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

include congenital eye disease, retinoschisis, uveitis, diabetic retinopathy, premature birth, inflammation, or a family history of detachments25 (http://www.nei.nih.gov/health/ retinaldetach/index.asp#5). In some cases there is a clear association with inherited diseases (Norrie disease, Stickler’s syndrome, X-linked retinoschisis) while in other cases a role for inheritance may be suggested but poorly understood. The database, Online Mendelian Inheritance in Man (http://www.ncbi.nlm.nih.gov/sites/entrez?db=omim), provides information suggesting many potential roles for inheritance in RD. Predicting risk in an individual is complex because of the number of interacting factors that can come into play. Although there have been major improvements in cataract surgery this procedure still produces a significant increase in risk for rhegmatogenous RD.26 Vitreous liquefaction and posterior vitreous detachment (PVD), which produces traction on the retina, are key pathogenic mechanisms in rhegmatogenous RD.25,27 Before the age of 60, about 10% of patients experience PVD, while this number rises to about 25% between the ages of 60 and 70 and to slightly over 60% in patients over the age of 80. Epidemiological data suggest that the incidence of detachment begins to rise in the fourth decade of life. There is presently no method for preventing vitreous liquifaction and subsequent PVD. Prophylactic vitrectomy or scleral buckle is rarely performed. Laser photocoagulation or cryotherapy is used around retinal breaks or sites of obvious viteroretinal adhesion to increase chorioretinal adhesion and prevent subsequent detachment but the results are not unequivocal.27 The prevention of detachment in eyes at risk is a worthy research goal.27

Pathophysiology

relatively rapidly, within a day, but the two cell types react differently in other ways. For example, rods continue synthesizing proteins specific to their outer segments, while cones appear to shut down this process.37 Detachment evokes a series of events in photoreceptors that has been described as “deconstruction”38 (Figure 71.1) to reflect the fact that the whole cell is affected, often resulting in apoptotic death39 mediated by caspase activation.40

The accumulation of opsin in the plasma membrane is a sensitive indicator of outer-segment damage41 (Figure 71.1). It also provides a good comparison of rods and cones. Rods show the presence of opsin in their plasma membrane in detachments of a month or more in duration. Cones, however, show the presence for a short period of time, usually 3–7 days.24,37 Photoreceptors lose the distinct compartmentalization of organelles in their inner segments and show a decrease in their mitochondrial population.39 Many rod synapses are withdrawn into the outer nuclear layer and their ultrastructural organization is distinctly altered, suggesting almost certain changes in the flow of information from rods to second-order neurons41,42 (Figure 71.5).

After reattachment rod terminals begin repopulating the outer plexiform layer. This regrowth appears to be imperfect after 28 days of reattachment and perhaps accounts for ling­ ering visual deficits in some reattachment patients. Some rod axons regrow beyond their target layer and into the inner retina in both experimental and human RD. This event also occurs in the early development of mammalian retina, suggesting that reattachment reinitiates some developmental programs.

Pathophysiology

In recent years it has been recognized that effects of RD occur well beyond the RPE–photoreceptor interface and range from rapid changes in gene expression and protein phosphorylation to neuronal remodeling.28–32 Many changes described in animal models (Figure 71.4) have been validated in data from human detachment specimens.33

The retinal pigmented epithelium

The responses of the RPE monolayer to detachment have not been extensively studied. Its two most prominent responses are proliferation and loss of specialized apical microvilli.9,34,35 Proliferation begins within a day of RD. A combination of proliferation and migration of the cells can result in complex layers or assemblies in the subretinal space. These do not appear to hinder outer-segment regeneration after reattachment if their orientation is correct.17 The RPE regenerates de novo its apical microvilli after reattachment, including those highly specialized to ensheath cones. The nature of the signal that induces regeneration is unknown.

Photoreceptors

Until recently, photoreceptors received the most attention in experimental studies of detachment. It is their regenerative capacity that allows the recovery of vision after reattachment. Outer-segment regeneration is a manifestation of the ongoing outer-segment renewal process.36 In the detached retina the outer segments of both rods and cones degenerate

Secondand third-order neurons

The withdrawal of rod synaptic endings raises the question of the response by cells that connect to them: rod bipolar and axon-bearing horizontal cells. There is no evidence for cell death among inner retinal neurons; however, confocal imaging shows clearly that these cells remodel the processes that connect them to rod photoreceptors. Rod bipolar cells show rapid neurite sprouting with fine thread-like processes extending deep into the outer nuclear layer, usually terminating near withdrawn rod terminals.43 Dendrites are probably pruned from these cells as well. Axon-bearing horizontal cells in feline retina rapidly upregulate their expression of neurofilament protein and the axon terminal portion of the cell sprouts neurites that grow into the outer nuclear layer (Figure 71.6). Many of these terminate near withdrawn rod terminals. Others, however, grow along reactive Müller’s glia into the subretinal space where they can extend for great lengths along subretinal glial scars.24

A subpopulation of ganglion cells, those with the largest cell bodies, undergo dramatic changes that mirror the responses of horizontal cells. They upregulate the expression of two proteins, GAP 43 and neurofilament protein, both of which are expressed at low levels in adult ganglion cell bodies and dendrites30 (Figure 71.6). The same population sprouts neurites as they structurally remodel. These neurites are extensive and may grow from the cell base into the vitreous, or across the retina and into the subretinal space. In all cases the aberrant processes that grow out of the neural retina are structurally associated with gliotic Müller cell scars.

Thus the detachment of the neural retina from the RPE initiates a series of events in neurons throughout the retina,

not just among photoreceptors. Ensuing changes in synaptic circuitry could have a profound effect on retinal function and there is evidence that the activity of ganglion cells is abnormal in the detached feline retina (Minglian Pu, personal communication). The reorganization of synaptic circuitry after reattachment may underlie the long-term changes in vision that are known to occur in many reattachment patients.

Müller cells

Müller cells are the complex radial glia of the retina (Figure 71.3). In simplest terms, Müller cells can be thought of as monitoring and regulating the retinal environment, and thus playing a critical role in normal retinal function.44 They also become highly reactive to detachment, showing changes in early-response genes within hours,29,31 and changes in structure and protein expression within a day. They proliferate,

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with a peak response reached 3–4 days after detachment, but continuing at a low level thereafter (Figure 71.7). These cells also undergo a stereotypical structural remodeling that results in the formation of glial scars on both surfaces of the retina, thus contributing to (and perhaps initiating) the diseases subretinal fibrosis and PVR (see Fisher et al24 for a review).

Müller cells alter their expression pattern for many proteins, including the enzymes glutamine synthetase and carbonic anhydrase, the retinoid-binding protein CRALBP, and the cytoskeletal proteins tubulin, GFAP, and vimentin. An accumulation of the latter two is a hallmark response of these cells to retinal injury (Figures 71.4, 71.6, and 71.7). While intermediate filaments are often regarded as scaffold proteins, there is increasing evidence that they do more. Mice lacking the expression of both (vim–/–GFAP–/–) show less photoreceptor cell death after detachment.45 The same knockout strain does not form subretinal scars after detach-

ment.22 An association between the upregulation of these proteins and expansion of the Müller cells seems obvious when observing the changes by immunocytochemistry (Figures 71.4, 71.6, and 71.7). There are also data suggesting that the predominant intermediate filament protein expressed in a Müller cell will determine whether they grow into the vitreous cavity or subretinal space.25

Proliferation, intermediate filaments, subretinal fibrosis, and PVR

Both PVR and subretinal fibrosis are considered “proliferative diseases,” and yet the link between the diseases and the actual proliferation of any cell type is weak. Bromodeoxyuridine (BrdU) labeling studies show that nuclei of Müller cells synthesizing DNA on the third day after detachment have migrated into subretinal membranes by day 7 (Figure 71.7). It seems logical that this correlation could be extrapolated to Müller cells forming membranes on the vitreal surface, but there are no actual experimental data. Thus, as mentioned earlier, agents that prevent proliferation or those that reduce intermediate filament synthesis may reduce the risk for these complications or even cause their regression, thus reducing the need for secondary surgical procedures.

Microglia and the immune response

Microglial cells are immune cells that in their unactivated state reside in the inner retina. After detachment they proliferate, assume a rounded shape, and migrate into the photoreceptor layer where they scavenge dead or dying cells.46 Microglia may cause or prevent photoreceptor cell death by modulating the release of trophic factors from Müller cells.47 Macrophages from the circulation enter the subretinal space, where they also scavenge debris from degenerated outer segments (Figures 71.4, 71.6, and 71.7). Microarray analysis of mRNA expression in porcine retinas detached for 24 hours identified significant increases in the expression of many genes involved in the immune and inflammatory responses.32 In reattached retina the presence of microglia correlates strongly with the degree of photoreceptor recovery.42 The immune system’s role in detachment is only beginning to be appreciated.

In summary, rhegmatogenous RD remains a serious retinal problem that can result in long-lasting visual deficits. The study of animal models and comparisons to data from human tissue are providing new information at the cellular and molecular levels that may help understand why successful anatomical reattachment can still leave a patient with imperfect vision,48 or why some detachments lead to PVR while others do not.

2.Bradbury MJ, Landers MB III. Pathogenetic mechanisms of retinal detachment. In: Ryan S (ed.) Retina, 4th edn. Philadelphia, PA: Elsevier Mosby, 2006:1987–1993.

6.Williams GA, Aaberg TM. Techniques of scleral buckling. In: Ryan S (ed.) Retina, 4th edn. Philadelphia, PA: Elsevier Mosby, 2006:2010–2046.

9.Marmor MF. Mechanism of normal retinal adhesion. In: Ryan S (ed.) Retina, 4th edn. Philadelphia, PA: Elsevier Mosby, 2006:1849–1869.

14.Joeres S, Kirchhof B, Joussen AM. PVR as a complication of rhegmatogeneous retinal detachment: a solved problem? Br J Ophthalmol 2006;90:796–797.

15.Burton TC. Recovery of visual acuity after retinal detachment involving the macula. Trans Am Ophthalmol Soc 1982;80:475– 497.

16.Tani P, Robertson DM, Langworthy A. 1981. Prognosis for central vision and anatomic reattachment in

rhegmatogenous retinal detachment with macula detached. Am J Ophthalmol 1981;92:611–620.

18.Fisher SK, Erickson PA, Lewis GP, et al. Intraretinal proliferation induced by retinal detachment. Invest Ophthalmol Vis Sci 1991;32:1739–1748.

24.Fisher SK, Lewis GP, Linberg KA, et al. Cellular remodeling in mammalian retina: results from studies of experimental retinal detachment. Prog Retina Eye Res 2005;24:395– 431.

28.Geller SF, Lewis GP, Fisher SK. FGFR1, signaling, and AP-1 expression following retinal detachment: reactive Müller and RPE cells. Invest Ophthalmol Vis Sci 2001;42:1363–1369.

30.Zacks DN, Han Y, Zeng Y, et al. Activation of signaling pathways and stress-response genes in an experimental model of retinal detachment. Invest Ophthalmol Vis Sci 2006;47:1691– 1695.

33.Sethi CS, Lewis GP, Fisher SK, et al. Glial remodeling and neural plasticity in human retinal detachment with proliferative vitreoretinopathy. Invest Ophthalmol Vis Sci 2005;46:329–342.

38.Lewis GP, Mervin K, Valter K, et al. Limiting the proliferation and reactivity of retinal Müller cells during detachment: the value of oxygen supplementation. Am J Ophthalmol 1999;128:165–172.

41.Lewis GP, Sethi CS, Charteris DG, et al. The ability of rapid retinal reattachment to stop or reverse the cellular and molecular events initiated by detachment. Invest Ophthalmol Vis Sci 2002;43:2412–2420.

46.Lewis GP, Sethi CS, Carter KM, et al. Microglial cell activation following retinal detachment: a comparison between species. Mol Vis 2005;11;491– 500.

Clinical background

Retinopathy of prematurity (ROP) is a leading cause of childhood blindness worldwide and develops after birth in preterm infants, especially those born at less than 1500 g birth weight or younger than 32 weeks’ gestational age. There are no symptoms or obvious signs of ROP. Therefore, longitudinal dilated examinations of the retinas of infants at risk are necessary to determine when treatment is needed, or that retinal vascular development is complete and the risk of ROP is no longer present. The goal of examinations is to detect and treat severe ROP in order to prevent progressive retinal detachment, in which poor vision occurs even when successful retinal surgery can be performed.

Based on the International Classification of ROP (ICROP),1 ROP is characterized by several parameters: zone, stage, extent of stage, and the presence or absence of plus disease. At any examination, the risk of a bad outcome depends on the presence of plus disease or stage 3 ROP (both defined below and important features of severe ROP) as well as the postgestational age of the infant (i.e., the gestational age + chronologic age from birth in weeks).

The zone of ROP is the retinal area supplied by retinal vessels and is an indicator of the extent of retinal vascular development (Figure 72.1). Zone I is the smallest, having the largest area of avascular retina. Zone III is the most vascularized (except for complete vascularization) and has a very low risk of a poor outcome. There are five stages of ROP. Stages 1 through 3 are the acute forms of ROP and are characterized by the appearance of the retina at the junction of vascular and avascular retina. A line (stage 1) or ridge (stage 2 (Figure 72.2A) can often regress without developing into severe ROP. Stage 3 ROP has intravitreous neovascularization, a feature of severe ROP (Figure 72.2B). Stages 4 (Figure 72.2C) and 5 (Figure 72.2D) describe partial or complete retinal detachment, respectively, and are associated with vitreous and fibrovascular changes. The extent of ROP indicates the number of clock hours of a stage. Plus disease is the presence of dilated and tortuous retinal vessels and is a feature of severe ROP (Figure 72.3).

One point of clarification is the difference between retinal drawings and images of dissected retinal flat mounts. The retina covers the inner sphere of the eyeball, and when dissected, must be cut with relaxing incisions in order to

flatten it on to a microscope slide. The result is a clover-leaf appearance (Figure 72.4). However, clinicians and surgeons represent the retina as a round clock face and use clock hours to describe the location of pathologic features on the retina.

Severe ROP portends an increased risk of developing retinal detachment and poor vision (Box 72.1). Therefore treatment, preferably with laser,2,3 is strongly considered at certain levels of severe ROP, threshold disease and type 1 prethreshold ROP2 (Table 72.1). A form of severe ROP is aggressive posterior ROP (APROP), which appears at young postgestational ages in preterm infants, who have immature retinal vascular development and large avascular retinal areas (Box 72.2). Neovascularization in stage 3 appears broad and flat in APROP (Figure 72.5). Despite standard of care treatment, these eyes often have poor outcomes.4,5

Historical development

In the 1940s, ROP manifested as a white pupil and was termed retrolental fibroplasia (RLF).6 Most RLF was stage 5 ROP with a retrolental membrane and occurred in older and larger infants. Michaelson,7 Ashton and Cook,8 and Patz9 described the hypothesis of hyperoxia-induced vaso-obliter- ation followed by relative hypoxia and the release of an “angiogenesis” or “vasoproliferative” factor. Further validation from studies with animal models (see below) led to improved monitoring of oxygen to preterm infants in neonatal intensive care units (NICUs). ROP virtually disappeared, because hyperoxia at birth was avoided. (Standard of care today is maintenance of infant oxygen saturation in the mid 80 and low 90 percentages.) But as infants of younger gestational ages and of lower birth weights have survived, ROP has re-emerged.10 Besides absolute oxygen

(Box 72.3).11–15

Xenon photocoagulation was reported as a treatment for ROP in 1976 by Nagata.16 The initial observations of Folkman et al17 of a tumor angiogenesis factor were described in the Friedenwald lecture presented by Arnall Patz in 1980.9 In 1984, ICROP1 described and characterized stages of ROP earlier than stage 5. The Multicenter Clinical Trial for Cryotherapy for Retinopathy of Prematurity (CRYO-ROP) found

Figure 72.1  Drawing showing zones used in classifying retinopathy of prematurity. Zone I represents the least mature retina, being a circle centered on the optic nerve with a radius twice the distance from the optic nerve to the macula. Zone II is a circle centered on the optic nerve with a radius equal to the distance from the optic nerve to the nasal ora serrata. Zone III is the most mature, with the lowest risk of a bad outcome, and represents the temporal crescent.

Table 72.1  Definitions of threshold and type 1 prethreshold retinopathy of prematurity (ROP)

The ETROP recognized plus disease as two quadrants of dilated and tortuous vessels149 whereas CRYO-ROP148,150 defined it as four quadrants.

CRYO-ROP, Multicenter Clinical Trial for Cryotherapy for Retinopathy of Prematurity; ETROP, Early Treatment for ROP.

that obliteration of the avascular retina in ROP with cryotherapy at a certain threshold of severity (Table 72.1) significantly reduced blindness and retinal detachment.18 The CRYO-ROP study group reported on the natural history of ROP (for review, see McColm and Hartnett19). Since the development of laser via indirect delivery, treatment of acute ROP has been preferentially performed using laser (Figure 72.6), which is less destructive and causes less inflammation than cryotherapy (Box 72.4).2,3 The Early Treatment for ROP Study (ETROP) found that treatment of eyes with type 1 prethreshold ROP (Table 72.1) further reduced the risk of a bad outcome. ETROP also emphasized plus disease and reduced the importance of extent of stage in defining highrisk eyes.

Epidemiology

The Institute of Medicine reported preterm births up 30% from 1981 (www.iom.edu/Object.File/Master/35/975/ pretermbirth.pdf), now accounting for 12.5% of all births in the USA. With increases in prematurity,20,21 ROP has also become a leading cause of childhood blindness worldwide.21 A report from a national registry of children in the USA

Clinical background

Box 72.1  Screening and care for acute severe

retinopathy of prematurity (ROP)

Box 72.2  Aggressive posterior retinopathy of

prematurity (APROP)

(Babies Count) indicated that ROP was the earliest cause of visual impairment and one of the three most prevalent visual conditions along with cortical visual impairment and optic nerve hypoplasia.22 ROP of any stage affects approximately 16 000 infants each year in the USA. Most early stages of ROP resolve and about 1100 infants require treatment. Even with treatment, blindness occurs in 550 infants/year (National Eye Institute statement on ROP, October 2007: http://www.nei.nih.gov/health/rop/). In the USA, ROP is seen more commonly in Caucasians than African Americans but once severe ROP occurs, the outcomes appear similar.23 Asians also have an increased risk of ROP.24 ROP in developing nations is seen in infants of larger birth weight and older gestational ages than in the USA,25 possibly because of variations in ethnic groups, regulation and monitoring of oxygen delivery, and the availability of prenatal care.

Genetics

A genetic component to ROP appears to be present, although the understanding of the contribution of genetic polymorphisms to the risk of ROP is incomplete. Based on a retrospective analysis in monozygotic and dizygotic twins, a 70%

Figure 72.3  Example of dilated and tortuous vessels in plus disease.

Figure 72.4  Retinal flat mount taken from a postnatal day-14 rat pup that was exposed to oxygen-induced retinopathy, demonstrating a peripheral avascular retina. Vessels are visualized with lectin staining. In the rodent the optic nerve is central and no macula is present. The ora serrata appears as fringe in the periphery of the image. To flatten the retina, four radial cuts are made and the result is a clover-leaf.

variance in the susceptibility of ROP was found to be from genetic factors.26

The Norrie disease gene produces the gene product, norrin, which is also a downstream ligand for receptors in the Wnt pathway. The Wnt pathway and norrin are important in retinal and vascular development27,28 and abnormalities are present in patients with Norrie disease. Genetic mutations in the Norrie disease gene [Xp11.2-11.3] were

Clinical background

Box 72.3  Oxygen exposure and risks to retinopathy

of prematurity (ROP)

Box 72.4  Treatment for severe retinopathy of

prematurity (ROP) and after laser

reported to account for 3% of cases of advanced ROP,29 but another study having racially diverse populations reported no significant increase in the prevalence of polymorphisms in infants with severe ROP compared to control premature infants with no or minimal ROP.30 One study reported on samples from 109 patients with diverse pediatric vitreoretinopathies including ROP and 54 controls. Mutations within the cysteine knot configuration of the Norrie disease gene were associated with severe retinal dysplasia whereas other polymorphisms within the gene had less severe vitreoretinopathies.31 This study suggested that, within severe ROP, polymorphisms in the Norrie disease gene may account for a subgroup with severe retinal dysplasia. Controversy in the association of mutations in the Norrie disease gene may also reflect differences based on ethnic variability.32

Figure 72.5  Aggressive posterior retinopathy of prematurity with broad lacy neovascularization in an eye that had previous laser treatment.

Figure 72.6  Laser treatment in avascular retina temporal to intravitreous neovascularization. There is evidence of an area where laser is not sufficiently confluent (“skip lesion”).

One study found an association of severe ROP with certain polymorphisms in the gene of vascular endothelial growth factor (VEGF),33 whereas another study found different associations.34 Overexpression of VEGF was reported in an unusual case of ROP.35 Some polymorphisms in VEGF may be linked differentially to others and the effects of these may differ among ethnic groups.32 Despite the finding that low serum systemic insulin-like growth factor-1 (IGF-1) was associated with more severe ROP,36 one study failed to show a relationship between a prevalent polymorphism in the IGF-1 receptor and the presence of ROP.37 The role of genetics requires greater study and will continue to be elucidated along with the effect of environmental factors on gene function.

Diagnostic workup and treatment

The published guidelines from the American Academy of Pediatrics, American Academy of Ophthalmology, and American Association for Pediatric Ophthalmology and Strabismus are:

infants with a birth weight of less than 1500 g or gestational age of 30 weeks or less and selected infants between 1500 and 2000 g or gestational age of more than 30 weeks with an unstable clinical course

should have retinal screening with pupil dilation and indirect ophthalmoscopy.38,39 The first examination is recommended at 4–6 weeks after birth or at 31 weeks’ postgestational age (whichever is later) and prior to discharge from the hospital. Examinations are performed approximately every 2 weeks if there is incomplete retinal vascular development without ROP or weekly with evidence of ROP until treatment is recommended (Table 72.1) or until regression of ROP occurs and retinal vascular development is completed.

The use of wide-angle photography or quantification of plus disease to detect high-risk ROP is being studied.40–42 Images would be obtained at a remote facility and transmitted for review to a reading center. The center would detect

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“clinically significant ROP” and notify the remote facility that the infant requires an examination and possible treatment by a qualified ophthalmologist. A successful system requires careful coordination to avoid missing any infant with severe ROP.

For eyes that progress to stage 4 ROP (partial retinal detachment), the vitreous appears to play an important role. Both changes at the junction and fibrovascular organization within the vitreous have been associated with and are predictive of progressive stage 4 ROP.43,44 The severity of the retinal detachment depends on the total area of the fibrovascular proliferation that grows and interacts with the vitreous collagen. The vitreous provides a scaffold for invading cells. Cell contraction on the vitreous collagen is believed to lead to tractional retinal detachments.43,44 Whereas most stage 4 ROP begins as a retinal detachment at the junction of vascular and avascular retina, APROP may produce more severe detachments because of extensive cell invasion into broad sheets of vitreous in the posterior retina, i.e. usually within zone I. From optical coherence tomography (OCT), changes at the vitreoretinal interface of the posterior retina are recognized (Figure 72.7).45 The role of transforming growth factor-β (TGF-β) in wound healing and the changes in concentrations of TGF-β and VEGF in the developing preterm infant have been proposed. Study of the mechanisms of stages 4 and 5 ROP is difficult because of lack of ideal animal models and the difficulty in studying human infants.46,47 Once progressive stage 4 ROP is diagnosed, surgery is performed to release vitreous tractional forces that detach the

retina.43,44,48

Differential diagnosis

Several conditions can manifest as either early or late stages of ROP based on the progression of the disease. Examples include familial exudative vitreoretinopathy (FEVR), Norrie disease, and incontinentia pigmenti. Other conditions cause media opacity from diseased cornea, lens, vitreous, or retina and produce a white pupil or leukocoria mimicking stage 5 ROP. Notable examples include persistent fetal vasculature,