Lebers Hereditary Optic Neuropathy (LHON) is the most common primary mitochondrial DNA disorder. It is characterized by bilateral severe central subacute vision loss due to specific loss of Retinal Ganglion Cells and their axons. Historically, treatment options have been quite limited, but ongoing clinical trials show promise, with significant advances being made in the testing of free radical scavengers and gene therapy. In this review, we summarize management strategies and rational of treatment based on current insights from molecular research. This includes preventative recommendations for unaffected genetic carriers, current medical and supportive treatments for those affected, and emerging evidence for future potential therapeutics.

Purpose

Future advances in ophthalmology will see a paradigm shift in diagnostics from a focus on dysfunction and disease to better measures of psychophysical function and health. Practical methods to define genotypes will be increasingly important and non-invasive nanotechnologies are needed to detect molecular changes that predate histopathology.

Methods

This is not a review nor meant to be comprehensive. Specific topics have been selected to illustrate the principles of important paradigm shifts that will influence the future of ophthalmic diagnostics. It is our impression that future evaluation of vision will go beyond visual acuity to assess ocular health in terms of psychophysical function. The definition of disease will incorporate genotype into what has historically been a phenotype-centric discipline. Non-invasive nanotechnologies will enable a paradigm shift from disease detection on a cellular level to a sub-cellular molecular level.

Results

Vision can be evaluated beyond visual acuity by measuring contrast sensitivity, color vision, and macular function, as these provide better insights into the impact of aging and disease. Distortions can be quantified and the psychophysical basis of vision can be better evaluated than in the past by designing tests that assess particular macular cell function(s). Advances in our understanding of the genetic basis of eye diseases will enable better characterization of ocular health and disease. Non-invasive nanotechnologies can assess molecular changes in the lens, vitreous, and macula that predate visible pathology. Oxygen metabolism and circulatory physiology are measurable indices of ocular health that can detect variations of physiology and early disease.

Conclusions

This overview of paradigm shifts in ophthalmology suggests that the future will see significant improvements in ophthalmic diagnostics. The selected topics illustrate the principles of these paradigm shifts and should serve as a guide to further research and development. Indeed, successful implementation of these paradigm shifts in ophthalmology may provide useful guidance for similar developments in all of healthcare.

We describe the course and likely pathophysiology of impending anterior ischemic optic neuropathy (AION) and retinal vein occlusion in a 56-year-old man with polycythemia vera managed with interferon alpha for 2 years. Our patient presented with decreased vision, scintillating scotomata, and floaters. Fundus examination findings and results of a fluorescein angiogram led to the diagnosis of impending AION and retinal vein occlusion. Considering that both polycythemia vera and interferon have possible influences on vascular occlusion and optic disc edema, we stopped interferon treatment and immediately attempted to treat the polycythemia vera empirically with pentoxifylline and any interferon-associated inflammation with prednisone. Our patient experienced complete resolution of fundus abnormalities and return of normal vision within 3 weeks, which may be attributed to our successful treatment of both etiologies. Thus, further study is warranted to elucidate the treatment of both polycythemia vera and interferon-induced impending AION.

The main objective of this study was to evaluate the retinas of severely or critically ill COVID-19 patients during their hospital stay, at varying time points after symptoms onset. This was a case series observed during May 2020 in two referral centers for COVID-19 treatment in Rio de Janeiro, Brazil. 47 eyes from 25 hospitalized patients with severe or critical confirmed illness were evaluated. A handheld retinal camera was used to acquire bilateral fundus images at several time points after symptoms onset. Electronic health records were retrospectively analyzed and clinical data collected. Severe and critical diseases were noticed in 52% (13/25) and 48% (12/25) of enrolled patients, respectively. Retinal changes were present in 12% (3/25) of patients: a 35 year-old male demonstrated bilateral nerve fiber layer infarcts and microhemorrhages in the papillomacular bundle, but required mechanical ventilation and developed severe anemia and systemic hypotension, acute kidney injury and neurologic symptoms during the course of the disease (critical illness); a 56 year-old male, who required full enoxaparin anticoagulation due to particularly elevated D-dimer (>5.0 mcg/mL), demonstrated unilateral and isolated flame-shaped hemorrhages; and a 49 year-old hypertensive male showed bilateral and discrete retinal dot and blot microhemorrhages. The other 22 patients evaluated did not demonstrate convincing retinal changes upon examination. There was no correlation between disease severity and admission serum levels of CRP, D-dimer and ferritin. This was the first study to show that vascular retinal changes may be present in not insignificant numbers of severe or critical COVID-19 inpatients. These retinal changes, only seen after morbid developments, were likely secondary to clinical intercurrences or comorbidities instead of a direct damage by SARS-CoV-2, and may be important and easily accessible outcome measures of therapeutic interventions and sentinels of neurologic and systemic diseases during COVID-19 pandemic.

We present the case of a 19-year-old female with a history of Down syndrome (DS) who was referred to our neuro-ophthalmology clinic for evaluation of Leber's hereditary optic neuropathy (LHON). The patient's family history was significant for a known G11778A mutation in a maternal relative, consistent with LHON. The patient was also positive for the G11778A mutation; however, the genotype demonstrated low penetrance in the pedigree, with only 1 out of 10 adult male offspring showing signs or symptoms of the disease. Mitochondrial mutations implicated in LHON have been shown to impair complex I of the electron transport chain and thereby reducing the effective generation of adenosine triphosphate and increasing the production of toxic reactive oxygen species. Although the partial or complete triplicate of chromosome 21 constitutes the etiology of DS, some of the pleiotropic phenotypes of the syndrome have been attributed to oxidative stress and mitochondrial dysfunction. Given the low penetrance of the mutation and the patient's sex, this case illustrates the possibility that the mitochondrial mutation demonstrated increased penetrance due to pre-existing mitochondrial dysfunction related to DS.

BACKGROUND: Peripapillary vitreous traction (PVT) occurring without any underlying eye disease has been contemplated as a distinct entity from nonarteritic ischemic optic neuropathy (NAION) for many years and is sometimes difficult to differentiate from classical NAION. We report 6 new cases to analyze the clinical features of PVT syndrome that would expand the clinical spectrum of anterior optic neuropathies. METHODS: Prospective case series. RESULTS: PVT syndrome seems to affect optic discs with a small area with a small cup-to-disc (C/D) ratio. The C/D ratio does not significantly increase in the chronic stage, as in NAION. Vitreous traction without detachment can either lead to mild retinal nerve fiber layer (RNFL) injury with attendant ganglion cell layer/inner plexiform layer (GCL/IPL) thinning in 29% or no injury at all in 71%. Eighty-six percent had good visual acuity (VA) and had no relative afferent pupillary defect (RAPD), whereas 14% had a transient RAPD; 71% had no color defect. Vitreous detachment after a period of severe and persistent traction can lead to more damage to the optic nerve head and RNFL that may look like NAION. Our hypothesized mechanically induced injury to the superficial optic nerve head may not lead to much visual impairment. In our study, no further therapeutic interventions were required. CONCLUSIONS: Based on our analysis of previously published cases and our own prospective case series of 6 patients, the PVT syndrome falls within the spectrum of anterior optic neuropathies, often affecting small optic discs with a small C/D ratio. Vitreous traction can lead to a partial or complete anterior optic neuropathy. The PVT syndrome may be a more anterior optic neuropathy distinct from classical NAION.

OCTA imaging in optic neuropathies.

Glaucoma, a group of diseases characterized by progressive optic nerve degeneration that results in irreversible blindness, can be considered a neurodegenerative disorder of both the eye and the brain. Increasing evidence from human and animal studies have shown that glaucoma shares some common neurodegenerative pathways with Alzheimer's disease (AD) and other tauopathies, such as chronic traumatic encephalopathy (CTE) and frontotemporal dementia. This hypothesis is based on the focal adhesion pathway hypothesis and the spreading hypothesis of tau. Not only has the Apolipoprotein E (APOE) gene been shown to be associated with AD, but also with primary open angle glaucoma (POAG). This review will highlight the relevant literature in the past 20 years from PubMed that show the pathogenic overlap between POAG and AD. Neurodegenerative pathways that contribute to transsynaptic neurodegeneration in AD and other tauopathies might also be similar to those in glaucomatous neurodegeneration.

Coordination of care for patients with neuro-ophthalmic disorders can be very challenging in the community emergency department (ED) setting. Unlike university- or tertiary hospital-based EDs, the general ophthalmologist is often not as familiar with neuro-ophthalmology and the examination of neuro-ophthalmology patients in the acute ED setting. Embracing image capturing of the fundus, using a non-mydriatic camera, may be a game-changer for communication between ED physicians, ophthalmologists, and tele-neurologists. Patient care decisions can now be made with photographic documentation that is then conveyed through HIPAA-compliant messaging with accurate and useful information with both ease and convenience. Likewise, external photos of the anterior segment and motility are also helpful. Finally, establishing clinical and imaging guidelines for common neuro-ophthalmic disorders can help facilitate complete and appropriate evaluation and treatment.

PURPOSE: Peripapillary vascular alterations have been classically described as hallmarks of Lebers Hereditary Optic Neuropathy (LHON). We recently demonstrated microvascular pathology involving the macula in patients affected with chronic LHON using optical coherence tomography angiography (OCTA). Macular vascular pathology in acute LHON has not previously been reported. METHODS: The macular superficial vasculature of an asymptomatic carrier and an affected patient with acute LHON, mitochondrial DNA mutation 3460, was assessed by OCTA. RESULTS: Similar findings of peripapillary microangiopathy and vascular telangiectasias were seen the affected patient, but in the parafoveal macula. These changes were most prominent nasally and inferiorly, corresponding to the proximal portions of the papillomacular bundle. The foveal avascular zone was markedly enlarged in the affected patient relative to the asymptomatic mother. CONCLUSIONS: These findings in acute LHON further supports the clinical utility of vascular parameters and suggest that further studies focused on macular pathology may be warranted to assess the natural history of LHON.