Treatment with GDF15, a TGFß superfamily protein, induces protective effect on retinal ganglion cells.

Growth differentiation factor 15 (GDF15) is a protein belonging to the transforming growth factor beta (TGF-ß) superfamily. The precursor GDF15 is cleaved and activated as a mature GDF15 by protease. GDF15 has been detected in the aqueous humor of the primary open angle glaucoma patients, however the localization and the effect on the retinal ganglion cells (RGCs) are still unknown. Thus, the purpose of this study was to elucidate the effect of GDF15 on mouse optic nerve crush (ONC) model and primary culture of rat RGCs. Immunostaining showed that the GDF15 was in the ganglion cell layer (GCL), and colocalized with GFAP-positive cells in the GCL and the optic nerve. Western blotting analysis showed that the mature GDF15 was upregulated in the retina and the optic nerve after the ONC. Intravitreal injection of GDF15 suppressed RGCs loss of the ONC model mice in vivo. The neurites length of the primary culture of rat RGCs were increased by mature GDF15 treatment. In addition, the neurotrophic effect of GDF15 was canceled by RET inhibitor treatment. These findings indicate that GDF15 has neuroprotective effect on RGCs via GFRAL-RET pathway. Therefore, GDF15 may be one of novel therapeutic targets in RGC degenerative diseases.

Effects of Pycnogenol on cisplatin-induced optic nerve injury: an experimental study.

AIM: To determine the effects of Pycnogenol on cisplatin-induced optic nerve damage. MATERIAL AND METHOD: Totally 18 albino Wistar male rats were assigned into three groups, with six rats in each group as follows: healthy controls (HC group), only cisplatin (2.5 mg/kg) administered group (CIS group) and Pycnogenol (40 mg/kg) + cisplatin (2.5 mg/kg) administered group (PYC group). We analyzed the levels of malondialdehyde (MDA) as a marker of lipid peroxidation and oxidative stress, total glutathione (tGSH) as a marker of antioxidant status, nuclear factor-kappa B (NF-κB) and tumor necrosis factor alpha (TNF-α) as inflammatory markers, total oxidative status (TOS) and total antioxidant status (TAS) on eye tissue together with histopathological evaluation of optic nerve in an experimental model. RESULTS: In CIS group MDA, TOS, TNF-α and NF-κB levels were statistically significantly higher (p < 0.001) than HC group while tGSH and TAS levels were significantly lower (p < 0.001). On the other hand, in PYC group MDA, TOS, TNF-α and NF-κB levels were statistically significantly lower (p < 0.001) than CIS group while tGSH and TAS levels were significantly higher (p < 0.001). CONCLUSION: Pycnogenol pretreatment was highly effective in preventing augmentation of cisplatin-induced oxidative stress and inflammation in eye tissue.

Calculation of an Optic Nerve Injury Risk Profile Before Sphenoid Sinus Surgery.

OBJECTIVES: Our objective was to analyze variations in the optic nerve (ON) course and surrounding structures in an effort to construct an optic nerve injury risk profile before endoscopic intranasal sphenoidal, or endoscopic endonasal transphenoidal, skull-base surgery, and eventually to construct and formulate a common classification by combining the known classes. The authors used computed tomography (CT) toward this end. METHODS: The authors retrospectively reviewed 200 consecutive CT scans (400 sides) of the paranasal sinuses. The pneumatization of the anterior clinoid process, the relationships of the ONs to the sphenoidal sinuses, and ON dehiscence were evaluated. The authors then created a formula by which risk profiles can be constructed for patients for whom sphenoid or parasellar surgery is planned. RESULTS: Pneumatization of the anterior clinoid process was evident in 28.25%. Dehiscence of the bony wall of the ON was evident in 9.5%. The ON course lay adjacent to the sphenoidal sinus, causing sinus wall indentation, in 23%. Cumulative optic nerve injury risk scoring showed that, radiologically, surgery on 8.5% and 1.5% of sphenoid sinuses described here carried severe or critical risk of ON injury, respectively. CONCLUSIONS: Head-and-neck surgeons and neurosurgeons should be aware of variations in ON course. The authors composed an optic nerve injury risk classification category based on the sum of individual weights of each of these classes. Reductions in ON injuries require careful evaluation of potential variant anatomies. Preoperative CT scans must be meticulously reviewed to avoid ON injury.

Low-dose carbon monoxide inhalation protects neuronal cells from apoptosis after optic nerve crush.

Glaucomatous optic neuropathy, including axonal degeneration and apoptotic death of retinal ganglion cells (RGCs), eventually leads to irreversible visual impairment. Carbon monoxide (CO) acts as a therapeutic agent against neural injury via its anti-apoptotic effect. Here we hypothesized that low-dose CO inhalation can protect RGCs in a rat model of optic nerve crush (ONC). ONC was performed on adult male Sprague Dawley rats to imitate glaucomatous optic damage. Low-dose CO (250 ppm) or air was inhaled for 1 h immediately after ONC, and all the tests were carried out 2 weeks later. Flash visual evoked potentials (FVEP) and pupil light relax (PLR) were recorded for the assessment of visual function. RGC density was evaluated by hematoxylin and eosin staining and Fluorogold labeling. Retinal apoptotic process was assessed by TUNEL staining and caspase-3 activity measurement. Low-dose CO treatment significantly ameliorated the abnormalities of FVEP and PLR induced by ONC. As expected, the RGC density was increased remarkably by CO inhalation after the glaucomatous optic nerve insult. Moreover, CO treatment after ONC significantly decreased the number of TUNEL-positive cells in ganglion cell layer and attenuated the retinal caspase-3 activity. Low-dose CO inhalation protects RGCs from optic nerve injury via inhibiting caspase-3 dependent apoptosis.

Neuroprotective effect of 4-(Phenylsulfanyl)butan-2-one on optic nerve crush model in rats.

This study is to investigate the effect of coral-related compound, 4-(phenylsulfanyl)butan-2-one (4-PSB-2) on optic nerves (ON) and retinal ganglion cells (RGC) in a rat model subjected to ON crush. The ONs of adult male Wistar rat (150-180 g) were crushed by a standardized method. The control eyes received a sham operation. 4-PSB-2 (5 mg/kg in 0.2 mL phosphate-buffered saline) or phosphate-buffered saline (PBS control) was immediately administered after ON crush once by subcutaneous injection. Rats were euthanized at 2 weeks after the crush injury. RGC density was counted by retrograde labeling with FluoroGold (FG) application to the superior colliculus, and visual function was assessed by flash visual evoked potentials (FVEP). TUNEL assay, immunoblotting analysis of inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX2) in the retinas, and immunohistochemistry of ED1 in the ON were evaluated. Two weeks after the insult, the RGC densities in the central and mid-peripheral retinas in ON-crushed, 4-PSB-2-treated rats were significantly higher than that of the corresponding ON-crushed, PBS-treated rats FVEP measurements showed a significantly better preserved latency of the P1 wave in the ON-crushed, 4-PSB-2-treated rats than the ON-crushed, PBS treated rats. TUNEL assays showed fewer TUNEL positive cells in the ON-crushed, 4-PSB-2-treated rats. The number of ED1 positive cells was reduced at the lesion site of the optic nerve in the ON-crushed, 4-PSB-2-treated group. Furthermore, administration of 4-PSB-2 significantly attenuated ON crush insult-stimulated iNOS and COX2 expression in the retinas. These results demonstrated that 4-PSB-2 protects RGCs and helps preserve the visual function in the rat model of optic nerve crush. 4-PSB-2 may work by being anti-apoptotic and by attenuation of the inflammatory responses involving less ED1 positive cells infiltration in ON as well as suppression of iNOS/COX-2 signaling pathway in the retinas to rescue RGCs after ON crush injury.

Autocrine protective mechanisms of human granulocyte colony-stimulating factor (G-CSF) on retinal ganglion cells after optic nerve crush.

This study investigated the role of autocrine mechanisms in the anti-apoptotic effects of human granulocyte colony-stimulating factor (G-CSF) on retinal ganglion cells (RGCs) after optic nerve (ON) crush. We observed that both G-CSF and G-CSF receptor (G-CSFR) are expressed in normal rat retina. Further dual immunofluorescence staining showed G-CSFR immunoreactive cells were colocalized with RGCs, Müller cells, horizontal and amacrine cells. These results confirm that G-CSF is an endogenous ligand in the retina. The semi-quantitative RT-PCR finding demonstrated the transcription levels of G-CSF and G-CSFR were up-regulated after ON crush injury. G-CSF treatment further increased and prolonged the expression level of G-CSFR in the retina. G-CSF has been shown to enhance transdifferentiation of the mobilized hematopoietic stem cells into tissue to repair central nervous system injury. We test the hypothesis that the hematopoietic stem cells recruited by G-CSF treatment can transdifferentiate into RGCs after ON crush by performing sublethal irradiation of the rats 5 days before ON crush. The flow cytometric analysis showed the number of CD34 positive cells in the peripheral blood is significantly lower in the irradiated, crushed and G-CSF-treated group than the sham control group or crush and G-CSF treated group. Nevertheless, the G-CSF treatment enhances the RGC survival after sublethal irradiation and ON crush injury. These data indicate that G-CSF seems unlikely to induce hematopoietic stem cell transdifferentiation into RGCs after ON crush injury. In conclusion, G-CSF may serve an endogenous protective signaling in the retina through direct activation of intrinsic G-CSF receptors and downstream signaling pathways to rescue RGCs after ON crush injury, exogenous G-CSF administration can enhance the anti-apoptotic effects on RGCs.

Immune protective mechanism of rMOMP protein ophthalmic vaccine regarding intraocular hypertension and retinal optic nerve injury in rats.

The aim of this study was to explore the immune protective mechanism of rMOMP protein vaccine in intraocular hypertension and retinal optic nerve injury in rats. The rMOMP protein ophthalmic vaccine was prepared and quality-controlled. Sixty normal adult SD rats were randomly divided into two groups to establish a chronic ocular hypertension model and an optic nerve injury model. The model rats were vaccinated with rMOMP-CS ophthalmic vaccine. Fluorogold retrograde tracing was used to observe retinal ganglion cells, and an immunofluorescence method to determine the expression of retinal GAP43, CD3, BDNF, and GDNF. rMOMP protein ophthalmic vaccine met the requirements for medicinal use. The number of retinal ganglion cells (RGCs) of the rMOMP-CS group in the chronic ocular hypertension model was significantly higher than that of the CS group (P < 0.05). The count of RGCs of the rMOMP-CS group in the optic nerve clamping injury model was significantly higher than that of the CS group (P < 0.01). Thus, rMOMP protein ophthalmic vaccine can induce an increase in the expression of retinal neurotrophic factors, thereby exerting a protective effect on damaged retinal optic nerve.

Effects of a conventional photocoagulator and a 3-ns pulse laser on preconditioning responses and retinal ganglion cell survival after optic nerve crush.

Previous research has demonstrated that laser photocoagulation treatment of the monkey retina affords protection against experimental glaucoma-induced retinal ganglion cell (RGC) loss in areas overlying laser spots. The underlying mechanism is unknown, but it is conceivable that the laser acted as a preconditioning stimulus, inducing localised, endogenous production of survival factors. The related purposes of the current study were firstly to examine whether preconditioning pathways are activated by either a conventional photocoagulator (CW) laser or a photoreceptor-sparing, short-pulse duration (2RT) laser in the rat retina, and secondly, to examine whether such preconditioning with either laser improves RGC survival after optic nerve (ON) crush. Pigmented rats were randomly assigned to one of three groups: sham, CW, 2RT. For the preconditioning study, laser spots were applied randomly to each retina in the posterior hemisphere of the eye taking care to avoid major blood vessels. Animals were killed at 6 h, 1d, and 7d after laser treatment, then analysed by qPCR, immunohistochemistry or Western immunoblotting. For the neuroprotection study, laser spots were administered to the mid-central retina of the right eye. The left eye served as a control. In two experiments, rats were lasered either 24 h or 7 days before ON crush, then killed a further 7 days later. Wholemount retinas were prepared and double labelling immunofluorescence performed. Nestin labelling allowed visualization of laser spots. Brn3a labelling identified viable RGCs. Photomicrographs of Brn3a labelling were taken in areas overlying nestin-positive laser spots. Quantification of Brn3a RGCs was then performed. Both the CW and 2RT lasers induced local glial cell activation. Moreover, both lasers induced localized upregulations of a number of well-documented (CNTF, FGF-2 Hsp27, pAKT) or putative (cFOS, ATF-3, IL-6) RGC survival factors. However, neither laser caused sustained increases in other factors associated with neuronal preconditioning, such as BDNF, Hsp70, IGF-1, bcl-2, and nitric oxide synthase. As regards neuroprotection, analysis of the data revealed that ON crush resulted in the loss of approximately 70% of Brn3a-labelled RGCs after 1 week. Neither the CW nor the 2RT laser augmented Brn3a-positive RGC survival in areas overlying and neighbouring laser spots. This was the case irrespective of whether lasering occurred 1 or 7 days before the ON crush. Our results showed that the CW and 2RT lasers both stimulated de novo synthesis of certain genes that are well-known RGC survival factors and/or that have been implicated in preconditioning-induced neuroprotection studies. Despite these findings, neither laser augmented survival of RGCs when delivered prior to ON crush.

Role of mTOR in neuroprotection and axon regeneration after inflammatory stimulation.

Mature retinal ganglion cells (RGCs) do not normally regenerate injured axons, but degenerate after axotomy. However, inflammatory stimulation (IS) enables RGCs to survive axotomy and regenerate axons in the injured optic nerve. Similar effects are achieved by the genetic deletion of phosphatase and tensin homolog (PTEN) and subsequent mammalian target of rapamycin (mTOR) activation. Here, we report that IS prevents the axotomy-induced decrease of mTOR activity in RGCs in a CNTF/LIF-dependent manner. Inactivation of mTOR significantly reduced the number of long axons regenerating in the optic nerve, but surprisingly, did not affect the initial switch of RGCs into the regenerative state, or the neuroprotective effects associated with IS. In vitro, inhibition of mTOR activity reduced regeneration on myelin or chondroitin sulfate proteoglycans (CSPGs), but not on a growth-permissive substrate. Thus, mTOR activity is not generally required for neuroprotection or switching mature neurons into an active regenerative state, but it is important for the maintenance of the axonal growth state and overcoming of inhibitory effects caused by myelin and CSPGs.

Dose-dependent treatment of optic nerve crush by exogenous systemic mutant erythropoietin.

The goal of the present study was to determine the minimum concentration of systemic erythropoietin-R76E required for neuroprotection in the retina. Erythropoietin (EPO) exhibits neuroprotective effects in both in vitro and in vivo models of neuronal cell death although its classical function is the regulation of red blood cell production. It can cross the blood brain barrier and therefore can be delivered systemically to affect the retina. However, long-term treatment with exogenous erythropoietin causes polycythemia. To decrease this potentially lethal effect, we generated and tested a modified form that contains a single arginine to glutamate mutation at the 76th position (EPO-R76E). In previous studies, this mutant protected retinal neurons in mouse models of retinal degeneration and glaucoma with similar efficacy as wild-type EPO. However, EPO-R76E has attenuated erythropoietic activity, therefore, neuroprotection can be achieved without causing a significant rise in hematocrit. BALB/cByJ mice received a single intramuscular injection of recombinant adeno-associated virus carrying enhanced green fluorescent protein, Epo, or Epo-R76E. To result in continuous production of four different doses of EPO-R76E, two doses of two different serotypes (2/5 and 2/8) were used. Mice were subjected to optic nerve crush and analysis was performed thirty days later. EPO-R76E showed dose-dependent protection of the retinal ganglion cell bodies, but was unable to prevent axonal degeneration. Furthermore, EPO-R76E induced a dose-dependent rise in the hematocrit that was still attenuated as compared to wild-type EPO.

Lack of protective effect of local administration of triamcinolone or systemic treatment with methylprednisolone against damages caused by optic nerve crush in rats.

The purpose of the present study was to investigate the effects of administrations of triamcinolone acetonide and systemic methylprednisolone sodium succinate on optic nerves (ON) and retinal ganglion cells (RGC) in a rat model of optic nerve crush. The treated groups either received triamcinolone immediately in the form of two pieces of soaked-gelform surrounding retrobulbar optic nerves (0.5 mg/per gelform) or methylprednisolone via peritoneal injection, and control group received intra-peritoneal injection with phosphate-buffered saline (PBS) after crush experiments. RGC density was counted by retrograde labeling with Fluorogold, and visual function was assessed by flash visual-evoked potentials. Terminal transferase dUTP nick end-labeling (TUNEL) assays, Western blot analysis of serine/threonine kinase (p-Akt), extracellular signal-regulated kinases (p-ERK) and signal transducer and activator of transcription 3 (p-STAT3) and immunohistochemistry of ED1, marker of macrophage/microglia in the optic nerve were conducted. Two and four weeks after optic nerve crush experiments, neither triamcinolone nor methylprednisolone treatment rescued the RGC from death in the central and mid-peripheral retinas compared with those of the corresponding optic nerve-crushed and PBS-treated rats. Visual-evoked potentials measurements showed a prolonged latency of the P(1) wave in all treated groups (triamcinolone-treated: 123 ± 23 ms, methylprednisolone-treated: 133 ± 25 ms and PBS-treated: 151 ± 55 ms) after two weeks. TUNEL assays showed that there was no decrease in apoptotic cells in the RGC layers of both triamcinolone treated and methylprednisolone-treated retinas. Western blot analysis showed that p-AKT, p-ERK and p-Stat3 were not up-regulated in either retina of the triamcinolone or methylprednisolone treated rats. In addition, the number of ED1-positive cells was not attenuated at the lesion sites of the ON in either treatment group. Based upon these results, we conclude that neither retrobulbar administration of triamcinolone nor systemic administration of methylprednisolone has any neuroprotective effects in a rat model of optic nerve crush.

Protective effects of human umbilical cord blood stem cell intravitreal transplantation against optic nerve injury in rats.

BACKGROUND: The majority of studies addressing traumatic optic neuropathy (TON) have focused on drugs, proteins, cytokines, and various surgical techniques. A recent study reported that transplantation of human umbilical cord blood stem cells (hUCBSCs) achieved therapeutic effects on TON, but the exact effects on optic nerve injury are still unknown, and the mechanisms underlying nerve protection remain poorly understood. METHODS: A total of 135 healthy Sprague-Dawley adult rats were randomly assigned to three groups: sham-surgery, model and transplantation, with 45 rats in each group. TON was induced in the model and transplantation groups via optic nerve crush injury. The crush injury was not performed in the sham-surgery group. Seven days after the injury, 10(6) hUCBSCs were injected into the rat vitreous cavity of transplantation group, and an equal volume of physiological saline was administered to the model and sham-surgery groups. Pathological observation of rat retina tissues was performed by hematoxylin-eosin (H&E) staining at days 3, 7, 14, 21 and 28 post-surgery. The number of retinal ganglion cells (RGCs) and mRNA expression levels of brain-derived neurotrophic factor (BDNF) and glial cell line-derived neurotrophic factor (GDNF) were assessed by the Fluorogold (FG) retrograde labeling and reverse transcriptase-polymerase chain reaction (RT-PCR) methods, respectively. RESULTS: The number of labeled RGCs and the expression of BDNF and GDNF mRNA obviously increased, and pathological injury was significantly ameliorated in the transplantation group compared to the model group (P < 0.05). CONCLUSIONS: Via intravitreal transplantation, the hUCBSCs resulted in a significant increase in the survival of the RGCs, and improved pathological changes in the rat retina, following TON. The protective mechanism is correlated with the continuous secretion of BDNF and GDNF in vivo of retina in optic nerve injury rats by the transplanted hUCBSCs.

The prevalence and pattern of pneumatization of Onodi cell in Thai patients.

BACKGROUND: The Onodi cell (sphenoethmoidal cell) is an anatomical variation of the most posterior ethmoid air cell the pneumatizes laterally and/or superiorly to the sphenoid sinus and is intimately in contact with the optic nerve. If it is infected or goes unrecognized during surgery it may result in serious damage to the optic nerve. Nowadays, computed tomographic scans of paranasal sinuses (CT PNS) have been used to detect variations in paranasal sinus anatomy However there is a lack of data about the variations of Onodi cell. OBJECTIVE: To determine the prevalence and various patterns of Onodi cell. MATERIAL AND METHOD: Axial, coronal, sagittal and sagittal oblique (parallel to the optic canal) CT scans of the paranasal sinuses, nasopharynx, neck and orbit performed at Srinagarind Hospital between January 1, 2004 and November 30, 2006 were reviewed A pilot study was carried out to investigate the inter-rater reliability of the identification of Onodi cell between the radiologist and rhinologist until the kappa value was 0.74. During the main study, the radiologist and rhinologist interpreted the CT scans independently. If there was a discordant opinion concerning the presence of Onodi cell, a consensus was reached by discussion between the rhinologist and the radiologist. RESULTS: 187 CT scans (374 sides) were included Sagittal oblique view detected Onodi cell in 185 sides 49.5% (95% CI: 44.4-54.5). The patterns of Onodi cell were classified into three patterns. In the first pattern, the Onodi cell extended only superiorly to sphenoid sinus (46%; 95% CI: 38.9-53.1). In the second pattern, it extended only laterally to sphenoid sinus (1%; 95% CI: 0.3-3.9). The last pattern was a combined type, lateral and superior to sphenoid sinus (53%; 95% CI: 45.8-60.0). CONCLUSION: The prevalence of Onodi cell diagnosed by CT scans was 49.5% (95% CI 44.4-54.5) and the most common pattern was the combined type. This information may be useful for those who perform endoscopic sinus surgery.

Upregulated neuregulin-1 protects against optic nerve injury by regulating the RhoA/cofilin/F-actin axis.

OBJECTIVE: In recent years, the roles of Neuregulin-1 (NRG-1) in optic nerve injury and retinal cells have been investigated. However, the molecular mechanism by which NRG-1 affects optic nerve injury remains elusive and merits deeper exploration. Hence, this study examined the specific function of NRG-1 in the RhoA/cofilin/F-actin axis in optic nerve injury. METHODS: Retinal cells were isolated and identified for subsequent experimental uses. Reverse transcription quantitative polymerase chain reaction and Western blot assays were performed to measure NRG-1 expression in retinal cells which were cultured under elevated pressure. TUNEL staining was used to detect the cell apoptosis rate, and Western blot assay was performed to detect the expression of related genes. The axon growth was examined by immunofluorescence. The effects of NRG-1 on RhoA activity, cofilin phosphorylation, and F-actin were detected by Western blot assay. In other studies we established a rat model of acute optic nerve injury, and tested for beneficial effects of NRG-1 in vivo. RESULTS: High expression of NRG-1 was evident in the retinal tissues of rats with optic nerve injury. Overexpressing NRG-1 successfully inhibited RhoA activity and the phosphorylation of cofilin and promoted F-actin expression. In cell experiments, overexpressed NRG-1 suppressed the apoptosis of retinal cells and promoted axon growth through the RhoA/cofilin/F-actin axis. In animal experiments, overexpressed NRG-1 relieved retinal injury. CONCLUSION: Our results strongly suggest that overexpressed NRG-1 is highly effective in the protection of normal optic nerve function by suppressing RhoA activity and the phosphorylation of cofilin and rescuing F-actin function.

The Whole Lateral Type of the Sphenoethmoidal Cell and Its Relevance to Endoscopic Sinus Surgery.

BACKGROUND: The sphenoethmoidal cell and the sphenoid sinus (SS) show great similarity in endoscopy and imaging. Hence, it is important to accurately identify the sphenoethmoidal cell preoperatively to prevent injury of the nerve and artery during endoscopic surgery. The aim of the present study was to investigate a special type of sphenoethmoidal cell. METHODS: A total of 365 inpatients whose paranasal sinus computed tomography (CT) was collected and reviewed from May 2018 to September 2019 were included. The anatomical imaging characteristics of the sphenoethmoidal cell were observed. RESULTS: A special type of the sphenoethmoidal cell was found on 9 sides in 730 sides (1.3%), according to its extension to the SS. Unlike Onodi cell (49.6%) and Jinfeng cell (1.3%), this cell simultaneously extends toward the superolateral, lateral, and inferolateral regions of the SS and is simultaneously closely attached to the optic canal and the maxillary nerve. Presently, this cell is named as the whole lateral type of the sphenoethmoidal cell, and the SS is located at the medial or inferomedial of it. CONCLUSIONS: When evaluating the paranasal sinus CT preoperatively, attention must be paid to the possibility of the whole lateral type of sphenoethmoidal cell appearing, not just Onodi cell, extending into the SS.

Surgical Treatment and Visual Outcomes of Adult Orbital Roof Fractures.

BACKGROUND: Fractures of the orbital roof require high-energy trauma and have been linked to high rates of neurologic and ocular complications. However, there is a paucity of literature exploring the association between injury, management, and visual prognosis. METHODS: The authors performed a 3-year retrospective review of orbital roof fracture admissions to a Level I trauma center. Fracture displacement, comminution, and frontobasal type were ascertained from computed tomographic images. Pretreatment characteristics of operative orbital roof fractures were compared to those of nonoperative fractures. Risk factors for ophthalmologic complications were assessed using univariable/multivariable regression analyses. RESULTS: In total, 225 patients fulfilled the inclusion criteria. Fractures were most commonly nondisplaced [n = 118 (52.4 percent)] and/or of type II frontobasal pattern (linear vault involving) [n = 100 (48.5 percent)]. Eight patients underwent open reduction and internal fixation of their orbital roof fractures (14.0 percent of displaced fractures). All repairs took place within 10 days from injury. Traumatic optic neuropathy [n = 19 (12.3 percent)] and retrobulbar hematoma [n = 11 (7.1 percent)] were the most common ophthalmologic complications, and led to long-term visual impairment in 51.6 percent of cases. CONCLUSIONS: Most orbital roof fractures can be managed conservatively, with no patients in this cohort incurring long-term fracture-related complications or returning for secondary treatment. Early fracture treatment is safe and may be beneficial in patients with vertical dysmotility, globe malposition, and/or a defect surface area larger than 4 cm2. Ophthalmologic prognosis is generally favorable; however, traumatic optic neuropathy is major cause of worse visual outcome in this population. CLINICAL QUESTION/LEVEL OF EVIDENCE: Risk, III.

Thioredoxins 1 and 2 protect retinal ganglion cells from pharmacologically induced oxidative stress, optic nerve transection and ocular hypertension.

Oxidative damage has been implicated in retinal ganglion cell (RGC) death after optic nerve transection (ONT) and during glaucomatous neuropathy. Here, we analyzed the expression and cell protective role of thioredoxins (TRX), key regulators of the cellular redox state, in RGCs damaged by pharmacologically induced oxidative stress, ONT and elevated intraocular pressure (IOP). The endogenous level of thioredoxin-1 (TRX1) and thioredoxin-2 (TRX2) in RGCs after axotomy and in RGC-5 cells after glutamate/buthionine sulfoximine (BSO) treatment showed upregulation of TRX2, whereas no significant change was observed in TRX1 expression. The increased level TRX-interacting protein (TXNIP) in the retinas was observed 2 and 5 weeks after IOP elevation. TRX1 level was decreased at 2 weeks and more prominently at 5 weeks after IOP increase. No change in TRX2 levels in response to IOP change was observed. Overexpression of TRX1 and TRX2 in RGC-5 treated with glutamate/BSO increased the cell survival by 2- and 3-fold 24 and 48 h after treatment, respectively. Overexpression of these proteins in the retina increased the survival of RGCs by 35 and 135% 7 and 14 days after ONT, respectively. In hypertensive eyes, RGC loss was approximately 27% 5 weeks after IOP elevation compared to control. TRX1 and TRX2 overexpression preserved approximately 45 and 37% of RGCs, respectively, that were destined to die due to IOP increase.

Differential susceptibility of retinal ganglion cell subtypes in acute and chronic models of injury and disease.

Retinal ganglion cells (RGCs) are a heterogeneous population of neurons, comprised of numerous subtypes that work synchronously to transmit visual information to the brain. In blinding disorders such as glaucoma, RGCs are the main cell type to degenerate and lead to loss of vision. Previous studies have identified and characterized a variety of RGC subtypes in animal models, although only a handful of studies demonstrate the differential loss of these RGC subtypes in response to disease or injury. Thus, efforts of the current study utilized both chronic (bead occlusion) and acute (optic nerve crush, ONC) rat models to characterize disease response and differential loss of RGC subtypes. Bead occlusion and ONC retinas demonstrated significant RGC loss, glial reactivity and apoptosis compared to control retinas. Importantly, bead occlusion and ONC retinas resulted in differential subtype-specific loss of RGCs, with a high susceptibility for alpha- and direction selective-RGCs and preferential survival of ipRGCs. Results of this study serve as an important foundation for future experiments focused on the mechanisms resulting in the loss of RGCs in optic neuropathies, as well as the development of targeted therapeutics for RGC subtype-specific neuroprotection.

Sudden blindness as a complication of percutaneous trigeminal procedures: mechanism analysis and prevention.

The authors describe the case of a 76-year-old man in whom reversible sudden blindness developed after a percutaneous balloon compression rhizotomy for trigeminal neuralgia. His eye became tense and swollen with intraocular pressures of 66 mm Hg. Acetazolamide was administered, and visual acuity (20/50) returned within several months. Despite correct needle placement, the intraocular pressure rose acutely because of transient occlusion of the orbital venous drainage through the cavernous sinus; this was reversed with aggressive medical treatment. In cadaveric studies (dried skull and formalin-fixed head), the authors studied the mechanism of optic nerve penetration. Their findings showed that excessive cranial angulation of the needle with penetration of the inferior orbital fissure can directly traumatize the optic nerve in the orbital apex. Direct trauma to the optic nerve can therefore be prevented by early and repeated confirmation of the needle trajectory with lateral fluoroscopy before penetration of the foramen ovale.

[Effect of VEGF-B on neuroprotection in mouse retinal ganglion cells].

OBJECTIVE: To investigate the expression of vascular endothelial growth factor-B (VEGF-B) in retina and its effect on neuroprotection in mouse retinal ganglion cells (RGCs). METHODS: It was a experimental study. 35 of C57BL/6 mice (adult male) were used. Optic nerve crush injury was made in 28 mice, 7 as control. Expression of VEGF-B in retina was detected by hybridization in situ in each group of 2 at 6 hours, 1 day, 1 and 2 weeks after optic nerve crush. A quantitative analysis of VEGF-B mRNA was determined by real time reverse transcription polymerase chain reaction (RT-PCR) in each group of 5 at 6 hours, 1 day, 1 and 2 weeks after optic nerve crush. Additional 36 mice were divided into 4 groups: control (8), optic nerve crush (9), optic nerve crash plus PBS intravitreal injection (7), and optic nerve crash plus VEGF-B (450 mg/L) intravitreal injection (12). RGCs were counted by retrograde tracing of Fluorogold to evaluate the effect of VEGF-B on neuroprotection by microscope. RESULTS: Compared with control group, the expression of VEGF-B was significantly increased in the retina of mice and peaked at one week after the optic nerve crush. The number of RGCs was 1.7 fold higher in optic nerve crush alone and 1.9 fold higher in optic nerve crush combined with intravitreal injection of VEGF-B, which reached statistically significance (t = 0.001, P < 0.01 and t = 0.001, P < 0.01, respectively). CONCLUSIONS: Our results indicate that VEGF-B is involved in the retinal recovery processes and plays a potent role of neuroprotection in RGCs after the optic nerve crush.