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Vision loss after optic neuropathy is considered irreversible. Here, repetitive transorbital alternating current stimulation (rtACS) was applied in partially blind patients with the goal of activating their residual vision. We conducted a multicenter, prospective, randomized, double-blind, sham-controlled trial in an ambulatory setting with daily application of rtACS (n = 45) or sham-stimulation (n = 37) for 50 min for a duration of 10 week days. A volunteer sample of patients with optic nerve damage (mean age 59.1 yrs) was recruited. The primary outcome measure for efficacy was super-threshold visual fields with 48 hrs after the last treatment day and at 2-months follow-up. Secondary outcome measures were near-threshold visual fields, reaction time, visual acuity, and resting-state EEGs to assess changes in brain physiology. The rtACS-treated group had a mean improvement in visual field of 24.0% which was significantly greater than after sham-stimulation (2.5%). This improvement persisted for at least 2 months in terms of both within- and between-group comparisons. Secondary analyses revealed improvements of near-threshold visual fields in the central 5° and increased thresholds in static perimetry after rtACS and improved reaction times, but visual acuity did not change compared to shams. Visual field improvement induced by rtACS was associated with EEG power-spectra and coherence alterations in visual cortical networks which are interpreted as signs of neuromodulation. Current flow simulation indicates current in the frontal cortex, eye, and optic nerve and in the subcortical but not in the cortical regions. rtACS treatment is a safe and effective means to partially restore vision after optic nerve damage probably by modulating brain plasticity. This class 1 evidence suggests that visual fields can be improved in a clinically meaningful way. ClinicalTrials.gov NCT01280877.

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.

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, a major cause of blindness worldwide, is a neurodegenerative optic neuropathy in which vision loss is caused by loss of retinal ganglion cells (RGCs). To better define the pathways mediating RGC death and identify targets for the development of neuroprotective drugs, we developed a high-throughput RNA interference screen with primary RGCs and used it to screen the full mouse kinome. The screen identified dual leucine zipper kinase (DLK) as a key neuroprotective target in RGCs. In cultured RGCs, DLK signaling is both necessary and sufficient for cell death. DLK undergoes robust posttranscriptional up-regulation in response to axonal injury in vitro and in vivo. Using a conditional knockout approach, we confirmed that DLK is required for RGC JNK activation and cell death in a rodent model of optic neuropathy. In addition, tozasertib, a small molecule protein kinase inhibitor with activity against DLK, protects RGCs from cell death in rodent glaucoma and traumatic optic neuropathy models. Together, our results establish a previously undescribed drug/drug target combination in glaucoma, identify an early marker of RGC injury, and provide a starting point for the development of more specific neuroprotective DLK inhibitors for the treatment of glaucoma, nonglaucomatous forms of optic neuropathy, and perhaps other CNS neurodegenerations.

Disorders of the optic nerves (optic neuropathies) are some of the most common causes of visual loss, and can present in isolation or with associated neurological or systemic symptoms and signs. Several optic neuropathies—especially inflammatory optic neuropathies—are associated with neurological disorders and thus are often diagnosed and treated by neurologists. The mechanisms underlying optic neuropathies are diverse and typically manifest with decreased visual acuity, altered colour vision, and abnormal visual field in the affected eye. Diagnosis is made on the basis of clinical history and clinical examination, of which several aspects are particularly important, including the mode of onset of visual loss, the presence of pain with eye movements, the visual acuity, and the retention of colour vision. Advances in optic nerve imaging—particularly retinal digital photography, optical coherence tomography, and MRI techniques—have revolutionised the diagnosis and follow-up of patients with an optic neuropathy. Furthermore, improvement and generalisation of some ancillary tests, such as diagnostic antibodies for neuromyelitis optica, allows better phenotyping of the heterogeneous inflammatory optic neuropathies.

Introduction Recent diagnostic criteria for optic neuritis include T2-hyperintensity of the optic nerve (ON), even without associated contrast enhancement. However, isolated ON-T2-hyperintensity is a nonspecific finding found in any optic neuropathy or severe retinopathy. We applied the 2022 optic neuritis diagnostic criteria to a cohort of patients with noninflammatory optic neuropathy and ON-T2-hyperintensity in at least one eye, to assess the rate of optic neuritis misdiagnosis using these criteria. Methods Retrospective study of consecutive patients who underwent brain/orbit MRI with/without contrast between 07/01/2019 and 06/30/2022. Patients with ON-T2-hyperintensity in at least one eye were included. The 2022 optic neuritis diagnostic criteria were applied to patients with noninflammatory optic neuropathies who had an ophthalmologic examination available for review. Results Of 150 patients included, 85/150 had compressive optic neuropathy; 32/150 had glaucoma; 12/150 had papilledema; 8/150 had hereditary (3), radiation-induced (3), nutritional (1), traumatic (1) optic neuropathies (none fulfilled the criteria); 13/150 had ischemic optic neuropathy and 4 fulfilled the criteria as definite optic neuritis due to contrast enhancement of the ON head. Seven additional patients would have satisfied the diagnostic criteria if red flags for alternative diagnoses had been overlooked. Discussion The application of the 2022 optic neuritis diagnostic criteria in patients with noninflammatory optic neuropathy and ON-T2-hyperintensity in at least one ON resulted in misdiagnosis of optic neuritis in only 4 patients because of ON head enhancement, all with nonarteritic anterior ischemic optic neuropathy. Neuro-ophthalmologic evaluation and exclusion of the ON head as a location in the MRI criteria would have prevented optic neuritis misdiagnosis in our study.

Radiation is a commonly used treatment modality for head and neck as well as CNS tumours, both benign and malignant. As newer oncology treatments such as immunotherapies allow for longer survival, complications from radiation therapy are becoming more common. Radiation-induced optic neuropathy is a feared complication due to rapid onset and potential for severe and bilateral vision loss. Careful monitoring of high-risk patients and early recognition are crucial for initiating treatment to prevent severe vision loss due to a narrow therapeutic window. This review discusses presentation, aetiology, recent advances in diagnosis using innovative MRI techniques and best practice treatment options based on the most recent evidence-based medicine.

To examine the prevalence of glaucomatous optic neuropathy (GON) in a medium myopic to highly myopic group of patients and its association with parapapillary gamma zone and parapapillary delta zone. The retrospective observational hospital-based study included patients who had attended the Tokyo High Myopia Clinics within January 2012 and December 2012 and for whom fundus photographs were available. GON was defined based on the appearance of the optic nerve head on the fundus photographs. The study included 519 eyes (262 individuals) with a mean age of 62.0±14.3 years (range:13-89 years) and mean axial length of 29.5±2.2 mm (range:23.2-35.3mm). GON was present in 141 (27.2%; 95% confidence intervals (CI): 23.3, 31.0%) eyes. Prevalence of GON increased from 12.2% (1.7, 22.7) in eyes with an axial length of <26.5mm to 28.5% (24.4, 32.5) in eyes with an axial length of ≥26.5mm, to 32.6% (27.9, 37.2) in eyes with an axial length of ≥28mm, to 36.0% (30.5, 41.4) in eyes with an axial length of ≥29mm, and GON prevalence increased to 42.1% (35.5, 48.8) in eyes with an axial length of ≥30mm. In multivariate analysis, higher GON prevalence was associated (Nagelkerke r2: 0.28) with larger parapapillary delta zone diameter (P<0.001; odds ratio (OR):1.86;95%CI:1.33,2.61), longer axial length (P<0.001;OR:1.45;95%CI:1.26,1.67) and older age (P = 0.01;OR:1.03;95%CI:1.01,1.05). If parapapillary delta zone width was replaced by the vertical disc diameter, higher GON prevalence was associated (r2:0.24) with larger vertical optic disc diameter (P = 0.04;OR:1.70;95%CI:1.03,2.81), after adjusting for longer axial length (P<0.001;OR:1.44;95%CI:1.26,1.64) and older age (P<0.001;OR:1.04;95%CI:1.02,1.06). Axial elongation associated increase in GON prevalence (mean: 28.1% in a medium to highly myopic study population) was associated with parapapillary delta zone as surrogate for an elongated peripapillary scleral flange and with larger optic disc size.

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.