Ординатура / Офтальмология / Английские материалы / Ocular Disease Mechanisms and Management_Levin, Albert_2010

harm than good, especially when it does not confer a statistically significant protection against development of ocular neovascularization, or offer any other significant benefit in NVG.112

The Central Retinal Vein Occlusion Group found that macular grid photocoagulation for macular edema resulted in no difference in visual acuity between treated and untreated eyes.115

BRVO and HCRVO

Most of the information on medical management of CRVO also applies to BRVO and HCRVO.

For management of macular edema, the Branch Vein Occlusion Study Group116 advocated doing macular grid laser photocoagulation to reduce edema. The study found visual acuity improvement in two-thirds of cases but the improvement was usually small and only occasionally significant. Complications of macular grid laser photocoagulation include development of multiple microscotomas corresponding to the sites of laser burns, which may be visually bothersome, so that, in spite of somewhat improved visual acuity in the treated eye, patients might prefer not to use that eye; occasionally retinal fibrosis may develop.

For management of retinal and disc neovascularization associated with BRVO, the Branch Vein Occlusion Study Group117 advocated scatter photocoagulation in the ischemic fundus area. The study showed that it reduces the likelihood of neovascularization development by 50%, and if neovascularization is already present, it reduces the likelihood of vitreous hemorrhages by 50%. The study did not recommend doing photocoagulation until neovascularization develops.

Another study118 of sectoral scatter photocoagulation in major BRVO showed a significant reduction of development of retinal neovascularization (but not optic disc neovascularization) and vitreous hemorrhage in lasered eyes compared to untreated eyes. As in ischemic CRVO,112 it also showed that photocoagulation resulted in significant worsening of the peripheral visual fields in the involved sector in lasered eyes compared to untreated eyes. The authors therefore recommended doing photocoagulation only when neovascularization develops and not otherwise, because in the latter case, the detrimental effects may outweigh the beneficial ones.

Prognosis

In RVO, the retinopathy spontaneously resolves after a variable length of time. There is marked interindividual variation in the time it takes to resolve – usually faster in younger than older people. Thus, RVO is a self-limiting disease, although during the period of activity the various types may produce diverse complications.

Prognosis

Natural history of visual outcome

CRVO

There is little firm information on the natural history of visual outcome in CRVO in the literature and, when described, that is based on either use of invalid criteria to differentiate the two types of CRVO119 or lumping the two types together.120 A recent preliminary report93 described final visual acuity and visual fields in a prospective study of 155 consecutive eyes with nonischemic CRVO in which the retinopathy and macular edema had completely resolved during follow-up. It showed that the final visual acuity in the entire group was 20/25 or better in 65%, 20/40 or better in 77%, 20/50–20/70 in 7%, 20/80–20/200 in 9%, and 20/400 to counting fingers in 7%. A permanent central scotoma, varying in size from tiny to large, was present in 30%, with normal peripheral visual fields in all eyes. By contrast, in ischemic CRVO, during the initial stages, the ganglion cells in the macular retina are irreversibly damaged by ischemia, causing a permanent central scotoma, and thus little chance of improvement of visual acuity in such an eye.

HCRVO

This is reported in a series of 41 eyes (27 with nonischemic HCRVO and 14 with ischemic HCRVO).53 The final visual acuity in eyes with nonischemic HCRVO was 20/25 or better in 40%, 20/30–20/80 in 29%, 20/100–20/200 in 18.5%, and 20/400 to counting fingers in 11%. In ischemic HCRVO, it was 7%, 14%, 43%, and 36%, respectively.

BRVO

The only study available so far is that of the Branch Vein Occlusion Study Group.116 In that study, in eyes with intact retinal capillaries in the macular region, one-third of eyes with visual acuity of 20/40 or worse showed improvement over 3 years on follow-up. Another study of 229 major BRVO showed that older patients had more visual acuity deterioration than younger patients.118

Long-term complications of CRVO

Nonischemic CRVO is a comparatively benign disease; the main long-term complications are: (1) development of permanent central scotoma (with normal peripheral visual fields) if chronic macular edema produces secondary macular changes93; and (2) some eyes may convert to ischemic CRVO (12.6% within 18 months of onset39). By contrast, ischemic CRVO is a malignant disease, with a high risk of development of ocular neovascularization and NVG (Figure 63.7) and other blinding complications. In our prospective study38 of 721 eyes with RVO, the risk of developing anteriorsegment neovascularization was only in eyes with ischemic CRVO and occasionally ischemic HCRVO, while the risk of developing posterior-segment neovascularization was in ischemic CRVO, ischemic HCRVO, and major BRVO. Eyes with nonischemic CRVO/HCRVO per se do not develop ocular neovascularization, unless there is associated diabetic retinopathy or ocular ischemia.

3.Hayreh SS, Zimmerman B. Central retinal artery occlusion: visual outcome. Am J Ophthalmol 2005;140:376–

391.

5.Hayreh SS. Prevalent misconceptions about acute retinal vascular occlusive disorders. Prog Retin Eye Res 2005;24: 493–519.

10.Hayreh SS, Zimmerman MB, Kimura A, et al. Central retinal artery occlusion. Retinal survival time. Exp Eye Res 2004;78:723–736.

20.Hayreh SS, Podhajsky PA, Zimmerman B. Role of nocturnal arterial hypotension in optic nerve head ischemic disorders. Ophthalmologica 1999;213:76–96.

25.Hayreh SS, Fraterrigo L, Jonas J. Central retinal vein occlusion associated with cilioretinal artery occlusion. Retina 2008;28:581–594.

37.Beatty S, Au Eong KG. Local intraarterial fibrinolysis for acute occlusion

of the central retinal artery: a metaanalysis of the published data. Br J Ophthalmol 2000;84:914–916.

38.Hayreh SS, Rojas P, Podhajsky P, et al. Ocular neovascularization with retinal vascular occlusion. III. Incidence of ocular neovascularization with retinal vein occlusion. Ophthalmology 1983;90:488–506.

39.Hayreh SS, Zimmerman MB, Podhajsky P. Incidence of various types of retinal vein occlusion and their recurrence and demographic characteristics. Am J Ophthalmol 1994;117:429–441.

51.Hayreh SS, Klugman MR, Beri M, et al. Differentiation of ischemic from non-ischemic central retinal vein occlusion during the early acute phase. Graefes Arch Clin Exp Ophthalmol 1990;228:201–217.

53.Hayreh SS, Hayreh MS. Hemi-central retinal vein occlusion. Pathogenesis, clinical features, and natural history.

Arch Ophthalmol 1980;98:1600– 1609.

86.Hayreh SS. Management of central retinal vein occlusion. Ophthalmologica 2003;217:167–188.

94.Opremcak ME, Bruce RA, Lomeo MD, et al. Radial optic neurotomy for central retinal vein occlusion. Retina 2001;21:408–415.

112.Hayreh SS, Klugman MR, Podhajsky P, et al. Argon laser panretinal photocoagulation in ischemic central retinal vein occlusion – a 10-year prospective study. Graefes Arch Clin Exp Ophthalmol 1990;228:281–296.

113.Hayreh SS. The CVOS group M and N reports. Ophthalmology 1996;103:350– 352.

116.The Branch Vein Occlusion Study Group. Argon laser photocoagulation for macular edema in branch vein occlusion. Am J Ophthalmol 1984;98: 271–282.

Overview

Retinal photoreceptors are paradoxically efficient in their ability to capture photons for visual transduction while being vulnerable to cellular damage from excess light. Although the molecular mechanism of visual transduction is now relatively well understood, our understanding of retinal phototoxicity, or retinal light damage, is less complete. Nonetheless, based to a degree on comparable endstage morphology, retinal photic injury in laboratory animals has served as a model of retinal degenerations of genetic origin, aging, and from light-induced trauma during ocular surgery for over 40 years.1,2 Likewise, a long-standing clinical interest in the potential for interactions between diet, light environment, and retinal injury has prompted studies with animal models. But are animal models of light-induced retinal degeneration appropriate models for human retinal disease? Furthermore, although high levels of light accelerate some forms of inherited retinal degeneration and might influence the incidence of age-related macular degeneration (AMD), what role does light environment play in retinal disease?

Clinical background

Light duration and intensity

Visible light-mediated photoreceptor cell damage is a photochemical process with a well-known inverse time and intensity relationship. This effect, often referred to as reciprocity, implies that a longer-duration light exposure can be shortened by the use of higher-intensity light, and vice versa. This concept is well recognized in anterior-segment surgery and during vitrectomy where light intensity and timedependent phototoxic lesions have been reported.3,4 These lesions appear hours to days after surgery and are often seen in or near the cone-rich foveal region of the eye. The outcome for most phototoxic lesions found outside the fovea is generally good while the prognosis for repair of foveal damage, more often seen following vitrectomy, is less favorable.3,4 Solar retinitis also presents with foveal damage. It is well known to occur in patients deliberately sungazing for extended periods, but a few cases have been reported follow-

ing relatively short periods of sunbathing in high (often reflective) light environments.5 Likewise, photic injury from an indirect ophthalmoscope following relatively brief exposure has been reported.6 There are limits on photochemical damage in the retina and reciprocity, however, in that shortduration high-intensity coherent light actually results in thermal damage. Discussion of laser light-induced damage, sometimes employed in treating choroidal neovascularization and routinely used in the treatment of retinal breaks, is beyond the scope of this chapter.

Spectral characteristics of damaging light

Retinal light damage is also wavelength-dependent, with green light most effectively causing damage in rod photoreceptors. In other words, the action spectrum for light damage closely approximates the absorption spectrum for rhodopsin.1,7,8 (Figure 64.1). However, blue light as well as fullspectrum white light also causes retinal damage by bleaching rhodopsin, albeit less efficiently. Blue light has a shorter wavelength than green light and is therefore more energetic (Planck’s relation: E = h/λ, where E = energy, h = the Planck constant, and λ = wavelength). Accordingly, blue light is capable of photoisomerizing free all-trans retinal, the aldehyde form of vitamin A, into the 11-cis stereoisomer required for rhodopsin regeneration.9 This reaction may short circuit the normal postrhodopsin-bleaching vitamin A cycle, involving migration of all-trans retinol into the retinal pigment epithelium (RPE) and enzymatic reisomerization to the 11-cis form.10 In primates, cone cells undergo damage from short intermittent pulses of blue light, which has also been attributed to rapid bleaching and regeneration of blue-cone visual pigment.11 RPE cell damage from blue light exposure probably involves different chromophores. For example, mitochondrial cytochrome proteins have been suggested as one chromophore, and a potential source for the generation of reactive oxygen species.12 Another potential source of blue light-mediated reactive oxygen in RPE is photosensitization of bis-retinaldehyde-phosphatidylethanolamine (A2E), a lipophilic molecule that accumulates with age.13 Epidemiological studies indicate that chronic light exposure may be a risk factor for the development of AMD, but this effect seems to be small compared to the risk factors of age (>70 years), race (caucasian), and smoking.14–16 Light exposure might indirectly predispose to AMD through a variety of mecha-

Wavelength (nm)

Figure 64.1  Absorption spectrum of rod outer segment (ROS) rhodopsin and the action spectrum of retinal light damage. Rhodopsin was extracted from rat ROS with a nonionic detergent61 and absorption spectra recorded in darkness (Dark) and after light exposure in vitro (Bleached). The Dark spectrum shows a rhodopsin absorption maximum at 500 nm and a peak of protein absorbance at 278 nm. Following light, rhodopsin absorbance is reduced to baseline while a new peak of absorbance appears at 367 nm. There is no change in 278-nm absorbance, indicating no loss of protein from the detergent extract. The 367-nm peak arises from free all-trans retinal released during rhodopsin bleaching. The action spectrum for retinal light damage (green line), superimposed on the rhodopsin absorption spectra, shows a nearly identical 500-nm maximum for the pathological effect of light. The light damage action spectrum was determined by morphological measurements of the outer nuclear layer in rat retinas several days after exposure to narrow band width visible light. (Light damage spectrum redrawn from Williams TP, Howell WL. Action spectrum of retinal light damage in albino rats. Invest Ophthalmol Vis Sci 1983;24:285–287, with permission from the Association for Research in Vision and Ophthalmology.)

nisms (see Chapter 68). For example, Zhou and coworkers have suggested that products of the photo-oxidation of bis- retinoid lipofuscin pigments in RPE cells may serve as a trigger for the complement system17 (Box 64.1).

Pathology

Photoreceptor cells are differentiated postmitotic retinal neurons that normally function throughout the life of an individual. Some visual cell dropout occurs naturally as a result of aging, but rod and cone survival into the seventh decade and beyond is normally more than sufficient to preserve vision. A higher rate of visual cell loss is seen in many genetic conditions, but the rate of loss is still relatively slow compared to most experimental animal models of retinal degeneration. At the same time the morphological endpoints of both genetic and experimental retinal degenerations are so similar that they invite comparisons and inferences into etiology and prevention based primarily on studies with animals. In the case of photic injury in animal models, one sees loss of rod photoreceptors, with a relative sparing of cones.18,19 Rod cell loss is graded, most pronounced in the central superior hemisphere, and often particularly severe in the region 1–2 mm superior to the optic nerve head.20 At least initially, Müller cells and the inner

Box 64.1  Features of retinal light damage

Box 64.2  Pathological findings in retinal

photic injury

retinal neurons, consisting of horizontal, bipolar, amacrine, and ganglion cells, appear to be immune to light. The reasons for this dichotomy are unknown; however, it is not a simple lack of cellular chromophores, as light-absorbing proteins such as melanopsin and cryptochromes are present in the inner retinal layers.21,22 Recently, it was suggested that the tripeptide glutathione may be absent, or nearly so, from photoreceptor cells while present in sufficient quantities in the inner retinal layers to prevent oxidative damage.23 As in some animal models, rod cell degeneration precedes that of cone cells in the early stages of AMD. However, in AMD the loss of both rods and cones appears to result from RPE dysfunction in the parafoveal/macular region.24 Irrespective of the reasons for their susceptibility, when photoreceptor cell loss is extensive remarkable changes in inner retinal neuron morphology, location, and synaptic function soon follow25 (Box 64.2).

Etiology

Genetic risk factors

Under ordinary conditions, eye pigmentation and pupil size play major roles in preventing photic injury. By constricting pupil diameter during high light (photopic) conditions much of the light entering the eye is focused on the cone-rich fovea, which is relatively resistant to damage. Because melanin in the RPE absorbs light that passes entirely through the retina, its presence may help to reduce light scatter and photosensitized reactions in the choriocapillaris or in Bruch’s membrane.26,27 In addition, because the RPE cell layer covers

the entire globe of the eye and melanin pigments are present in the iris, ciliary body, and choroid, extraneous light is largely prevented from entering the eye through the sclera. In fact, melanin is such an effective filter that, for photic damage to occur in pigmented animals, mydriatics are usually required. In low light (scotopic) conditions the pupils are also dilated, allowing a larger area of the retina to be illuminated, but the intensity of light is much reduced, as is the chance of retinal injury. Pigmented animals have the same action spectrum for retinal light damage (Figure 64.1) and exhibit the same morphological characteristics as nonpigmented animals.2,28 However, because albino strains lack melanin, they are approximately twofold more sensitive to photic injury.1,28

Other genetic mutations also exacerbate the effects of light exposure on the rate of retinal degeneration. For example, the most common form of autosomal-dominant retinitis pigmentosa (RP) involves a histidine for proline substitution at amino acid position 23 in rhodopsin (P23H). In patients having the P23H mutation, external factors appear to affect the rate of functional loss of both scotopic and photopic vision.29 Heckenlively et al found that patients working in bright light environments lost vision sooner than others working in dim light environments.30 In transgenic animal models with the P23H mutation, rod cell loss also precedes that of cone cells, and the rate of loss also depends on lighting conditions.31,32 While the P23H animal model does not mimic all of the electrophysiological findings in RP,31 it correctly predicts the effects of light environment on the rate of retinal degeneration and has provided insights into the mislocalization of mutated rhodopsin in rod outersegment disks. Similarly, Royal College of Surgeons (RCS) rats exhibit a retinal degeneration that depends on environmental light. Dark rearing delays the onset of photoreceptor cell loss, while normal light exposure greatly accelerates that loss.33,34 As they age, RCS rats also accumulate a partially degraded cellular “debris” layer between the RPE and retina, which results from an inability of RPE to phagocytose rod outer-segment material.33,34 This debris layer forms a barrier that impedes the exchange of metabolites and the flow of nutrients from choroid to retina, leading to cell death. Morphologically, the end-stage RCS retina resembles that of several human retinal diseases, but whether the inhibition of nutrient flow is an appropriate model for human disease is currently unknown. A number of mouse strains also present with variable light damage sensitivities.35 In several strains, their susceptibility to retinal photic damage has been shown to correlate with a mutation in RPE 65, an enzyme involved in vitamin A (retinol) processing.36,37 Mice having the RPE 65 Leu 450 variant are more easily damaged, while mice with the RPE 65 Met 450 variant are more resistant to the phototoxic effects of light38 (Box 64.3).

Dietary factors

Animal models lend themselves particularly well to understanding the role of diet on retinal development and disease progression. The effects of dietary retinol on rhodopsin levels and retinal light damage have been described for vitamin A-deficient rats39 and after inhibition of the visual cycle with 13-cis retinoic acid.40 In each case, a reduced level of available 11-cis-retinaldehyde leads to an increase in

Etiology

Box 64.3  Genetic and dietary factors influence

light damage

opsin levels and to reduced light damage susceptibility. A similar decrease in rhodopsin levels and increase in opsin in patients treated for acne with 13-cis retinoids is thought to lead to the development of deficits in scotopic vision.40 Insufficient dietary linolenic acid (18:3n-3), the essential fatty acid precursor of docosahexaenoic acid (22:6n-3; DHA), leads to a decrease in retinal DHA and to a decrease in susceptibility to photic damage.41–43 The amount of DHA in the retina is species-specific, but in rat rod outer segments it may represent as much as 50 mol% of the total.41–43 In other words, one of every two fatty acids found in rod outersegment lipids can be a polyunsaturated DHA. Rod outer segments from transgenic P23H rats contain lower levels of DHA than normal, but unpredictably these animals are more sensitive to the damaging effects of light than normal rats.44,45 Furthermore, feeding P23H rats diets high in omega-3 fatty acids has not proven to be effective in delaying photoreceptor cell loss.44,45 Some forms of RP are associated with low DHA levels in red blood cells,46 but in these cases dietary DHA seems to be beneficial. Thus, a link between the reduced levels of DHA in rod outer segments of transgenic animal models and the low circulating levels of DHA in some RP patients46 has not yet been established.

The importance of dietary omega-3 fatty acids during visual system development, however, has been established, for rats47 and for primates,48 and, more recently, for preterm infants.49 Following clinical trials with full-term infants,50 DHA is now routinely added to infant formulas, along with the omega-6 fatty acid, arachidonic acid. Dietary supplementation with these fatty acids has a positive outcome on the development of vision and, although total dietary fat intake is associated with AMD,51 omega-3 fatty acids appear to slow disease progression.51 Accordingly, as a part of the ongoing Age-Related Eye Disease Study (AREDS) II, DHA supplementation is now being tested in patients. A rationale for this clinical trial appears to be based on the neuroprotective effects of this omega-3 polyunsaturated fatty acid. In the RPE, small amounts of DHA are enzymatically converted to neuroprotectin D1 (NPD-1), which has been shown to be effective in reducing apoptotic cell death.52 However, DHA is also capable of being oxidized by molecular oxygen,53 leading to the formation of carboxyethylpyrrole (CEP) protein adducts.54 NPD-1 is a 22-carbon DHA derivative containing two hydroxyl groups, while CEP is a 7-carbon DHA oxidation fragment, with a pyrrole ring adducted to the amine side chain of amino acids such as lysine (Figure 64.2). Crabb and associates analyzed drusen dissected from the RPE layer of AMD and age-matched controls and found

Figure 64.2  Structures of docosahexaenoic acid (DHA) and two products formed by oxidative processes. The polyunsaturated fatty acid DHA is oxidized by an enzymatic process to produce neuroprotectin D1, a 22-carbon hydroxylated fatty acid derivative. The reactions occur in retina, but are particularly active in the retinal pigment epithelium.52 Molecular oxygen leads to the truncation of DHA53 to produce a 7-carbon derivative which is capable of forming covalent adducts with free amino groups

in proteins.54

higher than normal levels of these covalent adducts in AMD eyes.54 Recently a mouse model of AMD, prepared by immunization with CEP adducted to albumin, has been shown to exhibit RPE deposits and pathology.55 This model and others may be useful in preclinical studies to help sort out the protective and damaging effects of dietary DHA and its derivatives.

Pathophysiology

Initiation of retinal light damage

Mechanistically, the principal utility of the photic injury animal model resides in the synchronous involvement of rod photoreceptors. Unlike genetic or age-related conditions, where small numbers of visual cells are typically involved at any one time, nearly the entire complement of photoreceptors is affected by intense light. Noell et al were the first to report that extensive rhodopsin bleaching is the trigger for retinal light damage.1 Genetic modification of photoreceptor cell proteins also points to rhodopsin as the key mediator of retinal damage by light. Rhodopsin knockout (KO) and RPE-65 KO mice are both protected against photic injury.36,37,56 Because opsin, but not rhodopsin, is present in RPE-65 mice and rhodopsin KO mice lack the protein altogether, the rate of rhodopsin regeneration during light has been implicated in the damage mechanism. Ironically, whole-body hyperthermia during light exposure also accelerates rhodopsin regeneration and greatly exacerbates retinal light damage.1,57 Photic injury occurs under ordinary room light in arrestin KO mice and rhodopsin kinase KO mice, while dark rearing prevents damage.58,59 Arrestin and rhodopsin kinase both interact with light-activated rhodopsin and are involved in attenuating the photo response, implicating two additional visual transduction proteins in the damage mechanism. Young RCS rats are genetically pre-

disposed to retinal light damage, which correlates with the relative expression levels of arrestin and transducin.60 In both RCS and normal rats, dark rearing leads to increases in transducin mRNA and protein levels and enhances light damage, while a normal cyclic light environment increases arrestin levels and reduces susceptibility to damage.60–62 Other genetic evidence suggests that two distinct pathways of retinal damage may exist, one involving transducin and relatively low light exposure levels and a second pathway involving high light levels and the transcription factor activator protein-1.63

Antioxidants and oxidation

Compelling evidence exists that oxidative stress is an integral part of the light damage process, as both natural and synthetic antioxidants prevent photoreceptor cell damage and loss.64–66 Oxidation also appears to be a relatively early event in the damage process. Light-induced oxidation occurs within minutes in isolated photoreceptor cells,67 and the rapid appearance of blue light-induced reactive oxygen species, originating from mitochondria, has been reported.68 Lipid hydroperoxides in retina were found to be elevated in normal rats exposed to green light, as well as in an oxidatively susceptible, drug-induced rat model of Smith–Lemli–Opitz syndrome.69,70 The synthetic antioxidant dimethylthiourea (DMTU) was effective in preventing light damage when administered before lights on,70 but is ineffective when given after the onset of light71 (Figure 64.3). Retinal protein markers of oxidative stress are also altered by light and impacted by antioxidants. The expression of retinal heme oxygenase (HO-1) increases after intense light exposure.71,72 HO-1 is a 32-kDa inducible stress protein and the first enzyme in a pathway involved in converting a prooxidant heme into bilirubin, an antioxidant. Retinol dehydrogenase (RDH), an oxidatively sensitive rod outer-segment enzyme that converts retinaldehyde into retinol, is partially inhibited by light exposure.73 However, pretreatment of rats with DMTU prevents both the light-driven increase in HO-1 expression and the decrease in RDH activity.72,73 In mice, inhibition of nitric oxide formation has been shown to reduce retinal light damage,74 further implicating oxidative stress in retinal phototoxicity (Box 64.4).

Humans and nonhuman primates appear to be the only species with a well-developed capacity to accumulate carotenoids in the foveal-macular region of the retina. The primary carotenoids found there are lutein (L) and zeaxanthin (Z), which are dihydroxylated derivatives of betacarotene.75 The overall level of L and Z is affected by dietary intake,76 and together they give rise to a yellowish (macular pigment) appearance in the central retina. L and Z both absorb blue light, effectively reducing the level of highenergy photons reaching photoreceptors and the RPE, but they are also potent antioxidants.75 Accordingly, these carotenoids may function in two ways: (1) by preventing blue light stimulation of A2E in the RPE; and (2) by decreasing light-induced oxidative insult in photoreceptors. In either case, protection is concentration-dependent, and the highest concentrations of L and Z are found at the level of photoreceptor cell synapses in the cone-rich macular region.75 The amount of macular pigment decreases with eccentricity from the center of the macula, reaching near-baseline levels in the

+2 weeks later

D E F

Box 64.4  Mechanisms of retinal light damage

parafoveal region where AMD-associated photoreceptor (rod) loss is first observed.24,75,77 Macular pigment levels are also decreased by pro-oxidants present in cigarette smoke, a well-established risk factor in AMD,16,51,78 while high levels of carotenoids and other antioxidants in the circulation appear to reduce the probability of developing neovascular AMD.79

Photoreceptor and RPE cell death

Visual cell loss resulting from acute intense light exposure, chronic high light environments, or because of genetic inher-

itance occurs largely through an apoptotic process.80 RPE cell dysfunction is linked to photoreceptor cell degeneration, either as the initiating event or subsequent to toxic reactions in the retina. The intimate metabolic and morphologic relationships between retina and RPE, their high oxygen tension, and the rate and duration of photon flux are all reasons why reactive oxygen species generated in one tissue can lead to degeneration in the other. One of the hallmarks of apoptotic cell death is double-strand cleavage of DNA by endonucleases.80,81 The resulting DNA fragments appear within hours of lights on80 and continue to accumulate for several days after acute intense light exposure.63,80,82 Light-induced DNA fragmentation is prevented by antioxidants,82 suggesting that oxidation also initiates the apoptotic process.83 In addition, photoreceptor cell death from light is prevented by overexpression of the antiapoptotic protein BCL-2 and a variety of neurotrophic factors.84,85 However, while antioxidants have not proven effective in preventing genetic retinal degenerations,86 BCL-2 overexpression and neurotrophins are at least partially effective.87

Relationship between retinal light damage and macular degeneration

The pathogenesis of AMD is described in greater detail in Chapter 68. However, some relevant concepts are as follows. Lipofuscin accumulates in RPE cells over time, and A2E is the major photosensitizing chromophore in lipofuscin. When RPE cells are exposed to light in vitro A2E, conjugated to low-density lipoprotein, causes a loss of lysosomal integ-

rity88 and inhibition of phagolysosomal degradation of photoreceptor phospholipids.89 RPE cells with excessive A2E exhibit membrane blebbing and extrusion of cytoplasmic material into Bruch’s membrane. Epidemiological studies, AMD histochemistry, and drusen biochemistry indicate that oxidative reactions play a central role in AMD pathophysiology. AREDS demonstrated that among selected patients supplementation with vitamins (ascorbic acid, vitamin E, and beta-carotene) and minerals (zinc oxide, cupric oxide) reduces the risk of developing advanced AMD and the rate of at least moderate vision loss.79 The AREDS data may mean that oxidative damage plays a role in the progression of AMD in its clinically evident intermediate and late stages and that disease progression can be altered with antioxidant supplementation. However, zinc also affects the complement system by inhibiting C3 convertase activity,90 and C3a des Arg (a cleavage product of C3a that reflects complement activation) levels are higher in patients with AMD versus controls.91 Zhou and coworkers have suggested that products of the photo-oxidation of bis-retinoid lipofuscin pigments in RPE cells may also trigger the complement system.17 Given the relative abundance of lipofuscin in the submacular RPE, this trigger would predispose the macula to chronic inflammation and AMD. These experiments link RPE lipofuscin, oxidative damage, drusen, and inflammation, all of which have been implicated in the pathogenesis of AMD.17,92,93

Prolonged actinic light exposure can cause rod and cone degeneration in albino rats through a pathway that involves photoreceptor cell rhodopsin, retinoid metabolism, and the formation of reactive oxygen species in RPE cells.27,71 Lightinduced retinal damage kills three classes of cells almost concurrently: photoreceptors, RPE, and choriocapillary endothelium.25 Light-induced retinal degeneration mimics important features of retinal remodeling observed in inherited retinal degenerations, including glial hypertrophy and reorganization of the neural retina. In contrast to retinal degenerative diseases (e.g., RCS rat, P23H rat), however, light-induced retinal damage is associated with eruption of processes from retinal neurons and eventual emigration of Müller cells and neurons from the retina into the choroid.25 Marc and coworkers noted a striking parallel between atrophic zones in human geographic atrophy and severely damaged retina in light-induced retinal damage.25 Specifically, the gradient between apparently functional surviving retina and severely damaged retina is steep in both conditions, which indicates that similar neuronal migration events might be involved in the late stages of geographic atrophy (Box 64.5).

Retinal remodeling in retinal degenerative conditions (e.g., light damage, RP-like disease, retinal detachment, and AMD) occurs in three phases.25 In phase 1, photoreceptor outer-segment truncation, disease-dependent opsin mislocalization, and changes in synaptic architecture often lead to disconnection of bipolar and photoreceptor cells before photoreceptors die.94–99 In phase 2, photoreceptor death and active debris removal attenuate the outer nuclear layer in association with microglial activation.100–102 In phase 3, new processes from remaining neurons form neurite fascicles as well as novel synaptic tufts (termed microneuromas by Marc

Box 64.5  Light-induced retinal degeneration versus geographic atrophy in age-related macular degeneration (AMD)

et al25) that develop outside the normal lamination of the inner plexiform layer. Neuron migration across the retina occurs, often near hypertrophic Müller cells.98 In contrast to conditions such as RP or AMD, phase 1 and 2 remodeling occurs relatively quickly (weeks) in light-induced retinal damage, while phase 3 remodeling seems to progress with similar kinetics in all conditions, once cone photoreceptor death has occurred.25

Although the pathogenesis of light-induced retinal damage and of AMD are clearly distinct, light-induced retinal damage has several similarities to atrophic AMD that are not shared with RP-like diseases.25 First, both conditions exhibit spatially delimited areas of photoreceptor–RPE–choriocap- illaris atrophy. In contrast to RP, both light-induced retinal damage and geographic atrophy exhibit phase 1/phase 3 borders (versus phase1/phase2 and phase 2/phase 3 borders in RP). Choriocapillaris degeneration in both conditions is severe in affected areas but not in adjacent survivor areas.103,104 Second, both conditions seem to exhibit glial and neuron emigration from the retina.105,106 Third, both light-induced retinal damage and AMD are associated with oxidative stress.86,107,108 Thus, some biochemical features and morphological changes found in light-induced retinal damage may be useful models of the changes that occur in late atrophic AMD.

In conclusion, the morphological end-stages of human retinal degenerations often bear a striking resemblance to those found in experimental light-induced retinal damage. Laboratory animal models have also provided insights into the role of nutrition in retinal development and potential therapies to slow the progression of retinal disease. Questions remain about basic mechanisms and whether animal models of photic injury are really appropriate as models for human retinal degeneration. This chapter has highlighted the similarities and differences that do exist, with a focus on comparisons between genetic, environmental, dietary, and age-related factors.

1.Noell WK, Walker VS, Kang BS, et al. Retinal damage by light in rats. Invest Ophthalmol 1966;5:450–473.

9.Grimm C, Reme CE, Rol PO, et al. Blue light’s effects on rhodopsin: photoreversal of bleaching in living rat eyes. Invest Ophthalmol Vis Sci 2000;41:3984–3990.

15.Klein R, Klein BE, Jensen SC, et al. The five-year incidence and progression of age-related maculopathy: the Beaver Dam eye study. Ophthalmology 1997;104:7–21.

17.Zhou J, Jang YP, Kim SR, et al. Complement activation by photooxidation products of A2E, a lipofuscin constituent of the retinal pigment epithelium. Proc Natl Acad Sci 2006;103:16182–16187.

20.Vaughan DK, Nemke JL, Fliesler SJ, et al. Evidence for a circadian rhythm

of susceptibility to retinal light damage. Photochem Photobiol 2002;75:547– 553.

25.Marc RE, Jones CB, Vazquez-Chona F, et al. Extreme retinal remodeling triggered by light damage: implications

for age related macular degeneration. Mol Vis 2008;14:782–806.

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Overview

Diabetic retinopathy remains a major cause of morbidity in diabetic patients. To date, the retinopathy has been defined based on lesions that are clinically demonstrable, and all of those have been vascular in nature, including degeneration or nonperfusion of the vasculature, and excessive leakage of the vasculature (retinal edema, cottonwool spots, hemorrhage, hard exudates). Available clinical evidence strongly suggests that the late, clinically meaningful stages of the retinopathy are a direct consequence of the earlier changes. This chapter is an overview of the vascular changes associated with diabetic retinopathy. Macular edema is the specific focus of Chapter 67 and neovascularization of Chapter 66.

Clinical background

Clinical findings in nonproliferative diabetic retinopathy (NPDR) arise from progressive capillary cell damage, loss of blood–retina barrier integrity, and leakage of vascular components into adjacent retinal tissue.1 Clinical signs of microaneurysms, retinal edema, retinal exudate, and retinal hemorrhage are all associated with increased capillary permeability and worsening vasculopathy. Yellow-white precipitates (hard exudates) may accompany leaking microaneurysms. Increased permeability of the blood–retinal barrier is known to occur in patients with diabetes, and this defect contributes to retinal edema and visual impairment in diabetic patients. Macular edema is the most common cause of visual loss in diabetic retinopathy (Figure 65.1A).

Larger microaneurysms and diffuse microvascular damage result in retinal hemorrhage. Focal areas of ischemia further damage the inner retina. Cottonwool spots describe opaque yellow-white lesions and represent areas of inner retinal infarction. The term soft exudate is now seldom used but describes the soft, ill-defined borders of these lesions. Retinal fluorescein angiography reveals progressive enlargement of areas of nonperfusion in diabetic retinopathy2–4 (Figure 65.1B).

Proliferative diabetic retinopathy (PDR) occurs when progressive cell dysfunction, vascular nonperfusion, and/or ischemia stimulate the development of retinal neovascularization. Progressive growth of abnormal vessels may lead to vitreous hemorrhage, preretinal hemorrhage, and iris neo-

Vascular damage in diabetic retinopathy

Timothy S Kern and Suber Huang

vascularization. Neovascular glaucoma is painful and arises as neovascular iris vessels block aqueous outflow. Contraction of fibrovascular proliferation may lead to retinal tears, vitreous hemorrhage, and traction retinal detachment.

It has long been appreciated that vascular permeability is increased in diabetic retinopathy.5–7 In early NPDR, hyperpermeability arises primarily from well-defined microaneurysms and results in focal areas of edema. Capillary fenestration and gaps in the vascular wall allow egress of serum, serum proteins, lipoproteins, and cellular components of peripheral blood. Macular edema is defined as retinal edema involving or threatening the macula. Distortion of normal macular architecture results in visual symptoms of blurring. Moderate leakage is often accompanied by the presence of yellow-white intraretinal deposits – hard exudates. Exudate results from precipitation of soluble lipoproteins at the junction of edematous and nonedematous retina. This is discussed further in Chapter 67.

The prevalence of diabetic retinopathy varies widely depending on the population studied, but data from about 20 years ago indicate that nonproliferative stages of the retinopathy were almost universal after 20 years of diabetes, and PDR affected about half of the people with type 1 diabetes after 30 years’ duration.8 More recent assessments suggest that this may be changing.9 The retinopathies of type 1 and type 2 diabetes are fundamentally similar (Box 65.1).10

Studies have shown that familial predispositions to diabetic retinopathy can be detected,11 and there has been appreciable effort to identify the genetic component.12–14 Current knowledge on the genetics of diabetic retinopathy has come from family studies, population studies, or studies using candidate genes focused primarily on genes related to vascular complications. There are problems with many of the studies reported, however, because many use small sample sizes that are often limited to specific ethnic groups, or have detected only weak associations.

Current means of inhibiting development or progression of diabetic retinopathy

Clinical studies of diabetic retinopathy have primarily focused on sequelae of vascular lesions (microaneurysms,