16 Blue-Light-Filtering Intraocular Lenses

(1)

16.1 Introduction

The normal human crystalline lens filters not only ultraviolet light, but also most of the higher frequency blue wavelength light. How- ever, most current intraocular lenses (IOLs) filter only ultraviolet light and allow all blue wavelength light to pass through to the retina. Over the past few decades, considerable literature has surfaced suggesting that blue light may be one factor in the progression of age-related macular degeneration (AMD) [1].

In recent years, blue-light-filtering IOLs have been released by two IOL manufacturers. In this chapter we will review the motivation for developing blue-filtering IOLs and the rele- vant clinical studies that establish the safety and efficacy of these IOLs.

16.2 Why Filter Blue Light?

Even at the early age of 4 years, the human crystalline lens prevents ultraviolet and much of the high-energy blue light from reaching the retina (Fig. 16.1). As we age, the normal human crystalline lens yellows further, filtering out even more of the blue wavelength light [2]. In 1978, Mainster [3] demonstrated that pseudophakic eyes were more susceptible to retinal damage from near ultraviolet light sources. Van der Schaft et al. conducted postmortem examinations of 82 randomly selected pseudophakic eyes and found a sta-

tistically significant higher prevalence of hard drusen and disciform scars than in age- matched non-pseudophakic controls [4].

Pollack et al. [5] followed 47 patients with bilateral early AMD after they underwent extracapsular cataract extraction and implantation of a UV-blocking IOL in one eye, with the fellow phakic eye as a control for AMD progression. Neovascular AMD developed in nine of the operative versus two of the control eyes, which the authors suggested was linked to the loss of the “yellow barrier” provided by the natural crystalline lens.

Data from the Age-Related Eye Disease Study (AREDS), however, suggest a height- ened risk of central geographic retinal atrophy rather than neovascular changes after cataract surgery [6, 7]. There were 342 patients in the AREDS study who were observed to have one or more large drusen or geographic atrophy and who subsequently had cataract surgery. Cox regression analysis was used to compare the time to progression of AMD in this group versus phakic control cases matched for age, sex, years of follow-up, and course of AMD treatment. This analysis showed no increased risk of wet AMD after cataract surgery. However, a slightly increased risk of central geographic atrophy was demonstrated.

The retina appears to be susceptible to chronic repetitive exposure to low-radiance light as well as brief exposure to higher-radiance light [8–11]. Chronic, low-level exposure

Blue-Light-Filtering Intraocular Lenses

Robert J. Cionni

16

(2)

(class 1) injury occurs at the level of the pho- toreceptors and is caused by the absorption of photons by certain visual pigments with subsequent destabilization of photoreceptor cell membranes. Laboratory work by Sparrow and coworkers has identified the lipofuscin component A2E as a mediator of blue-light damage to the retinal pigment epithelium (RPE) [12–15]; although the retina has inher- ent protective mechanisms from class 1 pho- tochemical damage, the aging retina is less able to provide sufficient protection [16, 17].

Several epidemiological studies have con- cluded that cataract surgery or increased exposure of blue-wavelength light may be associated with progression of macular degeneration [18, 19]. Still, other epidemiologic studies have failed to come to this conclusion [20–22]. Similarly, some recent prospective trials have found no progression of diabetic retinopathy after cataract surgery [23, 24], while other studies have reported progression [25]. These conflicting epidemiological results are not unexpected, since both diabetic and age-related macular diseases are com- plex, multifactorial biologic processes. Cer- tainly, relying on a patient’s memory to recall

the amount of time spent outdoors or in spe- cific lighting environments over a large por- tion of their lifetime is likely to introduce er- ror in the data. This is why experimental work in vitro and in animals has been important in understanding the potential hazards of blue light on the retina.

The phenomenon of phototoxicity to the retina has been investigated since the 1960s.

But more recently, the effects of blue light on retinal tissues have been studied in more de- tail [8, 26–30]. Numerous laboratory studies have demonstrated a susceptibility of the RPE to damage when exposed to blue light [12, 31]. One of the explanations as to how blue light can cause RPE damage involves the accumulation of lipofuscin in these cells as we age. A component of lipofuscin is a com- pound known as A2E, which has an excitation maximum in the blue wavelength region (441 nm). When excited by blue light, A2E generates oxygen-free radicals, which can lead to RPE cell damage and death.At Colum- bia University, Dr Sparrow exposed cultured human retinal pigment epithelial cells laden with A2E to blue light and observed extensive cell death. She then placed different UV-

152 R. J. Cionni

Fig. 16.1. Light transmission spectrum of a 4-year-old and 53-year-old human crystalline lens compared to a 20-diopter colorless UV-blocking IOL [37, 42]

(3)

blocking IOLs or a blue-light-filtering IOL in the path of the blue light to see if the IOLs provided any protective effect. The results of this study demonstrated that cell death was still extensive with all UV-blocking colorless IOLs, but very significantly diminished with the blue-light-filtering IOL [32] (Fig. 16.2).

Although these experiments were laboratory in nature and more concerned with acute light damage rather than chronic long-term exposure, they clearly demonstrated that by filtering blue light with an IOL, A2E-laden RPE cells could survive the phototoxic insult of the blue light.

16.3 IOL Development

As a result of the mounting information on the effects of UV exposure on the retina [1, 33], in the late 1970s and early 1980s IOL manufacturers began to incorporate UV- blocking chromophores in their lenses to protect the retina from potential damage.

Still, when the crystalline lens is removed during cataract or refractive lens exchange surgery and replaced with a colorless UV- blocking IOL, the retina is suddenly bathed in much higher levels of blue light than it has ever known and remains exposed to this increased level of potentially damaging light ever after. Yet, until recent years, the IOL- manufacturing community had not provided the option of IOLs that would limit the exposure of the retina to blue light. Since the early 1970s, IOL manufacturers have researched Chapter 16 Blue-Light-Filtering Intraocular Lenses 153

Fig. 16.2. Cultured human RPE cells laden with A2E exposed to blue wavelength light. Cell death is significant when UV-blocking colorless IOLs are

placed in the path of the light, yet is markedly re- duced when the AcrySof Natural IOL is placed in the light path [32]

(4)

methods for filtering blue-wavelength light waves in efforts to incorporate blue-light protection into IOLs, although these efforts have not all been documented in the peer-re- viewed literature. Recently, two IOL manufacturers have developed stable methods to incorporate blue-light-filtering capabilities into IOLs without leaching or progressive discol- oration of the chromophore.

16.4 Hoya IOL

Hoya released PMMA blue-light-filtering IOLs in Japan in 1991 (three-piece model HOYA UVCY) and 1994 (single-piece model HOYA UVCY-1P). Clinical studies of these yellow-tinted IOLs (model UVCY, manufactured by Hoya Corp., Tokyo, and the Meniflex NV type from Menicon Co., Ltd., Nagoya) have been carried out in Japan [16, 17, 34]. One study found that pseudophakic color vision with a yellow-tinted IOL approximated the vision of 20-year-old control subjects in the blue-light range [35]. Another study found some improvement of photopic and mesopic contrast sensitivity, as well as a decrease in the effects of central glare on contrast sensitivity,

in pseudophakic eyes with a tinted IOL versus a standard lens with UV-blocker only [36].

Hoya also introduced a foldable acrylic blue- light-filtering IOL with PMMA haptics to some European countries in late 2003.

16.5 AcrySof Natural IOL

In 2002, the AcrySof Natural, a UV- and blue- light-filtering IOL, was approved for use in Europe, followed by approval in the USA in 2003. The IOL is based on Alcon’s hydropho- bic acrylic IOL, the AcrySof IOL. In addition to containing a UV-blocking agent, the AcrySof Natural IOL incorporates a yellow chromophore cross-linked to the acrylic mol- ecules. Extensive aging studies have been performed on this IOL and have shown that the chromophore will not leach out or discolor [37]. This yellow chromophore allows the IOL not only to block UV light, but selectively to filter varying levels of light in the blue wavelength region as well. Light transmission as- sessment demonstrates that this IOL approx- imates the transmission spectrum of the normal human crystalline lens in the blue light spectrum (Fig. 16.3). Therefore, in addi-

Fig. 16.3. Light transmission spectrum of the AcrySof Natural IOL compared to a 4-year-old and 53-year-old human crystalline lens and a 20-diopter colorless UV-blocking IOL [37, 42]

(5)

tion to benefiting from less exposure of the retina to blue light, color perception should seem more natural to these patients as op- posed to the increased blueness, clinically known as cyanopsia, reported by patients who have received colorless UV-blocking IOLs [38].

16.6 FDA Clinical Study

In order to gain approval of the Food and Drug Administration (FDA), a multi-cen- tered, randomized prospective study was conducted in the USA. It involved 300 patients randomized to bilateral implantation of either the AcrySof Natural IOL or the clear AcrySof Single-Piece IOL. One hundred and fifty patients received the AcrySof Natural IOL and 147 patients received the AcrySof

Single-Piece IOL as a control. Patients with bilateral age-related cataracts who were will- ing and able to wait at least 30 days between cataract procedures and had verified normal preoperative color vision were eligible for the study. In all bilateral lens implantation cases, the same model lens was used in each eye.

Postoperative parameters measured included visual acuity, photopic and mesopic contrast sensitivity, and color perception using the Farnsworth D-15 test. Results showed that there was no difference between the AcrySof Natural IOL and the clear AcrySof IOL in any of these parameters [39] (Figs. 16.4, 16.5, 16.6 and 16.7). More substantial color perception testing using the Farnsworth–Mun- sell 100 Hue Test has also demonstrated no difference in color perception between the AcrySof Natural IOL and the clear AcrySof IOL [39].

Chapter 16 Blue-Light-Filtering Intraocular Lenses 155

Fig. 16.4. Data from Alcon’s FDA study showing no significant difference in best corrected visual acuity between the AcrySof colorless IOL and the AcrySof Natural IOL

(6)

Fig. 16.5. Data from Alcon’s FDA study showing no significant difference in photopic contrast sensitivity between the AcrySof colorless IOL and the AcrySof Natural IOL

Fig. 16.6. Data from Alcon’s FDA study showing no significant difference in mesopic contrast sensitivity between the AcrySof colorless IOL and the AcrySof Natural IOL

Fig. 16.7. Data from Alcon’s FDA study showing no significant difference in color perception using the Farnsworth D-15 test between the AcrySof colorless IOL and the AcrySof Natural IOL

(7)

16.7 Blue-Light-Filtering IOLs and Low Light Conditions Both mesopic vision and scotopic vision refer to vision with low-light conditions. Wyszecki and Stiles point out that mesopic vision be- gins at approximately 0.001 cd/m² and ex- tends up to 5 cd/m²for a 3° diameter central- ly fixated target; however, the upper range could extend up to 15 cd/m²for a 25° diameter target [40]. Nevertheless, 3 cd/m² is the most often cited upper limit for mesopic vision. One can liken this to the low light conditions on a cloudless night with a full moon.

The contrast sensitivity tests performed un- der mesopic conditions in the FDA trials demonstrated that the AcrySof Natural IOL does not negatively affect mesopic vision.

Scotopic refers to light levels below the mesopic range, which can be likened to a moonless, starry night. Since blue wavelength light is imperative for scotopic vision, some are worried that attenuating blue light will negatively affect scotopic vision. Certainly, if all blue light were blocked, one might expect some decrease in scotopic vision. However, the AcrySof Natural IOL does not block all

blue light. Indeed, the most important wavelength for scotopic vision is at and around 507 nm [41]. The AcrySof Natural allows transmission of approximately 85% of light at 507 nm. In comparison, a UV-blocking colorless IOL transmits only 5% more. The normal human crystalline lens at any age transmits significantly less light at and near 507 nm than does the AcrySof Natural IOL and therefore, patients implanted with the AcrySof Natural IOL should have enhanced scotopic vision. It would be counterintuitive to believe that scotopic vision would be diminished instead of enhanced (Fig. 16.8).

16.8 Clinical Experience

Having implanted more than 1,000 AcrySof Natural IOLs over the past year, I have had the opportunity to gain insight into the quality of vision provided by this unique IOL. The IOL behaves identically to the clear AcrySof IOL in all aspects. It also has the advantage of be- ing easier to visualize during folding, loading and implantation due to its yellow coloration.

The visual results in my patients have been Chapter 16 Blue-Light-Filtering Intraocular Lenses 157

Fig. 16.8. Blue-light transmission spectrum showing low transmission of 441 nm light and high transmission of 507 nm light with the AcrySof Natural IOL

(8)

excellent without any complaints of color perception or night vision problems. I have implanted this blue-light-filtering IOL in the fellow eye of patients previously implanted with colorless UV-filtering IOLs. When asked to compare the color of a white tissue paper, 70% do not see a difference between the two eyes. Of the 30% that could tell a difference, none perceived the difference before I checked and none felt the difference was bothersome.With more than 1,000,000 AcrySof Natural IOLs implanted worldwide by the time of this writing, there are no confirmed reports of color perception or night vision problems.

16.9 Summary

Given the growing body of evidence implicat- ing blue light as a potential factor in the wors- ening of AMD and the positive collective clinical experience with this new IOL, the AcrySof Natural has become the lens of choice in cataract surgery patients for many ophthal- mologists worldwide. When performing refractive lens exchange, especially in the younger patient, one should ponder the potential consequences of exposing the retina to higher levels of blue light for the rest of that patient’s life. I believe that blue-light-filtering IOLs will become the lens of choice for these patients as well.

References

1. Ham WT, Mueller A, Sliney DH (1976) Retinal sensitivity to short wavelength light. Nature 260:153–155

2. Lerman S (1980) Biologic and chemical effects of ultraviolet radiation. In: Radiant energy and the eye. Macmillan, New York, pp 132–133 3. Mainster MA (1978) Spectral transmittance of

intraocular lenses and retinal damage from intense light sources. Am J Ophthalmol 85:

167–170

4. Van der Schaft TL, Mooy CM, de Bruijn WC, Mulder PG, Pameyer JH, de Jong PT (1994) Increased prevalence of disciform macular degeneration after cataract extraction with implantation of an intraocular lens. Br J Oph- thalmol 78:441–445

5. Pollack A et al (1996) Age-related macular degeneration after extracapsular cataract extraction with intraocular lens implantation. Oph- thalmology 103:1546–1554

6. Ferris FL (2002) The new AREDS findings. Pa- per presented at annual meeting of the Ameri- can Academy of Ophthalmology, 21 Oct 2002, Orlando, FL

7. Age-Related Eye Disease Study Group (2000) Risk factors associated with age-related macular degeneration. A case-control study in the Age-Related Eye Disease Study: Age-Related Eye Disease Study report number 3. Ophthal- mology 107:2224–2232

8. Marshall J (1991) The effects of ultraviolet radiation and blue light on the eye. In: Cronly- Dillon J (ed) Susceptible visual apparatus.

Macmillan Reference Ltd, London (Vision and visual dysfunction, vol 16)

9. Marshall J, Mellerio J, Palmer DA (1971) Dam- age to pigeon retinae by commercial light sources operating at moderate levels. Vision Res 11:1198–1199

10. Sperling HG, Johnson C, Harwerth RS (1980) Differential spectral photic damage to primate cones. Vision Res 20:1117–1125

11. Sykes SM, Robison WG Jr, Waxler M, Kuwabara T (1981) Damage to the monkey retina by broad-spectrum fluorescent light. Invest Oph- thalmol Vis Sci 20:425–434

12. Sparrow JR, Cai B (2001) Blue light-induced apoptosis of A2E-containing RPE: involvement of caspase-3 and protection by Bcl-2. Invest Ophthalmol Vis Sci 42:1356–1362

13. Ben-Shabat S, Parish CA, Vollmer HR, Itagaki Y, Fishkin N, Nakanishi K, Sparrow JR (2002) Biosynthetic studies of A2 E, a major fluorophore of retinal pigment epithelial lipofuscin.

J Biol Chem 277:7183–7190

14. Liu J, Itagaki Y, Ben-Shabat S, Nakanishi K, Sparrow JR (2000) The biosynthesis of A2 E, a fluorophore of aging retina, involves the for- mation of the precursor, A2-PE, in the photoreceptor outer segment membrane. J Biol Chem 275:29354–29360

(9)

15. Marshall J, Mellerio J, Palmer DA (1972) Dam- age to pigeon retinae by moderate illumina- tion from fluorescent lamps. Exp Eye Res 14:

164–169

16. Winkler BS, Boulton ME, Gottsch JD, Sternberg P (1999) Oxidative damage and age-related macular degeneration. Mol Vis 5:32

17. Roberts JE (2001) Ocular phototoxicity. J Pho- tochem Photobiol 64:136–143

18. Taylor HR, West S, Munoz B et al (1992) The long-term effects of visible light on the eye.

Arch Ophthalmol 110:99–104

19. Cruickshanks KJ, Klein R, Klein BE, Nondahl DM (2001) Sunlight and the 5-year incidence of early age-related maculopathy: the beaver dam eye study. Arch Ophthalmol 119:

246–250

20. Darzins P, Mitchell P, Heller RF (1997) Sun exposure and age-related macular degeneration.

An Australian case-control study. Ophthalmol- ogy 104:770–776

21. Delcourt C, Carriere I, Ponton-Sanchez A et al (2001) Light exposure and the risk of age-related macular degeneration: the Pathologies Oculaires Liees a l’Age (POLA) study. Arch Ophthalmol 119:1463–1468

22. McCarty CA, Mukesh BN, Fu CL et al (2001) Risk factors for age-related maculopathy: the Visual Impairment Project. Arch Ophthalmol 119:1455–1462

23. Krepler K, Biowski R, Schrey S et al (2002) Cataract surgery in patients with diabetic retinopathy: visual outcome, progression of diabetic retinopathy, and incidence of diabetic macular oedema. Graefes Arch Clin Exp Oph- thalmol 240:735–738

24. Squirrell D, Bhola R, Bush J et al (2002) A prospective, case controlled study of the natural history of diabetic retinopathy and maculopathy after uncomplicated phacoemulsifica- tion cataract surgery in patients with type 2 diabetes. Br J Ophthalmol 86:565–571 25. Chung J, Kim MY, Kim HS et al (2002) Effect of

cataract surgery on the progression of diabetic retinopathy. J Cataract Refract Surg 28:626–

630

26. Mainster MA (1987) Light and macular degeneration: a biophysical and clinical perspective.

Eye 1:304–310

27. Nilsson SE, Textorius O, Andersson BE, Swen- son B (1989) Clear PMMA versus yellow intraocular lens material. An electrophysiologic study on pigmented rabbits regarding “the blue light hazard”. Prog Clin Biol Res 314:539–553 28. Li ZL, Tso MO, Jampol LM, Miller SA,Waxler M

(1990) Retinal injury induced by near-ultraviolet radiation in aphakic and pseudophakic monkey eyes. A preliminary report. Retina 10:301–314

29. Rapp LM, Smith SC (1992) Morphologic comparisons between rhodopsin-mediated and short-wavelength classes of retinal light damage. Invest Ophthalmol Vis Sci 33:3367–

3377

30. Pang J, Seko Y, Tokoro T, Ichinose S, Yamamoto H (1998) Observation of ultrastructural changes in cultured retinal pigment epithelium following exposure to blue light. Graefe’s Arch Clin Exp Ophthalmol 236:696–701 31. Schutt F, Davies S, Kopitz J, Holz FG, Boulton

ME (2000) Photodamage to human RPE cells by A2-E, a retinoid component of lipofuscin.

Invest Ophthalmol Vis Sci 41:2303–2308 32. Sparrow J, Miller A, Zhou J (2004) Blue light-

absorbing intraocular lens and retinal pigment epithelium protection in vitro. J Cataract Refract Surg 30:873–878

33. Noell WK, Walker VS, Kang BS, Berman S (1966) Retinal damage by light in rats. Invest Ophthalmol Vis Sci 5:450–473

34. Miyake K, Ichihashi S, Shibuya Y et al (1999) Blood-retinal barrier and autofluorescence of the posterior polar retina in long-standing pseudophakia. J Cataract Refract Surg 25:891–

897

35. Ishida M,Yanashima K, Miwa W et al (1994) In- fluence of the yellow-tinted intraocular lens on spectral sensitivity (in Japanese). Nippon Gan- ka Gakkai Zasshi 98:192–196

36. Niwa K,Yoshino Y, Okuyama F, Tokoro T (1996) Effects of tinted intraocular lens on contrast sensitivity. Ophthalmic Physiol Optics 16:297–

302

37. Data on file, Alcon Laboratories, Inc., Fort Worth, Texas, USA

38. Yuan Z, Reinach P, Yuan J (2004) Contrast sensitivity and color vision with a yellow intraocular lens. Am J Ophthalmol 138:138–140 39. Cionni R (2005) Blue-light filtering IOLs. Opti-

cal downside no. Presented at AAO 2005, New Orleans, USA

Chapter 16 Blue-Light-Filtering Intraocular Lenses 159

(10)

40. Wyszecki G, Stiles WS (1982) Color science concepts and methods, quantitative data and formulae, 2nd edn. Wiley, New York

41. Swanson WH, Cohen JM (2003) Color vision.

Ophthalmol Clin North Am 16:179–203

42. Lerman S, Borkman R (1976) Spectroscopic evaluation of classification of the normal, aging and cataractous lens. Opthalmol Res 8:335–353 and data on file, Alcon Laboratories, Inc