Ординатура / Офтальмология / Английские материалы / Diabetes and Ocular Disease Past, Present, and Future Therapies 2nd edition_Scott, Flynn, Smiddy_2009

44 Diabetes and Ocular Disease

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46 Diabetes and Ocular Disease

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Figure 4.1. Anatomy of normal retina.

Neurons. The neurons and glial cells of the retina comprise more than 95% of the retinal mass, but they are transparent to visible light, so their structure and function are not readily apparent on clinical examination. As demonstrated in Figure 4.1, the retina is primarily a neural tissue, and retinal neurons, the cells that define vision, include photoreceptors, amacrine, bipolar, horizontal, and ganglion cells (reviewed in [1] and http://webvision.med.utah.edu). Electrical inputs from the first four types of neurons converge on the ganglia, and the ganglion cells’ electrical output is conducted to the brain via axons of the nerve fiber layer and optic nerve. The high degree of convergence and integration of retinal signals is evident in the 10:1 ratio of photoreceptors (≈130 million) to ganglion cells (≈1.2 million) per human eye. Therefore, disruption of any of the neuronal layers interferes with vision, but redundancy of the neuronal architecture allows for many cells to die or malfunction before visual function is impaired. For example, at least 50% of ganglion cells in an area are lost before a clinically detectable visual defect is apparent in patients with glaucoma, and an eye can retain 20/20 acuity with less than 10% of cone photoreceptors.

Glial Cells. The glial (“glue”) cells of the retina—Müller cells and astrocytes—serve as support cells for the neurons and blood vessels [2]. They regulate extracellular ion concentrations necessary for generating action potentials, metabolize neurotransmitters such as glutamate, and transport substrates for retinal metabolism

(glucose, lipids, and amino acids) from blood vessels to neurons. Their role in glutamate handling is particularly important because excess glutamate in response to retinal ischemia or diabetes is toxic to neurons and may contribute to neuronal cell death [3].

In addition to their effects on neurons, astrocytes guide fetal vascular development from the optic nerve to the peripheral retina and influence the function and integrity of mature vessels [4]. Vascular endothelial growth factor (VEGF) is a major cytokine involved in this process and is produced by astrocytes and Müller cells. Astrocytes also signal blood vessels to acquire barrier properties to form the blood–retina barrier [5] and influence the development of tight junctions in retinal endothelial cells [6], and regulate the function of retinal synapses [7] and, therefore, visual function [8]. However, many details of the means by which glial cells control normal retinal function remain uncertain.

Microglial Cells. Microglia are bone marrow-derived macrophages that reside in the retina and sense the retinal metabolic environment. They respond to a variety of stimuli, such as retinal detachment, infection or trauma (including laser photocoagulation) by proliferating, migrating, and releasing inflammatory cytokines, such as interleukin-1, VEGF, and tumor necrosis factor-α [9,10]. Retinal injury increases the migration of bone marrow-derived immune cells into the retina and their differentiation into microglia cells [11]. In the short term, these responses may represent a beneficial response to the injury, but prolonged activation results in chronic inflammation and cellular damage.

Blood Vessels. The retinal vascular circuit consists of conduits into and out of the retina (Fig. 4.2A) [12]. The microcirculation includes precapillary arterioles, capillaries, and postcapillary venules. Arterioles possess smooth muscle cells, which allow the arterioles to change their radius and dynamically regulate local delivery of blood to the retina. Precapillary arterioles are the primary resistance vessels, whereas venules have a high density of receptors for vasoactive agents, such as histamine. Venules are primarily passive conducting tubes, which drain blood out of the retina. Capillaries and venules are the primary sites of fluid diffusion into the retina under normal conditions, and this diffusion increases in pathologic conditions such as diabetes [13].

Autoregulation is a general feature of blood vessels of the central nervous system by which the organ maintains appropriate blood flow despite changes in systemic arterial pressure [12]. Retinal arterial vessels have smooth muscle cells, while capillaries, arterioles, and venules possess pericytes, which function as modified smooth muscle cells. These features allow the retinal circulation to autoregulate in response to systemic and local metabolic demands (Fig. 4.2B). Blood vessels also autoregulate in response to the partial pressure of the oxygen (pO2) and carbon dioxide (pCO2). Therefore, vessels constrict in response to hyperoxemia and dilate in response to hypercapnea.

Retinal arteriolar narrowing in patients with hypertension is an ophthalmoscopic sign of autoregulatory responses to maintain normal intravascular (hydrostatic)

Capillaries

Arteriole

Lumen

Postcapillary venule

Vein

Figure 4.2. Retinal microcirculation. (A) Broad capillary-free zone is present around artery (red), and much narrower zone is seen about vein (blue). (B) Human retinal capillary shows endothelium with tight junctional complexes between adjacent cells, intramural pericyte, and basement membrane material with cavities.

pressure across the vascular wall and volume flow through the retina. When autoregulatory mechanisms and the blood–retina barrier are overwhelmed in hypertension, blood, serous fluid, and lipid exudates accumulate in the macula, and the optic disc may swell. Thus, the features of hypertensive retinopathy can be understood in light of these pathophysiologic processes [14].

Under normal conditions, retinal blood flow balances nutrient delivery and waste removal with retinal metabolism. Diabetes, a systemic malfunction of carbohydrate, lipid, and protein metabolism, leads to vascular and tissue damage in organs such as the retina. Thus, diabetic retinopathy is fundamentally a disorder of retinal and systemic metabolism that damages the retinal tissue elements and associated vessels; that is, a neurovascular degeneration or sensory neuropathy.

PRECLINICAL RETINOPATHY

In patients with type 1 diabetes in whom the duration of diabetes is well known, the interval between diagnosis and development of any retinopathy (microaneurysms) in half the patients is 7 years [15]. In patients with type 2 diabetes, it is more difficult to determine this interval between the development of diabetes and the development of retinopathy because it is believed that 4 to 7 years generally elapse between the onset of non-insulin dependent diabetes and its diagnosis [16]. There is now ample evidence that functional and anatomic changes occur before the onset of vascular lesions in both types of diabetes, as discussed below and

shown in Table 4.1. This phase corresponds to Stage 0 in the International Diabetic Retinopathy classification [17].

Diabetic patients with clinically normal-appearing retinas generally lack specific visual symptoms. Nevertheless, sensitive testing methods have demonstrated subtle defects in neurosensory retinal function, including decreased blue-yellow color perception and contrast sensitivity [18,19]. In addition, the oscillatory amplitudes on the b-wave of electroretinogram (ERG) may be reduced. Mulifocal ERG and short-wavelength, and white-on-white perimetry testing reveal regional depression of retinal function in diabetic patients before the onset of vascular lesions [20,21]. These tests indicate dysfunction of the inner retina, especially bipolar, amacrine, and ganglion cell neurons. Nerve fiber layer defects may also be detected by redfree photography or scanning laser ophthalmoscopy in diabetic patients with minimal or no vascular lesions [22,23]. More than 45 years ago, Bloodworth [24] and Wolter [25] showed that diabetes damages retinal ganglion cells in regions remote from vascular pathology. Together, these findings provide strong evidence that retinal function may be altered prior to the onset of vascular lesions and that diabetic retinopathy is not strictly a vascular disease [19,26,27].

Experimental studies have demonstrated increased neural cell injury within 1 month of diabetes [28], long before the onset of typical vascular lesions. This accelerated cell death results in loss of the ganglion cell and inner plexiform layers, with retinal thinning. Recent studies reveal loss of cholingergic and dopaminergic amacrine cells [29], remodeling of dendrites [30], and reduction of essential proteins of synapses [31] as early neurodegenerative changes in diabetic retinopathy. Together, these subtle cellular changes may contribute to reduced oscillatory potentials in the ERG [32]. Optic nerve axon size also decreases [33] as part of the degenerative response of neural tissue to the metabolic stress of diabetes. The cause of these degenerative processes is highly complex but may include loss of neurotrophins (insulin, brain-derived neurotrophic factor), excess nutrients (glucose, amino