Benign Lobular Inner Nuclear Layer Proliferations of the Retina Associated with Congenital Hypertrophy of the Retinal Pigment Epithelium.

PURPOSE: To report the clinical and imaging findings of 4 patients with benign intraretinal tumors, 2 of which were associated with retinal pigment epithelium (RPE) hypertrophy. To our knowledge, this condition has not been described previously and should be distinguished from retinoblastoma and other malignant retinal neoplasms. DESIGN: Retrospective case series. PARTICIPANTS: Four patients from 3 institutions. METHODS: Four patients with intraretinal tumors of the inner nuclear layer (INL) underwent a combination of ophthalmic examination, fundus photography, fluorescein angiography, OCT, OCT angiography, and whole exome sequencing. MAIN OUTCOME MEASURES: Description of multimodal imaging findings and systemic findings from 4 patients with benign intraretinal tumors and whole exome studies from 3 patients. RESULTS: Six eyes of 4 patients 5, 13, 32, and 27 years of age were found to have white intraretinal tumors that remained stable over the follow-up period (range, 9 months-4 years). The tumors were unilateral in 2 patients and bilateral in 2 patients. The tumors were white, centered on the posterior pole, and multifocal, with some consisting of multiple lobules with arching extensions that extended beyond the central tumor mass. OCT demonstrated these lesions to be centered within the INL at the border of the inner plexiform layer. In addition, 2 patients demonstrated congenital hypertrophy of the RPE (CHRPE) lesions. Three of 4 patients underwent whole exome sequencing of the blood that revealed no candidate variants that plausibly could account for the phenotype. CONCLUSIONS: We characterize a novel benign tumor of the INL that, in 2 patients, was associated with separate CHRPE lesions. We propose the term benign lobular inner nuclear layer proliferation to describe these lesions. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found after the references.

Pattern ERGs suggest a possible retinal contribution to the visual acuity loss in acute optic neuritis.

PURPOSE: Macular involvement in optic neuritis (ON) is well-recognised but poorly understood and may be of clinical relevance. This study explores macular structure-function correlates in acute ON. METHODS: This cross-sectional cohort study recruited ON patients within 14 days of symptom onset. Subjects underwent pattern electroretinography (PERG), pattern visual evoked potentials (PVEP) and optical coherence tomography (OCT) imaging. PERG P50 and N95 components were correlated with OCT data. RESULTS: Twenty-six individuals with ON were recruited, comprising eleven multiple sclerosis (MS-ON), six myelin oligodendrocyte glycoprotein associated (MOG-ON) and nine with isolated ON. These were compared with 28 healthy controls. PVEPs were undetectable in 11 (42%) of individuals with ON. When detectable, PVEP P100 was delayed (median 136 ms range 110-173 ms) and amplitude reduced (median 6 µV, range 3-14 µV) in ON compared with controls (both p < 0.001). PERG P50 component amplitudes, largely reflecting macular function, were reduced in affected eyes (median 2.3 µV; range 0.8-5.0 µV) compared with controls (3.3 µV; range 2.8-5.7 µV) and compared with fellow eyes (p < 0.001). The N95:P50 ratio was below the reference range in the affected eyes of five patients. Eight cases (32%) had subnormal P50 amplitudes (< 2.0 µV), and these patients had poorer visual acuity (p = 0.020). P50 amplitudes were positively correlated with an increase in inner nuclear layer thickness (rs = 0.36; p = 0.009) and macular ganglion cell and inner plexiform layer (mGCIPL) thickness (rs = 0.44, p = 0.022). CONCLUSION: PERG P50 component reduction reveals dysfunction of inner macular layers in acute ON and correlates with structural alterations on OCT. These early macular pathologic processes are likely to contribute to the visual loss.

Resveratrol inhibits neural apoptosis and regulates RAX/P-PKR expression in retina of diabetic rats.

PURPOSE: This study was to investigate the effect of resveratrol (RSV) administration on diabetes-induced neural apoptosis and on RNA-dependent-protein-kinase (PKR)-associated protein X (RAX), PKR and phosphorylated PKR (P-PKR) expression and distribution in retina of diabetic rats. METHODS: Retina was obtained from normal and diabetic Sprague-Dawley rats with or without RSV (5 and 10 mg/kg/d) treatment at 30-, 32-, 34- and 36-weeks. Apoptosis of retinal neural cells and distribution of RAX/P-PKR was assessed by TUNEL and immunofluorescence methods. Expression of RAX, PKR and P-PKR was evaluated by qRT-PCR and western-blotting methods. RESULTS: Our study showed that the TUNEL-positive cells were mainly localized in ganglion cells layer (GCL), inner nuclear layer (INL) and outer nuclear layer (ONL) of the diabetic rat's retina at 30-, 32-, 34- and 36-weeks. RSV administration effectively suppressed the neural apoptosis in GCL, INL and ONL. Almost no TUNEL-positive cells were observed in retina of normal control and RSV-treated normal control rats. Our study also showed that the expression level of RAX, P-PKR in diabetic rats retina at 30-, 32-, 34-, and 36-weeks was elevated. With supplementation of 5 and 10 mg/kg/d RSV, the expression level of RAX and P-PKR was decreased (P < 0.05). The expression level of RAX and P-PKR in the retina of normal control rats was not altered by RSV. The expression level of PKR was not altered by streptozotocin injection and RSV treatment. CONCLUSIONS: Our results suggested that RSV attenuates retinal neural apoptosis in diabetic rats retina may be via regulation RAX/P-PKR expression.

Posterior segment spectral domain oct in the differential diagnosis of bilateral temporal optic neuropathy and its correlation with visual acuity.

PURPOSE: To identify the underlying etiologies and to evaluate the differential diagnostic value of posterior segment spectral domain OCT measurements and their correlation with best-corrected visual acuity (BCVA) in a group of patients with OCT documented bilateral optic neuropathy limited to the temporal quadrants. METHODS: Retrospective study. RESULTS: We included 61 patients: 35 presented with presumed "classic" acquired mitochondrial optic neuropathy (MON) (18 nutritional, 11 toxic, 6 mixed toxic-nutritional) and 2 with suspected hereditary MON. Nine patients were identified as 'MON mimickers' (especially multiple sclerosis), and 4 were found to have a mixed mechanism, while 11 remained undiagnosed. Across all etiologies, the strongest positive relationship between BCVA and tested OCT parameters was with macular GCL (ganglion cell layer) and GCIPL (combined ganglion cell and inner plexiform layer) volumes rather than peripapillary retinal nerve fiber layer (RNFL) thicknesses (all statistically significant). There was an inverse relationship between BCVA and inner nuclear layer (INL) volumes, with significant differences for BCVA and all tested OCT parameters between eyes with and without INL microcystoid lesions. OCT (absolute values and intereye differences) was not helpful in distinguishing between presumed acquired mitochondrial disease and patients with multiple sclerosis without optic neuritis. However, significantly greater intereye differences in global RNFL and inner plexiform layer and GCIPL volumes were found in patients with a previous history of unilateral optic neuritis. CONCLUSIONS: The strongest positive relationship with BCVA was found for macular GCL and GCIPL volumes. OCT could not differentiate between acquired mitochondrial disease and multiple sclerosis without optic neuritis.

[Biomarkers of retinal ischemia in thrombotic microangiopathy associated with malignant arterial hypertension on optical coherence tomography]. / Markery retinal'noi ishemii pri tromboticheskoi mikroangiopatii, assotsiirovannoi so zlokachestvennoi arterial'noi gipertenziei, po dannym opticheskoi kogerentnoi tomografii.

Malignant arterial hypertension is a clinical syndrome characterized by severe diastolic arterial hypertension with signs of ischemic damage to various organs. In some malignant arterial hypertension cases, thrombotic microangiopathy occurs - a rare life-threatening condition characterized by multiple systemic thrombosis of the microvasculature, including in the eyes, which can be clarified by optical scanning of the retina. PURPOSE: To determine markers of retinal ischemia in the eyes with thrombotic microangiopathy associated with malignant arterial hypertension. MATERIAL AND METHODS: The study included 6 patients (12 eyes) with thrombotic microangiopathy associated with malignant arterial hypertension who were examined by optical coherence tomography (OCT) and OCT angiography (OCT-A). All patients suffered from renal dysfunction, which etiology was determined by renal biopsy verifying the presence of renal thrombotic microangiopathy in all cases. RESULTS: According to OCT findings, there were bilateral local foci of thinning of the inner nuclear layer with elevation of the outer plexiform and outer nuclear layers of the retina in 5 out of 6 patients (83%). OCT-A revealed that in most cases (67%), these changes had perivascular localization and corresponded to the areas of attenuation of the deep capillary plexus. A statistically significant thinning of the inner nuclear layer of the retina was found in thrombotic microangiopathy associated with malignant arterial hypertension in comparison with the control group. CONCLUSION: Presence of renal thrombotic microangiopathy confirmed by renal biopsy and the anatomical similarity of the microvasculature of the kidneys and the eyes, give basis to consider the foci of «chronic¼ paracentral acute middle maculopathy detected with OCT in patients with malignant arterial hypertension as biomarkers of thrombotic microangiopathy of the eye.

Deep Learning in Toxicologic Pathology: A New Approach to Evaluate Rodent Retinal Atrophy.

Quantification of retinal atrophy, caused by therapeutics and/or light, by manual measurement of retinal layers is labor intensive and time-consuming. In this study, we explored the role of deep learning (DL) in automating the assessment of retinal atrophy, particularly of the outer and inner nuclear layers, in rats. Herein, we report our experience creating and employing a hybrid approach, which combines conventional image processing and DL to quantify rodent retinal atrophy. Utilizing a DL approach based upon the VGG16 model architecture, models were trained, tested, and validated using 10,746 image patches scanned from whole slide images (WSIs) of hematoxylin-eosin stained rodent retina. The accuracy of this computational method was validated using pathologist annotated WSIs throughout and used to separately quantify the thickness of the outer and inner nuclear layers of the retina. Our results show that DL can facilitate the evaluation of therapeutic and/or light-induced atrophy, particularly of the outer retina, efficiently in rodents. In addition, this study provides a template which can be used to train, validate, and analyze the results of toxicologic pathology DL models across different animal species used in preclinical efficacy and safety studies.

Angulation of the inner nuclear layer as an indicator of the severity of macular pseudohole.

PURPOSE: To investigate foveal morphologic parameters related to visual acuity and the stages classified in this study reflect the severity of the macular pseudohole (MPH). METHODS: Seventy-eight eyes of 78 consecutive patients diagnosed with MPH were studied. Quantitative optical coherence tomography (OCT) parameters including central foveal thickness, parafoveal thickness, parafoveal inner and outer retinal thickness (PIRT and PORT), pseudohole depth, pseudohole diameter, and inner nuclear layer (INL) angulation were measured and the morphologic features of the inner retina (disorganization of retinal inner layers (DRIL)) and the photoreceptor layer (external limiting membrane (ELM), ellipsoid zone (EZ), interdigitation zone (IZ), and cotton ball sign) were determined. Associations between OCT parameters and best-corrected visual acuity (BCVA) were analyzed. Based on the location of the inner margin of INL, all patients were divided into three stages and the mean comparison between the three stages was analyzed. RESULTS: PIRT (r = 0.6489; p < 0.0001) and pseudohole depth (r = 0.5266; p < 0.0001) had a statistically significant correlation with BCVA. Statistically significant visual acuity differences were found in eyes with DRIL (p < 0.001) and IZ disruption (p = 0.018), but not in ELM disruption (p = 0.916), EZ disruption (p = 0.581), and cotton ball sign (p = 0.075). According to the univariate and multivariate regression analyses, PIRT was associated with BCVA in both univariate (p < 0.001) and multivariate (p = 0.002) regression analyses. Defect diameters of both ELM (p = 0.025) and IZ (p = 0.006) were associated with BCVA in univariate regression analysis, but not in multivariate regression analysis. INL angulation and the ratio of the IZ disruption was significantly different in the three groups. Stage 3 (95.8%) had significantly higher disrupted IZ ratio than stage 1 (40%) and stage 2 (65.5%). The BCVA of stages 1, 2, and 3 were identified as 0.06 ± 0.07 (20/23 Snellen equivalent), 0.23 ± 0.17 (20/34 Snellen equivalent), and 0.48 ± 0.23 (20/60 Snellen equivalent), respectively, and the differences in BCVA between the three groups were significant (p < 0.0001). CONCLUSION: The parameters related to visual acuity were PIRT, pseudohole depth, DRIL, and IZ. The stage classification proposed in this study included morphologic changes of the inner retina and photoreceptor layer and is likely to be clinically useful for showing the severity of the MPH.

Evaluation of non-exudative microcystoid macular abnormalities secondary to retinal vein occlusion.

PURPOSE: We aimed to investigate non-exudative microcystoid macular abnormalities for visual and anatomical outcome in patients with retinal vein occlusion (RVO) with and without glaucomatous optic neuropathy (GON). METHODS: Medical records of 124 eyes (105 patients) with RVO were reviewed and analyzed. Eyes demonstrating microcystoid macular abnormalities were divided into 2 groups, those with evidence of glaucoma (group A) and those without glaucoma (group B). Best-corrected visual acuity (BCVA), the prevalence and number of microcystoid macular abnormalities, and number of intravitreal anti-vascular endothelial growth factor (anti-VEGF) injections were compared at baseline and follow-up. RESULTS: Seventy-one out of 105 eyes (67.6%) with RVO displayed microcystoid macular abnormalities. Thirty-eight out of 71 eyes (53.5%) presented with concomitant glaucoma (group A), while the remaining 33 eyes (42.6%) had no history of glaucoma (group B). At the end of the follow-up period, mean BCVA was worse in group A versus group B (20/80 versus 20/40, respectively; p = .003). The mean number of anti-VEGF injections was 10.1 ± 9.2 in group A versus 5.9 ± 6.9 in group B (p = .03). CONCLUSION: Eyes with RVO and concomitant glaucoma exhibited a significantly higher number of microcystoid macular abnormalities and worse BCVA versus eyes with RVO without glaucoma.

Anatomical effects of intravitreal anti-vascular endothelial growth factor injections on inner layers of the lesion-free retina.

PURPOSE: The primary aim of the study was to investigate the effects of anti-vascular endothelial growth factor (VEGF) injections on the inner retinal layer anatomy of the lesion-free retina in eyes treated for neovascular age-related macular degeneration (nAMD). The secondary aim was to compare the changes of inner retinal layers in the lesion-free region of treated eyes with the same region of the untreated, fellow eyes and, thus, to elucidate any adverse effect of anti-VEGF treatments independently of 1-year aging changes. METHODS: This was a retrospective, longitudinal, case-control study of 50 eyes of 25 patients. Twenty-five eyes with nAMD comprised the study group (16 eyes treated with aflibercept and 9 eyes treated with ranibizumab) and 25 fellow eyes with dry AMD (16 eyes in AREDS 2 and 9 eyes in AREDS 3) comprised the fellow eye group. Spectral-domain optical coherence tomography (SD-OCT) measurements were done at pre-treatment, 1 month after three loading anti-VEGF injections and at the end of 1 year. The retinal nerve fiber layer (RNFL), ganglion cell layer (GCL), inner plexiform layer (IPL), inner nuclear layer (INL) thicknesses and total retinal thickness in the macula were measured. Thicknesses of inner retinal layers which were lesion-free in the outer nasal subfield of ETDRS grid were analysed and the changes in thicknesses during the follow-up period were compared between study and fellow eye groups. Paired t-test for normally distributed variables was applied for analyses of differences for the comparison of the results across the pre-and the post-. A p value of less than 0.05 was considered statistically significant. RESULTS: The mean number of injections was 5.76 ± 1.26 in the study group in 1 year. The mean decrease in total retinal thickness was significant with 6.08 ± 9.05 µm (p= 0.003) in nAMD group and was insignificant with 0.32 ± 1.03 µm (p> 0.05) in fellow eye group with dry AMD. Most of the retinal thickness decrease was during first three injections in nAMD group. Total retinal thickness and GCL thickness were thinner in the study group at every follow-up examination, but the difference between groups was not statistically significant (p> 0.05). RNFL, GCL, IPL, and INL thicknesses did not demonstrate a statistically significant change in both study and fellow eye groups during 1 year follow-up period (p> 0.05). CONCLUSIONS: Repeated anti-VEGF injections in nAMD appear to have no significant effect on the RNFL, GCL, IPL, and INL thicknesses of the lesion-free retina. Additionally, there was no significant difference in inner retinal layer changes between in eyes treated with anti-VEGF injections for nAMD and fellow eye group during 1-year follow-up.

Regional analysis of segmented-macular structure in patients with myopic anisometropia.

PURPOSE: To compare intraretinal layers between the eyes in patients with myopic anisometropia, and evaluate the relationship between the layers with spherical equivalent (SE) and axial length (AL). METHODS: In this retrospective study, the more myopic (MM) and fellow (F) eyes of 41 patients with myopic anisometropia, and 38 emmetropic (± 0.50 diopter) control (C) eyes were inclueded. Intraretinal layer segmentation was performed by optical coherence tomography. Global volumes of retinal layers and their thicknesses in nine macular regions were compared. Correlation analysis was used to determine the relationship with SE and AL in each layer. RESULTS: Total retinal, ganglion cell (GCL), inner nuclear (INL), and outer plexiform (OPL) layer volumes in MM eyes were less than in C eyes, while INL and OPL were less than in F eyes. There was no difference in the fovea, except for the retinal pigment epithelium. In MM eyes, only INL and OPL were thin in at least one perifoveal and parafoveal quadrant compared to F eyes. Only INL and OPL thicknesses were significantly correlated with both SE and AL in all perifoveal quadrants. In contrast to the thinning found in MM eyes, the only layer in which thickening was detected to compare to C eye was nerve fiber layer (NFL), which correlated positively with SE and negatively with AL. CONCLUSION: While the fovea is less affected by myopia, thinning becomes remarkable in the perifoveal quadrants. Despite thinning in many layers, especially INL and OPL, NFL thickening may be seen due to myopia.

Progression of Anterograde Trans-Synaptic Degeneration in the Human Retina Is Modulated by Axonal Convergence and Divergence.

In the visual pathway of patients with multiple sclerosis (MS), the inner nuclear layer (INL) of the retina is a tight barrier for retrograde trans-synaptic degeneration. In this observational, retrospective cross-sectional study, segmented macular spectral domain optical coherence tomography (OCT) volume scans were reviewed to investigate if this observation also holds true for anterograde trans-synaptic degeneration. Significant thinning was found in all retinal layers in patients with outer retinal diseases compared with the healthy controls, while there was no significant attenuation of the outer retina in patients with MS. In contrast to the tight barrier function observed with retrograde trans-synaptic degeneration, the INL appears to be more permissive for the propagation of anterograde trans-synaptic degeneration. We speculate that this may be due to the size of the area affected and be explained by convergence and divergence of axons within the retinal layers. These findings are likely relevant to future restorative stem cell treatment of the outer retinal layers, as time may matter.

Improved analysis of foveal avascular zone area with optical coherence tomography angiography.

PURPOSE: To investigate the relationship between the foveal avascular zone (FAZ) and the inner nuclear layer (INL)-free zone in the center of the fovea in order to provide an improved approach to evaluation of the FAZ area with optical coherence tomography angiography (OCTA). METHODS: Thirty-six healthy individuals (36 eyes) and 15 age-matched patients (15 eyes) with nonproliferative diabetic retinopathy (nPDR) were included in this study. The FAZ, as well as INL-free zone, was measured on OCTA images. The FAZ area, INL-free zone area, and the ratio of the INL-free zone area to the FAZ area were compared between healthy subjects and nPDR patients. RESULTS: The mean FAZ area in healthy subjects and nPDR patients was 0.33 ± 0.1 mm2 and 0.41 ± 0.19 mm2 (p < 0.05), respectively. The mean INL-free zone area in healthy subjects and nPDR patients was 0.33 ± 0.07 mm2 and 0.25 ± 0.09 mm2 (p > 0.05), respectively. The INL-free zone area to the FAZ area ratio in healthy subjects and nPDR patients was 1.08 ± 0.25 and 0.56 ± 0.18 (p < 0.001), respectively. Receiver operating characteristic analysis showed that the INL-free zone area to the FAZ area ratio had a higher area under curve (0.94; 80.0% sensitivity and 97.2% specificity) compared to the FAZ area (0.61; 40.0% sensitivity and 94.4% specificity) for differentiating nPDR from healthy eyes. CONCLUSION: This study showed that analysis of the FAZ based on the ratio of the INL-free zone area to the FAZ area has better accuracy compared to the conventional FAZ area measurement in differentiating eyes with mild to moderate nPDR without any structural abnormalities in the fovea from healthy eyes.

Acetazolamide Reduces Retinal Inner Nuclear Layer Thickness in Microcystic Macular Edema Secondary to Optic Neuropathy.

Optic neuropathy (ON) is commonly complicated by microcystic macular edema (MME), that is, small vertical cystoid spaces in the inner nuclear layer (INL) of the macula. We performed a retrospective consecutive case series of 14 eyes from 11 patients with ON and MME that were treated with oral acetazolamide, acting on cellular water transport. Contralateral eyes without MME were used as controls. Segmentation of images obtained with OCT was used to determine changes of individual retinal layer thickness during treatment. Retinal INL thickness consistently decreased in all eyes after 2-3 weeks of treatment. Recurrence of MME was observed after treatment cessation. No significant change of retinal thickness was found in contralateral unaffected eyes. Visual function did not change with treatment. Acetazolamide significantly improved the MME in eyes with ON. However, visual function did not. Acetazolamide is a treatment option for MME associated with ON but without an impact on the visual function.

Inner nuclear layer cystoid spaces are a poor prognostic factor in typical age-related macular degeneration and polypoidal choroidal vasculopathy.

PURPOSE: To investigate predictive factors for changes in best-corrected visual acuity (BCVA) at 24 months after intravitreal ranibizumab (IVR) for neovascular age-related macular degeneration (nAMD). METHODS: This retrospective study included 55 eyes of 55 consecutive patients (32 men and 23 women) with nAMD who received three consecutive monthly IVR injections and were re-treated as needed over a 24-month period. We used the mean changes in logarithm of the minimal angle of resolution (logMAR) BCVA at 24 months as the dependent variable in regression analysis. RESULTS: The presence of intraretinal cystoid spaces in the inner nuclear layer (INLc, P = 0.004) and baseline subfoveal choroidal thickness (SFCT, P = 0.013) predicted BCVA changes from baseline to 24 months. The presence of INLc and thinning of SFCT were associated with decreased BCVA at 24 months. Thirty-five eyes without INLc showed improved logMAR BCVA, from 0.550 ± 0.273 to 0.368 ± 0.274 (P = 0.045); however, 20 eyes with INLc showed decreased logMAR BCVA, from 0.708 ± 0.347 to 0.971 ± 0.523 (P < 0.001) through the 24-month follow-up. The mean number of IVR injections during the follow-up period was 8.74 ± 4.76 in eyes without INLc and 10.63 ± 4.72 in eyes with INLc, without a statistically significant difference (P = 0.144). CONCLUSION: Eyes with INLc or thinned SFCT showed worse visual outcomes compared with eyes without the INLc or with thick SFCT. Furthermore, eyes without INLc showed improved BCVA; however, eyes with INLc showed decreased BCVA with an as-needed regimen.

Different foveal schisis patterns in each retinal layer in eyes with hereditary juvenile retinoschisis evaluated by en-face optical coherence tomography.

PURPOSE: To analyze the structures of schisis in eyes with hereditary juvenile retinoschisis using en-face optical coherence tomography (OCT) imaging. METHODS: In this retrospective observational study, we reviewed the medical records of patients with hereditary juvenile retinoschisis who underwent comprehensive ophthalmic examinations including swept-source OCT. RESULTS: OCT images were obtained from 16 eyes of nine boys (mean age ± standard deviation, 10.6 ± 4.0 years). The horizontal OCT images at the fovea showed inner nuclear layer (INL) schisis in one eye (6.3 %), ganglion cell layer (GCL) and INL schisis in 12 eyes (75.0 %), INL and outer plexiform layer (OPL) schisis in two eyes (12.5 %), and GCL, INL, and OPL schisis in one eye (6.3 %). En-face OCT images showed characteristic schisis patterns in each retinal layer, which were represented by multiple hyporeflective holes in the parafoveal region in the GCL, a spoke-like pattern in the foveal region, a reticular pattern in the parafoveal region in the INL, and multiple hyporeflective polygonal cavities with partitions in the OPL. CONCLUSIONS: Our results using en-face OCT imaging clarified different patterns of schisis formation among the GCL, INL, and OPL, which lead to further recognition of structure in hereditary juvenile retinoschisis.

Optical coherence tomography indicates disease activity prior to clinical onset of central nervous system demyelination.

BACKGROUND: Establishing biomarkers for predicting disease activity in demyelinating disease of the central nervous system is crucial for designing appropriate disease modifiying treatment strategies. OBJECTIVE: To investigate retinal findings and disease activity in patients with radiologically isolated and clinically isolated syndromes. METHODS: We performed retinal optical coherence tomography and cerebral magnetic resonance imaging in healthy control individuals (n=19), in individuals with non-specific white matter lesions (n=18), and in patients with clinically isolated syndromes (n=18) and radiologically isolated syndromes (n=20). RESULTS: Reduced volume of retinal nerve fibre layer and increased volume of inner nuclear layer at baseline correlated with subsequent disease activity as measured by an increase in cerebral T2 lesion load in patients with radiologically isolated syndromes. Reduced volume of retinal nerve fibre layer and increased volumes of inner and outer nuclear layer were associated with progression into multiple sclerosis in patients with clinically isolated syndromes. CONCLUSION: Patients with radiologically and clinically isolated syndromes behave similarly concerning paraclinical disease activity in cerebral magnetic resonance imaging. In both conditions, reduction of retinal nerve fibre layer and increased inner nuclear layer and outer nuclear layer volumes predict disease activity and are associated with progression into multiple sclerosis.

Longitudinal analysis of the structural pattern of pseudophakic cystoid macular edema using multimodal imaging.

PURPOSE: To describe the relationship between pseudophakic cystoid macular edema (CME) progression and retinal structural changes observed by spectral-domain optical coherence tomography (SD-OCT) and fluorescein angiography. METHODS: Retrospective, consecutive, longitudinal imaging analysis of patients with acute pseudophakic cystoid macular edema. Two observers at two study centers evaluated all images and categorized the macular structural features based on the retinal layer involved with cystic changes and/or subretinal fluid. A time series of the structural pattern and visual acuity was constructed for 1-month intervals over a 6-month study period. RESULTS: Thirty nine patients presented with CME. The mean time since cataract extraction was 48 ±38 days (range 5-71). CME included inner nuclear layer (INL) cystic changes, outer plexiform layer (OPL) cystic changes, and subretinal fluid. Isolated INL changes were observed in four phakic fellow eyes. Isolated OPL morphology was not observed, and additional inner layers remained uninvolved. Resolution occurred rapidly following administration of periocular glucocorticoids, and typically demonstrated a reverse structural pattern or delayed subretinal fluid resolution. Isolated subretinal fluid or a combined INL and subretinal fluid structure indicated CME resolution. CONCLUSION: Acute and recurrent pseudophakic CME involves a directional progression of the retinal layer involved with cystic changes and a clinical course. CME begins with INL cystic changes, progresses to combined INL and OPL morphology, and may continue to involve subretinal fluid. The inner nuclear layer is the most frequently involved layer, and isolated INL cysts may occur in phakic fellow eyes. A three-layer structure, the presence of OPL morphology, or isolated INL early in the postoperative period indicates disease activity.

Functional characterization of fish neuroglobin: zebrafish neuroglobin is highly expressed in amacrine cells after optic nerve injury and can translocate into ZF4 cells.

Neuroglobin (Ngb) is a recently discovered vertebrate heme protein that is expressed in the brain and can reversibly bind oxygen. Mammalian Ngb is involved in neuroprotection under conditions of oxidative stress, such as ischemia and reperfusion. We previously found that zebrafish Ngb can penetrate the mammalian cell membrane. In the present study, we investigated the functional characteristics of fish Ngb by using the zebrafish cell line ZF4 and zebrafish retina. We found that zebrafish Ngb translocates into ZF4 cells, but cannot protect ZF4 cells against cell death induced by hydrogen peroxide. Furthermore, we demonstrated that a chimeric ZHHH Ngb protein, in which module M1 of human Ngb is replaced by that of zebrafish, is a cell-membrane-penetrating protein that can protect ZF4 cells against hydrogen peroxide exposure. Moreover, we investigated the localization of Ngb mRNA and protein in zebrafish retina and found that Ngb mRNA is expressed in amacrine cells in the inner nuclear layer and is significantly increased in amacrine cells 3days after optic nerve injury. Immunohistochemical studies clarified that Ngb protein levels were increased in both amacrine cells and presynaptic regions in the inner plexiform layer after nerve injury. Taken together, we hypothesize that fish Ngb, whose expression is upregulated in amacrine cells after optic nerve injury, might be released from amacrine cells, translocate into neighboring ganglion cells, and function in the early stage of optic nerve regeneration. This article is part of a Special Issue entitled: Oxygen Binding and Sensing Proteins.

Benign Lobular Inner Nuclear Layer Proliferations of the retina.

PURPOSE: Report the clinical and imaging findings of a patient with an intraretinal benign tumor that was documented as an unexpected clinical finding after an ischemic stroke in the context of mitral valve disease. This tumor must be distinguished from retinoblastoma and other malignant neoplasms. METHODS: A patient with intraretinal tumor of the inner nuclear layer (INL) underwent a combination of ophthalmic examination, fundus photography, fluorescein angiography, optical coherence tomography (OCT), and optical coherence tomography angiography (OCT-A). RESULTS: A 64-year-old male patient with unilateral benign tumor lesions dependent on the internal retina, centered in the posterior pole, and multifocal. OCT showed that these lesions were centered within the INL at the edge of the inner plexiform layer and were not associated with other findings in the posterior pole. CONCLUSIONS: Benign Lobular Inner Nuclear Layer Proliferations (BLIP) of the Retina are recently described lesions that should be considered, given their distinctive characteristics that set them apart from other benign and malignant retinal lesions.

Thicker Inner Nuclear Layer as a Predictor of Glaucoma Progression and the Impact of Intraocular Pressure Fluctuation.

Background: Thickening of the inner nuclear layer (INL) or microcystic macular changes has been reported to be implicated in glaucoma patients, but their potential impact on disease progression remains unclear. We investigated the relationship between baseline microcystic macular edema in the INL or INL thickness and subsequent visual field (VF) progression in glaucoma patients. Methods: This retrospective observational study included primary open-angle glaucoma with follow-up exceeding 3 years. We identified macular cystic changes through Spectralis optical coherence tomography and measured the INL thickness using automated segmentation. Glaucoma progression was determined using the Guided Progression Analysis program of the Humphrey filed analyzer, calculating the mean deviation (MD) changes (dB/year). Results: Microcystic macular changes were observed in 12 (7.5%) of 162 patients. Patients with microcystic macular change had thicker INL thickness than those without it (p = 0.010). Progressors had a higher probability of having microcystic macular changes and a thicker average INL thickness than nonprogressors (p = 0.003, p = 0.019). Thicker INL thickness was associated with faster VF progression based on MD slope (dB/year) in the multivariate regression analysis (p = 0.045). Additionally, greater intraocular pressure (IOP) fluctuation was found to be associated with both a thicker INL and the presence of microcystic changes in the multivariate regression analysis (p = 0.003, 0.028). Conclusions: Increased macular INL thickness indicative of INL changes was linked to subsequent VF progression in glaucoma patients. These findings suggest that retinal inner nuclear change could serve as an indicator of progressive glaucoma.