Martin A. Mainster,
Michael E. Boulton
Light can cause photomechanical, photothermal, or photochemical retinal damage.[1-4] Photochemical (actinic) retinal injury occurs at retinal temperature elevations too low for tissue coagulation (photocoagulation).[5-10] It is generally termed photic retinopathy or retinal phototoxicity when it occurs without exogenous photosensitizers. Photic retinopathy is produced experimentally by prolonged intense light exposures ranging from seconds to hours at illuminances exceeding normal environmental levels that would probably be well tolerated if experienced only briefly. Solar eclipse and welding arc injuries are caused by retinal phototoxicity. Photochemical retinal damage has also provided valuable insight into the molecular biology of retinal degeneration.[11,12] This chapter summarizes current understanding of the pathogenesis and clinical consequences of photic retinopathy.
OPTICAL INTERACTIONS AND PROTECTION
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The retina is potentially vulnerable to damage from ultraviolet radiation (UV; ? < 400 nm), visible light (400 nm < ? < 700 nm), and infrared radiation (IR; ? > 700 nm). Violet (400-440 nm) and blue (440-500 nm) light comprise the shorter wavelength portion of the visible spectrum.[13,14] Retinal effects depend on the wavelength (nm), power (W), duration (s), lateral extent (cm), and location (macular vs elsewhere) of optical radiation exposures.[9,10,15-17] Photochemical effects also depend on oxygen tension[18,19] and body temperature.[7,20,21] The magnitude of a retinal exposure is usually specified in terms of its irradiance (power density in W/cm2) or fluence (energy density in J/cm2).
Thermal and photochemical retinal damage occur when photons are absorbed by chromophores, the light absorbing components of biomolecules. Melanin, hemoglobin, and macular xanthophyll are the most effective retinal light absorbers. Other retinal light absorbers include lipofuscin, rhodopsin, cone photopigments, melanopsin, porphyrins, and cytochrome c oxidase.
Absorption spectra describe how effectively tissue chromophores capture photons at different wavelengths. Absorption spectra for molecules such as hemoglobin or rhodopsin have peaks at specific wavelengths, with lower absorption at adjacent wavelengths. Alternatively, absorbers such as melanin and lipofuscin have absorption spectra that increase steadily with decreasing wavelength (increasing photon energy).[22-24] Figure 174.1 presents examples of both patterns. When photon absorption induces damaging reactive oxygen species, spectra that describe the effectiveness of photon capture at different wavelengths are known as action spectra. Action spectra characterize how effectively different optical radiation wavelengths produce photochemical effects.[25]
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FIGURE 174.1 Acute UV-blue type,[9,55,245] lipofuscin,[24,57] and all-trans-retinal phototoxicity rise rapidly in the violet (400-440 nm) part of the spectrum, where porphyrin[24,246] and cytochrome c oxidase[24,247] phototoxicities peak and macular xanthophyll protection declines.[248] The action spectrum of the blue-green type retinal phototoxicity peaks at 500 nm, similar to scotopic luminous efficiency (sensitivity), because rhodopsin mediates both processes. The absorption spectra of rhodopsin in rod photoreceptors and melanopsin in light-sensitive ganglion cells are similar in form but peak at ~500 nm[249] (blue-green) and 480 nm (blue),[67-69] respectively. Blue-green type phototoxicity in experimental studies occurs at lower retinal irradiances than UV-blue type phototoxicity.[26] The absorption spectrum for xanthophyll decreases rapidly with decreasing wavelength from its peak absorption at 460 nm.[44-47] Melanin absorption, shown for adults over 50 years of age, increases with decreasing wavelength in the visible and near-UV part of the spectrum, similar to that of lipofuscin absorption.[22-24] The spectral dependence of phototoxicity and absorption are shown, but ordinate (y-axis) units are arbitrary, so the relative magnitudes of different curves are not directly comparable in this figure. |
Photon absorption excites electrons in target molecules to higher energy states. Excited molecules release their excess energy in different ways. Energy can be converted into increased average molecular vibrational motion, raising retinal temperature and causing photocoagulation when tissue temperature elevation is sufficiently high.[4] Vibrational energy transferred to neighboring molecules diffuses heat beyond the directly irradiated area in a process known as heat conduction. Alternatively, if photon energy is coupled effectively to chemical bonds in target molecules, excess molecular electronic energy from photon absorption can break those bonds, producing photochemically induced structural changes in the molecules.[26]
Reactive oxygen species in the eye can be formed as a result of (1) the interaction of ionizing radiation with biological molecules, (2) an unavoidable byproduct of cellular respiration, (3) synthesis in phagocytic cells such as neutrophils and macrophages, or (4) a respiratory burst during phagocytosis. Reactive oxygen species are highly reactive oxygen radicals with the capacity to modify and damage cell membranes, proteins, carbohydrates, and nucleic acids. Most reactive oxygen species (e.g., hydroxyl radicals, superoxide anions, and lipid hydroperoxides) have an unpaired electron in their outer orbital and are referred to as free radicals. In addition, there are oxygen species in which electron pairing is normal but the molecule is in an excited state (e.g., singlet oxygen and hydrogen peroxide). Singlet oxygen is the lowest excited state of the di-oxygen molecule, its lifetime in solution is in the microsecond range, and it reacts readily with membrane lipids. Reactive oxygen species can react either directly with target tissues (type-1 photochemical or free radical reactions) or with molecular oxygen to produce singlet oxygen or superoxide which then reacts with target tissues (type-2 photochemical or photodynamic reactions).[26-28] Molecules that produce reactive oxygen species upon light absorption are referred to as photosensitizers.
Photochemical damage to retinal cells can lead to cellular dysfunction or death. The latter normally occurs by a process termed apoptosis, which is a common cell death pathway not only for photic retinopathy but also conditions such as age-related macular degeneration (AMD) and retinitis pigmentosa.[11] Normal cellular homeostasis balances cell proliferation and death. Apoptosis removes unneeded, injured, or diseased cells, spanning a broad complex of interrelated mechanisms for signaling and producing cell death.[11,29] Analyses of molecular mechanisms of rodent retinal phototoxicity provide insights into the genetics of inherited retinal disorders.[11,12]
Ocular media protect the retina from potentially harmful optical radiation. The cornea shields internal ocular structures by blocking UV radiation below 300 nm.[30] The crystalline lens protects the retina from UV radiation between 300 and 400 nm,[30-32] except in young eyes with clear crystalline lenses that transmit some UV around 320 nm to the retina.[30] The aging crystalline lens attenuates an increasing amount of visible light, particularly at shorter violet and blue wavelengths.[30-34] Additional extraretinal protection is provided by eyebrow shadowing, corneal reflection of light not incident perpendicular to its surface (Fresnel's law), and pupillary, aversion, squint, and blink responses.[35,36]
Macular xanthophyll is a yellowish pigment in the cone axon and inner plexiform layers of the macula that reduces the short wavelength light exposure of photoreceptors and retinal pigment epithelium (RPE) cells.[37,38] It is composed of the carotenoid pigments lutein and zeaxanthin, which can limit photosensitization reactions in the macula either by reducing the amount of incoming short wavelength light or by directly quenching reactive oxygen species generated by optical radiation.[38-40] Xanthophyll density declines rapidly with increasing retinal eccentricity from its foveolar peak, except for a ring of increased extrafoveolar density that is more common in women and may be related to the anatomy of the foveolar depression.[37,41-43] Light absorption by xanthophyll also decreases rapidly with decreasing wavelength from its peak absorption at 460 nm.[44-47] Thus, macular xanthophyll protection is least effective in the potentially hazardous violet and UV parts of the spectrum,[14,48] an issue of increased significance when the crystalline lens is removed in cataract surgery. Studies of how macular xanthophyll varies with retinal aging and AMD have produced inconsistent results.[49-52]
MECHANISMS OF PHOTIC INJURY
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CLASSIC PHOTOTOXICITIES
There are two classic types of photic retinopathy. Blue-green retinal phototoxicity in rodents was discovered by Werner Noell in 1966.[5,20] Its action spectrum is similar to scotopic visual sensitivity,[53,54] which peaks at 500 nm (blue-green), because rhodopsin mediates both processes. Blue-green phototoxicity is also termed 'class 1', 'Noell-type' or 'white light' photic retinopathy. Damage is typically located in the photoreceptor layer or both the photoreceptor and RPE layers.[5]
The second classic type of phototoxicity was discovered in young primates by William Ham and his colleagues in 1976.[9,16,26,55-57] UV-blue phototoxicity has an action spectrum that increases with decreasing wavelength, similar to that of lipofuscin which may be one of its primary mediators.[23,24,57] Thus, UV radiation is more hazardous than violet light, which in turn is more hazardous than blue light. UV-blue phototoxicity is also termed 'class 2', 'Ham-type', or 'blue light hazard' retinal phototoxicity. Damage is typically located in the RPE or both the RPE and photoreceptor layers.[9,58]
UV-blue phototoxicity requires ~100 times more retinal irradiance than blue-green phototoxicity.[16,26,59,60] UV-blue phototoxicity is the basis for the international consensus standard A? phototoxicity function used to estimate acute industrial retinal phototoxicity risks.[61] Blue-green and UV-blue photic retinopathies are archetypes of photopigment-mediated and photosensitizer-mediated retinal photoxicity damage mechanisms, respectively.[9,16,20,26,59] Figure 174.1 illustrates the action spectra of the classic retinal phototoxicities.
PHOTOPIGMENT-MEDIATED DAMAGE
There are three types of retinal photopigments: (1) cone photoreceptor photopigments that provide photopic (bright light) and mesopic (intermediate light) vision,[62,63] (2) rhodopsin in rod photoreceptors responsible for mesopic and scotopic (dim light) vision,[53,54] and (3) melanopsin in blue-light sensitive retinal ganglion cells that modulate circadian photoentrainment, pupillary function, and possibly conscious vision.[64-67] Cone photoreceptors in humans have absorption maxima around 426 nm (blue), 530 nm (green), and 552 or 557 nm (red).[62,63] Rod and light-sensitive retinal ganglion photoreceptors have peak spectral sensitivities of ~ 500 nm (blue-green)[53,54] and 480 nm (blue),[67-69] respectively.
A photoreceptor photopigment consists of an 11-cis retinal chromophore molecule bound to a transmembrane opsin protein in a photoreceptor outer segment disk.[70] Differences in rod, cone, and retinal ganglion photopigment absorption maxima results from different amino acid sequences in the opsin molecule adjacent to the 11-cis retinal binding site.[71] When a photopigment molecule absorbs a photon, 11-cis retinal is converted to all-trans retinal, initiating a conformational change in opsin and a sequence of transient photopigment states that include metarhodopsin II (activated rhodopsin).[70,72]
Metarhodopsin II catalyzes the activation of transducin, which continues the phototransduction cascade that converts absorbed photon energy into neurochemical signals.[73] Metarhodopsin II decays through hydrolysis, releasing all-trans retinal from its opsin binding site. All-trans-retinal is reduced to all-trans-retinol, and then re-isomerized and oxidized back to its original 11-cis retinal in a complex series of steps involving the RPE for rods and Muller cells for cone photoreceptors.[74,75] In general, a functional retinoid cycle is needed for both retinal photoreception and phototoxicity.
Most experimental studies of photopigment-mediated retinal phototoxicity use rodent models and protocols that differ in retinal irradiance, exposure duration, source wavelength, animal species, antioxidant status, and circadian timing.[5,11,12,20,71,76,77] Studies using knockout mice have demonstrated apoptotic pathways for photic damage that may or may not involve phototransduction.[78,79]
Light damage in mice requires effective retinoid recycling. The RPE65 protein is needed for the production of 11-cis retinal. RPE65-/? knockout mice without this protein are protected against photic retinopathy.[11,71] Photochemical damage thresholds depend on RPE65 protein levels in mice but not in rats.[12] The susceptibility of rats to photic injury has a circadian rhythm, with dark adaptation increasing the risk of damage.[80] Many other molecular, pharmacological, and environmental factors influence rodent retinal phototoxicity.[11,71]
Most rodent retinas adapt to ambient illumination, a phenomenon known as photostasis.[81-84] For example, changing from bright to dim environments upregulates rhodopsin and increases rod rhodopsin regeneration rates, rod outer segment lengths, and rhodopsin concentration in rod outer segments.[82] The reverse is true for changes from a dim to a bright environment. A significant fiding is that local rhodopsin concentration across a rodent retina is inversely proportional to local illuminance.[82] Autophagic degradation of opsin may contribute to downregulation of rhodopsin when ambient illumination is increased, possibly reducing the risk of retinal phototoxicity.[85] Bleached rhodopsin is more thermally labile than the unbleached photopigment, so bright sustained illumination that increases the percentage of bleached photopigment could contribute to increased opsin misfolding[86] and phototoxic injury.[8]
Cone photopigment-mediated phototoxicity data are limited. Experimental studies have shown that cones have lower phototoxicity susceptibility than rods in rodents[87] and greater susceptibility in pigeons and primates.[15,88] These latter observations are not consistent with the greater resistance of cones than rods to photic injury in a histopathologic study of human solar retinopathy,[89] possibly because of the relatively small number of photoreceptors per RPE cell in the primate foveola.[90] Repeated intermittent blue or green light stimulation in primates causes selective blue or green cone damage, respectively.[91]Photosensitive retinal ganglion cells which modulate circadian rhythmicity[92-95] may also be susceptible to phototoxicity mediated by their photopigment melanopsin.[4]
PHOTOSENSITIZER-MEDIATED DAMAGE
The retina is vulnerable to oxidative stress because of its high oxygen and light levels. Its internal defenses include: (1) circadian shedding of damaged photoreceptor outer segment disks, (2) enzymatic antioxidants, such as superoxide dismutase, catalase, and glutathione peroxidase, (3) nonenzymatic antioxidants including ?-tocopherol, ascorbate, lutein, and zeaxanthin, and (4) light-absorbing molecules such as melanin in the RPE and choroid or macular xanthophyll in the inner retina.[16,24,26,77,96-98] Retinal phototoxicity may be mediated by photosensitizers such as lipofuscin, all-trans-retinal, cytochrome c oxidase, and the porphyrins.[24,99-101] As shown in Figure 174.1, absorption spectra for these photosensitizers increase with decreasing wavelength or peak typically in the near-UV or violet part of the spectrum.
Lipofuscin accumulates with aging in the RPE because undegradable endproducts of either photoreceptor phagocytosis or autophagy of spent intracellular organelles such as mitochondria and endoplasmic reticulum cannot be removed effectively from cells. Lipofuscin may impair antioxidant activity, produce phototoxic damage or mechanically compromise cellular function.[24,102,103] It is a photoinducible generator of reactive oxygen species that can damage RPE cells.[24] Lipofuscin is comprised of many fluorophores, including the pyridinium bisretinoid A2E, which has received considerable recent attention. A2E is a retinoid cycle byproduct, formed from phosphatidylethanolamine and two molecules of all-trans-retinaldehyde.[104] The action spectrum of A2E peaks around 430 nm in the violet part of the spectrum. (cf Fig. 174.1)[104,105] A2E and its derivatives are only weakly photoreactive compared to lipofuscin and thus account for only a small fraction of the total photoreactivity of lipofuscin.[57,106]
All-trans-retinal is a potent intraretinal photosensitizer produced during the normal retinoid cycle. It plays an essential role in A2E and lipofuscin formation.[71] Increased all-trans-retinal concentration during prolonged bright light exposure[107] may cause photic retinopathy.[71] Other potential intraretinal photosensitizers include porphyrin containing molecules such as hemoglobin and enzymes, including cytochrome c oxidase. Cytochrome c oxidase is an important respiratory chain enzyme located in mitochondria and photoreceptors and may contribute to short wavelength light-induced mitochondrial damage in the RPE.[108] The role of melanin as a photosensitizer or photoprotective agent in the RPE remains unclear but there is evidence that it can become a photosensitizer in older adults.[24,60,109-111]
CLINICAL SYNDROMES
Solar and operating microscope exposures performed on eyes prior to enucleation for malignant melanoma have proven that these light sources can cause phototoxic injuries[89,112,113] at retinal temperature elevations too low for thermal damage.[4,114-116] Welding arc and solar maculopathies are similar, as are operating microscope and endoilluminator injuries.[4] The role of light in AMD has yet to be proven despite decades of investigation.[4,48]
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SOLAR AND WELDER'S MACULOPATHY
The solar disk forms a 160 ?m diameter retinal image, ~20% of the area of the 350 mm diameter foveola.[114,117] Unassisted observation of the sun at its zenith with a 3 mm pupil diameter produces only a 4°C retinal temperature rise, well below the 10°C temperature elevation needed for threshold retinal photocoagulation.[114,118] Thus, solar retinopathy is usually caused by retinal phototoxicity, not photocoagulation. Solar observation with a dilated 7 mm pupil or telescope-assisted solar inspection can cause significantly higher retinal temperature increases and photocoagulation injuries.[1,114,118]
Solar injuries can be severe or mild.[119,120] Visual acuity is typically decreased after an injury to 20/40 to 20/200, usually returning to 20/20 to 20/40 over 6 months.[121,122] Injuries have been reported after sungazing during drug abuse[123,124] and hypoglycemia.[125] They can occur with or without eclipses.[4] Pupil dilation during an eclipse makes eclipse observation particularly hazardous.[1] There are several safe methods for viewing solar eclipses.[1,117]
Acute solar injuries produce yellowish-white foveolar lesions, as illustrated in Figure 174.2.[112,121] Lesions gradually fade over several weeks. Months later, there may be foveal distortion, lamellar defects, pigment mottling, a macular hole or no apparent damage.[121] Lesion severity depends on viewing circumstances and an individual's defense mechanisms. The worst injuries occur with prolonged observation and good fixation, as when the solar disk is foveated through a defective optical filter. Foveal RPE defects can be demonstrated on fluorescein angiograms after severe solar injuries, but angiograms are often normal.[121,126] Optical coherence tomography typically shows foveal abnormalities affecting the outer neural retina and RPE.[124,126-128]
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FIGURE 174.2 An acute solar injury produces a yellowish-white foveola lesion, as seen in this 15-year-old female with 20/70 visual acuity. |
Histopathologic studies of the eyes of volunteers who gazed at the sun prior to ocular enucleation for choroidal melanoma show predominantly rod and cone photoreceptor damage, including vesiculation and fragmentation of outer segment lamellae, mitochondrial swelling and nuclear pyknosis.[89,112] Cones are more resistant to damage than rods, perhaps accounting for good visual acuity after many solar injuries.[89] RPE damage can be extensive[112] or limited and scattered.[89] Combined clinical and histopathological evidence to date does not permit determination of whether solar/welding arc maculopathy is a photoreceptor versus RPE injury or a photopigment-mediated versus photosensitizer-mediated process.
The term foveomacular retinitis was originally used to describe foveal abnormalities resembling solar retinopathy. These conditions include whiplash and blunt ocular injuries,[129-131] although similar findings have been reported in people with no prior history of photic or mechanical trauma.[132,133] Foveomacular retinitis was first described during World War II, with additional reports between 1966 and 1973.[134-137]
Experimental photic retinopathy is enhanced by higher core body temperatures,[7,20,21] so the risk of retinal phototoxicity may be increased by light exposures associated with exercise, infection, or warm environments. Increased chorioretinal pigmentation increases chorioretinal temperature elevations from solar observation, perhaps increasing the risk or extent of photic injury. High local irradiance from direct sungazing places the foveola at greatest risk for damage from solar observation, but solar retinopathy can occur in young sunbathers who deny sungazing,[138,139] possibly due to Henle layer fiberoptic channeling of short-wavelength photons from perifoveal regions to the center of the fovea.[46] Fiberoptic transmission increases and xanthophyll protection decreases below 450 nm where the risk of UV-blue type retinal phototoxicity increases.[45,46]
Photokeratitis is a common welding arc accident, but a foveal injury as shown in Figures 174.3 and 174.4 is rare.[1,115,140] Welding arc maculopathy has the same clinical appearance and course as solar retinopathy.[115,141-143] Welder's maculopathy usually occurs in young workers at risk for retinal injury because of clear ocular media, occupational inexperience, and inadequate protective filters. Violet and blue light from a welding arc may cause most damage, but 320 nm UV transmitted through the crystalline lens of younger eyes may contribute to the damage.[30,144] UV may also be responsible for the retinal injury from an intense flash due to a short-circuiting high-tension electric circuit.[145]
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FIGURE 174.3 Welding arc injuries typically produce yellowish-white foveolar lesions similar to those seen in solar maculopathy, as illustrated in this 17-year-old male 3 days after a welding arc exposure. |
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FIGURE 174.4 Optical coherence tomograms after welding arc and solar injuries typically show foveal abnormalities affecting the outer neural retina and RPE, as seen in this 17-year-old male with a localized hyporeflective defect 8 months after a welding arc exposure. |
OPERATING MICROSCOPE AND ENDOILLUMINATOR MACULOPATHY
Intense visible light from operating microscopes can produce retinal lesions that are usually oval shaped and 1-2 optic disk diameters in lateral extent.[146,147] The long axis of the lesion often has the same orientation as the filament of the operating microscope's lamp.[148] During cataract surgery, lesions typically occur in the inferior macula because of microscope tilt and illumination positioning.[149,150] Injuries occur after cataract, cornea, glaucoma, and retinal procedures.[146,147,151-155] Fiberoptic endoilluminators in vitreoretinal surgery can produce similar lesions in different retinal locations,[21,156,157] as shown in Figure 174.5.
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FIGURE 174.5 The endoilluminator lesion in the temporal macula of this 68-year-old male is accompanied by cystoid macular edema after epiretinal membrane surgery. |
Operating microscope maculopathy rates have declined with improved, faster cataract surgery techniques, but injuries can still occur in brief procedures.[158] Acute lesions usually have a yellowish-white appearance that fades quickly over several days. They can be associated with a transient serous detachment of the neural retina. Pigment mottling, RPE degeneration, and occasionally choroidal neovascularization may develop over months to years at injury sites.[4,159] Fluorescein angiography is useful when a lesion is suspected but not ophthalmoscopically apparent.[4] Damage was present in the RPE and photoreceptor layers of a volunteer's eye after it was exposed to an intense operating microscope exposure before ocular enucleation for a choroidal melanoma.[113] Experimental primate studies have reported similar findings.[160-162] Combined clinical and histopathological evidence to date does not permit determination of whether operating microscope/endoilluminator maculopathy is a primarily photoreceptor versus RPE injury or a photopigment-mediated versus photosensitizer-mediated process.
The size, location, and severity of operating microscope lesions determine their visual effects.[4,159] Immobilization and higher blood oxygen levels potentially increase the risk of retinal injuries in patients undergoing general rather than local anesthesia.[18,163] The hazard of a particular light exposure is also higher with (1) elevated core body temperature,[7] (2) increased chorioretinal pigmentation (absorption of light by pigmented tissues potentially elevates local chorioretinal temperature), and (3) systemic photosensitizing medications,[164,165] including hydroxychloroquine, hydrochlorothiazide, furosemide, allopurinol, and the benzodiazepines.[166] Diabetes mellitus and hypertension may also increase injury risks.[148,167]
Operating microscope hazard can be decreased by reducing illumination, minimizing coaxial exposure duration, and discontinuing systemic photosensitizing medications preoperatively, when possible.[116,160,165,168-170] Positioning a patient's eye in downgaze is potentially useful,[165] as is tilting the operating microscope appropriately,[150] using corneal occluders,[171-173] and avoiding supplemental oxygen usage and/or elevated patient core body temperatures.
Operating microscopes produce little UV radiation,[116,174,175] so UV-blocking filters are of limited value in reducing injury risks.[176] Some microscopes produce more short wave-length visible light than others,[116] increasing the risk of photosensitizer-mediated UV-blue type phototoxicity. Filtering out light with wavelengths below 450 nm reduces the risk of acute UV-blue type photic retinopathy,[168,170,177] but some blue light is useful for surgery and detecting inner retinal abnormalities.[168,178-180] Filtering out wavelengths greater than 700 nm eliminates unnecessary IR that could thermally enhance photochemical damage.[168,181]
Studies of the relationship between cataract surgery and AMD have produced differing results.[182-192] Positive studies[189,191,192] may have been confounded by the possibility that cataract surgery was performed for vision loss due to AMD rather than cataract.[191,193] The AREDS study found no correlation between cataract surgery and AMD after checking for the retinal status of all subjects prior to surgery.[193,194] If there is a correlation between AMD and cataract surgery, it is probably due to trauma or other sequellae of intraocular surgery and operating microscope illumination on aged susceptible maculas.[189,191,192]
AGE RELATED MACULAR DEGENERATION
Geographic RPE atrophy and choroidal neovascularization characterize the nonneovascular 'dry' and neovascular 'wet' forms of AMD, respectively. RPE lipofuscin accumulation increases with aging in a spatial pattern consistent with rod photoreceptor density, possibly contributing to the pathogenesis of both types of AMD.[195-197] Increased lipofuscin may (1) compromise RPE cell function mechanically, (2) promote expression of angiogenic factors, or (3) act as a photoinducible generator of reactive oxygen species.[24,102,103] Lipofuscin accumulation and photic retinopathy both probably involve direct and indirect oxidative stress.[24,57,198,199]
Rod photoreceptors and RPE cell numbers gradually decline with retinal aging,[102,195] accompanied by increasing thickness and hydraulic resistance of Bruch's membrane[200] and decreasing choriocapillaris vascular diameter.[201] Rod photoreceptor loss is more prominent in retinal aging and AMD than cone loss.[202-204] The density of RPE cells in the peripheral/equatorial retina decreases with increasing age, but the RPE appears to be relatively protected in the macular region.[205] Anatomic and physiologic factors beyond ordinary aging conspire to cause AMD, which is a complex multifactorial process affected by many factors including nutrition, smoking, and genetics.[202,206-211]. Oxidative stress may injure the RPE and choriocapillaris in AMD and possibly aging, potentially producing chronic local inflammation.[207]
Phototoxicity from environmental light exposure is a potential but unproven cause of AMD.[16,24,57,77,103,212-216] One origin for this phototoxicity-AMD hypothesis is a 1920 study which reported that AMD occurred less frequently in cataractous eyes.[212] Later studies showed, however, that the risk of AMD is increased in cataractous eyes.[189,192] It has been speculated that if light is a factor in the pathogenesis of AMD, then blue-green type phototoxicity is more likely to be involved than UV-blue phototoxicity because photopigment-mediated damage occurs at lower retinal irradiances.[217] There are many other theories for the pathogenesis of AMD, including those positing the primary mechanism to be (1) RPE dysfunction with subsequent basal laminar deposits,[206] (2) impaired choroidal perfusion,[218] (3) genetic defects,[219] and (4) retinoid deficiency.[204,220] These theories are of course not mutually exclusive.
The phototoxicity-AMD hypothesis remains popular despite its limitations. (1) Retinal illumination studies show that central retinal exposure is higher than peripheral exposure under Ganzfield illumination conditions[221] and that superior peripheral retinal illumination is higher than inferior peripheral retinal exposure in bright environments.[222] Retinal damage is worst centrally in people with AMD,[204] but there is no significant difference between superior and inferior retinal photoreceptor loss with aging,[203] and age-related photoreceptor loss is most pronounced adjacent to rather than in the center of the retina (possibly due to protective macular pigment).[202-204,223] (2) Lipofuscin accumulates with aging in the RPE, increasing the risk of retinal phototoxicity in older adults.[102,224,225] Additionally, in vivo fundus autofluorescence measurements of patients with nonneovascular AMD and retinitis pigmentosa show focal regions of lipofuscin hyperfluorescence prior to the occurrence of RPE atrophy.[197] Nonetheless, lipofuscin concentrations are highest adjacent to rather than in the center of the retina, where age-related photoreceptor loss but not AMD is most prominent.[196,223] (3) There are striking similarities in the retinal abnormalities caused by AMD and repetitive experimental acute phototoxicity.[213,214,226,227] This similarity is not surprising, however, because the retina and choroid have only a limited repertoire of responses to injury, inflammation, and senescence.
An important failing of the phototoxicity-AMD hypothesis is the lack of supportive epidemiological evidence despite two decades of careful investigation. Two large population-based studies did fid a weak correlation,[228,229] but four other large studies did not,[208,230-232] including a recent study by Taylor,[208] who had initially identified an association between light exposure and AMD in the Waterman study.[228]Additionally, three large case-control studies failed to show that AMD is correlated with environmental light exposure,[233-235] one of which actually found sunlight exposure to be lower in AMD subjects than controls.[234] This lack of evidence is due either to (1) difficulty in accurately estimating a subject's cumulative light exposure, retrospectively, (2) variability in genetic susceptibility, (3) potentially obfuscating factors such as differences in the age at which subjects experience bright environmental light exposure, or (4) the possibility that phototoxicity is not a significant factor in retinal aging or AMD.
Most ocular UV exposure comes from reflective terrain below or viewing the horizontal sky.[25,236] There is strong evidence that environmental UV exposure is a significant risk factor for cataractogenesis.[237-239] There is additional evidence that UV exposure, particularly in early life, may increase the risk of ocular melanoma.[240-242] Using UV-blocking sunglasses and IOLs as well as brimmed hats reduces both those risks[242,243] Photocarcinogenesis differs from retinal phototoxicity because it involves primarily UV-B (280 < ? < 315 nm) induced damage to DNA molecules[240,244] that is not induced by the longer wavelength UV-A (315 < ? < 400 nm) and visible optical radiation that causes retinal phototoxicity.
If sunlight is a risk factor in retinal aging and AMD, groups that might potentially benefit from wearing sunglasses and brimmed hats include: (1) young, lightly pigmented people, particularly in warm climates, (2) individuals taking photosensitizing medications, (3) people with malabsorption syndromes or other problems contributing to malnutrition, and (4) aphakes or pseudophakes. Contemporary IOLs that block UV or UV+visible light provide adequate photocarcinogenic protection against ocular melanoma. Conversely, they provide 20% less acute phototoxicity protection than a 53-year-old crystalline lens that does not prevent AMD.[48] Thus, if retinal phototoxicity is a retinal aging or AMD risk factor, pseudophakes should wear sunglasses in bright environments regardless of their IOL chromophores.[48] Conventional sunglasses are not safe for directly viewing the sun.[117,168]
CONCLUSION
Experimental studies have identified photopigment-mediated (e.g., Noell-type blue-green) and photosensitizer-mediated (e.g., Ham-type UV-blue) photic retinopathies. Clinical phototoxicities can be divided into solar/welding arc and operating microscope/endoilluminator injuries. Injuries localized primarily to the RPE or photoreceptor layers have been observed, but clinical phototoxicity studies often show that both layers are affected, due either to multifocal nature of photic effects or the suprathreshold exposure of one layer that directly or indirectly damages the other. Photopigments and photosensitizers are distributed throughout the retina, so clinical injuries currently cannot be reliably classified as being due to photopigment-mediated or photosensitizer-mediated processes.
Photopigment-mediated photic retinopathies have been studied most extensively in nocturnal rodent models, where the primary photopigment is rhodopsin. Nonetheless, it is possible that cone photopigments and light-sensitive ganglion cell melanopsin may cause clinical phototoxic damage during bright, sustained exposures. Lipofuscin in the RPE, all-trans-retinal in the photoreceptor layer and mitochondrial enzymes throughout the retina such as cytochrome c oxidase may be responsible for photosensitizer-mediated retinal phototoxicities. International standards for light exposure in older adults may need to be reconsidered because they are based largely on light exposure studies performed in young primates.
Appropriate protective measures are available for solar and welding arc maculopathies. Minimizing the intensity and duration of operating microscope and endoilluminator exposures reduces the risk of patient injuries. There is no proof at this time that environmental light exposure is a significant risk factor in AMD, but UV exposure is implicated in cataractogenesis and possibly ocular melanoma so it is prudent to wear sunglasses and a brimmed hat in bright environments such as beaches and skiing slopes.
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