Ординатура / Офтальмология / Английские материалы / Retinal and Vitreoretinal Diseases and Surgery_Boyd, Cortez, Sabates_2010

Retinal Pigment Epithelium (RPE)

The retinal pigment epithelium (RPE) is fundamentalto normal retinal function. Within its central position between the photoreceptor layer of cells (rods and cones) and the choriocapillaris (Figures 1C and 2C), it has a variety of essential functions which are metabolic, biochemical and physical. These include maintenance of the blood-retina barrier, transport of metabolites and other factors important for cell function from the choroid to the retina and vice versa. It is also essential in the processing of rhodopsin as part of the visual cycle and maintenance of retinal adhesion.30-32

The RPE is one of the highly specialized body tissues that rely on self-renewal and not regeneration. Its slow, continued, progressive failure in its many functions leads to significant changes in the surrounding macular tissues, ultimately causing retinal degeneration. Compare the normal photoreceptor cell layer, RPE, Bruch’s membrane, choriocapillaris and other surrounding macular tissues of normal retina with the abnormal changes shown in Figures 1C through Figure 3 and Figures 6-7.

The gradual failure of the RPE is a result of the increasing difficulty in processing cellular waste over time. The photoreceptor outer segments are being constantly shed and phagocytosed by the RPE. A byproduct of photoreceptor turnover is the accumulation of undigested residual bodies within the RPE

in the form of lipofuscin.33 This process of photoreceptorturnoverrequiresdegradationof the shed rods and cones and the elimination of this cellular waste through Bruch’s membrane which is adjacent to the RPE. Some of this cellular debris does not degrade and becomes accumulated within the RPE cells, slowly increasing with age, particularly in the macula in the form of drusen.

The metabolism of the RPE largely depends on the maintenance of the integrity of Bruch’s membrane (see Figures 1C through 3, 6-7). Bruch’s membrane is a five layer structure consisting of outer basement membranes of the RPE and choriocapillaris, and two collagenous zones surrounding a single elastic zone.34 It is situated between the RPE and the choriocapillaris and serves as a filter for the passage of nutrients and waste products between the two structures. Changes in Bruch’s membrane begin in the macula as early as the teen years. There is a progressive secondary thickening of Bruch’s membrane by a wide range of substances, including various forms of collagen, granular debris, and mineralized deposits. This thickening of Bruch’s membrane is also made worse by the progressive accumulation of lipids as a function of age. The severity of these changes increases dramatically beyond the sixth decade of life.35-37 These alterations in Bruch’s membrane continuously contribute to problems with the integrity of the RPE cell layer, thereby interfering with the normal transport of water, essential metabolites, and various modifiers of cellular activity within the macula, eventually leading to its dysfunction in a variety of forms (as illustrated in this Chapter).

Clinical significance of

Drusen

Morphologically, drusen can be classified into hard and soft varieties, which can be differentiated clinically. Hard drusen are small discrete nodules that appear flat and have sharp borders. Soft drusen tend to be larger and more amorphous with borders that are less well defined (Figures 1, 2, 8). They frequentlyexhibitconfluencewithsurrounding drusen and have a more notable elevation on biomicroscopic evaluation. Exudative drusen are important as clinical markers for dry forms

of the disease, in its earliest stages. More importantly, their characteristics may serve as predictors of future risk in the development of exudative forms of AMD. Specifically, large confluent drusen (defined as greater than or equal to 125 um in diameter with indistinct margins) and significant pigmentary changes within the retina are the major risk factors for the progression to more advanced forms of both dry and wet AMD.38-42 Discussion of the increased risk for progression, need for close clinical monitoring, and role of nutrition and antioxidant supplementation is therefore imperative in this subset of patients.

Figure 10: Exudative ARMD. Subretinal hemorrhage from subfoveal choroidal neovascularization. (Photo courtesy of Lawrence A. Yannuzzi, M.D., selected from his extensive retinal images collection with the collaboration of Kong-Chan Tang, M.D.)

Figure 11: Exudative ARMD. Disciform scarring - end result of choroidal neovascularization. (Photo courtesy of Lawrence A. Yannuzzi, M.D., selected from his extensive retinal images collection with the collaboration of Kong-Chan Tang, M.D.)

Vascular Endothelial Growth

Factor

Various growth factors and cytokines are implicated in the development of CNV, the most important of which is vascular endothelial growth factor (VEGF). VEGF serves as a regulator of angiogenesis and vascular permeability in embryogenesis and tumor growth and vascular protection and neuroprotection in adults. Experimental evidence supports a critical role in the maintenance of mature blood vessels with localization of VEGF and its receptors to cells of fenestrated and sinusoidal blood vessels, ocular choroid, choroid plexus, hepatocytes and other cell types.43,44 VEGF is produced by several different ocular cells, including glial cells, retinal pigment epithelium cells and endothelial cells.45 The production of VEGF is usually a reaction to an ischemic environment due to disease. Experimentally, it has been demonstrated that rubeosis iri-

dis and ischemic vascular changes can be induced by VEGF injection in monkeys.46,47 Furthermore, inhibition of VEGF in monkeys was shown to prevent these ischemic VEGFinduced changes.48 VEGF concentration was shown to be elevated in the ocular fluid of patients with retinal vascular ischemia secondary to diabetes and retinal vein occlusion.49 Additional studies linked VEGF specifically to age-related macular degeneration (AMD) by demonstrating the presence of VEGF in choroidal neovascular membranes removed from patients with the disease.50

VEGF blockade has become a mainstay therapy for the treatment of CNV in exudative AMD due to its antiangiogenic, antipermeability, and anti-inflammatory properties.51,52 The introduction of anti–vascular endothelial growth factor (VEGF) therapies, such as ranibizumab(Lucentis,Genentech),andbevacizumab (Avastin, Genentech) was a revolutionary advance and has been shown to significantly

improve visual acuity (VA) in many patients with choroidal neovascularization due to AMD. Vascular endothelial growth factor is central to the pathogenesis of angiogenesis and the development of CNV in AMD. Thus, its targeted inhibition by intravitreal injection has been a major breakthrough in the management of exudative AMD.

Imaging Modalities in AMD

A variety of imaging techniques and modalities are utilized in the diagnosis and management of patients with AMD. Patients with funduscopic findings of dry AMD such as drusen and RPE alterations can be monitored with serial fundus photography. Fundus photograghy is commonly utilized for baseline documentation and for close monitoring of progression of dry AMD. The use of fundus photography is also invaluable in educating patients on their condition. Alterations of the RPE including the identification of geographic atrophy are best demonstrated with the use of fundus autofluorescence. Fundus autofluorescence (FAF) imaging is a quick, non-invasive imaging tool for evaluating patients with nonexudative AMD (Figure 8). FAF demonstrates the topographic distribution of lipofuscin throughout the fundus, thereby providing a map of RPE integrity. A localized increase in FAF is observed in AMD patients with PED and within areas of focal hyperpigmentation.53,54 Geographic atrophy (GA) results in a well-demarcated area of decreased FAF corresponding to the atrophic lesion on fundus examination. Increased FAF

is often present along the margins of areas of GA.53,55 This increase in FAF along the margins of GA represents areas of oxidative stress or defective or altered metabolism affecting RPE integrity and might serve as markers of atrophic progression. FAF is useful for mapping an expansile creep of GA which may not be clinically apparent. This is important in reconciling the patient’s symptoms and the clinical exam.

Using fundus biomicroscopy, any patient that clinically presents with findings suspicious for choroidal neovascularization should be evaluated with fluorescein angiography. These signs may include PEDs, subretinal, intraretinal or sub-RPE hemorrhage, and neurosensory detachment of the retina (Figure 13). CNV lesions may be classified by their location. They may be subfoveal (located beneath the center of the foveal avascular zone [FAZ]), juxtafoveal (posterior border of the lesion 1 to 199 microns from the center of the FAZ), or extrafoveal (posterior border of the lesion >200 microns from the center of the FAZ). Most commonly CNV presents in a subfoveal location in AMD.56 In addition a CNV lesion can be classified based on its pattern of fluorescence into classic and occult lesion types.56 Classic CNV is distinguished as well demarcated bright areas of intense fluorescence that appear in the early frames of the angiographic sequence, usually before 1 minute and are associated with increasing leakage in later phase of the angiogram. In contrast, occult CNV (Figures 12-14) may have two separate patterns on fluorescein angiography: fibrovascular pigment epithelial

Figure 12: Exudative ARMD with Occult Choroidal Neovascularization. This is another manifestation of exudative age-related macular degeneration. Occult choroidal neovascularization with subretinal hemorrhage.

(Photo courtesy of Lawrence A. Yannuzzi, M.D., selected from his extensive retinal images collection with the collaboration of Kong-Chan Tang, M.D.)

Figure 13: Exudative ARMD - Poorly Defined Choroidal Neovascularization on Fluorescein Angiography. Blockage on the fluorescein angiogram from subretinal hemorrhage. An area of juxtafoveal neovascularization is suspected in the fluorescein study. (Photo courtesy of Lawrence A. Yannuzzi, M.D., selected from his extensive retinal images collection with the collaboration of Kong-Chan Tang, M.D.)

detachment (PED) or late leakage of an undetermined source. Fibrovascular PED is characterized by irregular elevation of the RPE. It displays a stippled hyperfluorescencethat typicallyappears later than with classic CNV. These areas demonstrate staining or leakage in the late phases and may have well or poorly defined borders. In contrast, late leakage of undetermined source is characterized by flat RPE with speckled hyperfluorescence that emerges only in the late phases of the angiogram study and that demonstrates poorly demarcated leakage. The term lesion component refers to the constituents of the lesion, which includes not only the CNV (eg, classic, occult) but also

features that may obscure CNV such as thick blood, hyperpigmentation, fibrous scar, or serous PED all of which will block fluorescence.

Figure 14: Exudative ARMD with Occult Neovascularization - Indocyanine Green Angiogram. Digital ICG video angiography reveals an area of neovascularization adjacent to the optic disc that could not be seen sufficiently clear on the fluorescein angiogram. (Photo courtesy of Lawrence A. Yannuzzi, M.D., selected from his extensive retinal images collection with the collaboration of Kong-Chan Tang, M.D.)

The identification of angiographic CNV lesion components was critical in clinical trials that evaluated natural history and treatment outcomes for the use of photodynamic therapy (PDT).56-58 During the PDT era, this information was invaluable in directing treatment but currently is not as crucial in clinical practice currently due to the prevalence of anti-angiogenic drugs.

Indocyanine green or ICG angiography enables enhanced imaging of the choroidal circulation. Compared to fluorescein, ICG has a higher molecular weight (775 kD vs. 375 kD) allowing for a slower rate of leakage. Due to its lipophilic and hydrophilic properties, ICG is 98% protein-bound allowing for enhanced imaging of choroidal vessels and choroidal lesions as less dye escapes from the fenestrated choroidal vasculature. In addition, ICG has peak absorption and emission wavelengths in the near infrared range (790-800 nm absorption and 830-840 nm emission).59 Since infrared light allows for deeper penetration in tissue, it enables imaging of the choroid through the RPE.

ICG is an extremely useful diagnostic adjunct to fluorescein angiography in the presence of blood, pigment, or exudate as its wavelength allows for imaging through these entities (Figure 14). ICG can be used to detect and outline the extent of CNV, identify subtypes of occult CNV such as polypoidal choroidal vasculopathy (PCV), and masquerading diseases such as central serous chorioretinopathy (CSC).

Destro and Puliafito60 evaluated patients with suspected choroidal neovascularization using FA and ICG. They found that ICG improved visualization of the choroidal circulation and enhanced visualization of some neovascular membranes. Yannuzzi et al61 evaluated patients with occult CNV based on FA. Using ICG, 39% of their patients were converted from occult into well-defined CNV. Guyer et al62 evaluated 1000 cases of CNV to describe the various types of neovascularization and determine the frequency and natural history of the various lesions. There were three types of CNV that can be observed by digital ICG videoangiography. Plaques were the most common type of lesion and overall had a poor natural history. Focal spots or hot spots were the next most common lesion and could potentially have been treated with laser photocoagulation. Combination lesions (in which both focal spots and plaques were noted) were rare. Therefore, ICG was useful in identifying lesions amenable for treatment with laser photocoagulation. In a separate study, Yannuzzi et al63 evaluated patients with ICG that had evidence of occult CNV with a serous PED on FA. The authors determined that 96% of these patients had a vascularized PED and ICG was useful in the classification and identification of lesions amenable to treatment with laser photocoagulation. In addition, ICG can be used to identify and treat feeder vessels connected to the actively leaking CNV.64 This was particularly important prior to the use of anti-VEGF medications in treating CNV as these lesions would have otherwise been considered ineligible for treatment without the use of ICG.

ICG is able to provide a more definitive diagnosis in cases of PCV. ICG clearly images the primary lesion and demonstrates dilated choroidal vessels terminating in polypoidal or aneurysmal excrescences.65 The vessels comprising the polypoidal lesion are often more extensive than observed with clinical examination alone. In the early-phase ICG, larger PCV vessels are filled before retinal vessels and the area within and immediately surrounding the polypoidal lesions remains hypofluorescent. In the late phase, the central polypoidal lesion is hypofluorescent surrounded by an area of hyperfluorescence. This pattern of late central hyperfluorescence persists in later frames in active lesions whereas inactive lesions become hypofluorescent due to disappearance of the fluorescence from the lesions.

A subtype of AMD, retinal angiomatous proliferation or RAP, in which angiomatous proliferation originates from the retina and extends posteriorly into the subretinal space, eventually communicating in some cases with choroidal new vessels has been well documented. Based on its chronicity it can present in one of three vasogenic stages: intraretinal, subretinal,orchoroidalneovascularization.ICG is invaluable in the diagnosis of RAP as it reveals a focal area of intense hyperfluorescence corresponding to the neovascularization (hot spot), and some late extension of leakage within the retina from the intraretinal neovascularization. More advanced cases can reveal a hot spot at the site of neovascularization within and beneath the retina. In cases of late RAP ICG can demonstrate a vascularized PED and the presence of a retinal-choroidal anastomosis.66

ICG can be particularly helpful in the diagnosis of challenging cases to differentiate occult CNV from CSC.67,68 Patients with CSC have a focal leak on FA which can be mistaken for CNV. ICG angiography of these patients often reveals early and mid hyperfluorescence which fades in the later phases. The hyperfluorescence is believed to represent widespread changes in choroidal hyperpermeability. The extent of these choroidal angiographic changes can be greater than would be expected by clinical examination alone. By demonstrating increased choroidal hyperpermeability in patients with CSC, ICG has aided in the understanding of this disorder as primarily a choroidal vascular disorder with a secondary dysfunction of the RPE. ICG can be used to guide treatment with PDT in chronic and progressive cases of CSC. Yannuzzi et al69 reported rapid reduction in subretinal fluid and improvement in visual acuity in cases of ICG guided PDT therapy for chronic CSC.

Optical coherence tomography (OCT) is a noninvasive imaging technique that has been used increasingly over the past several years to diagnose and monitor a variety of retinal diseases that affect the macula. Time domain OCT relies upon differential reflections of light to produce 2-dimensional cross-sections of the retina. OCT images are obtained rapidly and have a spatial resolution of approximately 8 mcm. OCT is particulary useful for quantifying retinal thickness and monitoring treatment efficacy.70 In neovascular AMD, OCT can be useful for identifying intraretinal, subretinal, or sub-RPE fluid. OCT serves as an adjunct to fluorescein angiography but is increasingly

used preferentially to assess presence of intraretinal and/or subretinal fluid in guiding the decision to retreat patients using anti-vascular endothelial growth factor agents.

Over the past 3 years spectral domain, or fourier domain OCT (SD-OCT) has been utilized to better image retinal pathology. Image acquisition times are reduced and greater resolution is obtained with SD-OCT to provide better anatomical detail and to diagnose subtle pathology. Motion artifacts can be reduced with eye tracking capability and better alignment and reproducibility of images is possible with tracking of corresponding retinal vessels. It is preferred in comparison to time domain technology in AMD patients in evaluating subtle pockets of sub-retinal or intra-retinal fluid and for more accurate retinal thickness quantification.71,72

Treatment

The procedures for the management of exudative AMD are vital in preserving and often times improving central vision. These procedures include but are not limited to intravitreal injection of an anti-VEGF (vascular endothelial growth factor) drug, laser photocoagulation, photodynamic therapy, photodynamictherapywithintravitrealsteroid, and surgical translocation of the macula. Multiple treatments may be required to achieve complete resolution of the leakage from CNV, and therefore patients are monitored closely for treatment response and for signs

of subsequent leakaage. The benefits of each treatment must be weighed against potential complications inherent to each treatment modality. Each of the possible available treatment options are limited in their effectiveness by the repeated need for intervention and the individual variability of tissue response to treatment.

Precautions for Higher Risk Patients

Persons at higher risk of macular degeneration with genetic susceptibility should see their ophthalmologist regularly. If indicated, they should have fluorescein angiography and optical coherence tomography. They can perform self assessment weekly or even daily using an Amsler grid or merely by looking at the same test object like a clock illuminated in the same way and at the same distance. Each eye should be tested separately. At the first sign of any blurring, distortion, or decreased acuity, the person should return to the ophthalmologist promptly for a check-up. Self-monitoring by patients is critical in the early detection and treatment of exudative AMD as visual symptomotology may be subtle and treatment response is greater for those lesions with early detection. This opportunity is often missed when these patients are slow to realize that their vision is somewhat reduced in one eye. Unfortunately in these instances the macular degeneration is often too advanced on presentation resulting in a less effective treatment response.

Prevention of ARMD

As previously mentioned, a great deal of currentresearchconcernsmorespecificidentification of patients who are at the greatest risk of developing macular degeneration so that precautions can be taken as outlined above. Other approaches are being considered, particularly in relation to nutrition, modification of cardiovascular risk factors and smoking cessation.

Nutritional Intervention

The Age-Related Eye Disease Study, an 11-center double-masked clinical trial enrolled 4753 patients to evaluate the effect of high-dose micronutrient supplementation consisting of antioxidants and vitamins (500 mg vitamin C, 400 IU vitamin E, and 15 mg beta carotene) and zinc (80 mg zinc oxide and 2 mg of cupric oxide to prevent zinc-induced anemia) on AMD. The recommendations were for patients with extensive intermediate size drusen, at least 1 large druse, noncentral geographic atrophy in 1 or both eyes, or advanced AMD or vision loss due to AMD in 1 eye, and without contraindications such as smoking, to supplement their diet with antioxidants and zinc.73 Higher dietary intake of lutein/zeaxanthin was independently associated with decreased likelihood of having exudative AMD, geographic atrophy, and large or extensive intermediate drusen.74 Recently, a multicenter clinic-based prospective cohort

studyfromaclinicaltrialincludingAge-Related Eye Disease Study (AREDS) participants was conducted to study the association of dietary omega-3 long-chain polyunsaturated fatty acids and fish intake with incident exudative AMD and central geographic atrophy. Dietary omega-3 long-chain polyunsaturated fatty acid intake was associated with a decreased risk of progression from bilateral drusen to central geographic atrophy.75 The current recommendation for patients with bilateral large drusen and those with advanced AMD in 1 eye is to take an AREDS-type supplementation. Caution should be exercised by smokers however, as they should avoid beta-carotene for the increased risk of lung carcinoma.

A retrospective epidemiologic study has found that people who eat large amounts of leafy green vegetables, particularly spinach and kale, 4 to 6 times per week seem to have a lower incidence of macular degeneration. Whether this diet would actually reduce the incidence of macular degeneration in people who are at increased genetic risk, no one knows for sure. But eating a well-balanced diet may offer some protection. Whether to take vitamins and mineral supplements at this time is an individual decision. Overall the modification of cardiovascular risk factors along with smoking cessation should be stressed to susceptible patients. Smoking has a harmful effect on many parts of the body, and confers an increased risk of macular degeneration.

AREDS 2 is a multi-center randomized trial currently underway designed to assess the effects of oral supplementation of high doses of macular xanthophylls (lutein and zeaxanthin) and omega-3 long-chain polyunsaturated fatty acids (DHA and EPA) on the progression to advanced AMD. Enrolled participants had either bilateral large drusen (>125 microns) or large drusen in one eye and advanced AMD in the fellow eye. Participants were followed for a minimum of 5 years and were offered additional treatment with the original AREDS formulation and 3 variations of this formula including no beta-carotene, lower amounts of zinc, and no beta-carotene and lower amounts of zinc. The results of this clinical trial are currently pending at the time of this publication.

Conclusion

AMD is a leading cause of vision loss in the elderly worldwide. Great strides have recently been made in the research arena with the enhanced imaging capability afforded by OCT, the identification of a variety of genetic markers and the development of effective medications specifically targeting VEGF inhibition. As the proportion of the elderly population continues to increase in the United States, further developments in the early identification and treatment of this disorder will be critical as will preventive measures determined through clinical trials. These measures will inevitably help to improve the visual outcomes of those affected by this disorder and hold great promise for the future.

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