Retinal Neurodegeneration in Different Risk Phenotypes of Diabetic Retinal Disease

Diabetic retinopathy (DR) has been considered a microvascular disease, but it has become evident that neurodegeneration also plays a key role in this complex pathology. Indeed, this complexity is reflected in its progression which occurs at different rates in different type 2 diabetic (T2D) individuals. Based on this concept, our group has identified three DR progression phenotypes that might reflect the interindividual differences: phenotype A, characterized by low microaneurysm turnover (MAT <6), phenotype B, low MAT (<6) and increased central retinal thickness (CRT); and phenotype C, with high MAT (≥6). In this study, we evaluated the progression of DR neurodegeneration, considering ganglion cell+inner plexiform layers (GCL+IPL) thinning, in 170 T2D individuals followed for a period of 5 years, to explore associations with disease progression or risk phenotypes. Ophthalmological examinations were performed at baseline, first 6 months, and annually. GCL+IPL average thickness was evaluated by optical coherence tomography (OCT). Microaneurysm turnover (MAT) was evaluated using the RetMarkerDR. ETDRS level and severity progression were assessed in seven-field color fundus photography. In the overall population there was a significant loss in GCL+IPL (−0.147 μm/year), independently of glycated hemoglobin, age, sex, and duration of diabetes. Interestingly, this progressive thinning in GCL + IPL reached higher values in phenotypes B and C (−0.249 and −0.238 μm/year, respectively), whereas phenotype A remained relatively stable. The presence of neurodegeneration in all phenotypes suggests that it is the retinal vascular response to the early neurodegenerative changes that determines the course of the retinopathy in each individual. Therefore, classification of different DR phenotypes appears to offer relevant clarification of DR disease progression and an opportunity for improved management of each T2D individual with DR, thus playing a valuable role for the implementation of personalized medicine in DR.

Myelinosome Organelles in the Retina of R6/1 Huntington Disease (HD) Mice: Ubiquitous Distribution and Possible Role in Disease Spreading

Visual deficit is one of the complications of Huntington disease (HD), a fatal neurological disorder caused by CAG trinucleotide expansions in the Huntingtin gene, leading to the production of mutant Huntingtin (mHTT) protein. Transgenic HD R6/1 mice expressing human HTT exon1 with 115 CAG repeats recapitulate major features of the human pathology and exhibit a degeneration of the retina. Our aim was to gain insight into the ultrastructure of the pathological HD R6/1 retina by electron microscopy (EM). We show that the HD R6/1 retina is enriched with unusual organelles myelinosomes, produced by retinal neurons and glia. Myelinosomes are present in all nuclear and plexiform layers, in the synaptic terminals of photoreceptors, in the processes of retinal neurons and glial cells, and in the subretinal space. In vitro study shows that myelinosomes secreted by human retinal glial Müller MIO-M1 cells transfected with EGFP-mHTT-exon1 carry EGFP-mHTT-exon1 protein, as revealed by immuno-EM and Western-blotting. Myelinosomes loaded with mHTT-exon1 are incorporated by naive neuronal/neuroblastoma SH-SY5Y cells. This results in the emergence of mHTT-exon1 in recipient cells. This process is blocked by membrane fusion inhibitor MDL 28170. Conclusion: Incorporation of myelinosomes carrying mHTT-exon1 in recipient cells may contribute to HD spreading in the retina. Exploring ocular fluids for myelinosome presence could bring an additional biomarker for HD diagnostics.

Paramacular Acute Middle Maculopathy Associated with Glyceryl Trinitrate

An unusual case of nitroglycerin-induced Paracentral Acute Middle Maculopathy (PAMM) is presented. A 50-year-old patient with sudden vision loss and scotoma was followed up with swept-source optical coherence tomography (SS-OCT), optical coherence tomography-angiography (OCT-A), and fluorescein angiography (FA). An anal fissure treated with glyceryl trinitrate (GTN) 0.2% ointment with headache and dizziness after application was reported. Fundoscopy OS revealed mild retinal venous dilatation and tortuosity with scattered blot hemorrhages and subtle, parafoveal, whitish lesions in the outer retina. SS-OCT revealed diffuse, hyperreflective lesions in the inner plexiform (IPL), inner nuclear (INL), and outer plexiform layers (OPL). OCT-A revealed focal dropout in the deep capillary plexus. FA showed masking due to blot hemorrhages and early punctuate leakage in the inner retina. This entity was identified as nitroglycerin-induced PAMM. Over the following 8 months, after discontinuation of the ointment application, the patient was symptom-free with stable visual acuity. OCT revealed INL/OPL thinning and confirmed complete lesion resolution. This first report of retinal vascular abnormalities due to nitrite ointment provides an insight into an unknown side effect of nitroglycerin ointment use. A dose-dependent correlation between GTN application and retinal vascular abnormalities remains to be confirmed.

Maculopathy Masquerading as Migraine

We describe a case of a 23-year-old Caucasian woman with a background history of migraines who presented with bilateral paracentral scotomata. The ophthalmoscopy and MRI head were originally thought to be normal, and the scotomata were attributed to be of migrainous origin: a persistent negative aura. However, persistence of her symptoms prompted further specialist review 10 months later, at which time subtle bilateral perifoveal changes were noted, which had been apparent but overlooked at the initial assessment. Near-infrared reflectance imaging enabled better visualization of the lesions, which were apparent prior to any abnormalities on clinical examination. Spectral-domain optical coherence tomography revealed the early findings of hyperreflectivity in the outer nuclear and outer plexiform layers characteristic of acute macular neuroretinopathy. Our case aims to emphasize the importance of scrutinising ancillary tests of the macula in patients presenting with scotomata or atypical migraine symptoms, and to caution clinicians against diagnosing migraine with persistent negative aura without these investigations.

Eye manifestations of COVID-19. Step one

In the past few months, medical practice has changed faster than in the past few decades. This was due to the coronavirus disease (COVID-19) pandemic. Ophthalmic problems are most significant in patients with severe pneumonia. The exact incidence of conjunctivitis in COVID-19 patients ranges from 0.8 to 31.6 %. Optical coherence tomography demonstrated hyperreflective lesions at the level of ganglion cells and inner plexiform layers, more pronounced in the papillomacular bundle of both eyes. Retinal hemorrhages were found in at least one eye in five patients (9.25 %), cotton wool spots were detected in four people (7.4 %), and drusen was observed in six patients (11.1 %). On examination of the fundus, dilated veins were revealed in 15 patients (27.7 %), tortuous vessels — in 7 individuals (12.9 %). The literature reports describe patients who were diagnosed with COVID-19 after the detection of diplopia and ophthalmoparesis. The incidence of ocular complications in patients of the intensive care units in different studies ranges from 3 to 60 %. The most common manifestations are ocular surface diseases, increased intraocular pressure, and disorders of the anterior and posterior segments.

Loss of active neurogenesis in the adult shark retina

Neurogenesis is the process by which progenitor cells generate new neurons. As development progresses neurogenesis becomes restricted to concrete neurogenic niches, where it persists during postnatal life. The retina of teleost fishes is thought to proliferate and produce new cells throughout life. Whether this capacity may be an ancestral characteristic of jawed vertebrates, shared with chondrichthyans, which diverged from osteichthyans prior to the gnathostome radiation is completely unknown. Previous work from our group revealed that the juvenile retina of the catshark Scyliorhinus canicula shows active proliferation and neurogenesis. Here, we compared the morphology and proliferative status of the retina between catshark juveniles and adults. Histological analyses revealed an important reduction in the size of the peripheral retina (where progenitor cells are mainly located), an increase in the thickness of the plexiform layers and a decrease in the thickness of the inner nuclear layer in adults. Contrary to what has been reported in teleost fish, we did not observe active mitotic activity in the catshark retina after sexual maturation, suggesting that there is no significant proliferation and neurogenesis in adult specimens. Based on these results, we carried out RNA-Sequencing (RNA-Seq) analyses comparing the retinal transcriptome of juveniles and adults, which revealed a statistically significant decrease in the expression of many genes involved in cell proliferation and neurogenesis in adult catsharks. Our RNA-Seq data provides an excellent resource to identify new signaling pathways controlling neurogenesis in the vertebrate retina.