Is the clinical course of non-arteritic ischemic optic neuropathy associated with oxidative damage and the dynamics of the antioxidant response?

PURPOSE: Oxidative stress is known to be a decisive factor in the wide etiopathogenesis of optic neuropathy. This study aimed to comprehensively evaluate the interaction of optic neuropathy's clinical course with systemic oxidative damage and antioxidant response dynamics in a large series. METHODS: This case-controlled clinical study included 33 non-arteritic anterior ischemic optic neuropathy (NAION) patients and 32 healthy individuals. Extensive systemic oxidation profiles were statistically compared between the two groups, and correlations between the clinical and biochemical data in the study group were analyzed. RESULTS: Vitamin E and malondialdehyde (MDA) levels were significantly higher in the study group. Significant correlations were observed in the analyses between clinical findings and oxidative stress parameters. Correlations between vitamin E and intraocular pressure (IOP), between B12 and cup-to-disk ratio (c/d), between antioxidant glutathione and superoxide dismutase (SOD) enzyme systems, and between uric acid (UA) and age were found to be very significant. As significant correlations were found in either clinical and biochemical data or in oxidative stress parameters, correlations between vitamin E and cholesterol, MDA were found to be very significant. CONCLUSIONS: This study not only supplies significant information regarding oxidative damage and antioxidant response in NAION, but also points out the specific interactions of neuromodulators, like vitamin E, in intracellular signaling pathways and regulation mechanisms. A better reading of these connections may help improve diagnosis, follow-ups and treatment criteria and strategies.

Early diffusion-weighted MRI at 3 Tesla detects ischemic changes of the optic nerve in anterior ischemic optic neuropathy.

OBJECTIVES: To assess the impact of timing from visual symptoms' onset to diffusion-weighted (DW) 3 T MRI completion to detect ischemic changes of the optic disc and optic nerve in AION patients. METHODS: This IRB-approved retrospective single-center study included 3 T MRI data from 126 patients with AION and 111 controls with optic neuritis treated between January 2015 and May 2020. Two radiologists blinded to all data individually analyzed imaging. A senior neuroradiologist resolved any discrepancies by consensus. The primary judgment criterion was the restricted diffusion of the optic disc and/or the optic nerve assessed subjectively on the ADC maps. ADC values were also measured. Spearman rank correlations were used to examine the relationships between timing from visual symptoms' onset to MRI completion and both the restricted diffusion and the ADC values. RESULTS: One hundred twenty-six patients (47/126 [37.3%] women and 79/126 [62.7%] men, mean age 69.1 ± 13.7 years) with AION were included. Restricted diffusion of the optic disc in AION eyes was more frequent in the early MRI group than in the late MRI group: 35/49 (71.4%) eyes versus 3/83 (3.6%) eyes, p < 0.001. ADC values of the pathological optic discs and optic nerves were lower in the early MRI group than in the late MRI group: 0.61 [0.52-0.94] × 10-3 mm2/s versus 1.28 [1.01-1.44] × 10-3 mm2/s, p < 0.001, and 0.74 [0.61-0.88] × 10-3 mm2/s versus 0.89 [0.72-1.10] × 10-3 mm2/s, p < 0.001, respectively. CONCLUSIONS: DWI MRI showed good diagnostic performance to detect AION when performed early after the onset of visual symptoms. KEY POINTS: • Restricted diffusion of the optic disc in eyes affected by AION was significantly more likely to be observed in patients who had undergone MRI within 5 days after onset of visual symptoms. • ADC values of the pathological optic discs and optic nerves were significantly lower in patients who had undergone MRI within 5 days after onset of visual symptoms of AION: 0.61 × 10-3 mm2/s versus 1.28 × 10-3 mm2/s, p < 0.001, and 0.74 × 10-3 mm2/s versus 0.89 × 10-3 mm2/s, p < 0.001, respectively. • The optimal threshold for timing from visual symptoms' onset to MRI completion to detect restricted diffusion of the optic disc and/or optic nerve was 5 days, with an AUC of 0.88 (CI95%: 0.82-0.94).

Post-cataract surgery optic neuropathy: a chronological narrative review of the literature and speculation on pathogenesis.

PURPOSE OF REVIEW: To appraise the literature on the incidence of an acute anterior optic neuropathy resembling spontaneous nonarteritic anterior ischemic optic neuropathy (NAION) following uncomplicated cataract surgery and to explore the proposed pathogenesis of both immediate and delayed onset post-cataract surgery optic neuropathy (PCSON). RECENT FINDINGS: A number of case reports, case series, and retrospective case-controlled, big data, and population-based studies have identified an apparent association between cataract surgery and the occurrence of an acute anterior optic neuropathy that can either be immediate or delayed in onset. However, a recent study found no link between modern day cataract surgery and an increased risk of an acute anterior optic neuropathy. SUMMARY: Immediate PCSON appears to be related to negative perfusion pressure at the level of the optic disc due to increased intraocular pressure. The pathogenesis of delayed PCSON is unknown but probably multifactorial. Patients who have experienced spontaneous NAION or PCSON in one eye may be at risk of PCSON in the fellow eye.

Histopathological effects of topical coenzyme q 10 + Vit E TPGS in experimental ischemic optic neuropathy.

We aimed to create a mechanical optic nerve damage model in rats and to investigate the neuroprotective effects of topical Coenzyme Q10 + Vitamin E TPGS (CoQ10+Vit E) molecule on retinal ganglion cells. In our study, 30 eyes of 20 male Wistar rats were used. Three groups, each consisting of 10 eyes, were formed as control, experimental, and treatment groups. The control group was used to test the formation of optic nerve damage. Topical CoQ10 + Vit E TPGS solution was applied to the rats in the treatment group, one drop twice a day for 3 weeks. On the other hand, physiological drops were applied to the experimental group 2 times a day for 3 weeks. After 3 weeks, the optic nerves of the rats were dissected and examined histopathologically. In electron microscopic examination of the treatment group, it was noted that the myelin sheath in the majority of myelinated nerve fibers and the normal structures of mitochondria, neurotubules, and neurofilaments in the axoplasm were preserved. It was observed that the oligodendrocytes surrounded the myelinated axons. In the experimental group, significant degenerative changes were observed in myelinated nerve fibers in many areas. The number of myelinated axons was significantly increased in the treatment group compared to the experimental group (p = .0028). In the light of the data obtained, the neuroprotective effect of the topically used CoQ10 + Vit E TPGS molecule was found to be histopathologically effective in our experimental study.Abbreviations: NAAION: Nonarteritic anterior ischemic optic neuropathy; CoQ10: Coenzyme q10; CG: Control group; EG: Experimental group; TG: Treatment group.

No Evidence of Varicella-Zoster Virus Infection in Temporal Artery Biopsies of Anterior Ischemic Optic Neuropathy Patients With and Without Giant Cell Arteritis.

BACKGROUND: To test the hypothesis that varicella-zoster virus (VZV) infection contributes to temporal arteritis pathogenesis, comprehensive in situ analysis was performed on temporal artery biopsies of 38 anterior ischemic optic neuropathy (AION) patients, including 14 (37%) with giant cell arteritis. METHODS: Biopsies were completely sectioned, and, on average, 146 serial sections per patient were stained for VZV glycoprotein E. RESULTS: Four of 38 AION patients showed VZV glycoprotein E staining, but VZV infection was not confirmed by staining for VZV IE63 protein and VZV-specific polymerase chain reaction on adjacent sections. CONCLUSIONS: This study refutes the premise that VZV is casually related to AION with and without giant cell arteritis.

Structural changes of macula and optic disk of the fellow eye in patients with nonarteritic anterior ischemic optic neuropathy.

PURPOSE: The aim was to assess the ganglion cell complex (GCC) thickness, retinal nerve fiber layer (RNFL) thickness and optic disk features in the affected eyes (AE) and unaffected fellow eyes (FE) of subjects with unilateral nonarteritic anterior ischemic optic neuropathy (NAION) and to compare with healthy control eyes (CE) using spectral domain-optical coherence tomography (SD-OCT). METHODS: This study included 28 patients and age, sex and refraction-matched 28 control subjects. Mean GCC thickness and peripapillary RNFL thickness in four quadrants measured by cirrus SD-OCT were evaluated in both AE and FE of patients and CE. In addition, optic disk measurements obtained with OCT were evaluated. RESULTS: Mean GCC thickness was significantly lower in AE compared with both FE and CE (P < 0.001), and mean GCC thickness in FE was significantly lower than CE (P = 0.022). In addition, mean RNFL thickness in superior and nasal quadrants significantly decreased in FE compared with CE (P = 0.020 and 0.010, respectively). Furthermore, AE had significantly greater optic disk cupping compared with both FE and CE (P < 0.001). CONCLUSIONS: GCC and RNFL thickness decreased significantly at late stages of NAION, in both AE and FE compared with CE, suggesting that some subclinical structural changes may occur in FE despite lack of obvious visual symptoms. In addition, there was no significant difference in optic disk features between the CE and FE. And significantly greater optic disk cupping in the AE compared with both FE and CE supports the acquired enlargement of cupping after the onset of NAION.

Reduction of Peripapillary Vessel Density by Optical Coherence Tomography Angiography from the Acute to the Atrophic Stage in Non-Arteritic Anterior Ischaemic Optic Neuropathy.

PURPOSE: To analyse superficial peripapillary vascularization in non-arteritic anterior ischaemic optic neuropathy (NAION) at acute and atrophic (3 months) stage. PROCEDURES: Prospective case-control study including 6 patients with NAION and 10 age-matched healthy controls evaluated with optical coherence tomography angiography (OCT-A; Angioplex-Cirrus) at acute and atrophic stage. Apart from the -commercially provided measurements for vessel density (VD) and perfusion density (PD), a custom image analysis was used to quantify the peripapillary capillary density (PCD). RESULTS: NAION-group demonstrated a significant decrease in the PCD, VD and PD compared with fellow unaffected and control groups at acute and atrophic stage. At 3 months, the average and the temporal sector in PCD correlated with logMAR VA (-0.943, p = 0.005 and -0.829, p = 0.042 for average and temporal sectors respectively) and with MD (0.943, p = 0.005; and 0.899; p = 0.015, respectively). Over 3 months, there was a significant PCD reduction at the temporal sector and at the inner circle in VD and PD, which correlated with ganglion cell-inner plexiform layer (GCIPL) thinning over the 3 months period after the acute NAION (0.749, p = 0.020; 0.885, p = 0.002; 0.767, p = 0.016 respectively). CONCLUSION: Both strategies demonstrated a significant peripapillary microvascular dropout in NAION, but the customized analysis detected them -earlier. A progressive vessel reduction occurs within the first 3 months, which correlates with GCIPL thinning.

Longitudinal Measurement of Hemodynamic Changes within the Posterior Optic Nerve Head in Rodent Nonarteritic Anterior Ischemic Optic Neuropathy.

Objective To assess the in vivo dynamic blood flow features of posterior optic nerve head (ONH) in rat model of nonarteritic anterior ischemic optic neuropathy (rNAION). Methods rNAION was established with Rose Bengal and argon green laser in Sprague-Dawley rats. Fundus photography and fundus fluorescein angiography (FFA) were performed to assess the dynamic changes of optic disc in morphology in 90 days and in blood perfusion in 3 hours after the induction of disease. Histological examinations were performed to evaluate the success of modeling. The dynamic blood flow kinetics of posterior ONH in rNAION were measured by Laser Doppler Flowmetry (LDF) on the day 3, 7, 14, 21, and 40 after the disease induction. One-way ANOVA, Student's t-test and Bonferroni adjustment were used for multiple comparisons of kinetic measurements of blood flow. Results Optic disc edema and subsequent resolution associated with the development of optic disc pallor were observed in rNAION. FFA showed that the optic disc was hypofluorescence in the early phase and hyperfluorescence in the late phase. Histological studies suggested edema and loosened tissues of ONH, loss of retinal ganglion cells (RGCs), optic nerve substance and gliosis. Compared to the naive rats, the blood flow kinetics of posterior ONH in rNAION significant reduced at each time point after modeling (F=175.06, P<0.0001). The reductions were specifically remarkable in 14 days after the disease induction (All P<0.01). Conclusions Continuous blood perfusion reduction was found in rNAION, with significant alteration in 14 days after disease induction. Our results provided important information for understanding the hemodynamic changes in rNAION.

Oligodendrocyte death, neuroinflammation, and the effects of minocycline in a rodent model of nonarteritic anterior ischemic optic neuropathy (rNAION).

Purpose: Optic nerve (ON) damage following nonarteritic anterior ischemic optic neuropathy (NAION) and its models is associated with neurodegenerative inflammation. Minocycline is a tetracycline derivative antibiotic believed to exert a neuroprotective effect by selective alteration and activation of the neuroinflammatory response. We evaluated minocycline's post-induction ability to modify early and late post-ischemic inflammatory responses and its retinal ganglion cell (RGC)-neuroprotective ability. Methods: We used the rodent NAION (rNAION) model in male Sprague-Dawley rats. Animals received either vehicle or minocycline (33 mg/kg) daily intraperitoneally for 28 days. Early (3 days) ON-cytokine responses were evaluated, and oligodendrocyte death was temporally evaluated using terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) analysis. Cellular inflammation was evaluated with immunohistochemistry, and RGC preservation was compared with stereology of Brn3a-positive cells in flat mounted retinas. Results: Post-rNAION, oligodendrocytes exhibit a delayed pattern of apoptosis extending over a month, with extrinsic monocyte infiltration occurring only in the primary rNAION lesion and progressive distal microglial activation. Post-induction minocycline failed to improve retinal ganglion cell survival compared with the vehicle treated (893.14 vs. 920.72; p>0.9). Cytokine analysis of the rNAION lesion 3 days post-induction revealed that minocycline exert general inflammatory suppression without selective upregulation of cytokines associated with the proposed alternative or neuroprotective M2 inflammatory pathway. Conclusions: The pattern of cytokine release, extended temporal window of oligodendrocyte death, and progressive microglial activation suggests that selective neuroimmunomodulation, rather than general inflammatory suppression, may be required for effective repair strategies in ischemic optic neuropathies.

Imaging of macrophage dynamics with optical coherence tomography in anterior ischemic optic neuropathy.

Anterior ischemic optic neuropathy (AION) is a relatively common cause of visual loss and results from hypoperfusion of the small arteries of the anterior portion of the optic nerve. AION is the leading cause of sudden optic nerve related vision loss with approximately 10 cases per 100'000 in the population over 50 years. To date there is no established treatment for AION and therefore a better understanding of the events occurring at the level of the optic nerve head (ONH) would be important to design future therapeutic strategies. The optical properties of the eye allow imaging of the optic nerve in vivo, which is a part of the CNS, during ischemia. Experimentally laser induced optic neuropathy (eLiON) displays similar anatomical features as anterior ischemic optic neuropathy in humans. After laser induced optic neuropathy we show that hyperreflective dots in optical coherence tomography correspond to mononuclear cells in histology. Using fluorescence-activated flow cytometry (FACS) we found these cells to peak one week after eLiON. These observations were translated to OCT findings in patients with AION, where similar dynamics of hyperreflective dots at the ONH were identified. Our data suggests that activated macrophages can be identified as hyperreflective dots in OCT.

Platelet activation by ADP is increased in selected patients with anterior ischemic optic neuropathy or retinal vein occlusion.

To investigate whether adenosine diphosphate (ADP)-induced platelet hyperaggregability is associated with nonarteritic anterior ischemic optic neuropathy (NAION) or retinal vein occlusion (RVO). We retrospectively reviewed thrombophilia screening data of patients with NAION or RVO without a history of arterial hypertension, diabetes mellitus, hyperlipidemia, obesity, and cigarette abuse. Patients with a positive family history for thromboembolism were not excluded. Platelet aggregation (area under the curve, AUC) after induction of 0.5, 1.0, and 2.0 µmol of ADP was estimated in 25 NAION and RVO patients and compared with 25 healthy controls. We observed significantly greater platelet aggregation post 0.5 (P = 0.002) and 1.0 (P = 0.008) µmol of ADP among NAION and RVO patients compared with healthy controls. Platelet hyperaggregability was significantly more prevalent in patients than in controls (56% vs. 8%; P = 0.0006). Our results suggest that in NAION and RVO patients without a history of arterial hypertension, diabetes mellitus, hyperlipidemia, obesity, and cigarette abuse, platelets are significantly hyperreactive after induction of very low concentrations of ADP when compared with healthy individuals. This hyperreactivity is particularly evident in patients with a family history of thromboembolism.

Choroidal thickness in Chinese patients with non-arteritic anterior ischemic optic neuropathy.

BACKGROUND: Non-arteritic anterior ischemic optic neuropathy (NA-AION) is one of the most common types of ischemic optic neuropathy. Several recent studies suggested that abnormalities of choroidal thickness might be associated with NA-AION. The main objective of this case-control study was to evaluate whether choroidal thickness is an ocular risk factor for the development of NA-AION by evaluating the peripapillary and subfoveal choroidal thicknesses in affected Chinese patients. METHODS: Forty-four Chinese patients with unilateral NA-AION were recruited and compared with 60 eyes of 60 normal age and refractive-error matched control subjects. Peripapillary and subfoveal choroidal thicknesses were measured by enhanced depth imaging optical coherence tomography. Choroidal thicknesses of eyes with NA-AION and unaffected fellow eyes were compared with normal controls. Choroidal thicknesses of NA-AION eyes with or without optic disc edema were also compared. The correlation between choroidal thickness and retinal nerve fiber layer (RNFL) thickness, logMAR best-corrected visual acuity (BCVA), and the mean deviation (MD) of Humphrey static perimetry in NA-AION eyes were analyzed. RESULTS: The peripapillary choroidal thicknesses at the nasal, nasal inferior and temporal inferior segments in NA-AION eyes with optic disc edema were significantly thicker compared with that of normal subjects (P < 0.05). There was no significant difference in the choroidal thicknesses between the unaffected fellow eyes of NA-AION patients and normal eyes of healthy controls; or between the NA-AION eyes with resolved optic disc edema and normal eyes (all P > 0.05). No significant correlation between choroidal thickness and RNFL thickness, logMAR BCVA and perimetry MD was found in eyes affected by NA-AION (all P > 0.05). CONCLUSIONS: Increase in peripapillary choroid thickness in some segments was found in NA-ION eyes with optic disc edema. However, our findings do not support the hypothesis that choroidal thickness is abnormal in Chinese patients with NA-AION compared with normal subjects with similar age and refractive error status.

[Temporal and spatial characteristics of RGC death and axon degeneration in the rat model of nonarteritic anterior ischemic optic neuropathy].

Objective: To investigate the temporal and spatial characteristics of retinal ganglion cell (RGC) death and axon degeneration in the rat model of nonarteritic anterior ischemic optic neuropathy (rNAION). Methods: Experimental study. The model of rNAION was induced by directly illuminating the optic nerve head with laser, after intravenous infusion with the photosensitizing agent rose Bengal. Seventy-one SD rats were randomly divided into five groups: 1-week (n=14), 2-week (n=14), 4-week (n=15) , 8-week (n=16) model group and the normal control group (n=12). Hematoxylin and eosin (H&E) staining and morphometric measurement with FG labeling were performed to assess rNAION-indeced histologic changes in the retina at different time points. RGCs were counted on retinal flat mounts in a masked fashion. Semithin sections stained with toluidine blue and transmission electron microscopy were performed to evaluate axonal degeneration. The differences of RGC density among multiple groups were tested with one-way ANOVA while the survival rate of RGC with kruskal-Wallis. Results: H&E-stained retina sections of rNAION revealed RGC loss. The density of labeled RGC was (2 273±219) cells/mm2 in the control group, (2 075±120) cells/mm2 in the 1-week group, (1 783±143) cells/mm2 in the 2-week group, (1 330±169) cells/mm2 in the 4-week group and (869±301) cells/mm2 in the 8-week group. There were significant differences between all pairs of groups (F=80.98, P<0.01). The impairment of RGC was aggravatedprogressively, which mainly in the upper quadrant. The survival rate of RGC was 99.9%±3.4%, 91.8%±2.9%, 72.6%±5.7%, 54.4%±7.0% and 37.5%±13.0%, respectively. There were significant differences between the 1-week and 2-week group(Z=-3.78, P<0.01), the 2-week and 4-week group(Z=-3.89, P<0.01), and the 4-week and 8-week group(Z=-3.23, P<0.01). Toluidine blue staining of the ON revealed significant demyelination 1 week after ischemic damage. Progressive axonal degeneration existed for several weeks, which mainly affected the central region of the optic nerve with extensive reactive gliosis. Ultrastructural study showed axonal edema and collapsed sheaths in the ischemic optic. Four weeks later, there were extensive axonal loss and severe glial scars. Conclusions: rNAION results in regional and later RGC death. The extended period of RGC death after rNAION induction is much more longer than previously recognized. (Chin J Ophthalmol, 2016, 52: 918-923).

Protective effects of systemic treatment with methylprednisolone in a rodent model of non-arteritic anterior ischemic optic neuropathy (rAION).

This study investigated the protective effects of the administration of steroids on optic nerves (ON) and retinal ganglion cells (RGCs) in a rodent model of non-arteritic anterior ischemic optic neuropathy (rAION). We induced rAION using rose bengal and argon laser irradiation in a photodynamic procedure on the optic discs of rats. The treated groups received methylprednisolone (MP) via peritoneal injection for 2 weeks. The control group received intraperitoneal injections of phosphate-buffered saline (PBS) post-rAION. At the 4th week post-infarct, MP treatments significantly rescued the RGCs (mm(2)) in the central retinas (1920 ± 210, p < 0.001) and mid-peripheral retinas (950 ± 240, respectively, p = 0.018) compared with those of the PBS-treated rats (central: 900 ± 210 and mid-peripheral: 440 ± 180). Functional assessment with flash visual-evoked potentials demonstrated that P1 latency (ms) was shortened in the MP group compared to the PBS group (108 ± 14 and 147 ± 9, respectively, p < 0.001). In addition, the P1 amplitude (uV) was enhanced in the MP group compared to the PBS group (55 ± 12 and 41 ± 13, respectively, p < 0.05). TUNEL assays showed a decrease in the number of apoptotic cells in the RGC layers of MP-treated retinas compared to the PBS-treated group (p < 0.05). ED1 positive cells (/HPF) were significantly decreased in the ONs of the MP group compared to the PBS group (p < 0.001). In conclusion, systemic administration of MP had neuroprotective effects on RGC survival and ON function in the rAION animal model.

Acute nonarteritic anterior ischemic optic neuropathy and exposure to phosphodiesterase type 5 inhibitors.

INTRODUCTION: Nonarteritic anterior ischemic optic neuropathy (NAION), a rare visual disorder, has been reported in men using phosphodiesterase type 5 inhibitors (PDE5i) for erectile dysfunction. AIM: We examined whether intermittent use of PDE5i is associated with acute NAION onset within approximately five half-lives following drug ingestion. METHODS: One hundred two ophthalmology centers in the United States and Europe identified potential cases of NAION. An expert adjudication committee conducted a blind review of the records of those with recent PDE5i use to classify cases as Definite, Possible, or not NAION. Subjects provided information on PDEi use via telephone interview. Each NAION case's PDE5i exposure immediately prior to onset was compared against his recent patterns of use in an observational case-crossover design. A sample size of 40 cases with intermittent PDE5i exposure in the 30 days prior to NAION onset was needed to detect an odds ratio (OR) of 3.0 with 80% power. MAIN OUTCOME MEASURES: The daily relative risk for acute NAION on days within five half-lives of PDE5i use vs. other days was estimated via an OR obtained from conditional logistic regression. RESULTS: Among 43 Definite NAION cases with PDE5i exposure in the prior 30 days, the OR was 2.15 (95% confidence interval [CI]: 1.06, 4.34). When 21 Possible NAION cases were included (n = 64), the OR was 2.36 (95% CI: 1.33, 4.19). CONCLUSIONS: We found an approximately twofold increased risk of acute NAION within five half-lives of PDE5i use compared with use in a more prior time period. Bias from inaccurate recall of exposure was unlikely to have substantially affected the results. Based on our results, we estimate that weekly use of PDE5i adds three NAION cases per 100,000 men 50 years and older annually.

[Morphological evaluation of the optic nerve and retina in the rat model of non-arteritic anterior ischemic optic neuropathy].

OBJECTIVE: To evaluate the morphology of optic nerve and retina in the model of the rat non-arteritic anterior ischemic optic neuropathy (rNAION). METHODS: Experimental study. Thirty-six SD rats were randomly divided into four groups: 6 for naïve group, 3 for laser group, 3 for Rose Bengal (RB) group and 24 for rNAION group. After rNAION was induced by RB and laser, the retina and optic nerve were observed by Hematoxylin-Eosin (HE) staining and the optic nerve was investigated by transmission electron microscope and toludidine blue staining at different time points. RESULTS: With these methods, significant changes were only found in the RB-laser induced eyes. The damage only occurred in the retinal ganglion cell (RGC) layer without any loss of the other layers of retina in the rNAION. Toludine blue-stained optic nerve showed that there was a loss of axons centrally and largely intact axons were spared in the peripheral nerve. More and more degenerative axons were observed with the transmission electron microscope as time went on. CONCLUSIONS: The morphological changes of HE staining, toludine blue staining and transmission electron microscopic finding were consistent with each other. The results made a contribution to further study.

Neuroprotective effects of recombinant human granulocyte colony-stimulating factor (G-CSF) in a rat model of anterior ischemic optic neuropathy (rAION).

The purpose of this study was to investigate the neuroprotective effects of recombinant human granulocyte colony stimulating factor (G-CSF), as administered in a rat model of anterior ischemic optic neuropathy (rAION). Using laser-induced photoactivation of intravenously administered Rose Bengal in the optic nerve head of 60 adult male Wistar rats, an anterior ischemic optic neuropathy (rAION) was inducted. Rats either immediately received G-CSF (subcutaneous injections) or phosphate buffered saline (PBS) for 5 consecutive days. Rats were euthanized at 4 weeks post infarct. Density of retinal ganglion cells (RGCs) was counted using retrograde labeling of Fluoro-gold. Visual function was assessed by flash visual-evoked potentials (FVEP) at 4 weeks. TUNEL assay in the retinal sections and immunohistochemical staining of ED1 (marker of macrophage/microglia) were investigated in the optic nerve (ON) specimens. The RGC densities in the central and mid-peripheral retinas in the G-CSF treated rats were significantly higher than those of the PBS-treated rats (survival rate was 71.4% vs. 33.2% in the central retina; 61.8% vs. 22.7% in the mid-peripheral retina, respectively; both p < 0.05). FVEP measurements showed a significantly better preserved latency and amplitude of the p1 wave in the G-CSF-treated rats than that of the PBS-treated rats (latency120 ± 11 ms vs. 142 ± 12 ms, p = 0.03; amplitude 50 ± 11 µv vs. 31 ± 13 µv, p = 0.04). TUNEL assays showed fewer apoptotic cells in the retinal ganglion cell layers of G-CSF treated rats [2.1 ± 1.0 cells/high power field (HPF) vs. 8.0 ± 1.5/HPF; p = 0.0001]. In addition, the number of ED1 positive cells was attenuated at the optic nerve sections of G-CSF-treated rats (16 ± 6/HPF vs. 35 ± 10/HPF; p = 0.016). In conclusion, administration of G-CSF is neuroprotective in the rat model of anterior ischemic optic neuropathy, as demonstrated both structurally by RGC density and functionally by FVEP. G-CSF may work via the dual actions of anti-apoptosis for RGC surviving as well as anti-inflammation in the optic nerves as evidenced by less infiltration of ED1-povitive cells.

Diffusion restriction of the optic nerve in patients with acute visual deficit.

PURPOSE: Diffusion magnetic resonance imaging (MRI) is commonly used in acute stroke, but not considered diagnostic in ischemic optic neuropathy. This study evaluates the presence of diffusion restriction in patients with acute visual loss by analyzing diffusion-weighted images (DWI). MATERIALS AND METHODS: A retrospective study of all patients who clinically presented with acute visual loss and who underwent MRI with DWI between January 2011 and May 2012 were evaluated. Patients with suspected brainstem ischemia were used as a control group. Two neuroradiologists evaluated the DWI for the presence of diffusion restriction within the optic nerve. RESULTS: In all, 34 patients with acute visual deficit and 32 controls were evaluated. In all five cases of acute optic ischemia, diffusion restriction with reduced apparent diffusion coefficient was present. In 2/25 patients with clinically defined optic neuritis, a diffusion restriction was present. No diffusion restriction was seen in the control cases or in cases with other causes for an acute visual deficit. CONCLUSION: DWI can identify ischemic lesions of the optic nerve. As in acute multiple sclerosis lesions, optic neuritis can also present in rare circumstances with diffusion restriction and can therefore not be ruled out solely by DWI MRI.

[Nonarteritic ischemic optic neuropathy animal model and its treatment applications].

Nonarteritic ischemic optic neuropathy (NAION) is one of the most common acute unilaterally onset optic nerve diseases. One management problem in terms of NAION is the difficulty of differential diagnosis between NAION and anterior optic neuritis (ON). A second problem is that there is no established treatment for the acute stage of NAION. A third problem is that there is no preventive treatment for a subsequent attack on the fellow eye, estimated to occur in 15 to 25% of patients with NAION. For differentiation of acute NAION from anterior optic neuritis, we investigated the usefulness of laser speckle flowgraphy (LSFG). In the normal control group, the tissue blood flow did not significantly differ between the right and left eyes. In the NAION group, all 6 patients had 29.5% decreased mean blur rate (MBR), which correlates to optic disc blood flow, of the NAION eye compared with the unaffected eye. In the anterior ON group, all 6 cases had 15.9% increased MBR of the anterior ON eye compared with the unaffected eye. Thus, LSFG showed a difference of the underlying pathophysiology between NAION and anterior ON despite showing disc swelling in both groups and could be useful for differentiating both groups. For the treatment of acute stage of NAION, we tried to reproduce the rodent model of NAION (rNAION) developed by Bernstein and colleagues. To induce rNAION, after the administration of rose bengal(RB) (2.5 mM) into the tail vein of SD rats, the small vessels of the left optic nerve were photoactivated using a 514 nm argon green laser (RB-laser-induction). In the RB-laser-induction eyes, the capillaries within the optic disc were reduced markedly, the optic disc became swollen, and fluorescein angiography showed filling defect in the choroid and the optic disc at an early stage, followed by hyperfluorescence at a late stage. Electrophysiological evaluation revealed that visual evoked potential (VEP) amplitude was significantly decreased but an electroretinogram (ERG) did not show a significant difference either in the b wave or in the oscillatory potentials. The scotopic threshold response (STR) was significantly reduced 3 days after induction. These findings are similar to those of rNAION and indicate that we succeeded in reproducing the rNAION. Histopathologic examination in the acute phase of rNAION, showed acellular NFL swelling anterior to the optic disc. No accumulation of inflammatory cells was noted in several microscopic sections of the optic nerve. In addition, immunochemical staining was negative throughout the retina and optic nerve. These results suggested that the rNAION-induced NFL swelling was not a result of inflammation. In the chronic phase of rNAION, the morphologic retinal changes were apparent in only the retinal ganglion cell(RGC) layer, with a reduction in the number of cells in the RGC layer. Thus, we need to evaluate the degree of the NFL swelling in the acute phase and the following thinning of the NFL in the chronic phase for efficacy of the treatment of rNAION. Therefore, we used optical coherence tomography (OCT) for the objective and quantitative evaluation of the retinal nerve fiber layer (RNFL) thickness around the optic disc changes in rNAION. The second method was to use the STR for the evaluation of the RGC function. The third method was to count the number of surviving RGCs observed and photographed through the fluorescence microscope with the Fluorogold staining. A possible rationale for treatment of NAION is that dilation of the posterior ciliary artery (PCA) increases the blood flow to the optic nerve and could improve the optic nerve function. To clarify the vasodilatory effects of medications, we used in vitro isometric tension recording methods and examined the vasodilatory effects of bevacizumab as an anti-vascular endothelial growth factor (VEGF) antibody, methylprednisolone as a corticosteroid and sodium nitroprusside (SNP, a nitric oxide donor) as a vasodilator on high-K (potassium) solution-induced contraction in isolated rabbit PCA. Bevacizumab did not relax rabbit PCA. Methylprednisolone relaxed rabbit PCA nitric oxide (NO) independently. SNP relaxed rabbit PCA by exogenous NO. On the basis of these results, we selected the following candidates for rNAION treatment: methylprednisolone as the corticosteroid and L-arginine as the NO related agent. Intravenous infusion of methylprednisolone significantly decreased the degree of acute disc edema but did not reduce inner retinal thinning, decrease STR amplitude, or decrease RGC numbers in rNAION. Intravenous infusion of L-arginine after rNAION induction significantly decreased the disc edema at the acute stage and the thinning of the inner retina, reduced the decrease in STR amplitude, and reduced the decrease in RGC numbers during rNAION. These results indicated that L-arginine treatment is effective for reducing the anatomical changes and improving visual function in the acute stage of rNAION. To strengthen the neuroprotective effect for rNAION, we tried treatment using transcorneal electric stimulation (TES). We evaluated the effect using STR and survival RGCs. Decreased amplitude in the STR of the TES group was significantly better preserved than in the control group on the 28th day after treatment. RGC survival in the TES group was significantly larger than in the control group on the 14th and 28th days. The neuroprotective effect of TES was better than that of L-arginine. For preventive treatment of subsequent attack in the fellow eye, we investigated whether pretreatment with L-arginine might reduce the severity of the anatomical changes associated with NAION and preserve the visual function when NAION occurs in the other eye. In the L-arginine pretreated eyes, the disc edema at the acute stage and the thinning of inner retina were significantly decreased, and the decrease of STR amplitude and the decrease in RGC numbers during rNAION were reserved. These results indicate that pretreatment with L-arginine is effective for the reduction of the severity during recurrence in the other eye. We will perform clinical trials in a small series of cases, and if the treatment is effective, we will proceed to multicenter randomized treatment trials. In addition to that, more work needs to be done to discover better treatment options for NAION.