Translational Research and Therapies for Neuroprotection and Regeneration of the Optic Nerve and Retina: A Narrative Review.

Most retinal and optic nerve diseases pose significant threats to vision, primarily due to irreversible retinal neuronal cell death, a permanent change, which is a critical factor in their pathogenesis. Conditions such as glaucoma, retinitis pigmentosa, diabetic retinopathy, and age-related macular degeneration are the top four leading causes of blindness among the elderly in Japan. While standard treatments-including reduction in intraocular pressure, anti-vascular endothelial growth factor therapies, and retinal photocoagulation-can partially delay disease progression, their therapeutic effects remain limited. To address these shortcomings, a range of neuroprotective and regenerative therapies, aimed at preventing retinal neuronal cell loss, have been extensively studied and increasingly integrated into clinical practice over the last two decades. Several of these neuroprotective therapies have achieved on-label usage worldwide. This narrative review introduces several neuroprotective and regenerative therapies for retinal and optic nerve diseases that have been successfully translated into clinical practice, providing foundational knowledge and success stories that serve as valuable references for researchers in the field.

Gene and cell-based therapies for retinal and optic nerve disease.

Leading causes of blindness worldwide include neurodegenerative diseases of the retina, which cause irreversible loss of retinal pigment epithelium (RPE) and photoreceptors, and optic neuropathies, which result in retinal ganglion cell (RGC) death. Because photoreceptor and RGCs do not spontaneously regenerate in mammals, including humans, vision loss from these conditions is, at present, permanent. Recent advances in gene and cell-based therapies have provided new hope to patients affected by these conditions. This chapter reviews the current state and future of these approaches to treating ocular neurodegenerative disease. Gene therapies for retinal degeneration and optic neuropathies primarily focus on correcting known pathogenic mutations that cause inherited conditions to halt progression. There are multiple retinal and optic neuropathy gene therapies in clinical trials, and one retinal gene therapy is approved in the United States, Canada, Europe, and Australia. Cell-based therapies are mutation agnostic and have the potential to repopulate neurons regardless of the underlying etiology of degeneration. While photoreceptor cell replacement is nearing a human clinical trial, RPE transplantation is currently in phase I/II clinical trials. RGC replacement faces numerous logistical challenges, but preclinical research has laid the foundation for functional repair of optic neuropathies to be feasible.

[Possibilities of physiotherapy in glaucomatous optic neuropathy after glaucoma surgery]. / Vozmozhnosti fizioterapevticheskoi stimulyatsii pri glaukomnoi opticheskoi neiropatii posle antiglaukomnykh operatsii.

The current primary approach to the therapeutic and surgical management of glaucoma is limited to lowering intraocular pressure (IOP). While normalization of IOP stabilizes some functional parameters, there is still potential for further restoration of lost visual function in the post-operative period while maintaining the "therapeutic window". Neuroprotection refers to the modification of retinal ganglion cells and the neuronal microenvironment to promote their survival and function. Numerous studies have identified effective neuroprotective methods for glaucoma; however, their implementation into clinical practice remains a significant challenge. This review presents the most clinically significant treatment strategies, as well as the latest therapeutic advances in physiotherapy.

Evaluating the impact of mesenchymal stem cell therapy on visual acuity and retinal nerve fiber layer thickness in optic neuropathy patients: a comprehensive systematic review and meta-analysis.

BACKGROUND: Stem cell therapy has emerged as a potential therapeutic avenue for optic neuropathy patients. To assess its safety and efficacy, we conducted a systematic review and meta-analysis, focusing on the latest evidence pertaining to the improvement of visual acuity (VA) through stem cell therapy. METHODS: We analyzed Each database from its inception until June 2024. PubMed, Scopus, and Google Scholar were systematically searched to identify the included studies. Data were extracted regarding the year of publication, the name of the first author, sample size, VA (Log Mar), and Retinal Nerve Fiber Layer (RNFL) thickness. PRISMA protocol was used as a guide to perform this meta-analysis. STATA 16 was used for statistical analysis. RESULTS: A total of 66 eyes were examined in seven papers. Based on the meta-analysis, the mean VA (Log MAR) of patients with optic neuropathy improved from 0.90 to 0.65 following stem cell therapy intervention (p-value = 0.001). The thickness of the RNFLs did not demonstrate a significant change (p-value was 0.174). CONCLUSION: According to this systematic review and meta-analysis, stem cell therapy may improve the visual acuity of patients with optic neuropathy. Aside from the traditional therapy that can be provided to patients with optic neuropathy, stem cell therapy may also be beneficial.

Application of electrostimulation and magnetic stimulation in patients with optic neuropathy: A mechanistic review.

Visual impairment caused by optic neuropathies is irreversible because retinal ganglion cells (RGCs), the specialized neurons of the retina, do not have the capacity for self-renewal and self-repair. Blindness caused by optic nerve neuropathies causes extensive physical, financial, and social consequences in human societies. Recent studies on different animal models and humans have established effective strategies to prevent further RGC degeneration and replace the cells that have deteriorated. In this review, we discuss the application of electrical stimulation (ES) and magnetic field stimulation (MFS) in optic neuropathies, their mechanisms of action, their advantages, and limitations. ES and MFS can be applied effectively in the field of neuroregeneration. Although stem cells are becoming a promising approach for regenerating RGCs, the inhibitory environment of the CNS and the long visual pathway from the optic nerve to the superior colliculus are critical barriers to overcome. Scientific evidence has shown that adjuvant treatments, such as the application of ES and MFS help direct thetransplanted RGCs to extend their axons and form new synapses in the central nervous system (CNS). In addition, these techniques improve CNS neuroplasticity and decrease the inhibitory effects of the CNS. Possible mechanisms mediating the effects of electrical current on biological tissues include the release of anti-inflammatory cytokines, improvement of microcirculation, stimulation of cell metabolism, and modification of stem cell function. ES and MFS have the potential to promote angiogenesis, direct axon growth toward the intended target, and enhance appropriate synaptogenesis in optic nerve regeneration.

[INTERVENTIONAL GLAUCOMA - A SHIFT IN THE TREATMENT PARADIGM].

INTRODUCTION: Glaucoma is a progressive optic neuropathy and is the leading cause of preventable irreversible blindness worldwide. Glaucoma causes progressive visual field loss and can have significant implications on the patient's quality of life. Lowering intraocular pressure (IOP) is the only treatment proven to prevent vision loss from glaucoma. It is achieved using medication, laser treatment and surgery. The treatment paradigm of glaucoma has been one whereby surgical intervention has been left for advanced cases due to a variety of reasons, mainly concerning safety and long term success. The past two decades have seen a paradigm shift towards earlier IOP lowering interventions using a wide array of different technologies in the laser and surgical spaces. This review aims to understand the background to this paradigm shift, its necessity, and its potential impact on the vision and life of glaucoma patients.

Inherited Optic Neuropathies: Real-World Experience in the Paediatric Neuro-Ophthalmology Clinic.

Inherited optic neuropathies affect around 1 in 10,000 people in England; in these conditions, vision is lost as retinal ganglion cells lose function or die (usually due to pathological variants in genes concerned with mitochondrial function). Emerging gene therapies for these conditions have emphasised the importance of early and expedient molecular diagnoses, particularly in the paediatric population. Here, we report our real-world clinical experience of such a population, exploring which children presented with the condition, how they were investigated and the time taken for a molecular diagnosis to be reached. A retrospective case-note review of paediatric inherited optic neuropathy patients (0-16 years) in the tertiary neuro-ophthalmology service at Moorfields Eye Hospital between 2016 and 2020 identified 19 patients. Their mean age was 9.3 ± 4.6 (mean ± SD) years at presentation; 68% were male, and 32% were female; and 26% had comorbidities, with diversity of ethnicity. Most patients had undergone genetic testing (95% (n = 18)), of whom 43% (n = 8) received a molecular diagnosis. On average, this took 54.8 ± 19.5 weeks from presentation. A cerebral MRI was performed in 70% (n = 14) and blood testing in 75% (n = 15) of patients as part of their workup. Continual improvement in the investigative pathways for inherited optic neuropathies will be paramount as novel therapeutics become available.

Dysthyroid optic neuropathy: a case series at a tertiary ophthalmic referral centre.

BACKGROUND/OBJECTIVES: To determine risk factors and treatment outcomes in dysthyroid optic neuropathy (DON) at a single tertiary ophthalmic centre. METHODS: Retrospective audit of DON patients who have received intravenous methylprednisolone (IVMP) therapy at Royal Victorian Eye and Ear Hospital, Melbourne, Australia from July 2015 to October 2021. RESULTS: Study included 24 patients (58% female) with an average age of 59.8 ± 14.7 years at DON diagnosis. Majority (92%) had Graves' hyperthyroidism and 77% had a smoking history. At diagnosis, average visual acuity (VA) of worse eye was LogMAR 0.46, and 48% had relative afferent pupillary defect. Proptosis (89%) and diplopia (73%) were most commonly present at diagnosis. 78% showed predominantly extra-ocular muscle enlargement, and apical crowding (52%) on radiology. 38% (n = 9/24) responded to IVMP alone, 58% (n = 14/24) progressed to surgical orbital decompression. The average total cumulative dose of IVMP during DON treatment was 6.8 ± 1.9 g. 29% required further treatment after IVMP and surgical decompression, 4 (17%) had additional radiotherapy, and three (13%) required immuno-modulatory therapy. Average final VA was LogMAR 0.207, with all patients having inactive TED at final follow-up (mean 1.7 years). In refractory DON cases, 71% retained VA ≥ 6/9 and 48% had DON reversal. CONCLUSIONS: DON patients typically present in late 50s, with a smoking history and predominant extra-ocular muscle enlargement. High-dose IVMP fully resolved DON in only 38%. A considerable proportion required urgent orbital decompression. Most patients retained good vision at final follow-up.

Therapeutic strategies for glaucoma and optic neuropathies.

Glaucoma is a neurodegenerative eye disease that causes permanent vision impairment. The main pathological characteristics of glaucoma are retinal ganglion cell (RGC) loss and optic nerve degeneration. Glaucoma can be caused by elevated intraocular pressure (IOP), although some cases are congenital or occur in patients with normal IOP. Current glaucoma treatments rely on medicine and surgery to lower IOP, which only delays disease progression. First-line glaucoma medicines are supported by pharmacotherapy advancements such as Rho kinase inhibitors and innovative drug delivery systems. Glaucoma surgery has shifted to safer minimally invasive (or microinvasive) glaucoma surgery, but further trials are needed to validate long-term efficacy. Further, growing evidence shows that adeno-associated virus gene transduction and stem cell-based RGC replacement therapy hold potential to treat optic nerve fiber degeneration and glaucoma. However, better understanding of the regulatory mechanisms of RGC development is needed to provide insight into RGC differentiation from stem cells and help choose target genes for viral therapy. In this review, we overview current progress in RGC development research, optic nerve fiber regeneration, and human stem cell-derived RGC differentiation and transplantation. We also provide an outlook on perspectives and challenges in the field.

Pembrolizumab-induced optic neuropathy - a case report.

Background: Immune checkpoint inhibitor (ICI) treatment has become important for treating various cancer types, including Hodgkin's lymphoma. However, ICI can overstimulate the immune system, leading to a broad range of immunological side effects, known as immune-related adverse events (irAEs). Here, we report a case of optic neuropathy caused by pembrolizumab. Case presentation: A patient with Hodgkin's lymphoma received pembrolizumab every three weeks. Twelve days after the sixth cycle of pembrolizumab, the patient was admitted to the emergency department with blurred vision, visual field impairment and altered color perception affecting the right eye. The diagnosis of immune-related optic neuropathy was established. Pembrolizumab was stopped permanently and high-dose steroid treatment was immediately started. This emergency treatment led to a satisfactory binocular vision and an improvement of visual acuity testing results. After another 7 months, the left eye was affected with the same symptoms. At this time, only an extended immunosuppressive therapy consisting of high-dose steroid treatment, plasmapheresis, immunoglobulin treatment, retrobulbar injection of steroids and mycophenolate mofetil, successfully reduced the symptoms. Conclusions: This case highlights the need for prompt recognition and treatment of rare irAEs, such as optic neuropathy. Urgent treatment with initial high-dose steroid treatment is required to avoid persistent loss of visual acuity. Options for further treatment are mainly based on small case series and case reports. In our case, a retrobulbar injection of steroids in combination with mycophenolate mofetil showed significant success in treating steroid-refractory optic neuropathy.

[Optic neuropathies as an interdisciplinary subject of research]. / Opticheskie neiropatii kak predmet mezhdistsiplinarnogo izucheniya.

Despite the wide range of clinical, instrumental and laboratory methods used in modern ophthalmology, the problem of diagnosing optic neuropathy and identifying its etiology remains relevant. A complex multidisciplinary approach involving various specialists is required in the differential diagnosis of immune-mediated optic neuritis, for example in multiple sclerosis, neuromyelitis optica spectrum disorder, and MOG-associated diseases. Of special interest is differential diagnosis of optic neuropathy in demyelinating diseases of the central nervous system, hereditary optic neuropathies and ischemic optic neuropathy. The article presents a summary of scientific and practical results of differential diagnosis of optic neuropathies with various etiologies. Timely diagnosis and early therapy start reduces the degree of disability in patients with optic neuropathies of different etiologies.

Understanding the molecular basis and pathogenesis of hereditary optic neuropathies: towards improved diagnosis and management.

Hereditary optic neuropathies result from defects in the human genome, both nuclear and mitochondrial. The two main and most recognised phenotypes are dominant optic atrophy and Leber hereditary optic neuropathy. Advances in modern molecular diagnosis have expanded our knowledge of genotypes and phenotypes of inherited disorders that affect the optic nerve, either alone or in combination, with various forms of neurological and systemic degeneration. A unifying feature in the pathophysiology of these disorders appears to involve mitochondrial dysfunction, suggesting that the retinal ganglion cells and their axons are especially susceptible to perturbations in mitochondrial homoeostasis. As we better understand the pathogenesis behind these genetic diseases, aetiologically targeted therapies are emerging and entering into clinical trials, including treatments aimed at halting the cascade of neurodegeneration, replacing or editing the defective genes or their protein products, and potentially regenerating damaged optic nerves, as well as preventing generational disease transmission.

Interprofessional Electronic Consultations for the Diagnosis and Management of Neuro-Ophthalmic Conditions.

BACKGROUND: Interprofessional electronic consultation (eConsult) is a telemedicine modality in which consulting providers review outside records and provide recommendations without in-person consultation. The purpose of this study was to describe the utilization of eConsults in the management of neuro-ophthalmic conditions. METHODS: Retrospective cohort study of all patients who received an eConsult for a neuro-ophthalmic condition at a single quaternary referral center from 2018 to 2020. Main outcome measures included proportion of eConsults in which sufficient data were provided to the neuro-ophthalmologist to generate a definitive management decision, proportion of patients for whom an in-person neuro-ophthalmology evaluation was recommended, and the eConsult's impact on patient care. RESULTS: Eighty eConsults were conducted on 78 patients during the 3-year study period. Forty-eight (60.0%) subjects were female, mean age was 54 years, and 65 (81.3%) were White. The median time from eConsult request to completion was 4 days (range: 0-34 days). The most frequent eConsult questions were vision/visual field disturbances in 28 (35.0%) cases, optic neuropathies in 22 (27.5%), and optic disc edema in 17 (21.3%). At the time of eConsult, sufficient prior information was provided in 35 (43.8%) cases for the neuro-ophthalmologist to provide a definitive management decision. In 45 (56.3%) eConsults, further diagnostic testing was recommended. In-person neuro-ophthalmology consultation was recommended in 24 (30.0%) cases. Sixty-one (76.3%) eConsults provided diagnostic and/or treatment direction, and 12 (15.0%) provided reassurance. CONCLUSION: eConsults increase access to timely neuro-ophthalmic care and provide diagnostic and treatment direction to non-neuro-ophthalmology providers when sufficient information is provided at the time of eConsult.

Global brain network modularity dynamics after local optic nerve damage following noninvasive brain stimulation: an EEG-tracking study.

Tightly connected clusters of nodes, called communities, interact in a time-dependent manner in brain functional connectivity networks (FCN) to support complex cognitive functions. However, little is known if and how different nodes synchronize their neural interactions to form functional communities ("modules") during visual processing and if and how this modularity changes postlesion (progression or recovery) following neuromodulation. Using the damaged optic nerve as a paradigm, we now studied brain FCN modularity dynamics to better understand module interactions and dynamic reconfigurations before and after neuromodulation with noninvasive repetitive transorbital alternating current stimulation (rtACS). We found that in both patients and controls, local intermodule interactions correlated with visual performance. However, patients' recovery of vision after treatment with rtACS was associated with improved interaction strength of pathways linked to the attention module, and it improved global modularity and increased the stability of FCN. Our results show that temporal coordination of multiple cortical modules and intermodule interaction are functionally relevant for visual processing. This modularity can be neuromodulated with tACS, which induces a more optimal balanced and stable multilayer modular structure for visual processing by enhancing the interaction of neural pathways with the attention network module.

Deep learning: applications in retinal and optic nerve diseases.

Deep learning (DL) represents a paradigm-shifting, burgeoning field of research with emerging clinical applications in optometry. Unlike traditional programming, which relies on human-set specific rules, DL works by exposing the algorithm to a large amount of annotated data and allowing the software to develop its own set of rules (i.e. learn) by adjusting the parameters inside the model (network) during a training process in order to complete the task on its own. One major limitation of traditional programming is that, with complex tasks, it may require an extensive set of rules to accurately complete the assignment. Additionally, traditional programming can be susceptible to human bias from programmer experience. With the dramatic increase in the amount and the complexity of clinical data, DL has been utilised to automate data analysis and thus to assist clinicians in patient management. This review will present the latest advances in DL, for managing posterior eye diseases as well as DL-based solutions for patients with vision loss.

Dysthyroid optic neuropathy: Demographics, risk factors, investigations, and management outcomes.

Purpose: To analyze the clinical presentations, risk factors, and management outcomes in patients presenting with dysthyroid optic neuropathy (DON). Methods: This is a retrospective, single-center study carried out on consecutive patients presenting with DON over a period of 4 years (2013-2016). The VISA classification was used at the first visit and subsequent follow-ups. The diagnosis was based on optic nerve function tests and imaging features. Demographic profiles, clinical features, risk factors, and management outcomes were analyzed. Results: Thirty-seven eyes of 26 patients diagnosed with DON were included in the study. A significant male preponderance was noted (20, 76.92%). Twenty patients (76.9%, P = 0.011) had hyperthyroidism, and 15 (57.69%, P = 0.02) were smokers. Decreased visual acuity was noted in 28 eyes (75.6%). Abnormal color vision and relative afferent pupillary defects were seen in 24 (64.86%) eyes, and visual field defects were seen in 30 (81.01%) eyes. The visual evoked potential (VEP) showed a reduced amplitude in 30 (96.77%, P = 0.001) of 31 eyes and delayed latency in 20 (64.51%, P = 0.0289) eyes. Twenty-six (70.27%) patients were treated with intravenous methyl prednisolone (IVMP) alone, whereas 11 (29.72%) needed surgical decompression. The overall best-corrected visual acuity improved by 0.2 l logMARunits. There was no statistically significant difference in outcome between medically and surgically treated groups. Four patients developed recurrent DON, and all of them were diabetics. Conclusion: Male gender, hyperthyroid state, and smoking are risk factors for developing DON. VEP, apical crowding, and optic nerve compression are sensitive indicators for diagnosing DON. Diabetics may have a more defiant course and are prone to develop recurrent DON.

Approach to the diagnosis and management of nutritional optic neuropathies.

PURPOSE OF REVIEW: Nutritional deficiency is an under-recognized cause of optic neuropathy. The purpose of this review is to discuss how to identify, diagnose, and appropriately manage patients with nutritional optic neuropathy. RECENT FINDINGS: Nutritional deficiencies have long been thought to be more prevalent in the developing countries. However, with the advent of bariatric surgery, restrictive/selective diets, and the increase in alcohol dependence, it is not uncommon to see nutritional optic neuropathies in the developed world. SUMMARY: Although nutritional optic neuropathy can cause severe and debilitating vision loss, it is often reversible when it is diagnosed and treated in a timely manner.

Optic Disc Drusen in Patients With Ocular Hypertension: A Case Series and Review of the Literature.

BACKGROUND: The identification of glaucomatous optic neuropathy in the setting of optic disc drusen (ODD) is a challenge, and the decision of whether to offer treatment in the form of intraocular pressure (IOP) reduction is controversial. Here, we present a series of patients with coexisting ocular hypertension and ODD to evaluate clinical features, treatment options, and progression of optic neuropathy. In addition, a review of the literature on ODD with elevated IOP is provided. METHODS: Six patients with ODD and a history of ocular hypertension are presented. Components of the examination and imaging modalities used to establish the diagnosis of ODD were recorded and a description of ocular hypertension history, glaucoma testing, and the potential treatment of IOP were also provided. RESULTS: In this series, 4 of 6 patients with concurrent ocular hypertension and ODD showed progression of optic neuropathy as assessed by visual field or retinal nerve fiber layer thickness. Of the 2 patients who did not show evidence of progression, 1 was treated with IOP-lowering medications and 1 was observed off treatment. Of the 4 patients who showed evidence of progression, all 4 were initially treated with IOP-lowering medications and 2 ultimately went on to have trabeculectomy surgery. In the patients with progressive optic neuropathy, lowering the IOP seemed to halt the progression suggesting there was a pressure-sensitive component. CONCLUSIONS: Distinguishing changes to the optic nerve, particularly the structural changes at the lamina cribrosa of true glaucomatous optic neuropathy in the setting of ODD, is a challenge. Careful consideration of risk factors including age, presenting features, progression indicators, and management goals is to be accounted for in the decision to offer treatment. We see the presence ODD in the patients with ocular hypertension as an additional risk for progressive changes to the nerve fiber layer and visual field that needs to be considered when determining whether to initiate therapy. Our data suggest that treatment of IOP in the patients with ocular hypertension with ODD and evidence of progression reduces the risk of further progression. Further work is needed to determine whether progression of optic neuropathy in the setting of coexisting ODD and ocular hypertension is related mechanistically to predominantly an ODD-type process, a glaucomatous process, or a combination thereof.