Muller glial cells span the entire thickness of the tissue, and ensheath all retinal neurons, in vertebrate retinae of all species. This morphological relationship is reflected by a multitude of functional interactions between neurons and Muller cells, including a 'metabolic symbiosis' and the processing of visual information. Muller cells are also responsible for the maintenance of the homeostasis of the retinal extracellular milieu (ions, water, neurotransmitter molecules, and pH). In vascularized retinae, Muller cells may also be involved in the control of angiogenesis, and the regulation of retinal blood flow. Virtually every disease of the retina is associated with a reactive Muller cell gliosis which, on the one hand, supports the survival of retinal neurons but, on the other hand, may accelerate the progress of neuronal degeneration: Muller cells protect neurons via a release of neurotrophic factors, the uptake and degradation of the excitotoxin, glutamate, and the secretion of the antioxidant, glutathione. However, gliotic Muller cells display a dysregulation of various neuron-supportive functions. This contributes to a disturbance of retinal glutamate metabolism and ion homeostasis, and causes the development of retinal edema and neuronal cell death. Moreover, there are diseases evoking a primary Muller cell insufficiency, such as hepatic retinopathy and certain forms of glaucoma. Any impairment of supportive functions of Muller cells, primary or secondary, must cause and/or aggravate a dysfunction and loss of neurons, by increasing the susceptibility of neurons to stressful stimuli in the diseased retina. On the contrary, Muller cells may be used in the future for novel therapeutic strategies to protect neurons against apoptosis (somatic gene therapy), or to differentiate retinal neurons from Muller/stem cells. Meanwhile, a proper understanding of the gliotic responses of Muller cells in the diseased retina, and of their protective vs. detrimental effects, is essential for the development of efficient therapeutic strategies that use and stimulate the neuron-supportive/protective-and prevent the destructive-mechanisms of gliosis.

https://www.springer.com/cda/content/document/productFlyer/productFlyer_978-1-4419-1671-6.pdf?SGWID=0-0-1297-173938007-0

Müller Cells in the Healthy and Diseased Retina

Objective: To demonstrate optical coherence tomography for high-resolution, noninvasive imaging of the human retina. Optical coherence tomography is a new imaging technique analogous to ultrasound B scan that can provide cross-sectional images of the retina with micrometer-scale resolution. Design: Survey optical coherence tomographic examination of the retina, including the macula and optic nerve head in normal human subjects. Settings Research laboratory. Participants: Convenience sample of normal human subjects. Main Outcome Measures: Correlation of optical coherence retinal tomographs with known normal retinal anatomy. Results: Optical coherence tomographs can discriminate the cross-sectional morphologic features of the fovea and optic disc, the layered structure of the retina, and normal anatomic variations in retinal and retinal nerve fiber layer thicknesses with 10- μm depth resolution. Conclusion: Optical coherence tomography is a potentially useful technique for high depth resolution, cross-sectional examination of the fundus.

Optical Coherence Tomography of the Human Retina

Advances in imaging are transforming our understanding of angiogenesis and the evaluation of drugs that stimulate or inhibit angiogenesis in preclinical models and human disease. Vascular imaging makes it possible to quantify the number and spacing of blood vessels, measure blood flow and vascular permeability, and analyze cellular and molecular abnormalities in blood vessel walls. Microscopic methods ranging from fluorescence, confocal and multiphoton microscopy to electron microscopic imaging are particularly useful for elucidating structural and functional abnormalities of angiogenic blood vessels. Magnetic resonance imaging (MRI), computed tomography (CT), positron emission tomography (PET), ultrasonography and optical imaging provide noninvasive, functionally relevant images of angiogenesis in animals and humans. An ongoing dilemma is, however, that microscopic methods provide their highest resolution on preserved tissue specimens, whereas clinical methods give images of living tissues deep within the body but at much lower resolution and specificity and generally cannot resolve vessels of the microcirculation. Future challenges include developing new imaging methods that can bridge this resolution gap and specifically identify angiogenic vessels. Another goal is to determine which microscopic techniques are the best benchmarks for interpreting clinical images. The importance of angiogenesis in cancer, chronic inflammatory diseases, age-related macular degeneration and reversal of ischemic heart and limb disease provides incentive for meeting these challenges.

Imaging of angiogenesis: from microscope to clinic

The progress in understanding and treatment of diabetic retinopathy

Regulation of retinal blood flow in health and disease

The blood-ocular barrier system is formed by 2 main barriers: the blood-aqueous barrier and the blood-retinal barrier (BRB). The BRB is particularly tight and restrictive and is a physiologic barrier that regulates ion, protein, and water flux into and out of the retina. The BRB consists of inner and outer components, the inner BRB being formed of tight junctions between retinal capillary endothelial cells and the outer BRB of tight junctions between retinal pigment epithelial cells. The BRB is essential to maintaining the eye as a privileged site and is essential for normal visual function. Methods of clinical evaluation of the BRB are reviewed and new directions using optical coherence tomography are presented. Alterations of the BRB play a crucial role in the development of retinal diseases. The 2 most frequent and relevant retinal diseases, diabetic retinopathy and age-related macular degeneration (AMD), are directly associated with alterations of the BRB. Diabetic retinopathy is initiated by an alteration of the inner BRB and neovascular AMD is a result of an alteration of the outer BRB. Macular edema is a direct result of alterations of the BRB.

Blood–Retinal Barrier

Ocular fundus imaging plays a key role in monitoring the health status of the human eye. Currently, a large number of imaging modalities allow the assessment and/or quantification of ocular changes from a healthy status. This review focuses on the main digital fundus imaging modality, color fundus photography, with a brief overview of complementary techniques, such as fluorescein angiography. While focusing on two-dimensional color fundus photography, the authors address the evolution from nondigital to digital imaging and its impact on diagnosis. They also compare several studies performed along the transitional path of this technology. Retinal image processing and analysis, automated disease detection and identification of the stage of diabetic retinopathy (DR) are addressed as well. The authors emphasize the problems of image segmentation, focusing on the major landmark structures of the ocular fundus: the vascular network, optic disk and the fovea. Several proposed approaches for the automatic detection of signs of disease onset and progression, such as microaneurysms, are surveyed. A thorough comparison is conducted among different studies with regard to the number of eyes/subjects, imaging modality, fundus camera used, field of view and image resolution to identify the large variation in characteristics from one study to another. Similarly, the main features of the proposed classifications and algorithms for the automatic detection of DR are compared, thereby addressing computer-aided diagnosis and computer-aided detection for use in screening programs.

/pdf/digital-ocular-fundus-imaging-a-review-6uzy4lzfqq.pdf

Digital ocular fundus imaging: a review.

Purpose: To characterize macular edema that occurs after uneventful cataract surgery. Setting: Centre of Ophthalmology, University Hospital, Institute of Biomedical Research on Light and Image, Faculty of Medicine, University of Coimbra, Coimbra, Portugal. Methods: Thirty-two eyes of 32 patients had uneventful phacoemulsification with implantation of a foldable intraocular lens. Postoperatively, patients were examined at 3, 6, 12, and 30 weeks. The examinations included retinal leakage analysis (Zeiss CSLO), optical coherence tomography (Humphrey Instruments), and retinal thickness analysis (Talia Technology, Ltd.). Results were compared with those in a control group comprising healthy subjects. Results: Increases in retinal thickness (ie, over the mean ± 2 SD in the control group) reached a maximum at 6 weeks in 13 of 32 eyes (41%), after which recovery was progressive. At 30 weeks, all eyes had good visual acuity, but 7 eyes (22%) still had macular edema. The edema was located primarily in the central macular region. Leaking sites involving the vascular areas of the macula, which indicated areas of abnormal blood–retinal barrier permeability, were a frequent finding. The number of sites remained relatively stable during the first 12 weeks (88%) and decreased to 68% at 30 weeks, indicating a trend toward recovery. Conclusion: Macular edema after cataract surgery occurred primarily in the central region of the macula and was associated with the presence of leaking sites, which were located predominantly in the vascular regions of the central macula.

/pdf/macular-alterations-after-small-incision-cataract-surgery-3l334wv7tl.pdf

Macular alterations after small-incision cataract surgery

Phenotypes and biomarkers of diabetic retinopathy.

Objective: To identify alterations of the blood-retinal barrier by mapping retinal fluorescein leakage into the vitreous and changes in retinal thickness occurring in the macular region in preclinical diabetic retinopathy. Methods: Ten eyes from 10 patients with type 2 diabetes and no lesions visible on fundus photography (level 10 of Wisconsin grading) were examined with the retinal leakage analyzer (RLA) (Confocal Scanning Laser Ophthalmoscope [modified]; Carl Zeiss Inc, Thornwood, NY) and the retinal thickness analyzer (RTA) (Talia Technology, Mevaseret Zion, Israel). The maps of retinal leakage and retinal thickness were aligned and integrated in the same image to correlate leakage with thickness. Data from the group of individuals with diabetes were compared with those of a healthy control population (N=14; mean age, 48 years; range, 42-55 years) and used to establish reference maps for the RLA and RTA. Results: Areas of abnormally increased fluorescein leakage were detected in 9 of 10 eyes examined. The increased leakage in 6 (67%) of 9 eyes reached values higher than 40% more than the mean +2 SD RLA control value. Areas of abnormally increased thickness were found in 7 of 10 eyes examined. For the most part, the increases in retinal thickness were not severe (ie, ,15% increase in 5 eyes and an 18% increase in 1 eye). The eyes with the most extensive leakage (cases 1, 3, and 9) showed relatively good coincidence between the location of the areas of increased leakage and the location of the areas of increased thickness. In 4 eyes (cases 2, 5, 7, and 8), no such correlation was apparent. The 3 remaining eyes showed little coincidence between these locations. Characteristically, the latter 3 eyes had areas of abnormally increased thickness that were much larger than the areas of increased fluorescein leakage, which were relatively moderate or absent of any leakage. Conclusions: Localized sites of increased fluorescein leakage and zones of increased retinal thickness were found in most eyes in a series of 10 eyes in the preretinopathy stage from 10 patients with type 2 diabetes. Increases in retinal thickness may be observed that do not coincide with sites of retinal leakage. Two types of increased retinal thickness may, therefore, be present in the preretinopathy stage of diabetic retinopathy, one directly associated with an alteration of the blood-retinal barrier, and another occurring without apparent breakdown of blood-retinal barrier.

https://rihuc.huc.min-saude.pt/bitstream/10400.4/836/1/Alterations%20of%20the%20blood-retinal%20barrier.pdf

Conceição Lobo

Papers

Blood–Retinal Barrier

Digital ocular fundus imaging: a review.

Macular alterations after small-incision cataract surgery

Phenotypes and biomarkers of diabetic retinopathy.

Alterations of the Blood-Retinal Barrier and Retinal Thickness in Preclinical Retinopathy in Subjects With Type 2 Diabetes