Explore the vast range of titles available.

Options for the effective treatment of hereditary optic neuropathies have been a long time coming. The successful launch of the antioxidant idebenone for Leber’s Hereditary Optic Neuropathy (LHON), followed by its introduction into clinical practice across Europe, was an important step forward. Nevertheless, other options, especially for a variety of mitochondrial optic neuropathies such as dominant optic atrophy (DOA), are needed, and a number of pharmaceutical agents, acting on different molecular pathways, are currently under development. These include gene therapy, which has reached Phase III development for LHON, but is expected to be  developed also for DOA, whilst most of the other agents (other antioxidants, anti-apoptotic drugs, activators of mitobiogenesis, etc.) are almost all at Phase II or at preclinical stage of research. Here, we review proposed target mechanisms, preclinical evidence, available clinical trials with primary endpoints and results, of a wide range of tested molecules, to give an overview of the field, also providing the landscape of future scenarios, including gene therapy, gene editing, and reproductive options to prevent transmission of mitochondrial DNA mutations.

Background Key clinical features of chronic relapsing inflammatory optic neuropathy (CRION) include relapsing inflammatory optic neuritis (ON) and steroid dependency, both of which have been reported among patients with myelin oligodendrocyte glycoprotein antibodies (MOG-Abs). We investigated the relevance of the presence of serum MOG-IgG with the current diagnostic criteria for CRION among patients with idiopathic inflammatory optic neuritis (iON). Methods Retrospective reviews of a database prospectively collated between 2011 and 2017 from the tertiary referral center for multiple sclerosis and neuromyelitis optica were performed. Sixty-four patients with iON, who did not meet the diagnostic criteria for multiple sclerosis, neuromyelitis optica (NMO) spectrum disorder with/without NMO-IgG, or acute disseminated encephalomyelitis and who had no symptomatic central nervous system (CNS) lesions other than on the optic nerve, were included from a cohort of 615 patients with inflammatory demyelinating diseases of the CNS. Fulfillment of the current diagnostic criteria for CRION, assay results for the serum IgG1 MOG-Ab, and characteristics of CRION patients with MOG-IgG were compared to those of non-CRION patients with MOG-IgG. Results Twelve iON patients fulfilled the current diagnostic criteria for CRION, 11 patients were positive for MOG-IgG, and one patient was borderline. Among the other 52 iON patients not meeting the criteria for CRION, 14 had relapsing disease courses and 38 had monophasic courses, of which MOG-IgG positivity were 0% and 29%, respectively. CRION patients with MOG-IgG had more relapsing disease courses (first steroid-dependent worsening/relapse in 2.3 months, range 0.4–7.0) and poorer optical coherence tomography outcomes at follow-up than non-CRION patients with MOG-IgG. However, patients in the two groups did not differ in terms of age of onset, sex, or steroid treatment duration after initial attack. Conclusions CRION, according to the current diagnostic criteria, is a relapsing optic neuritis associated with MOG-IgG. Among iON patients with MOG-IgG, the absence of steroid-dependent attacks in the early stages of the disease may predict a long-term non-relapsing disease course and a more favorable outcome.

Glaucoma is an optic neuropathy in which the degeneration of retinal ganglion cells (RGCs) results in irreversible vison loss. Therefore, neuroprotection of RGCs from glaucomatous afflictions is crucial for glaucoma treatment. In this study, we aimed to investigate the beneficial effects of statins in the protection of RGCs using a rat model. Glaucomatous injury was induced in rats by chronic ocular hypertension (OHT) achieved after performing a circumlimbal suture. The rats were given either statins such as simvastatin and atorvastatin or a solvent weekly for 6 weeks. Retina sections underwent hematoxylin and eosin, Brn3a, or cleaved casepase-3 staining to evaluate RGC survival. In addition, modulation of glial activation was assessed. While the retinas without statin treatment exhibited increased RGC death due to chronic OHT, statins promoted the survival of RGCs and reduced apoptosis. Statins also suppressed chronic OHT-mediated glial activation in the retina. Our results demonstrate that statins exert neuroprotective effects in rat retinas exposed to chronic OHT, which may support the prospect of statins being a glaucoma treatment.

Optic neuropathy can be of infectious or non-infectious/idiopathic aetiology. Many infectious organisms can cause optic neuropathy that can be of varied presentation including papillitis, retrobulbar optic neuritis, neuroretinitis, and optic perineuritis. Detailed history, ocular, systemic/neurologic examination along with appropriate laboratory evaluation can help clinicians to identify the infectious agent causing optic neuropathy. In spite of recent advanced techniques in serological testing and molecular diagnostics like polymerase chain reaction (PCR), the identification of these pathogens is still a diagnostic challenge. It is ideal to have an infectious disease (ID) consultant in the management team, as most of these infections are multisystem involving diseases. Most infectious agents can be effectively treated with specific antibiotics, with or without corticosteroid therapy, but visual recovery is highly variable and depends entirely on early diagnosis of the causative agent. This review article will provide an overview of common pathogens involved in ION and will describe their management paradigms.

Purpose To assess the effectiveness of tocilizumab in reverting the signs and symptoms of dysthyroid optic neuropathy (DON) in thyroid eye disease and the need for emergency orbital decompression. The secondary outcomes are to identify the optimal number of tocilizumab cycles to achieve the primary outcome, to analyze the association between thyroid stimulating immunoglobulin (TSI), clinical activity score (CAS) and proptosis in response to the treatment and the need for rehabilitative orbital decompression. Methods Prospective longitudinal cohort study that included 13 patients who had unilateral or bilateral dysthyroid optic neuropathy (DON) due to severe and progressive sight-threatening thyroid eye disease based on the CAS system. Patients were seen in this facility starting from July 2017, and all had received intravenous tocilizumab. Results Initial visual acuity mean was 0.52 ± 0.38 and the final were 0.93 ± 0.11 with a mean difference of 0.41 and P  < 0.00245. The mean CAS prior to the initiation of the treatment was 7.92 ± 0.66 and the final was 2.85 ± 1.03 with mean difference of 5.07 and P  < 0.00001. Initial mean proptosis was 24.85 ± 2.31 and the final was 21.78 ± 2.18 with a mean difference of 3.07 and P  < 0.000497. No emergency orbital decompression was performed. TSI was high initially in all cases with a wide range of 2.4 to 40 IU/L and with a mean of 10.70 ± 13.40. The final TSI mean was 2.90 ± 3.90 with a mean difference of 7.81 and significant P value ( P  < 0.0272). Conclusion Tocilizumab use in optic nerve compression showed promising results as it can be the primary or an alternative treatment option.

Programmed axon death is a druggable pathway of axon degeneration that has garnered considerable interest from pharmaceutical companies as a promising therapeutic target for various neurodegenerative disorders. In this review, we highlight mechanisms through which this pathway is activated in the retina and optic nerve, and discuss its potential significance for developing therapies for eye disorders and beyond. At the core of programmed axon death are two enzymes, NMNAT2 and SARM1, with pivotal roles in NAD metabolism. Extensive preclinical data in disease models consistently demonstrate remarkable, and in some instances, complete and enduring neuroprotection when this mechanism is targeted. Findings from animal studies are now being substantiated by genetic human data, propelling the field rapidly toward clinical translation. As we approach the clinical phase, the selection of suitable disorders for initial clinical trials targeting programmed axon death becomes crucial for their success. We delve into the multifaceted roles of programmed axon death and NAD metabolism in retinal and optic nerve disorders. We discuss the role of SARM1 beyond axon degeneration, including its potential involvement in neuronal soma death and photoreceptor degeneration. We also discuss genetic human data and environmental triggers of programmed axon death. Lastly, we touch upon potential therapeutic approaches targeting NMNATs and SARM1, as well as the nicotinamide trials for glaucoma. The extensive literature linking programmed axon death to eye disorders, along with the eye’s suitability for drug delivery and visual assessments, makes retinal and optic nerve disorders strong contenders for early clinical trials targeting programmed axon death.

PurposeIntravenously administered erythropoietin (EPO) was firstly commenced (phase 1) in patients with indirect traumatic optic neuropathy (TON) by this group in 2011. It was re-tested by another group (phase 2) in 2014. This multicenter clinical trial was designed to compare its effect with intravenous steroid and observation.MethodsIncluded were TON patients ≥5 years of age and with trauma-treatment interval of ≤3 weeks. Follow-up visits were set at 1, 2, 3, 7, 14, 30, and at least 90 days after treatment. EPO and methylprednisolone were infused intravenously every day for three consecutive days. Primary outcome measure was change in the best corrected visual acuity (BCVA). Secondary outcomes included change in color vision and relative afferent pupillary defect (RAPD), side effects, and factors affecting the final visual improvement.ResultsOut of 120 patients, 100 (EPO: 69, steroid: 15, observation: 16) were finally included. All three groups showed a significant improvement of BCVA which was not significantly different between the groups (adjusted for pretreatment BCVA). Color vision was significantly improved in the EPO group. Late treatment (>3 days) (odds ratio = 2.53) and initial BCVA of NLP (odds ratio = 5.74) significantly worsened visual recovery. No side effect was observed in any group.ConclusionEPO, steroid, and observation showed a significant improvement of BCVA in patients with TON. Initial BCVA of NLP and late treatment (>3 days) were significant risk factors for visual improvement.

Glaucoma is a group of optic neuropathies that leads to irreversible vision loss. The optic nerve head (ONH) is the site of initial optic nerve damage in glaucoma. ONH-derived lamina cribrosa (LC) cells synthesize extracellular matrix (ECM) proteins; however, these cells are adversely affected in glaucoma and cause detrimental changes to the ONH. LC cells respond to mechanical strain by increasing the profibrotic cytokine transforming growth factor-beta 2 (TGFβ2) and ECM proteins. Moreover, microRNAs (miRNAs or miR) regulate ECM gene expression in different fibrotic diseases, including glaucoma. A delicate homeostatic balance between profibrotic and anti-fibrotic miRNAs may contribute to the remodeling of ONH. This study aimed to determine whether modulation of miRNAs alters the expression of ECM in human LC cells. Primary human normal and glaucoma LC cells were grown to confluency and treated with or without TGFβ2 for 24 h. Differences in expression of miRNAs were analyzed using miRNA qPCR arrays. miRNA PCR arrays showed that the miR-29 family was significantly decreased in glaucomatous LC cell strains compared to age-matched controls. TGFβ2 treatment downregulated the expression of multiple miRNAs, including miR-29c-3p, compared to controls in LC cells. LC cells transfected with miR-29c-3p mimics or inhibitors modulated collagen expression.

Tocilizumab (TCZ) has been demonstrated to be effective in treating thyroid-associated ophthalmopathy (TAO); however, its efficacy in hormone-resistant dysthyroid optic neuropathy (DON) remains unclear. This study aims to identify baseline and post-treatment indicators that can predict the necessity for surgical intervention following TCZ therapy. Thirty-one hormone-resistant DON patients treated with TCZ were categorized into surgery (n=15, 7 males, 8 females) and non-surgery (n=16, 8 males, 8 females) groups based on their post-TCZ surgical status. Retrospective comparisons between the two groups were performed using pre- and post-treatment ophthalmic assessments, biomarkers, and orbital magnetic resonance imaging (MRI) scans. The predictive value of identified variables was evaluated through receiver operating characteristic (ROC) curve analysis and logistic regression analysis. The surgery group exhibited a significantly higher baseline thyroid-stimulating hormone receptor antibody (TRAb) ( =0.001) and a positive change in the maximal signal intensity ratio of extraocular muscle to temporalis muscle (SIR(EOM/temporalis) ), whereas the non-surgery group demonstrated a negative change ( <0.001). A TRAb cut-off value of ≤5.07 IU/L predicted non-surgery with 93.3% sensitivity and 81.2% specificity, while a SIR(EOM/temporalis) cut-off value of ≤-1.83 had 86.7% sensitivity and 87.5% specificity. The area under the curve was 0.846 for TRAb and 0.863 for SIR(EOM/temporalis) . Multivariate regression confirmed SIR(EOM/temporalis) change ( =0.017) as an independent predictor of surgical intervention. Linear regression revealed a significant correlation between SIR(EOM/temporalis) change and TCZ dosage in the non-surgery group ( =0.005), but not in the surgery group. The percentage change in SIR(EOM/temporalis) following TCZ treatment and baseline TRAb can serve as predictors of the necessity for surgical intervention in hormone-resistant DON. These indicators assist in the personalization of TCZ therapy and in the avoidance of unnecessary surgical procedures.

Glutamate excitotoxicity may contribute to retinal ganglion cell (RGC) degeneration in glaucoma and other optic neuropathies, leading to irreversible blindness. Growing evidence has linked impaired mitochondrial quality control with RGCs degeneration, while parkin, an E3 ubiquitin ligase, has proved to be protective and promotes mitophagy in RGCs against excitotoxicity. The purpose of this study was to explore whether a small molecule S3 could modulate parkin-mediated mitophagy and has therapeutic potential for RGCs. The results showed that as an inhibitor of deubiquitinase USP30, S3 protected cultured RGCs and improved mitochondrial health against NMDA-induced excitotoxicity. Administration of S3 promoted the parkin expression and its downstream mitophagy-related proteins in RGCs. An upregulated ubiquitination level of Mfn2 and protein level of OPA1 were also observed in S3-treated RGCs, while parkin knockdown resulted in a major loss of the protective effect of S3 on RGCs under excitotoxicity. These findings demonstrated that S3 promoted RGC survival mainly through enhancing parkin-mediated mitophagy against excitotoxicity. The neuroprotective value of S3 in glaucoma and other optic neuropathies deserves further investigation.