved treatment for LHON. Mutation-independent approaches to gene therapy under pre-clinical investigation for other neurodegenerative disorders may have the potential to benefit patients with LHON. Summary: Although approved treatments are presently limited, innovations in gene therapy and editing are driving the expansion of the therapeutic delivery pipeline for LHON.

BACKGROUND: Central retinal artery occlusion (CRAO) is a medical emergency, and patients who present acutely should be immediately referred to the nearest stroke center. We evaluated practice patterns for CRAO management at one academic center over the last decade. METHODS: This was a retrospective study on all adult patients diagnosed with a CRAO seen at one tertiary hospital and outpatient clinic affiliated with a comprehensive stroke center ("our institution") from 2010 to 2020. Our electronic medical records were searched for CRAO diagnoses, and patient medical records were reviewed. The exclusion criteria were incorrect diagnosis, unclear diagnosis, historical CRAO, or satellite clinic location. Demographics, distance and time to presentation to our institution, number and type of prior providers seen, diagnostic tests performed, and treatments provided were collected. Summary statistics of median, mean, and frequency were calculated and reported with measures of variance (interquartile range [IQR], ranges). F, Tukey, and Fisher exact tests were used for comparisons. RESULTS: We included 181 patients with a diagnosis of CRAO (80 [44.2%] women; median age 69 years [range 20-101]). The median distance from patient's home to our institution was 27.8 miles (IQR 15.5-57.4; range 2.4-930). The median time from visual loss to presentation at our institution was 144 hours (IQR 23-442 hours, range 0.5-2,920) from 2010 to 2013, 72 hours (IQR 10.5-372 hours, range 0-13,140) from 2014 to 2016, and 48 hours (IQR 7-180 hours, range 0-8,030) from 2017 to 2020 (P = 0.07). 91/181 (50%) patients presented to an outpatient provider. 73/181 (40%) presented to an emergency department. Eighty-six percent presented within 1 week of visual loss onset, and rates of comprehensive inpatient evaluation for acute CRAO improved from 44% in 2010-2013 to 82% in 2017-2020 (P < 0.01). CONCLUSIONS: Patients with CRAO often present late and only after evaluation by multiple outpatient providers. Improvement has occurred over the past decade, but delays underscore the barriers to performing clinical trials evaluating very acute treatments for CRAO. Educational interventions for healthcare providers and patients are necessary.

Objective REFLECT is the first randomised, double-masked, placebo-controlled multicentre phase 3 clinical trial that evaluated the efficacy and safety of bilateral intravitreal (IVT) injection of lenadogene nolparvovec in subjects with Leber hereditary optic neuropathy carrying the m.11778G>A mutation. Methods and analysis A total of 98 subjects were enrolled with vision loss of ≤12 months. The subjects were randomised to one of two treatment arms with all subjects receiving an intravitreal (IVT) injection of lenadogene nolparvovec in their first affected eye and the second-affected eye randomised to receive IVT of either lenadogene nolparvovec or placebo. Results The majority of subjects were male with a mean duration of vision loss of 8.3 months. All but one subject experienced bilateral loss of vision at the time of injection. The mean best-corrected visual acuity of first-affected eyes was worse compared with second/not-yet-affected eyes. Analysis of retinal anatomical parameters showed increased thinning in the first-affected eyes when compared with the second/not-yet-affected eyes with both treatment arms showing significant changes compared with unaffected individuals. Conclusion The REFLECT trial is the third and the largest phase 3 clinical study evaluating lenadogene nolparvovec in m.11778G>A Leber hereditary optic neuropathy (LHON) subjects. The observed demographics in REFLECT are consistent with previous reports in LHON subjects in the acute and dynamic phases of LHON disease. Combined with the visual function and anatomical parameters obtained in the previous RESCUE and REVERSE trials, REFLECT has provided a uniformly collected data set that should help direct future LHON clinical trials.

Background: Acute nonarteritic central retinal artery occlusion (CRAO) is an eye-stroke with poor visual prognosis and no proven effective therapies. Given advances in acute stroke care, thrombolysis in CRAO merits critical re-examination. We review the evidence for intravenous (IV) and intra-arterial (IA) tissue plasminogen activator (tPA) in CRAO management. Evidence acquisition: MEDLINE, Scopus, and Cochrane online databases were systematically searched from 1960 to present, for reports of acute IV or IA therapy with alteplase or tenecteplase in nonarteritic CRAO patients. English-language case-reports, case-series, interventional studies or randomized controlled trials were included. The study type, age and number of subjects, the regimen administered, the time since symptoms’ onset, visual outcome and safety reports were noted. Results: Use of IV thrombolysis with alteplase was reported in 7 manuscripts encompassing 111 patients, with 54% of them receiving IV-tPA within 4.5 hours of symptom onset, and none developing symptomatic intracranial or ocular hemorrhage. Six studies described IA alteplase administration, with only 18 out of a total of 134 patients (13.4%) treated within the first 6 hours after visual loss. The reported adverse events were minimal. Visual outcomes post-IV and IA thrombolysis (IAT) were heterogeneously reported; however most studies demonstrated benefit of the respective reperfusion therapies when administered very early. We found no reports of tenecteplase administration in CRAO. Conclusions: In 2020, nonarteritic CRAO patients should theoretically receive the same thrombolytic therapies, in the same time-window, as patients with acute cerebral ischemia. Eye-stroke and tele-eye-stroke code encounters must include an expert ophthalmologic evaluation to confirm the correct diagnosis and to evaluate for ocular signs that may help guide IV-tPA administration or intra-arterial management. Future research should focus on developing feasible retinal penumbra imaging studies that, similar to cerebral tissue viability or perfusion imaging, can be incorporated into the thrombolysis decision-making algorithm.

Objective: Acute central retinal artery occlusion (CRAO) is an emergency with poor visual outcome. Intravenous thrombolysis within 4.5 h of vision loss is safe and may improve vision, but is rarely administered because of frequent delays in presentation. We describe a subgroup of CRAO patients presenting within 24 h of vision loss to a tertiary care center affiliated with a comprehensive stroke center. Materials and Methods: Retrospective review of 181 consecutive CRAO patients seen at our institution from 2010 to 2020. Results: Out of 181 CRAO patients, 62 (34%) presented within 24 h of vision loss and tended to live closer to the hospital. These patients were more likely to be admitted to the hospital and receive comprehensive stroke work-up compared to patients who presented after 24 h of vision loss. Patients presenting after 24 h did not necessarily receive prior appropriate work-up at outside institutions. Conservative treatments for CRAO were administered to 20/181 patients, and only 3 patients received intravenous thrombolysis. Conclusions: Patients with CRAO do not present to the emergency department fast enough and diagnosis of CRAO is often delayed. Despite having a protocol in place, only 3/181 patients received IV thrombolysis, emphasizing the difficulty in administering very acute treatments for CRAO. Public education regarding CRAO is necessary to improve presentation times, management, and visual outcomes. Hospitals need to develop accelerated diagnostic pathway protocols for patients with acute vision loss so that CRAO patients may be diagnosed and be considered for potential acute treatments as quickly as possible.

Acute retinal vascular occlusions are common causes of visual impairment. Although both retinal artery occlusions and retinal vein occlusions are associated with increased age and cardiovascular risk factors, their pathophysiology, systemic implications, and management differ substantially. Acute management of retinal artery occlusions involves a multidisciplinary approach including neurologists with stroke expertise, whereas treatment of retinal vein occlusions is provided by ophthalmologists. Optimisation of systemic risk factors by patients’ primary care providers is an important component of the management of these two disorders.

Purpose: Brain tumors are the leading cause of death from childhood cancer. Although overall survival has improved due to earlier detection, better therapies, and improved surveillance, visual dysfunction and impaired vision-related quality-of-life (VR-QOL) are often unrecognized in children. This project investigated VR-QOL in pediatric brain tumor patients. Methods: We evaluated visual impairment and quality-of-life (QOL) in a quality improvement project at one tertiary care center. Patients ≤ 18, greater than 6 months from diagnosis of brain tumor, excluding intrinsic anterior visual pathway tumors, underwent standardized neuro-ophthalmologic examination. Health-related QOL (HR-QOL) (PedsQL Brain Tumor Module) and VR-QOL questionnaires [CVFQ (Children’s Visual Function Questionnaire) in children < 8, and EYE-Q in children 8–18] were obtained from patients and parents. Results: Among 77 patients, craniopharyngiomas (n = 16, 21%) and astrocytomas (n = 15, 20%) were the most common tumors. Among 44/77 (57%) visually impaired children, 7 (16%) were legally blind. Eye-Q median score was 3.40 (interquartile range 3.00–3.75), worse than average scores for normal children. Eye-Q score decreased 0.12 with every 0.1 increase in logMAR visual acuity (p < 0.001). Patients who were legally blind had a significantly lower Eye-Q score than those who were not [0.70 vs. 3.44 (p < 0.001)]. Cognitive HR-QOL scores decreased 1.3 for every 0.1 increase in logMAR visual acuity (p = 0.02). Conclusions: Pediatric brain tumor patients’ vision, HR-QOL, and VR-QOL were often severely affected even when tumors were considered cured. Visual acuity and legal blindness correlated with VR-QOL. Systematic neuro-ophthalmologic examinations in pediatric primary brain tumor patients are necessary to facilitate early preventative and corrective ophthalmologic interventions.