Optic nerve decompression through pterional and supraorbital approaches in the treatment of severe traumatic optic neuropathy.

To investigate the effectiveness of optic nerve decompression (OND) in the treatment of severe traumatic optic neuropathy (TON) through pterional and supraorbital approaches, and to identify the prognostic factor for postoperative visual acuity (VA) following OND. Patients with severe TON treated with OND through either pterional or supraorbital approach in our institute from September 2019 to June 2022 were retrospectively reviewed in this study. Demographic information, trauma factors, the interval between trauma and complete blindness, the interval between trauma and surgery, and the associated craniofacial traumas were recorded. Hospitalization days and the postoperative VA of patients in two groups were compared. There were 54 severe TON patients with NLP included in this study; 21 patients underwent OND through the pterional approach, and the other 33 underwent the supraorbital approach. Respectively, in groups of pterional and supraorbital approaches, the average hospitalization days were 9.8 ± 3.2 and 10.7 ± 2.9 days (p = 0.58), the mean durations of follow-up were 18.9 ± 4.3 and 20.8 ± 3.7 months (p = 0.09), and the average circumference of OND were 53.14 ± 15.89 ◦ (range 220 ◦ -278◦) and 181.70 ± 6.56◦ (range 173 ◦ -193◦) (p<0.001). The overall improvement rates of pterional and supraorbital approaches are 57.1% and 45.5% (p = 0.40), respectively. Optic canal fracture (OCF) was revealed to be significantly associated with postoperative VA in the supraorbital approach (Binary: p = 0.014, CI: 1.573-57.087; Ordinal: p = 0.003, CI: 1.517-5.503), but not in the pterional approach. In the group of supraorbital approach, patients with OFC had a higher rate of a better outcome (78.6%) than those without (21.4%). Patients with severe traumatic TON may benefit from OND through either the pterional or supraorbital approach. OCF is a potential prognostic factor for postoperative VA following OND through the supraorbital approach.

Brief Oxygen Exposure after Traumatic Brain Injury Hastens Recovery and Promotes Adaptive Chronic Endoplasmic Reticulum Stress Responses.

Traumatic brain injury (TBI) is a major public health concern, particularly in adolescents who have a higher mortality and incidence of visual pathway injury compared to adult patients. Likewise, we have found disparities between adult and adolescent TBI outcomes in rodents. Most interestingly, adolescents suffer a prolonged apneic period immediately post-injury, leading to higher mortality; therefore, we implemented a brief oxygen exposure paradigm to circumvent this increased mortality. Adolescent male mice experienced a closed-head weight-drop TBI and were then exposed to 100% O2 until normal breathing returned or recovered in room air. We followed mice for 7 and 30 days and assessed their optokinetic response; retinal ganglion cell loss; axonal degeneration; glial reactivity; and retinal ER stress protein levels. O2 reduced adolescent mortality by 40%, improved post-injury visual acuity, and reduced axonal degeneration and gliosis in optical projection regions. ER stress protein expression was altered in injured mice, and mice given O2 utilized different ER stress pathways in a time-dependent manner. Finally, O2 exposure may be mediating these ER stress responses through regulation of the redox-sensitive ER folding protein ERO1α, which has been linked to a reduction in the toxic effects of free radicals in other animal models of ER stress.

Neuroprotective Effects of Erinacine A on an Experimental Model of Traumatic Optic Neuropathy.

Erinacine A (EA), a natural neuroprotectant, is isolated from a Chinese herbal medicine, Hericium erinaceus. The aim of this study was to investigate the neuroprotective effects of EA in a rat model of traumatic optic neuropathy. The optic nerves (ONs) of adult male Wistar rats were crushed using a standardized method and divided into three experimental groups: phosphate-buffered saline (PBS control)-treated group, standard EA dose-treated group (2.64 mg/kg in 0.5 mL of PBS), and double EA dose-treated group (5.28 mg/kg in 0.5 mL of PBS). After ON crush, each group was fed orally every day for 14 days before being euthanized. The visual function, retinal ganglion cell (RGC) density, and RGC apoptosis were determined using flash visual-evoked potentials (fVEP) analysis, retrograde Fluoro-Gold labelling, and TdT-dUTP nick end-labelling (TUNEL) assay, respectively. Macrophage infiltration of ON was detected by immunostaining (immunohistochemistry) for ED1. The protein levels of phosphor-receptor-interacting serine/threonine-protein kinase1 (pRIP1), caspase 8 (Cas8), cleaved caspase 3 (cCas3), tumour necrosis factor (TNF)-α, tumour necrosis factor receptor1 (TNFR1), interleukin (IL)-1ß, inducible nitric oxide synthase (iNOS), nuclear factor erythroid 2-related factor 2 (Nrf2), haem oxygenase-1 (HO-1), and superoxide dismutase 1 (SOD1) were evaluated by Western blotting. When comparing the standard EA dose-treated group and the double EA dose-treated group with the PBS-treated group, fVEP analysis showed that the amplitudes of P1−N2 in the standard EA dose group and the double EA dose-treated group were 1.8 and 2.4-fold, respectively, higher than that in the PBS-treated group (p < 0.05). The density of RGC in the standard EA dose-treated group and the double EA dose-treated group were 2.3 and 3.7-fold, respectively, higher than that in the PBS-treated group (p < 0.05). The TUNEL assay showed that the standard EA dose-treated group and the double EA dose-treated group had significantly reduced numbers of apoptotic RGC by 10.0 and 15.6-fold, respectively, compared with the PBS-treated group (p < 0.05). The numbers of macrophages on ON were reduced by 1.8 and 2.2-fold in the standard EA dose-treated group and the double EA dose-treated group, respectively (p < 0.01). On the retinal samples, the levels of pRIP, Cas8, cCas3, TNF-α, TNFR1, IL-1ß, and iNOS were decreased, whereas those of Nrf2, HO-1, and SOD1 were increased in both EA-treated groups compared to those in the PBS-treated group (p < 0.05). EA treatment has neuroprotective effects on an experimental model of traumatic optic neuropathy by suppressing apoptosis, neuroinflammation, and oxidative stress to protect the RGCs from death as well as preserving the visual function.

Effect of orbital volume in unilateral orbital fracture on indirect traumatic optic neuropathy.

PURPOSE: This retrospective study aimed to analyze the relationship between the volume of the fractured and the normal orbit in patients with unilateral orbital fractures with and without indirect traumatic optic neuropathy (TON). SUBJECTS: Data of 25 patients with unilateral orbital fractures who underwent computer tomography between January 2016 and December 2020 were investigated. Emergency imaging was performed within 2 hours of arrival at the emergency room. The subjects were categorized into two groups: unilateral orbital fractures with and without TON. METHODS AND MEASURES: The assessment of TON was performed during a comprehensive ophthalmologic examination by an ophthalmologist. The stereographic orbit was reconstructed, and the volume was calculated. Other variables examined included age, sex, and cause of orbital trauma. The variables were compared using paired t-tests. Statistical significance was set at p < 0.05. RESULTS: The orbital volume of the non-fractured orbit was 27.50 ± 2.26 and 27.48 ± 2.64 cm3 in the groups with and without TON, respectively. The average volume of the fractured orbit in the TON group was 27.78 ± 2.56 cm3, and there was no significant volumetric difference between the fractured and non-fractured sides in this group. However, the average volume of the fractured orbit without TON was 28.76 ± 3.18 cm3, larger than that of the non-fractured orbit (p = 0.016). CONCLUSIONS: Non-expansion of the fractured orbit was a risk factor for indirect TON in patients with unilateral orbital fractures. Volumetric analysis from primary imaging would expedite the diagnosis and treatment of TON, resulting in optimal outcomes.

Progression of optic atrophy in traumatic optic neuropathy: retrograde neuronal degeneration in humans.

OBJECTIVE: We used optical coherence tomography (OCT) to document the time course of retrograde neuronal degeneration following indirect optic nerve injury. METHODS: We retrospectively studied patients diagnosed with unilateral indirect traumatic optic neuropathy (TON). Patients with total or near-total optic atrophy were included. All patients underwent complete ophthalmological examinations, including OCT imaging, within 1 day and at 1, 2, 3, 4, 6, 8, 12, 24, and 48 weeks after trauma. RESULTS: The mean thicknesses of the circumpapillary retinal nerve fiber layer (cpRNFL) and macular retinal ganglion cell-inner plexiform layer (mGCIPL) decreased significantly at 2 weeks after trauma (p = 0.027 and p = 0.043). Changes in mGCIPL thickness preceded changes in cpRNFL thickness. The rates of reduction in mGCIPL and cpRNFL thicknesses were greatest between 2 to 4 weeks and 4 to 6 weeks after trauma. The reduction in mGCIPL thickness then slowed, and stabilized at 12 weeks after trauma. The proportions of cpRNFL and mGCIPL losses at 2, 4, 6, 8, and 12 weeks compared to 24 weeks were 17.1, 33.7, 59.8, 77.9, and 87.9% and 30.0, 73.3, 76.1, 88.3, and 97.9%, respectively. CONCLUSIONS: OCT revealed optic atrophy progression 2 weeks after trauma, which was most rapid from 2 to 6 weeks, and then gradually stabilized. Loss of retinal ganglion cell bodies and dendrites seemed to precede the axonal degeneration. Observations of morphological changes in retinal layers using OCT in TON patients improve our understanding of retrograde neuronal degeneration of the central nervous system.

Differential susceptibility of retinal ganglion cell subtypes against neurodegenerative diseases.

Retinal ganglion cells (RGCs) are essential to propagate external visual information from the retina to the brain. Death of RGCs is speculated to be closely correlated with blinding retinal diseases, such as glaucoma and traumatic optic neuropathy (TON). Emerging innovative technologies have helped refine and standardize the classification of RGCs; at present, they are classified into more than 40 subpopulations in mammals. These RGC subtypes are identified by a combination of anatomical morphologies, electrophysiological functions, and genetic profiles. Increasing evidence suggests that neurodegenerative diseases do not collectively affect the RGCs. In fact, which RGC subtype exhibits the strongest or weakest susceptibility is hotly debated. Although a consensus has not yet been reached, it is certain that assorted RGCs display differential susceptibility against irreversible degeneration. Interestingly, a single RGC subtype can exhibit various vulnerabilities to optic nerve damage in diverse injury models. Thus, elucidating how susceptible RGC subtypes are to various injuries can protect vulnerable RGCs from damage and improve the possibility of preventing and treating visual impairment caused by neurodegenerative diseases. In this review, we summarize in detail the progress and status quo of research on the type-specific susceptibility of RGCs and point out current limitations and the possible directions for future research in this field.

Traumatic optic neuropathy: a review of current studies.

Traumatic optic neuropathy (TON) is a serious complication of craniofacial trauma that directly or indirectly damages the optic nerve and can cause severe vision loss. The incidence of TON has been gradually increasing in recent years. Research on the protection and regeneration of the optic nerve after the onset of TON is still at the level of laboratory studies and which is insufficient to support clinical treatment of TON. And, due to without clear guidelines, there is much ambiguity regarding its diagnosis and management. Clinical interventions for TON include observation only, treatment with corticosteroids alone, or optic canal (OC) decompression (with or without steroids). There is controversy in clinical practice concerning which treatment is the best. A review of available studies shows that the visual acuity of patients with TON can be significantly improved after OC decompression surgery (especially endoscopic transnasal/transseptal optic canal decompression (ETOCD)) with or without the use of corticosteroids. And new findings of laboratory studies such as mitochondrial therapy, lipid change studies, and other studies in favor of TON therapy have also been identified. In this review, we discuss the evolving perspective of surgical treatment and experimental study.

Vision improvement in indirect traumatic optic neuropathy treated by endoscopic transnasal optic canal decompression.

BACKGROUND: Indirect Traumatic optic neuropathy (ITON) is a severe disease characterized by a sudden decline of visual function after craniofacial injury. However, the best treatment for ITON is unknown. Endoscopic transnasal optic canal decompression (ETOCD) has gradually been used for ITON treatment worldwide in recent years. OBJECTIVE: To assess the effect of ETOCD on visual acuity in patients with ITON and identify factors that affect prognosis. METHODS: In this study, clinical characteristics of 44 ITON patients who underwent ETOCD in Qilu Hospital of Shandong University were retrospectively analyzed. Factors affecting prognosis were also evaluated. RESULTS: ETOCD treatment improved the vision of 20 (45.5%) patients with no patient suffering from vision deterioration. The mean value of visual acuity (VA) scores improved from 1.57 to 2.39 (P < 0.001). Patients with residual vision had a better VA improvement percent than those without light perception (66.67% versus 34.48%, χ2 = 4.13, P = 0.042). Although shorter duration before ETOCD was associated with better improvement score in ITON patients (r = -0.30, P = 0.044), optic canal fracture (OCF) and optic nerve sheath incision did not affect the prognosis of these patients. Five ITON patients with cerebrospinal fluid rhinorrhea were treated with free nasal mucosal flap during the surgery, and no other severe surgical complication occurred. CONCLUSIONS: ETOCD can effectively and safely improve the vision of ITON patients, patients with residual vision and those treated earlier may benefit more from this surgery.

Total Isolated Monocular Vision Loss in a Patient Who Suffered Closed Head Injury.

BACKGROUND: Head injuries are an important cause of morbidity and mortality in children and young adults. There are multiple sight-threatening complications of head injury, even in closed head injury without visible violation of the globe or orbits. One such entity is traumatic optic neuropathy. CASE REPORT: Herein we describe a case of traumatic optic neuropathy in an otherwise healthy teenage patient who suffered total monocular vision loss after a fall and without any other injuries on examination. Unfortunately, the prognosis for this condition is relatively poor in terms of visual recovery. Though much research has been conducted attempting to treat this condition, to date there have been no studies showing a clear benefit of medical or surgical intervention. Why Should an Emergency Physician Be Aware of This? Although there is no proven treatment for traumatic optic neuropathy, emergency physicians may encounter this in their practice while caring for both pediatric and adult patients presenting with head injury. Having more background knowledge on this condition will enhance emergency physicians' ability to consult with subspecialist providers as well as to educate patients and their families on their condition and prognosis.

[Optic nerve decompression-state of the art]. / Optikusdekompressionen ­ Stand der Technik.

Rarely, but often with serious consequences for the patient, the optic nerve is affected during the course of head injuries. Traumatic optic nerve compression is always an emergency situation, which is why time is of the essence for both diagnosis and treatment. Precise knowledge of this accident sequelae but also of the resulting conditions, especially in terms of traumatic optic neuropathy, is indispensable for adequate patient care. The aim of this paper is to provide an overview of this clinical picture, particularly with regard to etiology, diagnosis, and treatment options, and to discuss this in the context of the current literature.

Interventions for Indirect Traumatic Optic Neuropathy: A Report by the American Academy of Ophthalmology.

PURPOSE: To review the literature on the efficacy and safety of medical and surgical interventions for indirect traumatic optic neuropathy (TON), defined as injury to the nerve that occurs distal to the optic nerve head. METHODS: A literature search was conducted on October 22, 2019, and updated on April 8, 2020, in the PubMed database for English language original research that assessed the effect of various interventions for indirect TON. One hundred seventy-two articles were identified; 41 met the inclusion criteria outlined for assessment and were selected for full-text review and abstraction. On full-text review, a total of 32 studies met all of the study criteria and were included in the analysis. RESULTS: No study met criteria for level I evidence. Seven studies (1 level II study and 6 level III studies) explored corticosteroid therapy that did not have uniformly better outcomes than observation. Twenty studies (3 level II studies and 17 level III studies) assessed optic canal decompression and the use of corticosteroids. Although visual improvement was noted after decompression, studies that directly compared surgery with medical therapy did not report uniformly improved outcomes after decompression. Four studies (1 level II study and 3 level III studies) evaluated the use of erythropoietin. Although initial studies demonstrated benefit, a direct comparison of its use with observation and corticosteroids failed to confirm the usefulness of this medication. One study (level II) documented visual improvement with levodopa plus carbidopa. Complication rates were variable with all of these interventions. Pharmacologic interventions generally were associated with few complications, whereas optical canal decompression carried risks of serious side effects, including hemorrhages and cerebrospinal fluid leakage. CONCLUSIONS: Despite reports of visual improvement with corticosteroids, optic canal decompression, and medical therapy for indirect TON, the weight of published evidence does not demonstrate a consistent benefit for any of these interventions. In summary, no consensus exists from studies published to date on a preferred treatment for TON. Treatment strategies should be customized for each individual patient. More definitive treatment trials will be needed to identify optimal treatment strategies for indirect TON.

JNK/c-Jun-driven NLRP3 inflammasome activation in microglia contributed to retinal ganglion cells degeneration induced by indirect traumatic optic neuropathy.

BACKGROUND: Indirect traumatic optic neuropathy (ITON) is a major cause of permanent loss of vision after blunt head trauma. Neuroinflammation plays a crucial role in neurodegenerative diseases. The present study concentrated on JNK/c-Jun-driven NLRP3 inflammasome activation in microglia during the degeneration of retinal ganglion cells (RGCs) in ITON. METHODS: An impact acceleration (IA) model was employed to induce ITON, which could produce significant neurodegeneration in the visual system. Pharmacological approaches were employed to disrupt JNK and to explore whether JNK and the microglial response contribute to RGC death and axonal degeneration. RESULTS: Our results indicated that the ITON model induced significant RGC death and axonal degeneration and activated JNK/c-Jun signaling, which could further induce the microglial response and NLRP3 inflammasome activation. Moreover, JNK disruption is sufficient to suppress NLRP3 inflammasome activation in microglia and to prevent RGC death and axonal degeneration. CONCLUSIONS: ITON could promote JNK/c-Jun signaling, which further activates the NLRP3 inflammasome in microglia and contributes to the degeneration of axons and death of RGCs. JNK inhibition is able to suppress the inflammatory reaction and improve RGC survival. Although further work is needed to determine whether pharmacological inhibition of the NLRP3 inflammasome can prevent ITON, our findings indicated that such intervention could be promising for translational work.

Isolated-check visual evoked potential: a more sensitive tool to detect traumatic optic neuropathy after orbital fracture.

PURPOSE: To establish a more sensitive diagnostic tool for traumatic optic neuropathy (TON), we explored the diagnostic efficacy of isolated-check visual evoked potential (ic-VEP) for TON in orbital fracture and compared ic-VEP with pattern-reversal visual evoked potential (P-VEP) testing. METHODS: This was a prospective single-center study. A total of 137 eyes from 131 patients diagnosed between December 2016 and October 2019 with orbital fractures were included in the study. Injury history, best-corrected visual acuity (BCVA), visual field, computed tomography (CT), P-VEP, and ic-VEP data were collected. Parameters of ic-VEP (signal-to-noise ratio [SNR]) and P-VEP (peak latency and amplitude of P100) were compared and diagnostic accuracy was analyzed. RESULTS: TON was associated with worse BCVA than non-TON (median 0.52 versus 0.10 logMAR, P < 0.001). SNRs were negatively associated with the P100 peak latency while positively associated with the P100 amplitude. The sensitivity of ic-VEP for TON (79.6%) was higher than that of P-VEP (61.2%, P = 0.049), although this difference was not statistically significant after Bonferroni correction. Using ic-VEP and P-VEP together could increase sensitivity (87.8%). Maximum areas under curve were obtained using the SNR criteria of 1.3, 1.47, and 1.54 at 8%, 16%, and 32% depth of modulation, respectively. CONCLUSION: ic-VEP was more sensitive than P-VEP in diagnosing TON, and a combination of the two examination tests was recommended. The use of ic-VEP as the new diagnostic standard technique for TON should be considered.

The retinal vasculature pathophysiological changes in vision recovery after treatment for indirect traumatic optic neuropathy patients.

PURPOSE: To evaluate the retinal vasculature pathophysiological changes of indirect traumatic optic neuropathy (ITON) patients after effective surgery. METHODS: Monocular ITON patients who underwent endoscopic trans-ethmosphenoid optic canal decompression (ETOCD) or conservative treatments in Zhongshan Ophthalmic Center from January 2017 to June 2020 were recruited. Visual acuity (VA), visual evoked potential (VEP), oxygen saturation of retinal blood vessels (SO2), and optical coherence tomography angiography (OCT-A) were measured. All patients were followed up at least 3 months after treatments. RESULTS: A total of 95 ITON patients were recruited, including 77 patients who underwent ETOCD and 18 patients who underwent conservative treatments. After treatments, more patients received ETOCD (59/77 = 76.6%) presented with improved VA compared with the patients with conservative treatments (6/18 = 33.3%). Compared with the pre-therapeutic measurements, VEP were significantly improved after surgery in ETOCD-treated patients (P < 0.05). Latent periods of P1 and N2, as well as amplitude of P2 of VEP parameters, showed more sensitive to vision recovery (P < 0.05). Retinal artery SO2 and the differences between arteries and veins were improved in ETOCD-treated patients (P < 0.05). Meanwhile, with OCT-A examination, the retinal thickness and retinal vessel density were notably better in ETOCD-treated patients after surgery than that in patients received conservative treatments (P < 0.05). CONCLUSIONS: Vision recovery after effective treatment of ITON patients was associated with the increased oxygen saturation of retinal vessels, better availability of oxygen in the retina, greater vessel density, and thicker retinas, which might further underlie the vasculature mechanism of vision recovery in ITON patients.

An evolving perspective of endoscopic transnasal optic canal decompression for traumatic optic neuropathy in clinic.

Traumatic optic neuropathy (TON) is a serious complication of craniofacial trauma, which damages the optic nerve indirectly and leads to dysfunction of visual acuity. The clinical intervention for a patient with TON includes optic canal decompression (with or without steroids), treatment with corticosteroids alone, or observation only. Currently, there is a controversy among clinicians as to which treatment is optimal. An increasing number of retrospective studies have unveiled that patients could experience significant improvement in visual acuity after optic canal decompression surgery, particularly endoscopic transnasal/transethmosphenoid optic canal decompression (ETOCD), either with or without corticosteroids. In this review, we discuss the evolving perspective on surgical treatment, specifically ETOCD, for the management of patients with TON and focus mainly on the therapeutic efficacy, safety, and resulting prognosis in the clinic.

Combination analysis on the impact of the initial vision and surgical time for the prognosis of indirect traumatic optic neuropathy after endoscopic transnasal optic canal decompression.

To analyze the impact of the initial vision and surgical time for endoscopic transnasal/transethmosphenoid optic canal decompression (ETOCD) in the treatment of indirect traumatic optic neuropathy (TON). This retrospective case series analysis included 72 patients with indirect TON who underwent ETOCD from August 2017 to May 2019. Visual acuity (VA) was compared before and after surgery to estimate the improvement rate. The overall VA improvement rate of ETOCD was 54.2%. There were 83.3% and 33.3% improvement rate of patients with residual vision and blindness, respectively. VA was improved in 60.9% of patients treated within 3 days, 61.5% treated within 7 days, and 35.0% treated later than 7 days. Of the blindness patients, 50.0%, 37.5%, and 0.0% were treated within 3 days, 3-7 days, and later than 7 days, respectively. Of patients with residual vision, 85.7%, 92.3%, and 70.0% were treated within 3 days, 3-7 days, and later than 7 days, respectively. A statistically significant difference was found between patients with residual vision and those with blindness (P < 0.01), as well as between patients who received ETOCD within 7 days and those who received ETOCD later than 7 days (P = 0.043). The improvement rate of blindness patients managed within 3 days (P = 0.008) and 3-7 days (P = 0.035) was significantly higher than that for patients managed beyond 7 days. Indirect TON patients can directly benefit from ETOCD, and patients with residual vision have better improvement rates. ETOCD should be performed as soon as possible to salvage the patient's VA, especially within the first 7 days. For blindness patients, it is necessary to carry out the surgery within 7 days with increased benefit seen before 3 days.

Treatment of Optic Canal Decompression Combined with Umbilical Cord Mesenchymal Stem (Stromal) Cells for Indirect Traumatic Optic Neuropathy: A Phase 1 Clinical Trial.

PURPOSE: This study was aimed to investigate the safety and feasibility of umbilical cord-derived mesenchymal stem cell (MSC) transplantation in patients with traumatic optic neuropathy (TON). METHODS: This is a single-center, prospective, open-labeled phase 1 study that enrolled 20 patients with TON. Patients consecutively underwent either optic canal decompression combined with MSC local implantation treatment (group 1) or only optic canal decompression (group 2). Patients were evaluated on the first day, seventh day, first month, third month, and sixth month postoperatively. Adverse events, such as fever, urticarial lesions, nasal infection, and death, were recorded at each visit. The primary outcome was changes in best-corrected visual acuity. The secondary outcomes were changes in color vision, relative afferent pupillary defect, and flash visual evoked potential. RESULTS: All 20 patients completed the 6-month follow-up. None of them had any systemic or ocular complications. The change in best-corrected visual acuity at follow-up was not significantly different between group 1 and group 2 (p > 0.05); however, group 1 showed better visual outcome than group 2. Both groups showed significant improvements in vision compared with the baseline (p < 0.05); however, there were no statistically significant differences between the groups (p > 0.05). In addition, no adverse events related to local transplantation were observed in the patients. CONCLUSIONS: A single, local MSC transplantation in the optic nerve is safe for patients with TON.

Galantamine protects against synaptic, axonal, and vision deficits in experimental neurotrauma.

Our goal was to investigate the neuroprotective effects of galantamine in a mouse model of blast-induced indirect traumatic optic neuropathy (bITON). Galantamine is an FDA-approved acetylcholinesterase inhibitor used to treat mild-moderate Alzheimer's disease. We exposed one eye of an anesthetized mouse to repeat bursts of over-pressurized air to induce traumatic optic neuropathy. Mice were given regular or galantamine-containing water (120 mg/L) ad libitum, beginning immediately after blast and continuing for one month. Electroretinograms and visual evoked potentials were performed just prior to endpoint collection. Histological and biochemical assessments were performed to assess activation of sterile inflammation, axon degeneration, and synaptic changes. Galantamine treatment mitigated visual function deficits induced by our bITON model via preservation of the b-wave of the electroretinogram and the N1 of the visual evoked potential. We also observed a reduction in axon degeneration in the optic nerve as well as decreased rod bipolar cell dendritic retraction. Galantamine also showed anti-inflammatory and antioxidant effects. Galantamine may be a promising treatment for blast-induced indirect traumatic optic neuropathy as well as other optic neuropathies.

Mitochondrial targeted therapy with elamipretide (MTP-131) as an adjunct to tumor necrosis factor inhibition for traumatic optic neuropathy in the acute setting.

Traumatic optic neuropathy (TON) can occur following blunt trauma to the orbit and can lead to permanent vision loss. In this study, we investigated the effectiveness of elamipretide (MTP-131), a small mitochondrially-targeted tetrapeptide, in conjunction with etanercept, a tumor necrosis factor (TNF) inhibitor, as neuroprotective agents of retinal ganglion cells (RGCs) after optic nerve trauma with sonication-induced TON (SI-TON) in mice. Treatment with intravitreal MTP-131 and subcutaneous etanercept and MTP-131 showed a 21% increase (p < 0.01) in RGC survival rate compared to PBS-treated control eyes. Subcutaneous etanercept and MTP-131 had an 11% increase (p < 0.05) in RGC survival compared to controls. Subcutaneous etanercept only group showed 20% increase (p < 0.01) in RGC survival compared to controls, while subcutaneous MTP-131 alone showed a 17% increase (p < 0.01). Surprisingly, we did not observe a synergistic effect between the two drugs in the group receiving both etanercept and MTP-131. One possible explanation for the absence of a synergistic effect is that MTP-131 and etanercept may be acting on different portions of the same pathway.

Assessment of necroptosis in the retina in a repeated primary ocular blast injury mouse model.

Primary blast injury (caused by the initial rapid increase in pressure following an explosive blast) to the retina and optic nerve (ON) causes progressive visual loss and neurodegeneration. Military personnel are exposed to multiple low-overpressure blast waves, which may be in quick succession, such as during breacher training or in combat. We investigated the necroptotic cell death pathway in the retina in a mouse repeated primary ocular blast injury (rPBI) model using immunohistochemistry. We further evaluated whether intravitreal injections of a potent necroptosis inhibitor, Necrostatin-1s (Nec-1s), protects the retina and ON axons by retinal ganglion cells (RGC) counts, ON axonal counting and optical coherence tomography (OCT) analysis of vitreous haze. Receptor interacting protein kinase (RIPK) 3, increased in the inner plexiform layer 2 days post injury (dpi) and persisted until 14 dpi, whilst RIPK1 protein expression did not change after injury. The number of degenerating ON axons was increased at 28 dpi but there was no evidence of a reduction in the number of intact ON axons or RNA-binding protein with multiple splicing (RBPMS)+ RGC in the retina by 28 dpi in animals not receiving any intravitreal injections. But, when intravitreal injections (vehicle or Nec-1s) were given there was a significant reduction in RBPMS+ RGC numbers, suggesting that rPBI with intraocular injections is damaging to RGC. There were fewer RGC lost after Nec-1s than vehicle injection, but there was no effect of Nec-1s or vehicle treatment on the number of degenerating axons. OCT analysis demonstrated no effect of rPBI on vitreous haze, but intravitreal injection combined with rPBI increased vitreous haze (P = 0.004). Whilst necroptosis may be an active cell death signalling pathway after rPBI, its inhibition did not prevent cell death, and intravitreal injections in combination with rPBI increased vitreous inflammation and reduced RBPMS+ RGC numbers, implying intravitreal injection is not an ideal method for drug delivery after rPBI.