ResearchPad - optic-nerve https://www.researchpad.co Default RSS Feed en-us © 2020 Newgen KnowledgeWorks <![CDATA[Hemisphere opposite to vascular trunk deviation is earlier affected by glaucomatous damage in myopic high-tension glaucoma]]> https://www.researchpad.co/article/elastic_article_15760 To investigate whether the position of the central vascular trunk, as a surrogate of lamina cribrosa (LC) shift, is associated with the initial hemisphere of visual field defect in myopic high-tension glaucoma (HTG) eyes.MethodsThe deviation of the central vascular trunk was measured from the center of the Bruch’s membrane opening (BMO), which was delineated by OCT imaging. The angular deviation was measured with the horizontal nasal midline as 0° and the superior location as a positive value. The initial hemisphere developing visual field defect was defined as three connected abnormal points (having a P value with less than 0.5% probability of being normal) appearing in only one hemisphere in pattern deviation plots. If those points were observed in both hemispheres initially, the eye was classified as bi-hemispheric visual field defect.ResultsInitially, 36 eyes (44%) had superior visual field defects, 27 (33%) inferior visual field defects, and 18 (22%) bi-hemispheric visual field defects. After a mean follow-up of 5 years, the number of bi-hemispheric visual field defects had increased to 34 (42%). A logistic regression analysis revealed that inferior deviation of vascular trunk was the only factor associated with initial inferior visual field defect (P = 0.001), while initial bi-hemispheric visual field defects were associated with worse mean deviation at initial visits (P<0.001). A conditional inference tree analysis showed that both the angular deviation (P<0.001) and initial mean deviation (P = 0.025) determined the initial hemispheres developing visual field defect.ConclusionsAlthough both hemispheres were involved as glaucoma progression, the axons on the side counter to the vascular trunk deviation were damaged earlier in HTG. This finding implies the LC shift could add additional stress to axons exposed to high intraocular pressure. ]]> <![CDATA[Evaluation of optic nerve subarachnoid space in primary open angle glaucoma using ultrasound examination]]> https://www.researchpad.co/article/5c0841f8d5eed0c484fcb518

Objectives

To measure Optic Nerve Subarachnoid Space (ONSAS) in patients with primary open-angle glaucoma (POAG) and controls using A-scan ultrasound and to evaluate the measurement of the ONSAS in relation to age patient and OCT parameters.

Methods

This retrospective study included 53 consecutive eyes of 27 patients with POAG and 64 normal eyes of 32 controls. Both glaucomatous and control groups were divided into 2 subgroups according to age: <60 age (glaucomatous and control group 1) and 61–90 age (glaucomatous and control group 2).

Results

The ONSAS was significantly lower in all glaucomatous eyes (3.54 ± 0.38) versus normal eyes (3.87 ± 0.32) (p = 0.001). Significant reduction of ONSAS was showed in control group 2 (3.63 mm ± 0.37) compared to control group 1 (3.87 mm ± 0.32) (p = 0.014) and between glaucoma group 1 (3.54 mm ± 0.38) and control group 1 (p = 0.001). While no significant differences were observed between glaucomatous group 2 (3.48 mm ± 0.41) and control group 2 (p = 0.17) and between glaucoma group 1 and glaucoma group 2 (p = 0.609). Lastly, the ONSAS was not significantly associated with GCC and RNFL parameters except for Focal Loss Volume (FLV), Superior RNFL and ONSAS in glaucoma group 1 and for FLV and ONSAS in all glaucomatous group.

Conclusion

Standardized A-scan ultrasound is a non invasive imaging technique with which it is possible to monitor ONSAS changes in glaucomatous patients. The reduction of ONSAS confirm the importance of the lower orbital CSFP as further risk factor in the progression of glaucoma disease.

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<![CDATA[Macular choroidal thickness and peripapillary retinal nerve fiber layer thickness in normal adults and patients with optic atrophy due to acute idiopathic demyelinating optic neuritis]]> https://www.researchpad.co/article/5b28b401463d7e129299938e

Purpose

To evaluate the association between macular choroidal thickness and peripapillary RNFL thickness in patients with optic atrophy due to acute idiopathic demyelinating optic neuritis and in normal controls using spectral domain optical coherence tomography (SD-OCT).

Methods

We performed SD-OCT peripapillary RNFL circular scan centered on the optic disc with horizontal and vertical crosshair scans through the fovea using the enhanced depth technique in 62 eyes with optic atrophy due to acute idiopathic demyelinating optic neuritis and 86 eyes of normal controls. The association between RNFL thickness and macular choroidal thickness measurements was assessed.

Results

The mean age was 43 ± 14 years (mean ± SD) in patients with optic atrophy and 45 ± 16 years in healthy controls (p = 0.791). There was a significant association between nasal peripapillary RNFL thickness and choroidal thickness at 3.0 mm nasal to the foveal center in patients with optic atrophy in multivariate analysis (estimate = 1.398, p = 0.011). In controls, there were significant associations between global average, superior, and inferior peripapillary RNFL thickness and choroidal thickness at 3.0 mm superior to the foveal center (estimate = -60.112, p = 0.044, estimate = 15.821, p = 7.312, and estimate = 15.203, p = 7.222, respectively).

Conclusions

Our SD-OCT data revealed that there was a significant association between peripapillary RNFL thickness and macular choroidal thickness in patients with optic atrophy due to acute idiopathic demyelinating optic neuritis and in controls, although the mechanism remained unclear. The difference in the pattern of association between patients with optic atrophy and controls suggests that optic atrophy caused by acute idiopathic demyelinating optic neuritis could affect the pattern of association between peripapillary RNFL thickness and macular choroidal thickness.

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<![CDATA[Factors Associated with the Retinal Nerve Fiber Layer Loss after Acute Primary Angle Closure: A Prospective EDI-OCT Study]]> https://www.researchpad.co/article/5989db53ab0ee8fa60bdcbc7

Purpose

To determine the factors associated with retinal nerve fiber layer (RNFL) loss in eyes with acute primary angle-closure (APAC), particularly focusing on the influence of the change in the anterior lamina cribrosa surface depth (LCD).

Methods

After the initial presentation, 30 eyes with unilateral APAC were followed up at the following specific time points over a 12-month period: 1 week, 1~2 months, 2~3 months, 5~6 months, and 11~12 months. These follow-ups involved intraocular pressure measurements, enhanced depth-imaging spectral-domain optical coherence tomography (SD-OCT) scanning of the optic disc, and measurements of the circumpapillary RNFL thickness. The prelaminar tissue thickness (PLT) and LCD were determined in the SD-OCT images obtained at each follow-up visit.

Results

Repeated measures analysis of variance revealed a significant pattern of decrease in the global RNFL thickness, PLT, and LCD (all p<0.001). The global RNFL thickness decreased continuously throughout the follow-up period, while the PLT decreased until 5~6 months and did not change thereafter. The LCD reduced until 2~3 months and then also remained steady. Multivariable regression analysis revealed that symptoms with a longer duration before receiving laser peripheral iridotomy (LI) (p = 0.049) and a larger LCD reduction (p = 0.034) were significant factors associated with the conversion to an abnormal RNFL thickness defined using OCT normative data.

Conclusion

Early short-term decreases in the PLT and LCD and overall long-term decrease in the peripapillary RNFL were observed during a 12-month follow-up after an APAC episode. A longer duration of symptoms before receiving LI treatment and larger LCD reduction during follow-up were associated with the progressive RNFL loss. The LCD reduction may indicate a prior presence of significant pressure-induced stress that had been imposed on the optic nerve head at the time of APAC episode. Glaucomatous progression should be suspected in eyes showing LCD reduction after the APAC remission.

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<![CDATA[Clinical Factors Associated with Lamina Cribrosa Thickness in Patients with Glaucoma, as Measured with Swept Source Optical Coherence Tomography]]> https://www.researchpad.co/article/5989db4cab0ee8fa60bdaaa7

Purpose

To investigate the influence of various risk factors on thinning of the lamina cribrosa (LC), as measured with swept-source optical coherence tomography (SS-OCT; Topcon).

Methods

This retrospective study comprised 150 eyes of 150 patients: 22 normal subjects, 28 preperimetric glaucoma (PPG) patients, and 100 open-angle glaucoma patients. Average LC thickness was determined in a 3 x 3 mm cube scan of the optic disc, over which a 4 x 4 grid of 16 points was superimposed (interpoint distance: 175 μm), centered on the circular Bruch’s membrane opening. The borders of the LC were defined as the visible limits of the LC pores. The correlation of LC thickness with Humphrey field analyzer-measured mean deviation (MD; SITA standard 24–2), circumpapillary retinal nerve fiber layer thickness (cpRNFLT), the vertical cup-to-disc (C/D) ratio, and tissue mean blur rate (MBR) was determined with Spearman's rank correlation coefficient. The relationship of LC thickness with age, axial length, intraocular pressure (IOP), MD, the vertical C/D ratio, central corneal thickness (CCT), and tissue MBR was determined with multiple regression analysis. Average LC thickness and the correlation between LC thickness and MD were compared in patients with the glaucomatous enlargement (GE) optic disc type and those with non-GE disc types, as classified with Nicolela’s method.

Results

We found that average LC thickness in the 16 grid points was significantly associated with overall LC thickness (r = 0.77, P < 0.001). The measurement time for this area was 12.4 ± 2.4 minutes. Average LC thickness in this area had a correlation coefficient of 0.57 with cpRNFLT (P < 0.001) and 0.46 (P < 0.001) with MD. Average LC thickness differed significantly between the groups (normal: 268 ± 23 μm, PPG: 248 ± 13 μm, OAG: 233 ± 20 μm). Multiple regression analysis showed that MD (β = 0.29, P = 0.013), vertical C/D ratio (β = -0.25, P = 0.020) and tissue MBR (β = 0.20, P = 0.034) were independent variables significantly affecting LC thickness, but age, axial length, IOP, and CCT were not. LC thickness was significantly lower in the GE patients (233.9 ± 17.3 μm) than the non-GE patients (243.6 ± 19.5 μm, P = 0.040). The correlation coefficient between MD and LC thickness was 0.58 (P < 0.001) in the GE patients and 0.39 (P = 0.013) in the non-GE patients.

Conclusion

Cupping formation and tissue blood flow were independently correlated to LC thinning. Glaucoma patients with the GE disc type, who predominantly have large cupping, had lower LC thickness even with similar glaucoma severity.

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<![CDATA[Sub-Chronic Neuropathological and Biochemical Changes in Mouse Visual System after Repetitive Mild Traumatic Brain Injury]]> https://www.researchpad.co/article/5989da88ab0ee8fa60b9cdf3

Repetitive mild traumatic brain injury (r-mTBI) results in neuropathological and biochemical consequences in the human visual system. Using a recently developed mouse model of r-mTBI, with control mice receiving repetitive anesthesia alone (r-sham) we assessed the effects on the retina and optic nerve using histology, immunohistochemistry, proteomic and lipidomic analyses at 3 weeks post injury. Retina tissue was used to determine retinal ganglion cell (RGC) number, while optic nerve tissue was examined for cellularity, myelin content, protein and lipid changes. Increased cellularity and areas of demyelination were clearly detectable in optic nerves in r-mTBI, but not in r-sham. These changes were accompanied by a ~25% decrease in the total number of Brn3a-positive RGCs. Proteomic analysis of the optic nerves demonstrated various changes consistent with a negative effect of r-mTBI on major cellular processes like depolymerization of microtubules, disassembly of filaments and loss of neurons, manifested by decrease of several proteins, including neurofilaments (NEFH, NEFM, NEFL), tubulin (TUBB2A, TUBA4A), microtubule-associated proteins (MAP1A, MAP1B), collagen (COL6A1, COL6A3) and increased expression of other proteins, including heat shock proteins (HSP90B1, HSPB1), APOE and cathepsin D. Lipidomic analysis showed quantitative changes in a number of phospholipid species, including a significant increase in the total amount of lysophosphatidylcholine (LPC), including the molecular species 16:0, a known demyelinating agent. The overall amount of some ether phospholipids, like ether LPC, ether phosphatidylcholine and ether lysophosphatidylethanolamine were also increased, while the majority of individual molecular species of ester phospholipids, like phosphatidylcholine and phosphatidylethanolamine, were decreased. Results from the biochemical analysis correlate well with changes detected by histological and immunohistochemical methods and indicate the involvement of several important molecular pathways. This will allow future identification of therapeutic targets for improving the visual consequences of r-mTBI.

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<![CDATA[Changes in Expression of Aquaporin-4 and Aquaporin-9 in Optic Nerve after Crushing in Rats]]> https://www.researchpad.co/article/5989dac1ab0ee8fa60bb0ead

The purpose of this study was to determine the temporal and spatial changes in the expression of AQP4 and AQP9 in the optic nerve after it is crushed. The left optic nerves of rats were either crushed (crushed group) or sham operated (sham group), and they were excised before, and at 1, 2, 4, 7, and 14 days later. Four optic nerves were pooled for each time point in both groups. The expression of AQP4 and AQP9 was determined by western blot analyses. Immunohistochemistry was used to determine the spatial expression of AQP4, AQP9, and GFAP in the optic nerve. Optic nerve edema was determined by measuring the water content in the optic nerve. The barrier function of the optic nerve vessels was determined by the extravasated Evans blue dye on days 7 and 14. The results showed that the expression of AQP4 was increased on day 1 but the level was significantly lower than that in the sham group on days 4 and 7 (P<0.05). In contrast, the expression of AQP9 gradually increased, and the level was significantly higher than that in the sham group on days 7 and 14 (P<0.05, Tukey-Kramer). The down-regulation of AQP4 was associated with crush-induced optic nerve edema, and the water content of the nerve was significantly increased by 4.3% in the crushed optic nerve from that of the untouched fellow nerve on day 7. The expression of AQP4 and GFAP was reduced at the crushed site where AQP4-negative and AQP9-positive astrocytes were present. The barrier function was impaired at the crushed site on days 7 and 14, restrictedly where AQP4-negative and AQP9-positive astrocytes were present. The presence of AQP9-positive astrocytes at the crushed site may counteract the metabolic damage but this change did not fully compensate for the barrier function defect.

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<![CDATA[Mammalian-Specific Central Myelin Protein Opalin Is Redundant for Normal Myelination: Structural and Behavioral Assessments]]> https://www.researchpad.co/article/5989db1bab0ee8fa60bce3fb

Opalin, a central nervous system-specific myelin protein phylogenetically unique to mammals, has been suggested to play a role in mammalian-specific myelin. To elucidate the role of Opalin in mammalian myelin, we disrupted the Opalin gene in mice and analyzed the impacts on myelination and behavior. Opalin-knockout (Opalin−/−) mice were born at a Mendelian ratio and had a normal body shape and weight. Interestingly, Opalin−/− mice had no obvious abnormalities in major myelin protein compositions, expression of oligodendrocyte lineage markers, or domain organization of myelinated axons compared with WT mice (Opalin+/+) mice. Electron microscopic observation of the optic nerves did not reveal obvious differences between Opalin+/+ and Opalin−/− mice in terms of fine structures of paranodal loops, transverse bands, and multi-lamellae of myelinated axons. Moreover, sensory reflex, circadian rhythm, and locomotor activity in the home cage, as well as depression-like behavior, in the Opalin−/− mice were indistinguishable from the Opalin+/+ mice. Nevertheless, a subtle but significant impact on exploratory activity became apparent in Opalin−/− mice exposed to a novel environment. These results suggest that Opalin is not critical for central nervous system myelination or basic sensory and motor activities under conventional breeding conditions, although it might be required for fine-tuning of exploratory behavior.

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<![CDATA[Measurements of the parapapillary atrophy zones in en face optical coherence tomography images]]> https://www.researchpad.co/article/5989db52ab0ee8fa60bdc8da

Objective

To measure the parapapillary atrophy (PPA) area in en face images obtained with swept-source optical coherence tomography (SS-OCT), and to evaluate its relationship to glaucoma, myopia, and age in non-highly myopic subjects.

Design

Retrospective, cross-sectional study.

Participants

Fifty eyes of 30 subjects with open-angle glaucoma (G group) and forty-three eyes of 26 healthy control subjects (C group). Eyes with high myopia (spherical equivalent refractive error ≤ -8 diopters or axial length ≥ 26.5 mm) were excluded.

Methods

Mean age ± standard deviation was 59.9 ± 12.4 years. The beta zone and the gamma zone PPA areas were measured in en face images reconstructed from three-dimensional SS-OCT images. Relationship between the PPA areas and patient characteristics such as glaucoma, axial length, and age was statistically evaluated using multivariate mixed-effects models.

Main outcome measures

Areas of the beta zone and the gamma zone PPA measured on en face OCT images.

Results

Average ± standard deviation area of the beta and the gamma zone was 0.64 ± 0.79 and 0.16 ± 0.30 mm2, respectively. In multivariate models, the gamma zone significantly correlated with axial length (P = 0.001) but not with glaucoma (P = 0.944). In contrast, the beta zone significantly correlated with age (P = 0.0249) and glaucoma (P = 0.014).

Conclusions

En face images reconstructed from 3D SS-OCT data facilitated measurements of the beta and the gamma PPA zones even in eyes with optic disc distortion. The OCT-defined beta zone is associated with glaucoma and age, whereas the gamma zone correlated with myopia but not with glaucoma. This study confirmed the clinical usefulness of OCT-based classification of the PPA zones in distinguishing glaucomatous damage of the optic nerve from myopic damage in non-highly myopic eyes.

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<![CDATA[Macular Ganglion Cell Imaging Study: Covariate Effects on the Spectral Domain Optical Coherence Tomography for Glaucoma Diagnosis]]> https://www.researchpad.co/article/5989dab4ab0ee8fa60bac56c

Purpose

To evaluate the effect of multiple covariates on the diagnostic performance of the Cirrus high-definition optical coherence tomography (HD-OCT) for glaucoma detection.

Methods

A prospective case-control study was performed and included 173 recently diagnosed glaucoma patients and 63 unaffected individuals from the Macular Ganglion Cell Imaging Study. Regression analysis of receiver operating characteristic were conducted to evaluate the influence of age, spherical equivalent, axial length, optic disc size, and visual field index on the macular ganglion cell-inner plexiform layer (GCIPL) and peripapillary retinal nerve fiber layer (RNFL) measurements.

Results

Disease severity, as measured by visual field index, had a significant effect on the diagnostic performance of all Cirrus HD-OCT parameters. Age, axial length and optic disc size were significantly associated with diagnostic accuracy of average peripapillary RNFL thickness, whereas axial length had a significant effect on the diagnostic accuracy of average GCIPL thickness.

Conclusions

Diagnostic performance of the Cirrus HD-OCT may be more accurate in the advanced stages of glaucoma than at earlier stages. A smaller optic disc size was significantly associated with improved the diagnostic ability of average RNFL thickness measurements; however, GCIPL thickness may be less affected by age and optic disc size.

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<![CDATA[Topotecan Delivery to the Optic Nerve after Ophthalmic Artery Chemosurgery]]> https://www.researchpad.co/article/5989da41ab0ee8fa60b89e45

Extraocular retinoblastoma is a major challenge worldwide, especially in developing countries. Current treatment involves the administration of systemic chemotherapy combined with radiation, but there is a clear need for improvement of chemotherapy bioavailability in the optic nerve. Our aim was to study the ophthalmic artery chemosurgery (OAC) local route for drug delivery assessing ocular and optic nerve exposure to chemotherapy and to compare it to exposure after intravenous infusion (IV) of the same dose in an animal model. Topotecan was used as a prototype drug that is active in retinoblastoma and based on the extensive knowledge of its pharmacokinetics in preclinical and clinical settings. Five Landrace pigs received 4mg of topotecan via OAC as performed in retinoblastoma patients. At the end of the infusion, the eyes were enucleated, the optic nerve and retina were dissected, and the vitreous and plasma were separated. After recovery and a wash-out period, the animals received a 30-min IV infusion of topotecan (4 mg). The remaining eye was enucleated and tissues and fluids were separated. All samples were stored until quantitation using HPLC. A significantly higher concentration of topotecan in the optic nerve, vitreous, and retina was obtained in eyes after OAC compared to IV infusion (p<0.05). The median (range) ratio between topotecan concentration attained after OAC to IV infusion in the optic nerve, retina and vitreous was 84(54–668), 143(49–200) and 246(56–687), respectively. However, topotecan systemic exposure after OAC and IV infusion remained comparable (p>0.05). The median optic nerve-to-plasma ratio after OAC and IV was 44 and 0.35, respectively. Topotecan OAC delivery attained an 80-fold higher concentration in the optic nerve compared to the systemic infusion of the same dose with similar plasma concentrations in a swine model. Patients with retinoblastoma extension into the optic nerve may benefit from OAC for tumor burden by increased chemotherapy bioavailability in the optic nerve without increasing systemic exposure or toxicity.

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<![CDATA[Fibromyalgia Is Correlated with Retinal Nerve Fiber Layer Thinning]]> https://www.researchpad.co/article/5989d9e1ab0ee8fa60b69cea

Objective

To investigate whether fibromyalgia induces axonal damage in the optic nerve that can be detected using optical coherence tomography (OCT), as the retinal nerve fiber layer (RNFL) is atrophied in patients with fibromyalgia compared with controls.

Methods

Fibromyalgia patients (n = 116) and age-matched healthy controls (n = 144) were included in this observational and prospective cohort study. All subjects underwent visual acuity measurement and structural analysis of the RNFL using two OCT devices (Cirrus and Spectralis). Fibromyalgia patients were evaluated according to Giesecke’s fibromyalgia subgroups, the Fibromyalgia Impact Questionnaire (FIQ), and the European Quality of Life-5 Dimensions (EQ5D) scale. We compared the differences between fibromyalgia patients and controls, and analyzed the correlations between OCT measurements, disease duration, fibromyalgia subgroups, severity, and quality of life. The impact on quality of life in fibromyalgia subgroups and in patients with different disease severity was also analyzed.

Results

A significant decrease in the RNFL was detected in fibromyalgia patients compared with controls using the two OCT devices: Cirrus OCT ganglion cell layer analysis registered a significant decrease in the minimum thickness of the inner plexiform layer (74.99±16.63 vs 79.36±3.38 μm, respectively; p = 0.023), nasal inferior, temporal inferior and temporal superior sectors (p = 0.040; 0.011 and 0.046 respectively). The Glaucoma application of the Spectralis OCT revealed thinning in the nasal, temporal inferior and temporal superior sectors (p = 0.009, 0.006, and 0.002 respectively) of fibromyalgia patients and the Axonal application in all sectors, except the nasal superior and temporal sectors. The odds ratio (OR) to estimate the size effect of FM in RNFL thickness was 1.39. RNFL atrophy was detected in patients with FIQ scores <60 (patients in early disease stages) compared with controls in the temporal inferior sector (78.74±17.75 vs 81.65±3.61; p = 0.020) and the temporal superior sector (78.20±14.50 vs 80.74±3.88; p = 0.039) with Cirrus OCT; in the temporal inferior sector (145.85±24.32 vs 150.18±19.71; p = 0.012) and temporal superior sector (131.54±20.53 vs 138.13±16.67; p = 0.002) with the Glaucoma application of the Spectralis OCT; and in all sectors, except the average, nasal superior, and temporal sectors, and parameters with the Axonal application of the Spectralis OCT. Temporal inferior RNFL thickness was significantly reduced in patients with severe fibromyalgia (FIQ≥60) compared with patients with mild fibromyalgia (FIQ<60; 145.85±24.32 vs 138.99±18.09 μm, respectively; 145.43±13.21 vs 139.85±13.09 μm, p = 0.032 with the Glaucoma application and p = 0.021 with the Axonal application). The subgroup with biologic fibromyalgia exhibited significant thinning in the temporal inferior and superior sectors (115.17±20.82 μm and 117.05±24.19 μm, respectively) compared with the depressive (130.83±22.97 μm and 127.71±26.10 μm, respectively) and atypical (128.60±26.54 μm and 125.55±23.65 μm, respectively) subgroups (p = 0.005 and 0.001 respectively).

Conclusions

Fibromyalgia causes subclinical axonal damage in the RNFL that can be detected using innocuous and non-invasive OCT, even in the early disease stages. The impact on the RNFL in the temporal sectors is greater in patients with biologic fibromyalgia, suggesting the presence of neurodegenerative processes in this subgroup of patients with fibromyalgia.

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<![CDATA[Dendrimers Target the Ischemic Lesion in Rodent and Primate Models of Nonarteritic Anterior Ischemic Optic Neuropathy]]> https://www.researchpad.co/article/5989db4aab0ee8fa60bd9ef9

Introduction

Polyamidoamine dendrimer nanoparticles (~ 4 nanometers) are inert polymers that can be linked to biologically active compounds. These dendrimers selectively target and accumulate in inflammatory cells upon systemic administration. Dendrimer-linked compounds enable sustained release of therapeutic compounds directly at the site of damage. The purpose of this study was to determine if dendrimers can be used to target the optic nerve (ON) ischemic lesion in our rodent and nonhuman primate models of nonarteritic anterior ischemic optic neuropathy (NAION), a disease affecting >10,000 individuals in the US annually, and for which there currently is no effective treatment.

Methods

NAION was induced in male Long-Evans rats (rNAION) and in one adult male rhesus monkey (pNAION) using previously described procedures. Dendrimers were covalently linked to near-infrared cyanine-5 fluorescent dye (D-Cy5) and injected both intravitreally and systemically (in the rats) or just systemically (in the monkey) to evaluate D-Cy5 tissue accumulation in the eye and optic nerve following induction of NAION.

Results

Following NAION induction, Cy-5 dendrimers selectively accumulated in astrocytes and circulating macrophages. Systemic dendrimer administration provided the best penetration of the ON lesion site when injected shortly after induction. Systemic administration 1 day post-induction in the pNAION model gave localization similar to that seen in the rats.

Conclusions

Dendrimers selectively target the ischemic ON lesion after induction of both rNAION and pNAION. Systemic nanoparticle-linked therapeutics thus may provide a powerful, targeted and safe approach to NAION treatment by providing sustained and focused treatment of the cells directly affected by ischemia.

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<![CDATA[Oroxylin A promotes retinal ganglion cell survival in a rat optic nerve crush model]]> https://www.researchpad.co/article/5989db5fab0ee8fa60be119d

Purpose

To investigate the effect of oroxylin A on the survival of retinal ganglion cells (RGC) and the activation of microglial cells in a rat optic nerve (ON) crush model.

Methods

Oroxylin A (15mg/Kg in 0.2ml 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. The density of RGC was counted by retrograde labeling with FluoroGold and immunostaining of retina flat mounts for Brn3a. Electrophysiological visual function was assessed by flash visual evoked potentials (FVEP). TUNEL assay, immunoblotting analysis of glial fibrillary acidic protein (GFAP), inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) in the retinas, and immunohistochemistry of GFAP in the retinas and ED1 in the ON were evaluated.

Results

Two weeks after the insult, the oroxylin A-treated group had significantly higher FG labeled cells and Brn3a+ cells suggesting preserved RGC density in the central and mid-peripheral retinas compared with those of the PBS-treated group. FVEP measurements showed a significantly better preserved latency of the P1 wave in the ON-crushed, oroxylin A-treated rats than the ON-crushed, PBS treated rats. TUNEL assays showed fewer TUNEL positive cells in the ON-crushed, oroxylin A-treated rats. The number of ED1 positive cells was reduced at the lesion site of the optic nerve in the ON-crushed, oroxylin A-treated group. Increased GFAP expression in the retina was reduced greatly in ON-crushed, oroxylin A-treated group. Furthermore, administration of oroxylin A significantly attenuated ON crush insult-induced iNOS and COX-2 expression in the retinas.

Conclusions

These results demonstrated that oroxylin A hasss neuroprotective effects on RGC survival with preserved visual function and a decrease in microglial infiltration in the ONs after ON crush injury.

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<![CDATA[Neuroprotection by α2-Adrenergic Receptor Stimulation after Excitotoxic Retinal Injury: A Study of the Total Population of Retinal Ganglion Cells and Their Distribution in the Chicken Retina]]> https://www.researchpad.co/article/5989db23ab0ee8fa60bcfc05

We have studied the effect of α2-adrenergic receptor stimulation on the total excitotoxically injured chicken retinal ganglion cell population. N-methyl-D-aspartate (NMDA) was intraocularly injected at embryonic day 18 and Brn3a positive retinal ganglion cells (Brn3a+ RGCs) were counted in flat-mounted retinas using automated routines. The number and distribution of the Brn3a+ RGCs were analyzed in series of normal retinas from embryonic day 8 to post-hatch day 11 retinas and in retinas 7 or 14 days post NMDA lesion. The total number of Brn3a+ RGCs in the post-hatch retina was approximately 1.9x106 with a density of approximately 9.2x103 cells/mm2. The isodensity maps of normal retina showed that the density decreased with age as the retinal size increased. In contrast to previous studies, we did not find any specific region with increased RGC density, rather the Brn3a+ RGCs were homogeneously distributed over the central retina with decreasing density in the periphery and in the region of the pecten oculli. Injection of 5–10 μg NMDA caused 30–50% loss of Brn3a+ cells and the loss was more severe in the dorsal than in the ventral retina. Pretreatment with brimonidine reduced the loss of Brn3a+ cells both 7 and 14 days post lesion and the protective effect was higher in the dorsal than in the ventral retina. We conclude that α2-adrenergic receptor stimulation reduced the impact of the excitotoxic injury in chicken similarly to what has been shown in mammals. Furthermore, the data show that the RGCs are evenly distributed over in the retina, which challenges previous results that indicate the presence of specific high RGC-density regions of the chicken retina.

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<![CDATA[Glaucoma in high myopia and parapapillary delta zone]]> https://www.researchpad.co/article/5989db50ab0ee8fa60bdc1f8

Purpose

To examine the prevalence of glaucomatous optic neuropathy (GON) in a medium myopic to highly myopic group of patients and its association with parapapillary gamma zone and parapapillary delta zone.

Methods

The retrospective observational hospital-based study included patients who had attended the Tokyo High Myopia Clinics within January 2012 and December 2012 and for whom fundus photographs were available. GON was defined based on the appearance of the optic nerve head on the fundus photographs.

Results

The study included 519 eyes (262 individuals) with a mean age of 62.0±14.3 years (range:13–89 years) and mean axial length of 29.5±2.2 mm (range:23.2–35.3mm). GON was present in 141 (27.2%; 95% confidence intervals (CI): 23.3, 31.0%) eyes. Prevalence of GON increased from 12.2% (1.7, 22.7) in eyes with an axial length of <26.5mm to 28.5% (24.4, 32.5) in eyes with an axial length of ≥26.5mm, to 32.6% (27.9, 37.2) in eyes with an axial length of ≥28mm, to 36.0% (30.5, 41.4) in eyes with an axial length of ≥29mm, and GON prevalence increased to 42.1% (35.5, 48.8) in eyes with an axial length of ≥30mm. In multivariate analysis, higher GON prevalence was associated (Nagelkerke r2: 0.28) with larger parapapillary delta zone diameter (P<0.001; odds ratio (OR):1.86;95%CI:1.33,2.61), longer axial length (P<0.001;OR:1.45;95%CI:1.26,1.67) and older age (P = 0.01;OR:1.03;95%CI:1.01,1.05). If parapapillary delta zone width was replaced by the vertical disc diameter, higher GON prevalence was associated (r2:0.24) with larger vertical optic disc diameter (P = 0.04;OR:1.70;95%CI:1.03,2.81), after adjusting for longer axial length (P<0.001;OR:1.44;95%CI:1.26,1.64) and older age (P<0.001;OR:1.04;95%CI:1.02,1.06).

Conclusions

Axial elongation associated increase in GON prevalence (mean: 28.1% in a medium to highly myopic study population) was associated with parapapillary delta zone as surrogate for an elongated peripapillary scleral flange and with larger optic disc size.

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<![CDATA[Fzd4 Haploinsufficiency Delays Retinal Revascularization in the Mouse Model of Oxygen Induced Retinopathy]]> https://www.researchpad.co/article/5989dafcab0ee8fa60bc51e4

Mutations in genes that code for components of the Norrin-FZD4 ligand-receptor complex cause the inherited childhood blinding disorder familial exudative vitreoretinopathy (FEVR). Statistical evidence from studies of patients at risk for the acquired disease retinopathy of prematurity (ROP) suggest that rare polymorphisms in these same genes increase the risk of developing severe ROP, implying that decreased Norrin-FZD4 activity predisposes patients to more severe ROP. To test this hypothesis, we measured the development and recovery of retinopathy in wild type and Fzd4 heterozygous mice in the absence or presence of ocular ischemic retinopathy (OIR) treatment. Avascular and total retinal vascular areas and patterning were determined, and vessel number and caliber were quantified. In room air, there was a small delay in retinal vascularization in Fzd4 heterozygous mice that resolved as mice reached maturity suggestive of a slight defect in retinal vascular development. Subsequent to OIR treatment there was no difference between wild type and Fzd4 heterozygous mice in the vaso-obliterated area following exposure to high oxygen. Importantly, after return of Fzd4 heterozygous mice to room air subsequent to OIR treatment, there was a substantial delay in retinal revascularization of the avascular area surrounding the optic nerve, as well as delayed vascularization toward the periphery of the retina. Our study demonstrates that a small decrease in Norrin-Fzd4 dependent retinal vascular development lengthens the period during which complications from OIR could occur.

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<![CDATA[Dichoptic Metacontrast Masking Functions to Infer Transmission Delay in Optic Neuritis]]> https://www.researchpad.co/article/5989da1dab0ee8fa60b7d7bb

Optic neuritis (ON) has detrimental effects on the transmission of neuronal signals generated at the earliest stages of visual information processing. The amount, as well as the speed of transmitted visual signals is impaired. Measurements of visual evoked potentials (VEP) are often implemented in clinical routine. However, the specificity of VEPs is limited because multiple cortical areas are involved in the generation of P1 potentials, including feedback signals from higher cortical areas. Here, we show that dichoptic metacontrast masking can be used to estimate the temporal delay caused by ON. A group of 15 patients with unilateral ON, nine of which had sufficient visual acuity and volunteered to participate, and a group of healthy control subjects (N = 8) were presented with flashes of gray disks to one eye and flashes of gray annuli to the corresponding retinal location of the other eye. By asking subjects to report the subjective visibility of the target (i.e. the disk) while varying the stimulus onset asynchrony (SOA) between disk and annulus, we obtained typical U-shaped masking functions. From these functions we inferred the critical SOAmax at which the mask (i.e. the annulus) optimally suppressed the visibility of the target. ON-associated transmission delay was estimated by comparing the SOAmax between conditions in which the disk had been presented to the affected and the mask to the other eye, and vice versa. SOAmax differed on average by 28 ms, suggesting a reduction in transmission speed in the affected eye. Compared to previously reported methods assessing perceptual consequences of altered neuronal transmission speed the presented method is more accurate as it is not limited by the observers’ ability to judge subtle variations in perceived synchrony.

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<![CDATA[Tyrosine-mutated AAV2-mediated shRNA silencing of PTEN promotes axon regeneration of adult optic nerve]]> https://www.researchpad.co/article/5989db50ab0ee8fa60bdc008

Activating PI3K/AKT/mTOR signaling pathway via deleting phosphatase and tensin homolog (PTEN) has been confirmed to enhance intrinsic growth capacity of neurons to facilitate the axons regeneration of central nervous system after injury. Considering conditional gene deletion is currently not available in clinical practice, we exploited capsid residue tyrosine 444 to phenylalanine mutated single-stranded adeno-associated virus serotype 2 (AAV2) as a vector delivering short hairpin RNA to silence PTEN to promote retinal ganglion cells (RGCs) survival and axons regeneration in adult rat optic nerve axotomy paradigm. We found that mutant AAV2 displayed higher infection efficiency to RGCs and Müller cells by intravitreal injection, mediated PTEN suppression, resulted in much more RGCs survival and more robust axons regeneration compared with wild type AAV2, due to the different extent of the mTOR complex-1 activation and glutamate aspartate transporter (GLAST) regulation. These results suggest that high efficiency AAV2-mediated PTEN knockdown represents a practicable therapeutic strategy for optic neuropathy.

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<![CDATA[Optical coherence tomography angiography in eyes with good visual acuity recovery after treatment for optic neuritis]]> https://www.researchpad.co/article/5989db4fab0ee8fa60bdbadf

Objective

To evaluate the retinal perfusion using optical coherence tomography (OCT) angiography in eyes with good visual acuity recovery after treatment for optic neuritis (ON).

Methods

Seven eyes of seven patients with good visual acuity recovery after treatment for monocular ON and seven eyes of each fellow eye used as controls were studied. Retinal perfusion around the disc and at the macula was evaluated using OCT angiography. The retinal nerve fiber layer thickness was measured around the disc. The ganglion cell layer complex thickness or the ganglion cell layer plus the inner plexiform layer thickness were measured at the macula.

Results

The retinal perfusions in all eyes with ON decreased around the disc and at the macula compared with those of the fellow eyes, as shown by OCT angiography (disc, P = 0.003; macula, P = 0.001). The retinal thicknesses in all eyes with ON also decreased around the disc and at the macula compared with those of the fellow eyes (disc, P < 0.001; macula, P = 0.003).

Conclusions

Optic neuritis may cause not only retinal structural damage but also decreased retinal perfusion, even after the visual acuity recovered well after treatment.

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