Severe Optic Disc Cupping Following the Methanol Toxicity in a 20-Year-old Man: A Case Report.

In April 2018, a 20-year-old man with a history of methanol intoxication from an alcoholic drink two years ago, when he was 18 years old, was referred to Nikookari Eye Hospital in Tabriz, Iran. He was admitted to emergency service and underwent eight hours of hemodialysis at the time of poisoning. His past medical history was negative, and he did not take any medication after discharge. The patient had a driving license and never experienced any visual problems before. At presentation, his visual acuity was 160/200 in both eyes with the main complaint of visual field deterioration. Other neurologic exams and brain magnetic resonance imaging (MRI) were reported normal by a neurologist. Optic disc cupping was near total in both eyes with a very narrow remaining rim. Optic disc cupping was very similar to glaucomatous cupping. Intraocular pressure was checked several times via Goldmann tonometry and was 13 mmHg. There was no history of refractive surgery leading to thin cornea. Based on this case, methanol poisoning can mimic glaucomatous optic disc cupping. This is the first case report of methanol toxicity-related optic disc cupping from Iran.

Mirna Expression in Glaucomatous and TGFß2 Treated Lamina Cribrosa Cells.

Glaucoma is a group of optic neuropathies that leads to irreversible vision loss. The optic nerve head (ONH) is the site of initial optic nerve damage in glaucoma. ONH-derived lamina cribrosa (LC) cells synthesize extracellular matrix (ECM) proteins; however, these cells are adversely affected in glaucoma and cause detrimental changes to the ONH. LC cells respond to mechanical strain by increasing the profibrotic cytokine transforming growth factor-beta 2 (TGFß2) and ECM proteins. Moreover, microRNAs (miRNAs or miR) regulate ECM gene expression in different fibrotic diseases, including glaucoma. A delicate homeostatic balance between profibrotic and anti-fibrotic miRNAs may contribute to the remodeling of ONH. This study aimed to determine whether modulation of miRNAs alters the expression of ECM in human LC cells. Primary human normal and glaucoma LC cells were grown to confluency and treated with or without TGFß2 for 24 h. Differences in expression of miRNAs were analyzed using miRNA qPCR arrays. miRNA PCR arrays showed that the miR-29 family was significantly decreased in glaucomatous LC cell strains compared to age-matched controls. TGFß2 treatment downregulated the expression of multiple miRNAs, including miR-29c-3p, compared to controls in LC cells. LC cells transfected with miR-29c-3p mimics or inhibitors modulated collagen expression.

Role of the PGE2 receptor in ischemia-reperfusion injury of the rat retina.

Purpose: To investigate the function and expression of the PGE2 receptors EP1-4 in rat retinal ischemia-reperfusion (I/R) injury and to determine the regulatory role of resveratrol (RES) in this process. Methods: In vitro, we stimulated primary astrocytes extracted from the optic disc of rats with epidermal growth factor (EGF) and RES, and detected the location of EP1-4 expression with immunofluorescence. The expression of antiglial fibrillary acidic protein (GFAP), EGF receptor (EGFR), inducible NOS (iNOS), and EP1-4 in astrocytes was detected with western blotting. In vivo, we established an I/R injury model and RES treatment model with Sprague-Dawley rats. Changes in the thickness of the inner retina were observed with hematoxylin and eosin (H&E) staining. EP1-4 localization in the retina was observed with immunohistochemistry. The expression of COX-2, iNOS, and EP1-4 in the control and model groups was detected with western blotting. Results: In this study, immunofluorescence and immunohistochemistry showed that EP1-4 are expressed in astrocytes and the rat retina. EGF stimulation increased the expression of EGFR, iNOS, EP1, EP2, and EP4 in astrocytes. The expression of EP1-4 was statistically significantly increased on the third day after model induction, and EP1-4 expression decreased to normal levels on day 7. EGF and RES mediated the decrease in the expression of EP2. RES treatment significantly reduced retinal damage and RGC loss, as demonstrated by the relatively intact tissue structure on day 7 observed with H&E staining. Moreover, inflammation was associated with this I/R injury model, as demonstrated by the early induction of proinflammatory mediators, and this inflammation was significantly attenuated after RES treatment. Conclusions: These results indicate that the COX-2/PGE2/EPs pathway is involved in retinal damage and astrocyte inflammation. In addition, the results suggest that the neuroprotective effects of RES may be associated with decreased production of inflammatory mediators. These results suggest that the PGE2 receptor may be a key factor in the treatment of neurodegenerative diseases, and that RES may be used as a possible therapeutic strategy for glaucoma.

Changes in Ocular Blood Flow after Ranibizumab Intravitreal Injection for Diabetic Macular Edema Measured Using Laser Speckle Flowgraphy.

PURPOSE: To evaluate the effects of intravitreal ranibizumab (IVR) treatment on the blood flow of the optic nerve head (ONH) and of retinal vessels of the peripapillary region of eyes with diabetic macular edema (DME) assessed using laser speckle flowgraphy (LSFG). METHODS: Forty eyes of 30 patients treated with IVR for DME were included in this prospective clinical study. Mean blur rate (MBR) and relative flow volume (RFV) of the ONH and of a superior retinal artery and an inferior retinal vein of the peripapillary region were measured using LSFG at baseline, 2 weeks (T1), and 1 month (T2) after IVR injection. In addition, best-corrected visual acuity (BCVA) and central retinal thickness (CRT) were measured in all cases. RESULTS: The BCVA improved and CRT decreased significantly during the follow-up period (p < 0.010). MBR-related parameters of the ONH such as MBR of all area (MA), MBR of vascular area (MV), and MBR of tissue area (MT) decreased significantly at 2 weeks after IVR compared to baseline values (MA, p < 0.010). MBR-related parameters of the ONH such as MBR of all area (MA), MBR of vascular area (MV), and MBR of tissue area (MT) decreased significantly at 2 weeks after IVR compared to baseline values (MA, p < 0.010). MBR-related parameters of the ONH such as MBR of all area (MA), MBR of vascular area (MV), and MBR of tissue area (MT) decreased significantly at 2 weeks after IVR compared to baseline values (MA, p < 0.010). MBR-related parameters of the ONH such as MBR of all area (MA), MBR of vascular area (MV), and MBR of tissue area (MT) decreased significantly at 2 weeks after IVR compared to baseline values (MA, p < 0.010). MBR-related parameters of the ONH such as MBR of all area (MA), MBR of vascular area (MV), and MBR of tissue area (MT) decreased significantly at 2 weeks after IVR compared to baseline values (MA, p < 0.010). MBR-related parameters of the ONH such as MBR of all area (MA), MBR of vascular area (MV), and MBR of tissue area (MT) decreased significantly at 2 weeks after IVR compared to baseline values (MA, p < 0.010). MBR-related parameters of the ONH such as MBR of all area (MA), MBR of vascular area (MV), and MBR of tissue area (MT) decreased significantly at 2 weeks after IVR compared to baseline values (MA, p < 0.010). MBR-related parameters of the ONH such as MBR of all area (MA), MBR of vascular area (MV), and MBR of tissue area (MT) decreased significantly at 2 weeks after IVR compared to baseline values (MA, p < 0.010). MBR-related parameters of the ONH such as MBR of all area (MA), MBR of vascular area (MV), and MBR of tissue area (MT) decreased significantly at 2 weeks after IVR compared to baseline values (MA. CONCLUSION: IVR injection leads to a reduction of ocular blood flow both in the ONH and in the retinal peripapillary vessels associated with peripapillary vessel constriction. The reduction of CRT and related improvement of vision may be related to the changes in ocular blood flow.

Survival of Alpha and Intrinsically Photosensitive Retinal Ganglion Cells in NMDA-Induced Neurotoxicity and a Mouse Model of Normal Tension Glaucoma.

Purpose: We assess if α retinal ganglion cells (αRGCs) and intrinsically photosensitive retinal ganglion cells (ipRGCs) survive in mouse models of glaucoma. Methods: Two microliters of N-methyl-D-aspartate (NMDA; 1 mM) or PBS were injected intraocularly 7 days before sacrifice. Immunohistochemical analyses of the retina were performed using antibodies against RNA-binding protein with multiple splicing (RBPMS), osteopontin, and melanopsin. Immunohistochemical analyses also were performed in adult mice with glutamate/aspartate transporter (GLAST) deletion (GLAST knockout [KO] mice), a mouse model of normal tension glaucoma. Results: NMDA-induced loss of RBPMS-positive total RGCs was 58.4% ± 0.4% compared to PBS-treated controls, whereas the loss of osteopontin-positive αRGCs was 5.0% ± 0.6% and that of melanopsin-positive ipRGCs was 7.6% ± 1.6%. In GLAST KO mice, the loss of total RGCs was 48.4% ± 0.9% compared to wild-type mice, whereas the loss of αRGCs and ipRGCs was 3.9% ± 0.4% and 9.3% ± 0.5%, respectively. The distribution of survived total RGCs, αRGCs, and ipRGCs was similar regardless of the location of the retina. Conclusions: These results suggest that αRGC and ipRGC are highly tolerant to NMDA-induced neurotoxicity and NTG-like neurodegeneration in GLAST KO mice.

Acute and chronic optic nerve head biomechanics and intraocular pressure changes in patients receiving multiple intravitreal injections of anti-VEGF.

PURPOSE: To evaluate acute and chronic changes in optic nerve head (ONH) structures and intraocular pressure (IOP) in patients receiving intravitreal injections (IVIs) of anti-VEGF. METHODS: Twenty-nine eyes receiving IVIs for the first time were studied. IOP, retinal nerve fiber layer (RNFL) thickness, and ONH structures were evaluated by Spectralis optical coherence tomography with enhanced depth imaging technology. Structures were measured before and 5 min after each one of the three monthly injections of a loading dose treatment. In 13 eyes (44.8%) with more than six IVIs, another evaluation pre and immediately postinjection was performed after 1 year. RESULTS: A significant acute and transient IOP increase (all p ≤ 0.001), Bruch's membrane opening (BMO) enlargement (p ≤ 0.001), cup widening (p < 0.05) and deepening (p ≤ 0.001), and prelaminar tissue thinning (p ≤ 0.001) were observed 5 min after each injection. Compared with baseline values, a significant BMO expansion (p = 0.001) and RNFL thinning (p < 0.001) were observed in the third month. In eyes with more than six IVIs, similar immediate postinjection changes, including IOP increase (p = 0.001), prelaminar tissue thinning (p = 0.007), and cup deepening (p = 0.012) were observed at 1 year, while BMO expansion was not significant (p = 0.556). Compared with baseline preinjection values, a significant BMO expansion (p = 0.003), prelaminar tissue thinning (p = 0.011), and cup deepening (p = 0.006) in the inferior region of the ONH occurred. No change in IOP was observed at the end of follow-up. CONCLUSIONS: Repeated IVIs could lead to irreversible changes in ONH structures. Large-scale, prospective studies are required to determine the long-term effects of anti-VEGF treatments in ONH tissues.

[Clinical evaluation of the effectiveness of cholinesterase inhibition with neuromidin in the treatment of primary glaucoma patients]. / Klinicheskaia otsenka éffektivnosti ingibitora kholinésterazy neĭromedina v lechenii bol'nykh s pervichnoĭ glaukomoĭ.

AIM: to investigate neuromidin effectiveness in the treatment of patients with primary glaucoma and compensated intraocular pressure (IOP). MATERIAL AND METHODS: A total of 40 patients (80 eyes) were examined. Of them, 10 eyes with early glaucoma, 36 eyes with moderate-stage glaucoma, 33 eyes with advanced glaucoma, and 1 eye with end-stage glaucoma. In 19 eyes, IOP was controlled through beta-blockers, in 11 eyes - through carbonic anhydrase inhibitors, in 10 eyes - through prostaglandin analogues, and in 39 eyes - through combination drugs. Twenty-six eyes had received glaucoma surgery some time earlier. Ipidacrine was prescribed in tablets at 20 mg 2 times daily for 25 days. Treatment effectiveness was judged by visual functions, hydrodynamics, and morphometric parameters of the optic disc. RESULTS: In moderate-stage eyes, visual acuity improved in 66.6% of cases and remained unchanged in 33.3%. In advanced-stage eyes, visual acuity improved in 51.5% of cases and remained unchanged in 48.5%. Visual field broadened in all cases. Moreover, under the neuromidin therapy, the number of scotomas in early-stage eyes decreased, while the number of areas with normal sensitivity of the retina increased by 14.9%. In advanced-stage glaucoma, the effect was less pronounced: the number of type 1 and type 2 scotomas decreased by 3.0±0.6% and 2.9±0.8%, respectively; the number of absolute scotomas did not change; the number of areas with normal sensitivity of the retina increased by 7.4±2.0%. Also, P0 was found to be reduced and intraocular fluid outflow - activated. In early and moderate glaucoma, there was a significant reduction in the cup area as well as an increase in the neuroretinal rim area and retinal nerve fiber layer thickness. In advanced-stage cases, it was only the retinal nerve fiber layer thickness that changed. CONCLUSION: Neuromidin has a positive impact on visual function, hydrodynamics, and morphometric parameters of the optic disc.

Discovery of novel inhibitors for the treatment of glaucoma.

INTRODUCTION: Glaucoma is a neurodegenerative disease with heterogeneous causes that result in retinal ganglionic cell (RGC) death. The discovery of ocular antihypertensives has shifted glaucoma therapy, largely, from surgery to medical intervention. Indeed, several intraocular pressure (IOP)-lowering drugs, with different mechanisms of action and RGC protective property, have been developed. AREAS COVERED: In this review, the authors discuss the main new class of kinase inhibitors used as glaucoma treatments, which lower IOP by enhancing drainage and/or lowering production of aqueous humor. The authors include novel inhibitors under preclinical evaluation and investigation for their anti-glaucoma treatment. Additionally, the authors look at treatments that are in clinics now and which may be available in the near future. EXPERT OPINION: Treatment of glaucoma remains challenging because the exact cause is yet to be delineated. Neuroprotection to the optic nerve head is undisputable. The novel Rho-associated kinase inhibitors have the capacity to lower IOP and provide optic nerve and RGC protection. In particular, the S-isomer of roscovitine has the capacity to lower IOP and provide neuroprotection. Combinations of selected drugs, which can provide maximal and sustained IOP-lowering effects as well as neuroprotection, are paramount to the prevention of glaucoma progression. In the near future, microRNA intervention may be considered as a potential therapeutic target.

Optic nerve head tubercular granuloma successfully treated with anti-VEGF intravitreal injections in addition to systemic therapy.

PURPOSE: To describe a case of optic nerve head tubercular granuloma, unresponsive to conventional therapy (antitubercular drugs and systemic steroids), successfully treated with anti-vascular endothelial growth factor (VEGF) intravitreal injections in addition to systemic drugs. METHODS: Case report. RESULTS: A 44-year-old patient was referred to our clinic for progressive vision decrease in his left eye during the preceding 4 months. A large granuloma infiltrating optic nerve head was visible at funduscopic examination along with diffuse intraocular inflammation. Workup for granulomatous uveitis supported the diagnosis of presumed intraocular tuberculosis. However, the large granulomatous lesion did not show a good response to conventional therapy for tubercular uveitis (antitubercular drugs and systemic steroids). Anti-VEGF (bevacizumab) intravitreal injections were performed as an adjunct to the ongoing therapy. After 2 injections, the patient showed an almost complete regression of the lesion (demonstrated by optical coherence tomography) and a restoration of vision. CONCLUSIONS: Anti-VEGF intravitreal injections should be considered in the treatment of large tubercular granulomatous lesions in addition to conventional systemic therapy. Optical coherence tomography could be a suitable tool for studying and following optic nerve head granulomas.

Mechanosensitive release of adenosine 5'-triphosphate through pannexin channels and mechanosensitive upregulation of pannexin channels in optic nerve head astrocytes: a mechanism for purinergic involvement in chronic strain.

As adenosine 5'-triphosphate (ATP) released from astrocytes can modulate many neural signaling systems, the triggers and pathways for this ATP release are important. Here, the ability of mechanical strain to trigger ATP release through pannexin channels and the effects of sustained strain on pannexin expression were examined in rat optic nerve head astrocytes. Astrocytes released ATP when subjected to 5% of equibiaxial strain or to hypotonic swelling. Although astrocytes expressed mRNA for pannexins 1-3, connexin 43, and VNUT, pharmacological analysis suggested a predominant role for pannexins in mechanosensitive ATP release, with Rho kinase contribution. Astrocytes from panx1(-/-) mice had reduced baseline and stimulated levels of extracellular ATP, confirming the role for pannexins. Swelling astrocytes triggered a regulatory volume decrease that was inhibited by apyrase or probenecid. The swelling-induced rise in calcium was inhibited by P2X7 receptor antagonists A438079 and AZ10606120, in addition to apyrase and carbenoxolone. Extended stretch of astrocytes in vitro upregulated expression of panx1 and panx2 mRNA. A similar upregulation was observed in vivo in optic nerve head tissue from the Tg-MYOC(Y437H) mouse model of chronic glaucoma; genes for panx1, panx2, and panx3 were increased, whereas immunohistochemistry confirmed increased expression of pannexin 1 protein. In summary, astrocytes released ATP in response to mechanical strain, with pannexin 1 the predominant efflux pathway. Sustained strain upregulated pannexins in vitro and in vivo. Together, these findings provide a mechanism by which extracellular ATP remains elevated under chronic mechanical strain, as found in the optic nerve head of patients with glaucoma.

A rare case of toxic optic neuropathy secondary to consumption of neem oil.

A 35-year-old female was referred to our hospital with bilateral loss of vision of two days duration. She gave history of consumption of about 150 ml of neem oil five days back.Examination revealed no perception of light in both eyes. Both pupils were dilated and sluggishly reacting to light. Her fundus examination showed bilateral hyperemic, edematous discs and also edema extending along the superior and inferior temporal vascular arcade. Magnetic resonance imaging (MRI) scan showed bilateral putaminal regions with altered signal, hypointensities in T1-weighted images, hyperintensities on T2-weighted, images and hyperintense on Fluid Attenuation Inversion Recovery (FLAIR) images suggestive of cytotoxic edema due to tissue hypoxia. Her vision improved to 20/200 in both eyes with treatment after two months. This is the first case report of such nature in the literature to the best of our knowledge.

Changes in the blood flow of the optic nerve head induced by different concentrations of epinephrine in intravitreal infusion during vitreous surgery.

PURPOSE: We investigated whether intravitreal infusion solution containing epinephrine affects optic nerve head (ONH) blood flow during vitreous surgeries. METHODS: The subjects were 22 patients with epimacular membrane or idiopathic macular hole. During vitreous surgery, ONH blood flow was examined before and 10 minutes after intravitreal infusion of solution containing epinephrine, via a laser speckle flowgraphy (LSFG) technique modified for acquiring measurements in a supine position. Epinephrine concentration was set at 1.0 mg/500 mL (1:500,000) or 0.5 mg/500 mL (1:1,000,000), with each concentration assigned to 11 consecutive patients. Relative pupil diameter, IOP, blood pressure, and pulse rate also were measured. RESULTS: A significant reduction in blood flow throughout the ONH was induced by intravitreal infusion of epinephrine at 1:500,000, but not at 1:1,000,000. Blood flow in ONH tissue was diminished at both concentrations, while that in vessels of the ONH was not altered significantly by either concentration. Both epinephrine concentrations induced significant pupillary dilatation, but no significant changes in IOP, blood pressure, or pulse rate. CONCLUSIONS: This study suggests that epinephrine, used in combination with intravitreal infusion solution, may decrease ONH blood flow during vitreous surgeries, as indicated by measurements obtained via a modified LSFG technique. Attention must be paid to the effects of intravitreal infusion of epinephrine on ocular circulation, particularly ONH blood flow.

Effect of intravitreal injection of bevacizumab on optic nerve head leakage and retinal ganglion cell survival in a mouse model of optic nerve crush.

PURPOSE: To evaluate the effect of bevacizumab, a VEGF inhibitor, on optic nerve edema and retinal ganglion cell (RGC) loss in a mouse model of optic nerve crush (ONC). METHODS: Two hundred C57BL/6 wild-type mice were anesthetized. Right ONC was induced in 150 mice, of which half (n = 75) received an intravitreal injection of bevacizumab immediately thereafter and half (n = 75) did not. The remaining 50 received only bevacizumab. The left eyes served as a control. Findings were analyzed by fluorescein angiography (days 0, 1, 3), histologic and immunohistochemical tests (days 1, 3, 4, 21), and quantitative real-time PCR. RESULTS: Angiography revealed a reduction in postinjury disc leakage following bevacizumab injection (days 1, 3), confirmed with IgG staining. On PCR, expression of HO-1 and SOD-1 mRNA increased following ONC and further increased with bevacizumab. VEGF gene expression decreased following bevacizumab injection without ONC, remained at baseline after ONC, and increased slightly after ONC+bevacizumab. Histologically, there was a 38% RGC loss 21 days after ONC alone, which dropped to 14% with bevacizumab treatment; it was close to 15% with bevacizumab alone. Mean (SEM) microvascular perfusion in the optic nerve 4 days after ONC was significantly higher in the bevacizumab-treated (85% ± 10%) than the vehicle-treated (33% ± 13%) animals. CONCLUSIONS: Bevacizumab treatment following ONC induction exerts a protective effect, manifested by reduced optic nerve head edema. The underlying mechanism probably involves a lesser interruption of axonal transport. Reduced expression of antioxidative and ischemic genes may contribute to RGC preservation.

Delta-opioid receptors attenuate TNF-α-induced MMP-2 secretion from human ONH astrocytes.

PURPOSE: We examined the signaling mechanisms involved in δ-opioid-receptor agonist, SNC-121-mediated attenuation of TNF-α-induced matrix metalloproteinase-2 (MMP-2) secretion from human optic nerve head (ONH) astrocytes. METHODS: Human ONH astrocytes were treated with SNC-121 (1 µmol/L) for 15 minutes followed by TNF-α (25 ng/mL) treatment for 6 or 24 hours. Cells were pretreated with inhibitors of p38 mitogen-activated protein (MAP) kinase (SB-203580) or NF-κB (Helenalin) prior to TNF-α treatment. Changes in phosphorylation and expression of p38 MAP kinase, IκBα, NF-κB, and MMP-2 were measured by Western blotting. Translocation of NF-κB was determined by immunocytochemistry. RESULTS: TNF-α treatment increased MMP-2 secretion from ONH astrocytes to 236% ± 17% and 142% ± 8% at 6 and 24 hours, respectively; while SNC-121 treatment reduced MMP-2 secretion to 149% ± 11% and 108% ± 7% at 6 and 24 hours, respectively. The SNC-121-mediated inhibitory response was blocked by the δ-opioid-receptor antagonist naltrindole. TNF-α treatment resulted in a sustained phosphorylation of p38 MAP kinase up to 24 hours (226% ± 15% over control levels), which was reduced to 150% ± 20% by SNC-121 treatment. TNF-α treatment increased the expression of NF-κB to 179% ± 21% and 139% ± 6% at 6 and 24 hours, respectively, which was significantly blocked by SNC-121 treatment. Furthermore, TNF-α-induced MMP-2 secretion was blocked by 100% and 78% in the presence of SB-203580 and Helenalin, respectively. CONCLUSIONS: Evidence is provided that SNC-121 attenuated TNF-α-induced MMP-2 secretion from ONH astrocytes. Data also supported the idea that p38 MAP kinase and NF-κB played central roles in TNF-α-induced MMP-2 secretion, and both were negatively regulated by SNC-121.