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Blue light-filtering intraocular lenses: Review

of potential benefits and side effects

Article in Journal of Cataract and Refractive Surgery August 2009

DOI: 10.1016/j.jcrs.2009.04.017 Source: PubMed

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 REVIEW/UPDATE

Blue lightfiltering intraocular lenses:

Review of potential benefits and side effects
Fiona M. Cuthbertson, FRCOphth, Stuart N. Peirson, PhD, Katharina Wulff, PhD, Russell G. Foster, PhD,
Susan M. Downes, FRCOphth, MD

Blue lightfiltering intraocular lenses (IOLs) have become part of the modern cataract surgeons
armamentarium and are widely used. Their advocates suggest they may protect against light-
induced retinal damage and also affect the development or progression of age-related macular
degeneration. Much of the evidence for photoprotection is theoretical or based on observations
in cell culture or animal experiments, with little clinical information to date. Although arguments
remain theoretical, there is now emerging clinical data on the use of these IOLs in patients looking
at the benefits and potential side effects. In this review, we consider the background to the devel-
opment of these IOLs, the evidence for a reduction in short-wavelength light exposure protecting
retinal cells and function, and the possible disadvantages of IOLs resulting from their reduced light
transmission. We place this information in context with regard to patients having cataract surgery
and the day-to-day conditions in which they live.
J Cataract Refract Surg 2009; 35:12811297 Q 2009 ASCRS and ESCRS

Electromagnetic radiation can be classified by its
wavelength. Visible light consists of radiation with
wavelengths falling between 400 nm and 700 nm.
Ultraviolet (UV) light has a shorter wavelength (215
to 400 nm) and infrared a longer wavelength (750 to
1 nm). Properties of the ocular media limit transmis-
sion of certain wavelengths of electromagnetic radia-
tion. The cornea absorbs radiation of wavelengths
below 300 nm but allows transmission of radiation of
Submitted: November 12, 2008.
Final revision submitted: February 20, 2009.
Accepted: April 7, 2009.
From the Nuffield Laboratory of Ophthalmology (Cuthbertson,
Peirson, Wulff, Foster, Downes), University of Oxford, and Oxford
Eye Hospital (Cuthbertson, Downes) John Radcliffe Hospital,
Headington, Oxford, United Kingdom.
No author has a financial or proprietary interest in any material or
method mentioned.
Funded in part by NIHR Biomedical Research Centre Programme,
Oxford, United Kingdom, and the Wellcome Trust (UK) Programme
Grant 069714, and by a bursary from the Nuffield Laboratory of
Ophthalmology, University of Oxford (Dr. Cuthbertson), United
Kingdom.
A.J. Bron, FRCOphth, provided valuable comments.
Corresponding author: Miss Susan Downes, Oxford Eye Hospital,
John Radcliffe Hospital, Headley Way, Headington, Oxford OX3
9DU, United Kingdom. E-mail: susan.downes@orh.nhs.uk.
wavelengths between 300 nm and 400 nm, which is
then absorbed by the iris or, where it passes through
the pupillary aperture, by the lens.1,2 As the lens
ages it accumulates yellow chromophores, which re-
sults in a steady reduction in transmission of short-
wavelength visible light (violet and blue light with
wavelengths between 400 nm and 500 nm).3 Different
morphologies of cataract can affect violet and blue-
light transmission to varying extents, with nuclear
sclerotic cataract having the greatest effect.4 Violet
and blue light reaching the retina is partially absorbed
in the inner retinal layers by carotenoids such as lutein
and zeaxanthin, which are found in greatest concen-
tration at the fovea.1
As the eye ages and increasingly as cataract de-
velops, transmission of short-wavelength blue light
to the retina is reduced.59 Removing the protective
crystalline lens and replacing it with a clear (UV-block-
ing) intraocular lens (IOL) allows a greater amount of
blue and violet light to enter the eyedmore so than
that allowed by the normal adult crystalline lens. Im-
plantation of a UV-blocking IOL results in altered
color perception known as cyanopsia (blue-tinted vi-
sion).10 Blue lightfiltering IOLs have been available
and in use for several years. The impetus for develop-
ment of these IOLs was twofold: first, to reduce cya-
nopsia10 and second, to protect the retina from
possible light-induced damage.
There are several unresolved issues regarding the
introduction of these IOLs with respect to their

Q 2009 ASCRS and ESCRS 0886-3350/09/$dsee front matter 1281

Published by Elsevier Inc. doi:10.1016/j.jcrs.2009.04.017
1282 REVIEW/UPDATE: BLUE LIGHTFILTERING IOLs
potential benefits and possible side effects. Benefits
that have been suggested include protection against
retinal damage due to blue light, with a possible role
in preventing the development or exacerbation of
age-related macular degeneration (AMD); improve-
ment in contrast sensitivity and reduced glare under
photopic and mesopic conditions10; and reduction in
disturbance of blue color vision.11,12 Possible side ef-
fects of these IOLs, including detrimental effects on
color vision and scotopic sensitivity as well as interfer-
ence with the sleepwake cycle, have been cited. This
article reviews the evidence for these statements.
Historically, 2 types of light-induced retinal damage
have been described, with some overlap in mechanism
and toxicity. The first was identified by Noell et al. in
196613 as retinal damage caused by low light levels
and long exposures. Noell et al. excluded a thermal
cause for the damage and, having noted that the action
spectrum of damage was similar to that of scotopic
sensitivity, proposed involvement of an intermediate
molecule such as rhodopsin, a photopigment. This
type of light damage is sometimes referred to as class
I photochemical damage or bluegreen toxicity.10 The
extent of the damage seen is related to the duration of
exposure and the wavelength of light used, with short-
er wavelength blue light having a greater effect (due to
its higher energy) than longer wavelength green light.
A second type of light-induced retinal damage
(sometimes referred to as class II photochemical dam-
age or blue-light hazard) was described by Ham
et al.14 This type of damage relates to short retinal ex-
posures of high intensity. Ham et al.1517 showed that
toxicity decreases with increasing wavelength from
UV through violet to the blue part of the spectrum
and that damage is related to exposure time and inten-
sity in addition to wavelength.17 An excitation peak
for damage to the phakic eye has been suggested to
be around 440 nm.18 Damage is mediated through for-
mation of reactive oxygen species after absorption of
photons by chromophores such as photopigments, lip-
ofuscin, and possibly melanin, in the presence of oxy-
gen. It is possible there is some overlap in mechanism
between these 2 types of damage.10
At least 2 pathways for light-induced retinal photo-
receptor apoptosis have been identified in mice. Induc-
tion at low light intensity requires the presence of
transducin; however, there is also an apoptotic path-
way induced at high light intensity that is independent
of transducin but is accompanied by induction of the
transcription factor activator protein-1 (AP-1).19 It is
unclear from the literature how these mechanisms re-
late to the types of light damage described above.
Light damage as a possible contributing factor to
the development of AMD was first suggested in
the 1980s.20,21 Since then, several investigators have
J CATARACT REFRACT SURG - VOL 35, JULY 2009
evaluated this area in more depth to determine possible
mechanisms.
MECHANISMS INVOLVED IN LIGHT-INDUCED DAMAGE
Oxidative Reactions
One proposed mechanism of light-induced cellular
damage is through oxidative processes.21 The outer
retina is constantly exposed to a high oxygen level
due to the abundant blood supply of the choriocapilla-
ris. Formation of reactive oxygen species at the level of
the retinal pigment epithelium (RPE) leads to cellular
damage, with secondary photoreceptor degenera-
tion.22 Reactive oxygen species, such as free radicals,
hydrogen peroxide, or singlet oxygen, form when an
incident photon of light is absorbed by an intermediate
molecule in the presence of oxygen. These species are
highly reactive and capable of inducing damage to lo-
cal and surrounding cells23,24 and macromolecules,
such as proteins, lipids, and DNA.25 They are believed
to play a significant role in aging.26 Liang and God-
ley27 suggested that DNA damage by reactive oxygen
species in RPE cells is a primary mechanism in the
development of AMD. Susceptibility to oxidative
damage is increased by the high percentage of
polyunsaturated fatty acids in photoreceptor outer
segments2830 and to light damage by a regular diurnal
pattern of exposure to visible light.31
The reactive oxygen species generated by these pro-
cesses are removed by cellular defensive systems, thus
protecting against and disposing of these potentially
harmful products. Protective mechanisms include ab-
sorption of radiation by the ocular media, which can
reduce the light incident on the retina1; the action of
enzymes such as catalase, superoxide dismutase, and
phospholipase; and the presence of molecules such
as the macular pigments lutein and zeaxanthin, which
are capable of neutralizing the damaging effects of
these species.2830,32 The putative role of oxidative
stress in AMD explains the focus on antioxidant vita-
min supplementation in the prevention of AMD.30,33
Winkler et al.28 describe an additional mechanism of
RPE damage that suggests that the primary phototoxic
injury in the development of AMD is to the chorioca-
pillaris, leading to increased type IV collagen synthe-
sis, thickening of Bruch membrane, and deposits
similar to the basal laminar deposits seen in AMD.34
Intermediate Molecules
Noell35 proposed that light-induced damage occurs
in the presence of an intermediate molecule that, by
absorbing the incident photon of light, starts a cascade
of reactions that lead to cellular damage. Several mol-
ecules (as discussed below) have been proposed to
fulfill this role, and it is likely that more than one of
 REVIEW/UPDATE: BLUE LIGHTFILTERING IOLs
them is involved in this process. The action spectrum
of a particular type of light damage depends on the ab-
sorption patterns of the molecule involved, and action
spectra have been used to identify those substances
that are implicated.36
Visual Pigments
Noell35 was the first to note that the action spectrum
of light-induced retinal damage was similar to that of
scotopic sensitivity and to suggest that such damage
was mediated by rhodopsin or its photoproducts. Re-
sults in later studies support this as a mechanism.3739
Grimm et al.38 reported that mice lacking rhodopsin
were completely protected against light-induced apo-
ptosis. Remes work40 supports the finding that the
availability of unbleached rhodopsin during light ex-
posure is necessary for light-induced cellular damage
and death to occur. Lawwill41 suggested that there
may be additional mechanisms leading to light-in-
duced damage that involve cone opsins.
Lipofuscin
Many studies have considered the possible role of
lipofuscin as a potential photosensitizing molecule.
Lipofuscin contains lipid and retinoids42 and is derived
from phagocytosis of photoreceptor outer segment ma-
terial. It accumulates with age and is found in RPE cells
in granular organelles,28,4245 with increased density in
the parafoveal areas of the macula compared with that
in the peripheral retina.46 Lipofuscin is considered to be
a marker of cellular senescence.14 Lipofuscin,4752 in
particular a component of lipofuscin, the fluorophore
A2E (a bisretinoid pyridinium53), has been implicated
in photooxidative damage.5461 Support for a signifi-
cant role for lipofuscin in the class II type of photo-
chemical damage comes from experimental work by
Rozanowska
_ et al.48 They found that exposing human
RPE cells to light induced significant oxygen uptake
and generation of reactive oxygen species in the pres-
ence of lipofuscin. They postulated that lipofuscin
acts as a photosensitizing molecule, increasing the
risk for light-induced retinal damage and potentially
contributing to the development of AMD. Margrain
et al.36 reviewed these results and concurred, com-
menting that the action spectrum for photochemical
damage to RPE cells in the primate retina and the pho-
toreactivity of lipofuscin were coincident, suggesting
that lipofuscin may be responsible for this type of
damage.
The A2E component of lipofuscin has been shown to
act as a free-radical generator56,62 that can interfere
with the antioxidant mechanisms in RPE cells.52,57,59,60
It is known to accumulate in the mitochondria of RPE
cells59,63,64 and is thought to be responsible for the
J CATARACT REFRACT SURG - VOL 35, JULY 2009
1283
cells increased rate of oxygen uptake with age.49 The
A2E fluorophore is maximally excited by light in the
blue part of the spectrum and is capable of mediating
damage in response to blue light,57,58,62 but not light of
longer wavelengths, such as amber light (550 to 800
nm).58 It has been suggested that greater damage
from light at short wavelengths may be due to in-
creased generation of free radicals in lipofuscin.54,56
Further evidence supporting that the A2E compo-
nent plays a part in lipofuscins role in phototoxicity
is that the action spectrum of light-related retinal in-
jury corresponds to the absorption spectrum of
A2E.58,65 Phototoxicity of lipofuscin is thought to in-
crease with age as a result of its increased concentra-
tion. It has been suggested that focal accumulations
of lipofuscin act as hot spots for local oxidative dam-
age and may be implicated in the development of geo-
graphic atrophy.36,66,67
Other Molecules
Other potential photosensitizing molecules have
been studied. These include mitochondrial respiratory
chain enzymes such as cytochrome C oxidase,30,59,68
melanin,69 and the product of expression of the imme-
diate early gene, c-fos.40,70,71 Recently, Margrain et al.36
suggested that melanin was unlikely to play a role in
light-induced damage in AMD given the reduced
AMD risk associated with increased fundus pigmenta-
tion,72 the decrease in melanin content of the retina
with age,73 and the lack of correlation of light-induced
damage with the absorption spectrum of melanin.74
Light damage after indirect ophthalmoscopy has
been reported in a human eye with light fundus
pigmentation.75
RELATIONSHIP OF PHOTOTOXICITY TO WAVELENGTH
OF LIGHT
Light of a shorter wavelength carries more energy.
Short, rather than long, wavelength light has been im-
plicated in retinal phototoxicity. There is evidence of
this in a study by Gorgels and van Norren,76 who
found different types of damage in rat retinas after ex-
posure to different wavelengths of light. Damage to
the rhesus monkey retina was seen after exposure to
a 460 nm blue lightemitting diode for 40 minutes,77
and albino rat retinas showed apoptotic cell death
when exposed to blue light (403 nm) but not when ex-
posed to green light (550 nm).78 Other studies also
show that exposure to shorter wavelengths of light is
associated with increased cell damage and bloodret-
inal barrier (BRB) breakdown.79
There is evidence that macular pigments, such as lu-
tein and zeaxanthin, act to protect against blue light
damage at the fovea by absorbing incident blue light
1284 REVIEW/UPDATE: BLUE LIGHTFILTERING IOLs
and acting as free-radical scavengers.80 This protection
is greatest at 460 nm, leaving the retina more vulnera-
ble at shorter wavelengths.8184 The distribution of
macular pigment shows greatest concentration at or
around the fovea, with a rapid decline in concentration
with increasing eccentricity. This may leave the para-
foveal areas of the retina more vulnerable to develop-
ing light-induced damage.36
IMPLICATIONS FOR THE DEVELOPMENT OF AGE-RELATED
MACULAR DEGENERATION
Light toxicity results in animal and cell culture exper-
iments are not necessarily an accurate reflection of the
process in humans. Animals have a shorter life span
than humans; as a result, it is difficult to mimic the
sort of chronic low-level, long-term light exposure to
which humans are subjected. To compensate for the
shorter time line, many experiments are performed us-
ing short durations of high-intensity light. These ex-
periments have limitations in accurately simulating
the kind of light damage that is implicated in aging.29
Although acute light exposure in humans has been
shown to cause retinal damage, the effects of chronic
light exposure are more difficult to assess.36
Beatty et al.30 reviewed the evidence for the role of
light-induced oxidative stress in the development of
AMD and concluded that this theory was enticing
but unproven. Other authors8588 have voiced similar
opinions. Recently published results in the European
Eye Study (EUREYE)89 provide additional support of
the theory of light-induced oxidative damage. In the
study, an association between blue-light exposure
and neovascular AMD was seen in a subgroup of pa-
tients with low antioxidant levels. It has been sug-
gested that the bluegreen phototoxicity described
by Noell et al.13 is more likely to play a role in AMD
development than the higher intensity light damage
described by Ham et al.14 because the former occurs
at much lower light levels that more closely resemble
those in day-to-day life.
Epidemiology
Risk factors for AMD have been identified in long-
term epidemiologic studies of patients with AMD.90
Several cohort studies looked specifically at the devel-
opment of AMD in selected populations. A link be-
tween light exposure and AMD was identified in
a study of Chesapeake Bay watermen.91,92 Members
of this population had high levels of sunlight exposure
during their working lives. Development of advanced
AMD was associated with increased light exposure
over the preceding 20 years. No differences in light ex-
posure were seen earlier in life. The Beaver Dam Eye
Study,9395 which included a cohort aged 43 to 86 years
J CATARACT REFRACT SURG - VOL 35, JULY 2009
drawn from all eligible individuals living in Beaver
Dam, Wisconsin, showed an association between in-
creased development of early AMD with high levels
of sun exposure during the second and third decades
of life but found no link between sun exposure and
progression of AMD. Simons96 also suggested that
light exposure early in life may play a role in develop-
ment of AMD. These studies all used estimates of
cumulative light exposure or behaviors that would
suggest light exposure. One study,97 by analyzing
skin samples, looked for a relationship between quan-
tifiable solar damage and the development of AMD.
An insignificant positive association was seen in this
small study. Several other studies98102 failed to iden-
tify an association between light exposure and the
development or progression of AMD. The recent
EUREYE,89 although showing no overall association
between blue-light exposure and neovascular or early
AMD, identified a subgroup of patients with low anti-
oxidant levels in whom an association between blue-
light exposure and neovascular AMD was seen.
There are inherent difficulties with epidemiologic
studies such as the ones discussed. Most have esti-
mated cumulative light exposure, which is difficult
to do retrospectively. It may not be lifetime light expo-
sure that is important but rather exposure to specific
spectral compositions or intensities of sunlight or arti-
ficial light103 in certain parts of the world or at certain
times of life. Other confounding variables, such as
diet, concurrent illnesses, and ocular comorbidity,
may have an effect and confuse interpretation of
data. All these are difficult to quantify. A prospective
study taking into account ambient light and sun pro-
tective measures (eg, wearing a broad-brimmed hat
and sunglasses) to better quantify light entering the
eye, with a life-long follow-up of a large cohort of in-
dividuals, would optimize accumulation of meaning-
ful epidemiologic data. The feasibility of such an
undertaking is debatable.
CATARACT SURGERY AND AGE-RELATED MACULAR
DEGENERATION
Role of Inflammation
The relationship between cataract surgery and the
subsequent development of AMD is controversial.18
Factors that may influence the development include
inflammatory effects of the surgical procedure itself
and altered light exposure postoperatively. Separating
these factors is difficult. Pooled data from the Beaver
Dam and Blue Mountains Eye studies and data from
the Salisbury Eye Evaluation, Proyecto VER, and the
Baltimore Eye Survey show that cataract surgery in-
creases the risk for the development of AMD, in partic-
ular neovascular AMD (Martin DF, et al. IOVS 2002;
 REVIEW/UPDATE: BLUE LIGHTFILTERING IOLs
43:ARVO E-Abstract 1907. Available at: http://
abstracts.iovs.org/cgi/content/abstract/43/12/1907.
Accessed April 19, 2009).104-111 However, a recent
study reporting results in 1152 eyes of 696 patients112
does not support this finding. There are several possi-
ble reasons that might explain the occurrence of AMD
after cataract surgery. One is that breakdown of the
bloodocular barrier may be sufficient to activate an
inflammatory pathway, triggering development of
AMD in a susceptible population. There is evidence
that AMD is an inflammatory disease; recent genetic
studies identified strong and independent associations
between the development of AMD and sequence var-
iation in a gene that is involved in the complement fac-
tor pathway; complement factor H (CFH).113 It is now
recognized that several genes that code for proteins in-
volved in the complement cascade can significantly in-
crease the risk for AMD, including both CFH and
complement component C3.114116 Carrying the
Y402H polymorphism in the CFH gene increases the
risk for AMD 2.7-fold and accounts for up to 50% of
the population-attributable risk for AMD.113 Identifi-
cation of this association with AMD has redefined
the condition as a disease of complement dysregula-
tion in a significant proportion of patients.117 Comple-
ment activity can lead to tissue injury and
inflammation, and strict regulation of the complement
cascade is important. New therapeutic approaches di-
rected at the complement cascade are being evaluated,
including C3 and integrin inhibitors and monoclonal
antibodies against C5, thus highlighting the impor-
tance now given to the role of inflammation in the
pathogenesis of AMD.118 The observation that dexa-
methasone may prevent light-induced cell death in
mice is consistent with this.40 It is known that C-reac-
tive protein (CRP) is elevated in patients with AMD.119
A recent study120 reported that patients with coexist-
ing moderate cataract and AMD have a significantly
higher level of serum CRP than patients with just 1
of these pathologies. The same authors commented
that a rise in serum CRP is seen after cataract surgery
only in those patients with AMD.
Potential Toxic Effect of Light
Another factor that may play a role in AMD develop-
ment is increased light transmission to the retina in the
postoperative period. Loss of the protective effect of the
natural lens renders the retina vulnerable to the poten-
tial toxic effect of short-wavelength light.18 This sugges-
tion has led to the development of IOLs that not only
block UV light but also reduce transmission of the violet
and blue wavelengths. These yellow pigment-contain-
ing IOLs were first developed by Hoya in Japan in the
late 1980s,121 followed by Menicon Co. Ltd. in the
J CATARACT REFRACT SURG - VOL 35, JULY 2009
1285
mid-1990s. Alcon Laboratories developed the first fold-
able version in 2004, and several IOL companies have
since followed suit.10,122,123 A reduction in transmission
of short-wavelength light occurs with increasing age
and development of cataract; therefore, removing a cat-
aractous lens increases the amount of UV and short-
wavelength visible light incident on the retina. The
properties of the implanted IOL will influence the trans-
mission of specific wavelengths. It is possible to calcu-
late how much light is transmitted to the retina
through the human lens at various ages.124,125 This
has led to the development of an IOL that used the hy-
pothetically beneficial blocking properties of a natural
lens without the opacity of a cataractous lens, with
the aim of mimicking the light transmission of the hu-
man crystalline lens (Alcon Laboratories. Product infor-
mation: AcrySof Natural Single Piece IOL SN60AT,
2003).10,123,124,126 Figure 1 shows the transmission spec-
tra of different IOLs.122,123,127 These include blue light
filtering IOLs1517 currently on the market, allowing
comparison between UV-blocking IOLs122,127 and the
human crystalline lens.128
Animal and cell culture studies have examined the
effect of blue lightfiltering IOLs on retinal photore-
ceptors and RPE health. Nilsson et al.129 evaluated
electroretinogram (ERG) changes in rabbit retinas ex-
posed to light through materials simulating the trans-
mission characteristics of different IOLs, finding that
a yellow filter offered some protection against ERG
changes. Sparrow et al.130 showed that a culture of
A2E-laden RPE cells showed a significant reduction
in cell loss when exposed to light through a blue-filter-
ing IOL compared with cell loss with a standard UV-
blocking IOL. In a similar study, Rezai et al.131 exposed
human RPE cells to blue light and found a more signif-
icant reduction in apoptosis when an AcrySof blue fil-
ter was used than when an AcrySof UV filter was used.
Miyake et al.132 assessed BRB disruption after cataract
surgery and found it to be less in eyes with a particular
blue lightfiltering IOL than in eyes with a UV-block-
ing IOL. Yanagi et al.133 took an alternative approach;
they studied vascular endothelial growth factor
(VEGF) production as an indicator of cell damage in
A2E-laden RPE cells exposed to white light. They
found that cells exposed to the light through a blue
lightfiltering lens material had significantly less
VEGF upregulation than those exposed to light
through a UV-blocking lens material.
A model evaluating the effectiveness of different
IOL materials in protecting the retina from lipofus-
cin-mediated toxicity134 showed that the AcrySof Nat-
ural IOL provided the highest theoretical protection of
the 6 IOLs tested, including UV-transmitting, UV-
blocking, violet lightfiltering, and blue lightfiltering
models.
1286 REVIEW/UPDATE: BLUE LIGHTFILTERING IOLs
POTENTIAL SIDE EFFECTS OF FILTERING BLUE LIGHT
Several potential disadvantages may become evident
if short-wavelength light transmission is reduced (or
allowed in excess, as in the case of cyanopsia with
UV-blocking IOLs). Potential side effects of a reduction
in blue-light transmission include color-vision distur-
bance, decreased scotopic sensitivity (which can lead
to poorer performance in dim lighting conditions),
and sleepwake timing disruption.
Color Vision and Contrast Sensitivity
Several clinical studies have evaluated contrast sensi-
tivity and color vision in patients who have IOLs that fil-
ter blue light. No significant difference in color vision
between eyes with blue-filtering IOLs and eyes with
UV-blocking IOLs was found in these studies,135148 in-
cluding eyes with preexisting color-vision defects.149
One study did find a difference in blue color perception
between eyes with a blue lightfiltering IOL and eyes
with a UV-blocking IOL;150 however, both patient
groups fell within normal limits. A questionnaire-based
study assessing color vision and quality of life found no
difference in either measure between eyes with an IOL
that blocks UV light only and eyes with a blue lightfil-
tering IOL.151 There is 1 case report of IOL exchange due
to reported color vision disturbance after unilateral im-
plantation of a blue lightfiltering IOL.152 In view of the
number of clinical studies that show no color-vision ab-
normalities, color-vision disturbance does not appear to
be a significant problem with this type of IOL.
J CATARACT REFRACT SURG - VOL 35, JULY 2009
Figure 1. Comparison of transmis-
sion spectra of different IOLs,
including UV-transmitting,127 UV-
blocking,122,127 violet lightfilter-
ing,127 and blue lightfiltering122,123
(Tekia, Inc. Single-piece IOL; blue
light-filter IOL. Available at:
http://www.tekia.com/singlepiece.
htm. Accessed April 18, 2009)
models. Representations of the hu-
man crystalline lens at ages 30 years,
50 years, and 70 years are also given
to show how the IOL transmission
compares with that of the human
lens.128
Studies to date have also failed to show a detrimental
effect of blue lightfiltering IOLs on photopic and mes-
opic contrast sensitivity in normal eyes136,138,139,142147,153
and have found improved photopic contrast sensitivity
in eyes of diabetic patients.137 Niwa et al.152 report im-
proved photopic and mesopic vision at middle spatial
frequencies with these IOLs, with a reduction in the ef-
fect of central glare.
Scotopic Sensitivity
The peak spectrum of scotopic sensitivity is approx-
imately 500 nm (Figure 2).154156 In the healthy eye, an
age-related decline in rods is seen, even in the absence
of disease.157 This results in a slowing of rod-mediated
dark adaptation and a greater decrease in scotopic sen-
sitivity with age than seen with mesopic sensitiv-
ity.158164 This loss is most marked at the blueviolet
end of the spectrum.165 Poor dark adaptation has
been associated with an increased risk for falls in an el-
derly population with no evident ocular pathology.166
In an eye with early AMD or AMD, rods are prefer-
entially lost from the parafovea167169 and rod function
is significantly affected.170 This decline in scotopic sen-
sitivity in AMD patients has been associated with dif-
ficulty in night driving.171174 There is concern that
using a yellow IOL in patients whose scotopic vision
is already compromised will cause a further decline
in function. Werner175 evaluated the theoretical de-
crease in scotopic vision that can be expected when
the transmission differences between the 2 IOL types
 REVIEW/UPDATE: BLUE LIGHTFILTERING IOLs
are considered and concluded that the predicted dif-
ference in scotopic vision is unlikely to be detectable
clinically. Pons et al.176 calculated that a 20.0 diopter
(D) AcrySof Natural IOL would be expected to de-
crease scotopic sensitivity by 14%; Mainster and Spar-
row177 and Mainster127 estimated a 14% to 25%
decrease. Schwiegerling178 calculated a decrease of
14.6% but also suggested that removal of the crystal-
line lens and implantation of an AcrySof Natural IOL
would, in fact, increase the amount of light entering
the eye by 52%. This estimate was challenged by Main-
ster.179 In a small clinical study, Greenstein et al.148
found that implantation of the AcrySof Natural IOL
had no significant effect on scotopic sensitivity. Muf-
tuoglu et al.136 agreed with this finding but found a de-
crease in scotopic vision with increasing age in
patients with UV-blocking or blue lightfiltering
IOLs. Although there is a theoretical argument that
these IOLs may decrease scotopic sensitivity, there is
no clinical evidence to date. The theoretical data
should be considered, bearing in mind the limitations
of the aging eye.
Sleep and Circadian Rhythms
The circadian system coordinates the timing of multi-
ple biological events to a specific phase of the 24-hour
environmental cycle and ensures that the phases of mul-
tiple rhythmic events are appropriately coupled. In the
eye, for example, several functions have a circadian pat-
tern, including rod outer segment shedding, signal pro-
cessing in the retina, and cellular metabolism.180183
Maintenance of this circadian rhythm can only occur
when biological time is adjusted to local time, and the
most important environmental signal (zeitgeber) that
provides time-of-day information is the changing qual-
ity of light at dawn and dusk.183 The classic example of
J CATARACT REFRACT SURG - VOL 35, JULY 2009
1287
Figure 2. Spectral sensitivity curves
for photopic vision, scotopic vision,
and pRGCs. Note the greater con-
tribution of blue light to circadian
entrainment compared with scoto-
pic or photopic visual responses
(pRGCs Z photoreceptive retinal
ganglion cells).
a mismatch between biological and environmental time
is the phenomenon of jet lag. Travel across multiple time
zones leaves an individual poorly adjusted to the
demands of local time. On arrival, the physiology of
sleep and decreased activity is initiated by the circadian
system at an inappropriate phase of the day. However,
after several days of exposure to the altered lightdark
cycle, biological and local time will once more become
synchronized or entrained.
Studies using retinally degenerate and transgenic
mice to evaluate the roles of rods, cones, and other ret-
inal cells in circadian entrainment led to the discovery
of a nonvisual photoreceptor that provides input to the
circadian system.184,185 This photoreceptor, known as
photoreceptive retinal ganglion cells (pRGCs), con-
tains a photopigment called melanopsin that has max-
imum sensitivity to light in the blue part of the
spectrum (lmax 480 nm/OP480). Figure 2 shows how
the sensitivity of these cells compares with the spectral
sensitivity curves for photopic and scotopic vision.
The photopic and scotopic sensitivity curves are avail-
able as an international standard.186 No such standard
exists for the pRGC system. The curve for sensitivity of
pRGCs was generated using the spectral sensitivity of
a vitamin Abased visual pigment with maximum
sensitivity (lmax) at 480 nm.187 The role of these cells
was confirmed by showing that the genetic ablation
of melanopsin in mice lacking all functional rods and
cones abolishes circadian and pupil responses to
light.188 Subsequent studies found that a similar sys-
tem exists in primates, including humans.189,190 These
cells provide the primary light input that brings about
circadian entrainment and stability of sleepwake tim-
ing.191 There has been discussion on whether the clas-
sic photoreceptor system (rods and cones) has a role in
the maintenance of circadian rhythm in addition to the
role of pRGCs. Mice lacking pRGCs still show
1288 REVIEW/UPDATE: BLUE LIGHTFILTERING IOLs
circadian entrainment; however, it is attenuated.192195
In the macaque and human retina, cones have been
shown to provide some input into pRGCs, with
short-wavelength cones attenuating their response
and mid- or long-wavelength cones providing excit-
atory input.189 Other studies181,196,197 confirm the
structural connections between these cell types. The
relative contributions of pRGCs and the classic photo-
receptor systems to circadian entrainment in a healthy
human eye remain unclear. It is possible that although
the pRGCs provide the primary input for circadian en-
trainment, rods and cones still play a role.198,199 Al-
though the peak sensitivity of the pRGCs in isolation
in mice and primates has been shown to be approxi-
mately 480 nm,184,189 a significant contribution by
other photoreceptors could alter this. Studies of in
vivo measurements of circadian entrainment in hu-
mans (melatonin suppression and phase-shifting) in-
dicate maximum responses that range from 460 to
500 nm (Cooper HM, et al. IOVS 2004; 45:ARVO E-Ab-
stract 4345. Available at: http://abstracts.iovs.org/
cgi/content/abstract/45/5/4345. Accessed April 20,
2009).198,200,201 The pRGCs provide input into the
suprachiasmatic nucleus of the hypothalamus.
The effects of light on the human circadian system
can be measured in many ways. Two commonly
used measures are the effect on the timing of the
sleepwake cycle and the effect on melatonin suppres-
sion. Melatonin is a hormone released in a cyclical
fashion by the pineal gland. Serum levels rise during
the early evening to reach a peak in the early morning.
Exposure to light of sufficient intensity during this
time can cause acute suppression of melatonin produc-
tion, with a consequent drop in serum level. This acute
melatonin suppression is often used as an indicator
of the effect of light on the circadian system.202 In ad-
dition to suppressing melatonin, sufficient light sti-
mulation will stabilize sleepwake timing, or if
inappropriately timed, change the timing of the entire
sleepwake cycle (phase-shifting).
There is considerable interindividual variation in
the light exposure required for robust melatonin sup-
pression and phase-shifting, with high intensities of
light previously considered to be necessary.203205
Some studies suggest that young adults with normal
vision fail to entrain with exposure to light levels of ap-
proximately 200 lux206 or 80 lux,207 both of which can
be encountered in the home. As well as intensity, the
duration, spectrum, and timing relative to the circa-
dian cycle are important in determining effect.208 A
study by Zeitzer et al.202 evaluated the duration and
intensity of exposure to white light required to induce
melatonin suppression and phase-shifting of the circa-
dian system in humans. They found an increase in
melatonin suppression with increasing illuminance;
J CATARACT REFRACT SURG - VOL 35, JULY 2009
however, they saw effects with light levels lower
than those previously thought to be sufficient. For
a light pulse of 6.5 hours duration, maximum melato-
nin suppression was achieved with illuminances
greater than 200 lux and minimal suppression with
those lower than 80 lux. Fitting this to a logistic model
showed a half-maximum melatonin suppression re-
sponse to a white-light source between 50 lux and
130 lux. Zeitzer et al. also evaluated phase-shifting.
With the same light-exposure duration, no phase shift
occurred with light levels below 15 lux; the maximum
(3-hour) shift occurred at 500 lux and above. A half-
maximum response was seen between 80 lux and
160 lux. These light levels are on the order of what
one might expect to find indoors without a significant
contribution from daylight. A study of melatonin sup-
pression to light at 505 nm209 showed significant sup-
pression at an intensity of just 5.5 mW/cm2 (roughly
equivalent to 21 lux). A therapeutic approach to pa-
tients with delayed sleep-phase disorder uses light
exposure to help realign sleeping patterns. Lack and
Wright210 reported effective treatment using a 3-hour
morning exposure to white light of 2500 lux or blue
light of 1000 lux. Despite recognition of the increased
efficacy of short-wavelength light (420 to 530 nm)
over that of longer wavelengths in this situation, con-
cerns about the possibility of blue-light hazard have
led to the suggestion that light in the region of 500 to
530 nm be used for treatment.
Many of those who develop visually significant cat-
aract are older than 60 years. In this population, there
is evidence of considerable age-related change in the
circadian system. Age-related disruption has been de-
scribed for hormonal rhythms, core body temperature,
sleepwake timing, and other behavioral cycles. The
disruption of circadian rhythms and the increased in-
cidence of disturbed sleep during aging appear to be
paralleled by age-related alterations in the neural
and temporal organization of the suprachiasmatic nu-
cleus and decreased photic input into the circadian
clock.211 Sleep problems are common in this popula-
tion, and several factors in addition to light input
may contribute to this, including stress or anxiety, de-
pression, medication side effects, chronic disease, caf-
feine, and alcohol.212 However, supplementary light
in the home environment of elderly people has been
shown to have a significant effect on their ability to
consolidate their sleepwake timing.213215 The extent
to which the aging lens or IOLs contribute to the de-
creased photic input into the clock remains poorly
studied. We know that aging of the healthy lens and,
to a greater extent, development of cataract decrease
transmission of blue light to the retina.7,8 There is evi-
dence of improved sleep patterns after cataract sur-
gery in patients with IOLs that block UV light
 REVIEW/UPDATE: BLUE LIGHTFILTERING IOLs
only.216218 It remains unclear at this stage whether the
reduction in transmission of short-wavelength visible
light by the newer blue lightfiltering IOLs is of suffi-
cient magnitude to affect circadian control. What is
likely to be important in sleep regulation and main-
taining scotopic sensitivity is the absolute amount of
light reaching the retina. This will depend on the indi-
viduals exposure to light on a day-to-day basis and
their pupil size, as well as the transmission of their
IOL.208 Mainster127 calculated that a 20.0 D AcrySof
Natural IOL would reduce melanopsin photorecep-
tion (with a maximum sensitivity for melanopsin of
480 nm) by 18% and melatonin suppression (based
on a maximal sensitivity at 460 nm) by 27%. Our
data support this estimate (unpublished data) based
on irradiance measurements of indoor light sources
and the relative reduction in photon flux produced
by different IOLs available for absorption by a visual
pigment with maximum sensitivity at 480 nm.
The exposure of individuals to light over 24 hours
varies enormously depending on factors such as age,
geographic location, lifestyle, and time spent outdoors.
An individual who is housebound in Northern Europe,
for example, will likely have significantly less natural
light exposure than an active person in a tropical or
subtropical climate. Turner and Mainster208 estimated
that a young adult in an industrialized country has
a light exposure exceeding 1000 lux of only 20 to 120
minutes a day, with elderly adults receiving between
one third and two thirds that amount and elderly living
in nursing homes receiving fewer than 10 minutes
a day. In the latter population, median illuminances
of approximately 54 lux have been reported.208,219
When considering the effect of a reduction in blue-light
transmission on circadian rhythm in pseudophakic pa-
tients, it must be remembered that even if transmission
of a particular wavelength of light is less than that of
other wavelengths, regular exposure to an adequate
overall lighting level could ensure that the absolute
amount of light at that wavelength is sufficient to main-
tain these functions. Artificial lighting is much less
bright than sunlight, even on a cloudy day, and differ-
ent artificial lights have different spectral profiles, pro-
viding different amounts of light at each wavelength
(Figure 3). The population we would be most con-
cerned about with respect to sleep problems includes
people who spend most of their time indoors with rel-
atively poor lighting, such as those in nursing homes or
those in their own homes who have illnesses or disabil-
ities that make it difficult to spend time outside.220 This
population may benefit from increased light exposure,
not just in improved sleep but also in improved mood
and cognition.214 The time of yeardthat is, short days
in winterdreduces the opportunity for natural light
exposure. Losing the morning exposure to daylight
J CATARACT REFRACT SURG - VOL 35, JULY 2009
1289
can have a significant effect on circadian rhythm and
general well-being. If light exposure in already com-
promised individuals is further decreased by blue
lightfiltering IOL implantation after cataract surgery,
it may be necessary to counteract the consequent light
reduction by improving home lighting conditions. This
could be achieved by selecting a light source with
a spectral profile that contains little short-wavelength
light, by increasing the intensity of home lighting, or
by increasing exposure to natural light during the day.
DISCUSSION
Although studies using animals show a link between
retinal damage in response to short-wavelength light,
convincing epidemiologic evidence for humans is
sparse. The mechanisms underlying the pathogenesis
of AMD are complex, involving many factors of vary-
ing importance that contribute to its development in
susceptible individuals. In addition to the possibility
of damage due to light exposure, inflammatory and
genetic factors likely to play significant roles.
Animal and cell culture experiments provide valu-
able information; however, their interpretation and
application to humans is not straightforward. Rodents
are nocturnal animals, naturally sleeping during the
day and awake and active during the night. It is not
only their sleepwake cycle that is different from that
of humans but rather all functions of the eye that
have a circadian pattern, including rod outer segment
shedding, signal processing in the retina, and cellular
metabolism.180183 Retinal response to an insult, such
as exposure to short-wavelength light, will vary de-
pending on the time of day or night the insult occurs.
Much experimental work in this area has been per-
formed during the sleep phase of nocturnally active ro-
dents, and the results have been extrapolated to the
daytime activity of a diurnal human. The outcomes
of such experimental insults differ depending on their
timing relative to the circadian cycle of the animal be-
ing studied.221 What has been interpreted as a photo-
toxic effect of light may be, at least in part, due to the
different physiological responses at different times of
the day, and this should be taken into account when
interpreting data from such experiments.
It would seem sensible to reduce short-wavelength
light exposure using blue lightfiltering IOLs, espe-
cially in cases in which damage may be accelerated
due to underlying pathology, such as early AMD,
and in the aging eye, which has increased lipofuscin
deposition. It is important, however, to consider pos-
sible disadvantages of the use of these IOLs. Aging
eyes, in particular those with AMD, already have sig-
nificant loss of rod function. A reduction in scotopic
sensitivity in these patients after implantation of
1290 REVIEW/UPDATE: BLUE LIGHTFILTERING IOLs
a blue lightfiltering IOL is a possibility based on the-
oretical data, although clinical evidence of this is lack-
ing at present. Another important issue is the potential
disruption of the sleepwake cycle, particularly in
those with preexisting poor daytime light exposure.
A further decrease in short-wavelength transmission
in these individuals may result in destabilization of
the sleepwake cycle with failure to entrain. This
could have implications for mood and quality of life.
Additional in-home lighting may be required when
preexisting lighting is dim, and particular consider-
ation should be given to the spectral composition
and intensity of artificial lighting that is used. It has
been argued that matching lens transmission in a pseu-
dophakic eye to that in a young adult should not have
adverse effects on scotopic sensitivity or circadian
rhythm because no effects are seen in early adult-
hood.222 What this argument fails to take into account
is that changes with increasing age are seen in other
areas, such as pupil size, rod function, and neural
processing.
Development of an IOL to specifically reduce trans-
mission of very-short-wavelength visible light (corre-
sponding to violet light) would be expected to
provide retinal protection from short-wavelength light
damage but would permit transmission of the short
wavelengths important for circadian and sleep regula-
tion. It is, however, unclear whether such an IOL
would confer sufficient protection and whether un-
wanted side effects, such as disturbed color vision,
will occur. Similar protection can be achieved by im-
planting a standard UV-blocking IOL and encourag-
ing sunglasses use when outdoors.223
As well as those living in dimly lit environments,
cataract patients with higher levels of sunlight expo-
sure must be considered. These individuals are likely
to develop cataract at an earlier age than those without
such exposure to sunlight and therefore may live
J CATARACT REFRACT SURG - VOL 35, JULY 2009
Figure 3. Spectral profile of 2 com-
mon indoor artificial light sources
and winter daylight to show the
difference between types of light
source. All spectra were measured
using a radiometrically calibrated
spectrometer (Ocean Optics
USB2G1931, processed with Spec-
traSuite software). Note the differ-
ing scales for the different light
sources. The total photopic lux for
the daylight measurement is 546
lux; for the incandescent light, 19
lux; and for the fluorescent light,
62 lux.
longer with pseudophakia. Blue lightfiltering IOLs
will reduce, but not eliminate, exposure to short-wave-
length light and with sufficient overall light exposure,
these individuals may remain at risk for retinal dam-
age from phototoxicity. This may particularly hold
true for those with low levels of antioxidants.89 These
patients are much less likely to develop problems due
to a reduction in blue-light transmission, such as re-
duced scotopic sensitivity or disturbed circadian
rhythm; however, it may be necessary for them to
seek additional protection by using sunglasses and
hats to limit ocular exposure to sunlight.
In view of the heterogeneous climatic conditions in
different parts of the world, it is likely that a single
IOL type will not be appropriate for every individual
having cataract surgery. In choosing an ideal IOL for
a particular individual, it is important to balance the
potential benefits of reducing phototoxicity with the
potential side effects on scotopic vision and circadian
rhythm. This balance will depend on the individuals
age, geographic location, local climate, lifestyle, and
time spent outdoors as well as other protective mea-
sures that are taken against sun exposure and the pres-
ence of coexisting ocular disease.
In the context of an aging population world-
wide,10,224 cataract surgery and AMD are likely to be-
come more common. It is important to consider all the
issues discussed above in the light of this. Large long-
term epidemiologic studies are needed to determine
whether blue lightfiltering IOLs are effective in pre-
venting the development or progression of AMD.
Such studies will require large numbers of participants
and will have to account for numerous variables re-
lated to light exposure and other known risk factors
for AMD. These studies would also provide the oppor-
tunity to evaluate in more detail the effects of blue
lightfiltering IOLs on scotopic sensitivity and the
sleepwake cycle in the cataract population.
 REVIEW/UPDATE: BLUE LIGHTFILTERING IOLs 1291

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