Indirect traumatic optic neuropathy (TON) is associated with severe vision loss and no proven treatment. To evaluate the safety and exploratory functional outcomes of intravitreal pegfilgrastim in patients with indirect TON. Single-center, open-label, single-arm phase 1/2a proof-of-concept study. Twelve adults with acute unilateral indirect TON received a single intravitreal injection of 0.15 mL pegfilgrastim and were followed for 3 months. Outcomes included adverse events, best-corrected visual acuity (BCVA), visual field mean deviation, retinal nerve fiber layer thickness, and flash visual evoked potentials (VEP). No serious ocular or systemic treatment-related adverse events were observed. Transient leukocytosis occurred after treatment and resolved spontaneously. Within-subject improvements in BCVA were observed at 1 week, 1 month, and 3 months (p < 0.05), and visual field mean deviation improved at 3 months (p < 0.05). Retinal nerve fiber layer thickness declined progressively during follow-up. No significant change was detected in VEP latency or amplitude. Intravitreal pegfilgrastim was feasible and well tolerated in this first-in-human study of indirect TON. Exploratory functional improvements were observed in a subset of participants, but controlled studies are required to determine whether these changes exceed the natural history of the disease.

Glaucoma is a progressive optic neuropathy marked by the irreversible degeneration of retinal ganglion cells (RGCs), leading to vision loss. RGC injury is also central to other optic and neurodegenerative conditions, including traumatic optic neuropathy. We evaluated whether extracellular vesicles (EVs) derived from retinal precursor cells could serve as an effective platform for the delivery of neuroprotective microRNAs (miRNAs), focusing on miR-181a-3p, to preserve RGC viability and function. Based on prior profiling of miRNAs differentially expressed in injured RGCs, four candidate miRNAs were screened for neuroprotective effects in primary rat retinal cultures and human embryonic stem cell-derived RGCs. miR-181a-3p, which showed the strongest preservation of RGC survival, was selected for further study. EVs were isolated from R-28 retinal precursor cells, loaded with miR-181a-3p via electroporation, and characterized for particle size, charge, and loading efficiency. EV uptake and neuroprotective efficacy were evaluated in vitro by fluorescence imaging, qPCR, and Ca2+-activity assays, and in vivo by intravitreal injection of labelled EVs to assess retinal distribution and cellular uptake. EV-mediated delivery of miR-181a-3p enhanced RGC survival and preserved intracellular Ca2+ dynamics compared to free miRNA or lipofectamine-based transfection. EVs improved miRNA stability, enabled selective targeting of retinal cell types, and partially modulated the p38/MAPK signalling axis. EV loading also improved the delivery of miRNA to the retina in vivo. Our findings demonstrate that EVs offer a biocompatible, cell-specific, and functionally effective platform for miRNA delivery to the retina. EV-based administration of miR-181a-3p may represent a novel neuroprotective strategy for glaucoma and related optic neuropathies.

Caution in Interpreting Treatment Effects in Retrospective Studies of Traumatic Optic Neuropathy.

Traumatic optic neuropathy (TON) occurs due to trauma to the optic nerve, resulting in blindness. Current management focuses primarily on supportive care, highlighting an urgent need to identify novel treatment targets. Neuronal expression of the enzyme histone deacetylase 3 (HDAC3) has been previously implicated in retinal ganglion cell (RGC) degeneration after optic nerve crush (ONC), a model of TON. Here we investigated the role of myeloid HDAC3 (i.e., HDAC3 expressed in microglia and macrophages) in RGC loss, axonal degeneration, and efferocytosis, a reparative process by which phagocytic myeloid cells engulf apoptotic cells. ONC injury was performed on myeloid-specific HDAC3 knockout (KO) and floxed control mice. Neurodegeneration and efferocytosis assays were assessed using retina flatmount immunolabeling and confocal imaging. RGC function was evaluated using pattern electroretinography (PERG). Axonal sprouting was quantified by anterograde transport of cholera toxin B injected intravitreally. Myelin debris clearance was assessed in optic nerves in vivo and in vitro using bone-marrow-derived macrophages isolated from myeloid HDAC3 KO and control mice. Myeloid HDAC3 deletion preserved RGC and improved axonal regeneration after ONC, together with improved retinal function assessed by PERG. Furthermore, the deletion of HDAC3 enhanced the phagocytic function of myeloid cells to effectively remove apoptotic cells and myelin debris, both in vivo and in vitro. These protective effects were associated with the deletion of HDAC3 specifically in macrophages, since microglial-only deletion of HDAC3 did not preserve RGC count or function. The enhanced efferocytosis function of HDAC3 KO macrophages was at least partly dependent on increasing the expression of the phagocytic tyrosine kinase receptor, MerTK. The deletion of myeloid HDAC3 enhances efferocytosis, leading to neuroprotection, regeneration, and functional recovery following ONC. Targeting myeloid-HDAC3 presents a novel therapeutic strategy for TON.

Retinal ganglion cell death occurs following injury to the optic nerve either by trauma or in disease such as glaucoma, leading to severe vision loss. Recent innovations have demonstrated that optic nerve regeneration is feasible; however, the regeneration is limited. The aim of the present study is to identify genomic elements enhancing axon regeneration. We have taken a forward genetics approach using the BXD recombinant mouse strains to identify a gene that increases the extent of optic nerve regeneration. Axon regeneration was induced by knocking down Pten in retinal ganglion cells using adeno-associated virus to deliver an shRNA followed by an intravitreal injection of Zymosan with CPTcAMP that produced a mild inflammatory response. Retinal ganglion cell axons were damaged by optic nerve crush. Following a 12-day survival period, regenerating axons were labeled by intravitreal injection of Cholera Toxin B conjugated with Alexa Fluor 647. Two days later, labeled axons within the optic nerve were examined to determine the number of regenerating axons and the distance they traveled down the optic nerve. The analysis revealed a surprising difference in the amount of axonal regeneration across all 33 BXD strains. There was a 7.5-fold difference in the number of regenerating axons and a 4-fold difference in the distance traveled by regenerating axons. These data were used to generate an interval map defining genomic loci that modulate enhanced axonal regeneration. A quantitative trait locus modulating axon regeneration was identified on Chromosome 14 (115 to 119 Mb). Within this locus were 16 annotated genes. Subsequent testing revealed that one candidate gene, Dnajc3, modulated axonal regeneration. Dnajc3 encodes heat shock protein 40 (HSP40), a molecular chaperone. Knocking down Dnajc3 in the high regenerative strain (BXD90) led to a decreased regeneration response, whereas, overexpression of Dnajc3 in a low regenerative strain (BXD34) resulted in an increased regeneration response. These findings reveal that Dnajc3 not only increases the number of regenerating axons, but also increases the distance that axons travel. The enhanced regeneration will prove to be critical for functional recovery in humans, where the distance axons travel to their targets is considerably longer than that of mice.

Traumatic optic neuropathy (TON) is a devastating cause of irreversible vision loss for which no effective treatment currently exists. Its poor prognosis stems from two major challenges: the limited regenerative capacity of retinal ganglion cells (RGCs) and the hostile, inflammation-driven environment that follows injury. In this work, using transcriptomic bioinformatic and histopathological analysis, we discovered that mechanical trauma and subsequent neuroinflammation trigger microglial pyroptosis through the NLRP3/CASP1/GSDMD pathway. This process amplifies inflammatory cascades and exacerbates RGC degeneration via microglia-neuron interactions. To overcome these dual barriers, we engineered a microglia-targeted lipid nanoparticle (LNP) platform co-delivering disulfiram (DSF), a selective GSDMD inhibitor, together with self-amplifying mRNA (saRNA) encoding ciliary neurotrophic factor (CNTF). We found that this combinatorial strategy concurrently suppresses pyroptosis-driven neuroinflammation while providing sustained neurotrophic support. Through comprehensive in vitro and in vivo evaluations, the co-delivery system showed enhanced RGC survival, remarkable axonal regeneration, and eventually significant restoration of visual function. In summary, our results demonstrate that a coordinated strategy targeting both neuroinflammatory mechanisms and regenerative pathways yields superior therapeutic outcomes in TON. This work underscores the potential of integrated RNA-small molecule therapies as a promising multi-target treatment paradigm, with broad applicability for other neuroinflammatory and neurodegenerative diseases.

Oriented porous microtubules combined with CNTF-delivery directional guide axonal regeneration after traumatic optic neuropathy.

Up to half of patients with traumatic optic neuropathy (TON) develop permanent vision loss. The diagnosis and management of TON are challenging. Here, we aim to identify craniofacial fractures associated with TON and compare visual outcomes in TON patients under observation versus steroid-based management. We reviewed CT scans of patients after acute facial trauma at the R Adams Cowley Shock Trauma Center from 2018 to 2022 to determine craniofacial fractures associated with TON. TON patient outcomes between 2013 and 2022 were analyzed to compare steroid treatment versus observation. Primary outcomes were improvement in visual acuity and time to improvement. Multivariate logistic and linear regressions were performed. Among 2374 patients presenting with acute facial fractures between 2018 and 2022, 21 (0.9%) had TON. Sphenoid sinus fractures were associated with the greatest odds of TON (aOR [95% CI], 25 [9-68]) followed by LeFort III and naso-orbitoethmoid (NOE) fractures (aOR [95% CI], 13 [4-42] and 7 [2-24], respectively), compared with patients without these fractures. Between 2013 and 2022, treatment outcomes were analyzed in 86 TON patients (96 eyes). Their median (IQR) follow-up was 9 (4-31) months. Patients treated with IV methylprednisolone, ranging from 250 to 1000 mg for a maximum of 3 days, were more likely to have improvement in visual acuity compared to those managed with observation (8/13 [62%], 27/83 [33%], P < 0.05). Steroids were also associated with a 57-day quicker improvement in visual acuity compared to observation (B = -57.1, P = 0.007). Patients with sphenoid sinus fractures should be carefully examined for the presence of a TON. At our institution, steroid therapy results in a more rapid improvement and a better final visual acuity than observation in patients with TON.

Peripheral macrophages and T-cells accumulate in the degenerating optic tract after repetitive head impact.

Misdiagnosed ocular perforating injury with direct traumatic optic neuropathy from gun pellet confirmed intraoperatively.

Retinal ganglion cell (RGC) degeneration caused by optic nerve injury and diseases such as glaucoma leads to irreversible vision loss, yet effective neuroprotective treatments remain elusive. Secondary degeneration driven by astrocytic gliosis and neuroinflammation contributes substantially to neuronal death. Connexin 43 (Cx43), a gap junction protein abundantly expressed in astrocytes, is a key mediator of these secondary responses. Using an optic nerve crush (ONC) mouse model that recapitulates traumatic optic neuropathy, we found that Cx43 haploinsufficiency significantly preserved visual function, limited inner retina thinning, and protected RGCs from apoptosis and macrophage infiltration. Mechanistically, cytokine stimulation of astrocytes triggered Cx43 hemichannel opening and the release of inflammatory ATP and neurotoxic glutamate, which in turn promote RGC apoptosis. A novel Cx43(M1) antibody selectively inhibited astrocytic hemichannels, prevented the release of these factors, and reduced RGC death. Remarkably, a single administration of Cx43(M1) 30min after ONC improved visual function and RGC survival for at least four weeks, accompanied by attenuated gliosis and reduced Cx43 expression. Together, these findings identify astrocytic Cx43 hemichannels as key mediators of secondary RGC neurodegeneration and demonstrate that their targeted inhibition confers sustained neuroprotection following optic nerve injury.

Traumatic optic neuropathy and endoscopic surgical treatment

Clinical features, management, and prognosis factors of traumatic optic neuropathy.

ObjectiveIn the present study, we established a rat model of optic nerve injury to evaluate whether direct local delivery of neurotrophic agents following traumatic optic neuropathy (TON) enhances retinal ganglion cells (RGCs) survival and its potential effects on axonal regeneration.MethodsForty-eight rats were randomly assigned to treatment (n = 24) and control (n = 24) groups. A standardized optic nerve crush injury was induced, followed by optic nerve decompression. In the treatment group, a gelatin sponge soaked with 10-μL mouse NGF (mNGF) solution was applied directly to the injury site. In the control group, a gelatin sponge soaked with 10-μL normal saline was applied. Retinal structure and cellular changes were evaluated via hematoxylin–eosin (H&E) staining at postoperative days 1, 8, and 14. RGC survival was quantified via immunofluorescence staining. Axonal survival was assessed using cholera toxin B subunit–488 (CTB-488) anterograde tracing.ResultsCompared with the control group, H&E staining showed better preservation of retinal morphology in the mNGF-treated group. CTB-488 anterograde tracing showed no significant differences between groups in mean axonal fluorescence intensity at the injury site. Immunofluorescence analysis revealed significantly higher RGC survival in the treatment group at days 1 (1/2 retinal eccentricity), 8 (1/6 and 1/2 eccentricities), and 14 (1/6 eccentricity).ConclusionIn this Sprague–Dawley rat model of optic nerve injury, direct local delivery of mNGF may enhance RGC survival with effects showing time-dependent and spatially heterogeneous patterns. However, this intervention does not significantly promote the survival or regeneration of optic nerve axons.

ABSTRACT Introduction: Traumatic Optic Neuropathy (TON) is uncommon, with an overall incidence of 0,7-2,5%, and yet significantly vision threatening. Characteristics of TON cases are of great aid in basing diagnosis, research, and therapy, and are documented in lengths in developed nations such as Canada and UK. This study aims to paint a picture of TON cases in Indonesia, especially Cicendo Eye Hospital. Methods: Descriptive data are retrospectively collected from Electronic Medical Record (EMR) of Cicendo Eye Hospital. The data is collected from Diagnosed cases of TON from 2022-2024, amounting to 147 cases. Result: There are 147 diagnosed cases of TON in Cicendo eye hospital from 2022-2024, age of TON patients averages 31,7 ± 16.0, with 79,6% are of male gender, etiology of TON are traffic related trauma (61.8%), occupation related (15.3%), violence related (4.1%), and others (22.9%). Most cases (88.4%) received therapy after 24 hours of onset of trauma. Cases have varied initial visual acuity, ranging from no light perception (18.4%), light perception (8.2%), hand movement (17.7%), finger counting (21.1%), and better(20.4%). Management of TON includes oral citicoline alone(60.5%), with oral corticosteroid (18.4%), or with intravenous corticosteroid (21.1%). Conclusion: Within the 147 TON cases in Cicendo eye hospital from 2022-2024, TON patients are of age 31,7 ± 16.0, mostly male (79.6%), related to traffic accident (61.8%), evaluated 24 hours after onset (88.4%), have visual acuity for finger counting (21.1%), and treated with oral citicoline alone (60.5%).

Traumatic optic neuropathy (TON) is a vision-threatening complication of craniofacial trauma that often progresses to optic nerve atrophy and irreversible visual loss. However, the optimal management strategy remains controversial. This systematic review and meta-analysis aimed to compare the efficacy and safety of surgical optic canal decompression versus corticosteroid therapy in patients with TON. A comprehensive literature search was conducted in PubMed, Embase, Web of Science, and the Cochrane Library for studies published between January 2005 and July 2025. Both randomized controlled trials and observational studies reporting visual or structural outcomes were included. Data were pooled using a random-effects model, and subgroup analyses were performed according to intervention timing, type of injury, and baseline severity. Risk of bias was assessed with RoB 2.0 and the Newcastle-Ottawa Scale. Thirty-four studies involving 1046 patients were included. Surgical decompression significantly improved visual outcomes compared with corticosteroids (62% vs. 37%; OR = 2.35, 95% CI: 1.55-3.56). Subgroup analyses indicated superior outcomes with early surgery (≤ 7 days; OR = 2.91, 95% CI: 1.74-4.88) and in indirect TON (OR = 2.62, 95% CI: 1.70-4.04), whereas benefits were less pronounced in direct injuries. Structural outcomes also favored surgery, with greater retinal nerve fiber layer preservation (mean difference = +9.4 μm) and lower incidence of optic atrophy (OR = 0.44, 95% CI: 0.27-0.71). Adverse events were mild and comparable between groups. Funnel plot analysis revealed no significant asymmetry, suggesting minimal publication bias. This systematic review and meta-analysis provides indicative evidence that early surgical decompression may offer superior outcomes compared with corticosteroid therapy, especially for indirect injuries. Specifically, this meta-analysis suggests that surgical intervention may offer superior outcomes without increasing adverse events. Nevertheless, the evidence base remains limited, and these results should be interpreted with caution. While corticosteroids alone show limited benefit and may be considered adjunctive when surgery is not feasible, high-quality multicenter randomized trials are urgently needed to standardize treatment protocols and optimize patient outcomes.

"Traumatic brain injury (TBI) frequently produces visual symptoms along the visual pathway, from the eye and optic nerve to cortical visual processing and oculomotor control. Manifestations include decreased visual acuity and visual fields, traumatic optic neuropathy (TON), oculomotor dysfunctions (saccades, vergence, tracking), photophobia/"visual snow", and higher-level visuo-perceptual problems. Recognition of these symptoms by ophthalmologists and optometrists is essential, as many deficits are treatable (vision therapy, optical aids, medical/surgical management for TON, multidisciplinary rehabilitation), yet underdiagnosis is common. Significant gaps include standardized diagnostic protocols, objective biomarkers, and high-quality studies on rehabilitation strategies. Recent advances in imaging methods allow noninvasive quantification of retinal thickness, retinal vessel density, blood flow, and oxygen saturation. SD-OCTA provides high-resolution three-dimensional (3D) images of blood flow and vessel density in the superficial and deep retinal plexuses. This novel, noninvasive imaging technique may offer insights into neural pathologies with vascular components, such as TBI.

Optic nerve (ON) injury by trauma induces progressive retinal ganglion cell (RGC) death and axonal loss, which leads to irreversible visual impairment and even blindness. Recently, we discovered that cellular senescence is involved in RGC survival regulation post-ON injury, and senolytic (dasatinib and quercetin) treatments can promote RGC survival and electroretinography activity. Here, we aimed to further evaluate the effects of dasatinib and quercetin on RGC dendrites and axons in mice with an ON crush injury. Longitudinal in vivo imaging analysis demonstrated that the RGC dendritic shrinkage was significantly reduced in mice with both individual and combined treatment of dasatinib and quercetin as compared to the vehicle treatment group. Similarly, dasatinib and quercetin treatments significantly promoted axonal regeneration post-ON injury as compared to the vehicle-treated mice. RNA sequencing analysis showed that the differentially expressed genes were enriched in the response to glucocorticoid, calcium ion binding, and cerebral cortex development. Sybr green PCR and immunofluorescence analyses validated that the axonal extension-related gene, meteorin (Metrn), was significantly upregulated in the dasatinib-only and combined dasatinib and quercetin treatments. In summary, this study revealed that dasatinib and quercetin alleviated RGC dendritic shrinkage and promoted axonal regeneration in mice after ON injury, probably mediated through meteorin, suggesting the dendrite repair and axonal regeneration potentials of dasatinib and quercetin for traumatic optic neuropathy treatment.

Traumatic optic neuropathy (TON) is a rare entity resulting in vision loss after a head trauma, predominantly affecting men due to accidents, falls, violence, or sports injuries.The chances of recovery from an insult to the optic nerve depend on whether it is a direct or an indirect injury.Injuries to the optic nerve of direct nature often lead to immediate and severe vision loss that may not improve over time.On the other hand, injuries to the optic nerve which are indirect may cause delayed vision loss, sometimes even after the initial injury.Fractures in the optic canal are effectively detected using thin-section CT scans.MRI is recommended only when intracranial injuries cannot be fully assessed using CT scans.The management of TON includes observation, corticosteroids, and surgery.It is typically recommended to observe the condition, if there are no signs of blood clots or fractures in the optic canal.The treatment for TON involves giving very high doses of intravenous methylprednisolone, followed by slowly tapering with oral prednisolone.Surgical management should be done only when there are compression signs.

Traumatic optic neuropathy (TON), often resulting from repetitive mild traumatic brain injury (r-mTBI), is a major contributor to irreversible visual impairment, with few preventive therapeutic options available. This study evaluates the prophylactic efficacy of ST266, a biologically active secretome derived from amnion epithelial cells, in mitigating TON-related visual and cognitive dysfunction in a murine model of r-mTBI. Mice received five closed-head injuries spaced 48h apart, preceded by intranasal delivery of ST266 starting 24h before the first injury and administered twice daily for ten days. Behavioral performance was assessed using the Barnes Maze and optomotor response (OMR). Pathological and biochemical analyses were conducted on the eye and optic nerve tissues. Prophylactic treatment with ST266 preserved retinal ganglion cell (RGC) count, significantly attenuated optic nerve inflammation, and reduced microgliosis, TLR4, and NLRP3 expression in the intracanalicular segment of the optic nerve. ST266 protected spatial learning in the Barnes Maze during the acquisition phase but did not improve memory retention or visual function by OMR. Importantly, this model reflects translationally relevant features of human TON, such as RGC degeneration and visual-cognitive impairments. Our findings identify ST266 as a potential prophylactic therapy for TON, especially in populations at elevated risk (e.g., athletes, military personnel, or individuals prone to falls). Its non-invasive intranasal administration, established safety profile, and anti-inflammatory and neuroprotective effects make it a viable candidate for clinical translation. This is the first study to demonstrate protection against optic nerve injury before trauma onset, addressing a critical unmet need in neuro-ophthalmology.