Clinical Ophthalmology

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Radiation Retinopathy: Detection and

Management Strategies

Niroj Kumar Sahoo, Richa Ranjan, Mudit Tyagi, Hitesh Agrawal & Subhakar
Reddy

To cite this article: Niroj Kumar Sahoo, Richa Ranjan, Mudit Tyagi, Hitesh Agrawal & Subhakar
Reddy (2021) Radiation Retinopathy: Detection and Management Strategies, Clinical
Ophthalmology, , 3797-3809, DOI: 10.2147/OPTH.S219268

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Clinical Ophthalmology Dovepress
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REVIEW

Radiation Retinopathy: Detection and Management

Strategies

1
Niroj Kumar Sahoo Abstract: A gradual shift in trend from primary enucleation to globe salvaging radiation
Richa Ranjan 2 therapy for the management of ocular tumors has resulted in the rise of several post-
Mudit Tyagi 3 treatment ocular complications including radiation retinopathy. Radiation retinopathy is
Hitesh Agrawal 3 a chronic, progressive, and occlusive vasculopathy that can manifest anytime between 1
month to 15 years after starting radiation therapy. The aim of treatment in most of these cases
Subhakar Reddy 3
is to prevent further vision loss. Treatment options such as laser photocoagulation, anti-
1
Department of Retina and Vitreous, vascular endothelial growth factor and intraviral steroids have been described. However,
L V Prasad Eye Institute, Vijayawada,
India; 2Bharti Eye Foundation and despite several advances in diagnostic and therapeutic modalities, a significant proportion of
Hospital, New Delhi, India; 3Smt. Kanuri eyes with radiation retinopathy eventually go blind. This review summarises some of the
Santhamma Centre for Vitreo-Retinal
clinical features, investigative modalities, and recent therapeutic strategies used in the
Diseases, L V Prasad Eye Institute,
Hyderabad, India management of radiation retinopathy.
Keywords: radiation retinopathy, radiation maculopathy, anti-VEGFs, laser
photocoagulation, ocular tumors

Introduction
Radiation therapy is an invaluable tool in the management of ocular tumors. It has been
a popular alternative to enucleation for patients with choroidal melanoma, retinoblastoma,
and ocular metastases,1–3 and has proven to be a life-saving treatment for several orbital,
peri-orbital, and intracranial tumors. Since its inception, radiotherapy has evolved sig­
nificantly, both in terms of efficacy and safety. The popularity of radiation therapy in
ocular tumors also stems from the Collaborative Ocular Melanoma Study (COMS),
which showed similar survival rates to radiotherapy when compared to enucleation.4
The results of COMS led to a shift towards globe-salvaging therapeutic strategies.5
Despite advances in precise localization and dosage calculation, patients encounter
several forms of ocular complications as collateral damage. Radiation retinopathy (RR)
is a chronic progressive vasculopathy developing secondary to ionizing radiation to the
retina. Stallard, in 1933, was the first to describe the hazardous effects of ionizing
radiation on retina, in patients with retinoblastoma 3–6 weeks after treatment with
radon seeds.6 The author described the occurrence of retinal hemorrhages, vascular
sheathing, disc edema, and exudation following irradiation. Since then, there have been
Correspondence: Mudit Tyagi several reports of RR following brachytherapy, external beam radiotherapy, proton beam
Smt. Kanuri Santhamma Centre for radiation, helium ion radiotherapy, and gamma knife radiotherapy for various intraocular
Vitreo-Retinal Diseases, L V Prasad Eye
Institute, Banjara Hills, Hyderabad, 34, or orbital cancers.1,7–10
India
Tel +91-9553339042
Various retrospective and prospective studies have explored several treatment
Email [email protected] options; however, there is no standard treatment for RR. This article comprises

Clinical Ophthalmology 2021:15 3797–3809 3797

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 Sahoo et al Dovepress

a review of clinical features and investigations of radiation Extrinsic factors responsible for the development of
retinopathy and the current strategies being studied for its RR are related to the radiation itself. These include the
treatment. type of radiation, radiation dose, fractionation schedule,
elapsed time in the course of treatment, and errors in
treatment.20,21,27–31 Parsons et al reported a 53% rate of
Epidemiology and Risk Factors
RR in patients who received 45 to 55 Gy doses to half or
While radiotherapy offers an eye-sparing alternative for
more of the retina during external beam radiation for
patients and allows them to maintain some level of visual
extracranial tumors.27 Most small to medium-sized tumors
acuity, an increase in the incidence of radiation-related
(≤10 mm in height or ≤16 mm in largest base diameter) are
complications has been seen.11,12 COMS reported that
treated with radiation therapy, whereas most large tumors
after 3 years of treatment, nearly 50% of patients had
(>10 mm in height or >16 mm in largest base diameter)
a visual acuity of 20/200 or worse.13 Several factors
are treated solely by enucleation.32 Shields et al found that
determine the incidence of radiation retinopathy. The risk
tumor base ≥10 mm, tumor thickness >8 mm, the radiation
factors can be divided into intrinsic or extrinsic. One of the
dose to the tumor base of ≥33,300 cGy, and increasing
most important intrinsic/patient factors is the presence of
radiation dose to the optic disk to be significant predictors
concurrent diabetes. There appears to be a synergistic
of long-term poor visual acuity.33 However, Horgan et al
action of radiation and diabetes on the capillaries that
found no such association.34 The authors found pre-
predisposes these eyes to retinopathy and can increase
treatment tumor size to be the single most significant
the risk of visual loss by 300%.14,15 The cumulative effect
predictor for maculopathy in multivariate analysis.
of pericytes damage seen in diabetes and endothelial
Gunduz et al reported in their study that 42% of patients
damage seen with radiation exposure culminates in the
develop non-proliferative RR within 5 years of treatment
severe occlusive arteritis, which is commonly seen in for posterior uveal melanoma.12 Krema et al further
cases of radiation retinopathy. Diabetes has also been reported that 30% of patients treated with plaque bra­
associated with poor visual outcomes due to a higher chytherapy for melanoma developed evidence of RR
incidence of developing neovascular glaucoma16 and dia­ within 2 years of treatment.8 Ruthenium-106 has been
betic papillopathy.17 The risk of disease is also increased shown to have limited depth of penetration, resulting in
for patients with other vasculopathies like hypertension less radiation exposure to surrounding retinal
and coronary artery disease.14,15,18 Tumor characteristics structures.35,36 However, when compared to Iodine-125,
and patient demographics play a crucial role in the devel­ rates RR have been seen to be similar between the two,37
opment of RR.14,15,18 Eyes with larger tumors may require although a few studies have reported slightly higher rates
high doses of radiation, increasing the chance of develop­ for Iodine-125.35,36 Considering the slight advantage of
ing RR.19 Also, eyes with tumor proximity to the critical Iodine-125 in certain cases in terms of tumor control,37,38
structures of the eye such as the optic disc or macula are at the choice of plaque can be individualised on a case-to-
high risk for developing vision loss in the form of radia­ case basis. The risk of RR following proton beam irradia­
tion optic neuropathy or radiation maculopathy (RM).20 tion has been reported to be higher, with rates ranging
Concomitant chemotherapy makes the retinal vasculature between 85% and 90%.39–41 Inclusion of more posteriorly
more vulnerable to radiation damage by increasing oxy­ located tumors in these studies could have resulted in the
gen-derived free radicals.21 It also increases the risk of higher incidence seen. Hyper-fractionation with a dose of
progression to the proliferative stage,22 higher visual less than 1.9G/fraction has been demonstrated to decrease
morbidity,21,23 development of retinopathy at lower radia­ the risk of RR development.27,31 Although the worst visual
tion dose,23 and decrease in the latent period between outcome has been seen after gamma knife treatment
exposure and retinopathy.23,24 Krema et al also reported (reported to cause complete vision loss in as many as
clinical risk factors for the development of RR, and found 50% of the eyes),10 it needs to be emphasized here that
pre-existing diabetes, prior or concurrent chemotherapy, gamma knife treatment still remains a valid treatment
larger irradiated retinal area, and posterior location of the option in selected cases, with excellent results.42 The
irradiated area in the ocular fundus, to have a higher area of retina irradiated also plays a significant role in
association.25 Pregnancy has been thought to accelerate RR manifestations. Takeda et al showed that eyes receiv­
radiation retinopathy.26 ing more than 50 Gy to greater than 60% of the retina have

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 Dovepress Sahoo et al

a higher risk of developing RR.20 RR usually develops Clinical Features

after around 6 months to 3 years (range 1 month to 15 RR can closely resemble diabetic retinopathy, as the man­
years) following radiation therapy. In one study, the mean ifestations and patterns of progression of these two entities
time to development of proliferative RR was found to be are very similar. Both diseases progress from a non-
32 months and was found in 7% of patients at 10 to 15 proliferative to a proliferative stage and can result in
years after treatment.43 The type of radiation therefore rapid deterioration of vision. Clinical manifestations of
plays an important role in this latency period, with higher RR include microaneurysms, macular edema, cotton-
dose and single fraction regimen resulting in lower latency wool spots, hard exudates, retinal edema, telangiectasia,
period.44 Thus, we recommend close monitoring, with 6 and perivascular sheathing, which may follow in variable
monthly follow-ups if there are no signs of retinopathy, sequence and latency (Figures 1 and 2).51,52
and subsequent follow-ups can be tailored on a case-to- Microaneurysms are the first ophthalmoscopically detect­
case basis. Detection and follow-up of RR can be espe­ able structural changes to appear in RR and are almost
cially challenging when the patients are being treated with universally present.51 The clinical manifestations of RR
external beam radiotherapy (EBRT) and are less likely to are more often severe in the posterior than in the anterior
be seen by an ophthalmologist. retina, which is due to higher blood flow of the macula.52
Ischemic retinal changes include macular capillary non­
perfusion, nerve fiber layer infarcts, retinal neovasculari­
Pathogenesis sation, choriocapillaris non-perfusion, choroidal ischemia,
Following radiotherapy, the primary retinal vascular event
vitreous hemorrhage, tractional retinal detachment, exuda­
is an endothelial cell loss followed by vascular occlusion
tive retinal detachment, and neovascular glaucoma
and capillary dropout, which results in vascular incompe­
(Figure 3).52 Ghost vessels can appear in the later part of
tence and retinal ischemia.45 Radiation significantly alters
the disease. The retina is the most common site of neo­
the structure and function of the retinal microvasculature
vascularization. The percentage of eyes with neovascular­
due to the compromised blood-retinal barrier.46
ization elsewhere (NVE) only is around 43%, which is
It is hypothesized that exposure to radiation causes
similar to those seen in diabetic retinopathy, while the
preferential loss of vascular endothelial cells with
percentages for neovascularization of disc (NVD) only
a relative sparing of the pericytes.45 Ionizing radiation
and NVD with NVE are less than that seen in proliferative
can cause direct damage to molecular bonds, resulting in
diabetic retinopathy (PDR).22 Rarely, choroidal
damage to DNA base-pairs, cell membranes rupture and
neovascularization,53 retinal angiomatous proliferation,54
lysosome disruption.47 This affects the cell’s ability to
intravitreal polypoidal choroidal vasculopathy,55 can
divide, and they undergo senescence and eventually die. occur after radiotherapy. Also, RR can also often coexist
Radiation can also cause indirect damage to cells by with other ocular complications of radiotherapy like radia­
exposing the endothelial cells to high concentrations of tion keratopathy, cataract, and radiation optic
free radicals that result in cell membrane damage.47,48 This neuropathy.56 It is particularly important to distinguish
leads to occlusion of capillary beds and subsequent micro­ RR from another post-radiotherapy complication, known
aneurysm formation. The areas of retinal non-perfusion as “toxic tumor syndrome”, which is characterized by
cause retinal ischemia, which eventually leads to macular exudative retinal detachment and iris rubeosis. While RR
edema, neovascularization, vitreous hemorrhage, and trac­ develops as a result of direct damage of the healthy retina
tional retinal detachment. This could be one of the reasons by the ionizing radiation, toxic tumor syndrome has been
why signs of retinopathy predominate in the macular hypothesized to result from radiation-induced vasculopa­
region, where oxygen concentration is highest. Non- thy within the tumor, which causes exudation from the
replicating cells like photoreceptors are relatively resistant damaged and incompetent tumor vasculature.57
to radiation damage. Patchy degeneration of the RPE in Several factors influence the progression of the disease
the form of loss of melanin, accumulation of lipofuscin, from the non-proliferative to the proliferative stage of the
and hyperplasia, and beading, telangiectasia, microaneur­ disease. Kinyoun et al showed an increased risk of devel­
ysm, sclerosis and closure of choroidal vessels, have also oping proliferative retinopathy in eyes with shorter latency
been described.47,49,50 (less than 24 months) between the administration of

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Figure 1 (A) Non-proliferative stage of radiation retinopathy following external beam radiation therapy for adenocarcinoma of lung with brain metastasis. White arrow
points towards area of choroidal metastasis. Fundus photo (B) of a patient with proliferative stage of radiation retinopathy after radiotherapy for cerebellar metastasis,
showing preretinal hemorrhage (white arrow) over macula, while fundus fluorescein angiography (C) confirmed the presence of a leaking neovascularization of disc (red
asterisk).

treatment and appearance of retinopathy than those with occlusive disorders. Thus, a dilated ophthalmic examina­
a higher period. On the other hand, eyes that have been tion, a careful documentation of history, along with
followed up for 4 years or more have been seen to have a thorough review of the treatment records, is usually
a lesser risk of converting to proliferative retinopathy. The necessary to reach a diagnosis.
authors also suggested that a decreased initial visual acuity RR should be considered as a differential diagnosis
(less than 20/40) was associated with conversion to the after cephalic radiation for head and neck malignancies.
proliferative stage. These baseline factors described indi­ Diabetic retinopathy and RR are closely associated and
cate a more severe ischemic status of the retina with sometimes both may coexist. RPE atrophy and, possibly,
greater stimulus for new vessel formation. Eyes with pro­ unilaterality of the disease are the two features of RR that
liferative retinopathy invariably progress to legal blindness can distinguish it from diabetic retinopathy. There are also
without treatment and even those in the non-proliferative fewer microaneurysms in cases of RR as compared to
stage tend to gradually lose vision over time.22 diabetic retinopathy.58 Other conditions that can closely
mimic radiation retinopathy are retinal vein occlusions,
Differential Diagnosis ocular ischemic syndrome, hypertensive retinopathy,
Clinical features of RR can be difficult to distinguish from Coats’ disease, and parafoveal telangiectasia [12].
other vascular diseases of the retina like diabetic retino­ Apart from meticulous clinical examination and ade­
pathy, hypertensive retinopathy, and other vascular quate history taking, newer multimodal imaging such as

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Figure 2 Clinical picture (A) fundus fluorescein angiography (B) demonstrating severe macular ischemia in a case of radiation retinopathy.

optical coherence tomography (OCT), OCT angiography Other features include the presence of hyper-reflectivity in
(OCTA), fundus fluorescein angiography (FFA), and indo­ the inner retinal layers (suggestive of ischemia), hyperre­
cyanine green angiography (ICGA) are useful in making flective dots corresponding to the intraretinal exudates,
diagnosis and treatment of RR. disorganization of retinal inner layers, or outer retinal
disruption in late stages. Based on the severity of macular
Investigation edema, Horgan et al described a five-point classification
Clinical features of radiation retinopathy can often be scale:34
unremarkable in the early stages of the disease, and it
might be necessary to take the help of adjunctive 1. Grade 1: Extra-foveolar non-cystoid edema.
investigations. 2. Grade 2: Extra-foveolar cystoid edema.
3. Grade 3: Foveolar non-cystoid edema.
Optical Coherence Tomography (OCT) 4. Grade 4: Foveolar cystoid edema-mild to moderate.
One of the earliest manifestations of radiation retinopathy 5. Grade 5: Foveolar cystoid edema-severe.
is macular edema and has been seen in as many as 33% of
eyes with no clinically apparent retinopathy.34,41,59 Thus, Increasing severity of macular edema was also shown to
OCT can be one of the most sensitive modalities for the correlate with the foveal thickness and a decreasing visual
detection of early retinopathy. Macular edema on OCT can acuity.
manifest almost 5 months earlier than clinically detectable
retinopathy, and it has been found as early as 4 months Fundus Fluorescein Angiography
following plaque radiotherapy (peak incidence at 12 The primary lesion responsible for the manifestations of
months with a plateau between 18 and 24 months).34 radiation retinopathy is vascular endothelial damage and
Depending upon the severity of the retinopathy, radia­ thus can lead to variable degrees of vascular occlusion.
tion maculopathy may manifest as cystoid or non-cystoid The vascular obliteration can range from retinal capillary
edema that involves the foveal or extra-foveal macula. obliteration, retinal arterial branch occlusion, or central
A neuro-sensory detachment may or may not be present. retinal artery occlusion.60 Retinal veins, although less

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Figure 3 A 49-year old male presented with decreased vision in his left eye 3 years after treatment with external beam radiotherapy for orbital lymphoma. His visual acuity
at presentation was 20/100. Fundus examination (A) showed few hemorrhages over macula with clinically evident macular edema . Fundus fluorescein angiography (B)
demonstrated multiple microaneurysms and leaking capillaries with enlarged, irregular foveal avascular zone (FAZ) . Optical coherence tomography (OCT) showed center
involving macular edema (C). The patient received multiple anti-VEGF injections. At the end of 12 months follow-up, vision was maintained at 20/125. Fundus examination at
12 months visit showed a few hard exudates and few hemorrhages over macula (D). OCT (E) at this visit showed a chronic refractory macular edema and an increase in
FAZ size could be seen demonstrated on OCT angiography in both superficial (F) and deep capillary (G) slab.

susceptible to damage, have also been reported.61 leakage due to perivascular sheathing, intraretinal exuda­
Capillary non-perfusion areas are one of the most consis­ tion, and retinal or optic disk neovascularization.
tent findings in RR and appear before larger vessels are Amoaku et al used fluorescein angiography to classify
affected.23 The authors suggested that the finding is so changes in radiation retinopathy based on microvascular
common that the diagnosis of radiation retinopathy is changes into four stages:62
difficult to entertain without it. Other changes visible on
angiography include microaneurysms, hypo-fluorescence ● Grade 1: Small foci of dilated and irregular retinal
from retinal hemorrhages, nerve fiber layer infarcts, and capillaries along with isolated or small clusters of

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microaneurysms. Subtle evidence of capillary clo­ Stage 3 included additional macular edema and extra­
sure, without detectable microvascular incompetence macular retinal neovascularization.
or fluid accumulation, can be seen. Vision is usually Stage 4 encompassed vitreous hemorrhage and at least
very good. 5 disc areas of retinal ischemia.
● Grade 2: Multiple foci of dilated and telangiectatic The study showed that macular edema appears early in
capillaries and zones of capillary closure up to one the disease, and in the absence of ischemia, has a good
optic disc area. Usually, numerous microaneurysms prognosis. However, the classification combined the macu­
and focal leakage of dye from defective capillaries in lar and extramacular changes and thus did not gain much
later phase angiograms can be seen. It may be asso­ popularity.
ciated with clinically observable retinal edema.
Visual acuity is relatively good. OCT Angiography
● Grade 3: Characterised by widespread capillary Being a disease primarily of retinal microvasculature,
dilatation, telangiectatic-like channels, microvascu­ OCTA is extremely sensitive in detecting early disease.
Apart from being a non-invasive test, OCTA delineates
lar incompetence, and significant areas of capillary
most of the changes seen on FFA better, and scores above
closure (1–4 disc areas). These eyes can have sig­
FFA in many other aspects. The high definition and the
nificant macular edema with or without cystoid
ability to segment individual layers of the retina allow
macular degenerative changes. Microaneurysms
quantification at the capillary level. Shields et al demon­
and intra-retinal microvascular abnormalities com­
strated enlargement of FAZ and decreased parafoveal
monly occur at the border of perfused and non-
capillary density in both superficial and deep capillary
perfused retina. These eyes usually have poor
plexuses, even in eyes without clinically evident macular
visual acuity.
edema.64,65 These OCTA features have also been shown to
● Grade 4: Characterised by widespread disorganiza­
have a significant impact on visual acuity.40 Skalet et al
tion of the retinal microvasculature with extensive found a reduced peripapillary capillary density compared
inner retinal ischemia, non-perfused retina more to the fellow eye, which correlated inversely with the
than four disc-areas, pre-retinal neovascularisation, radiation dose to the optic nerve and visual acuity.66
rubeosis iridis and vitreous hemorrhage. Visual These changes appear before the appearance of clinically
acuity is usually very poor. apparent retinopathy and have been seen to progress with
the progression of retinopathy.
Based on FFA, macular edema can also be classified
into diffuse, focal, and mixed patterns based on the pattern Treatment
of dye leakage. Over time, an increase in the number of Although spontaneous improvement can occur, it is very
microaneurysms and area of non-perfused retina, despite uncommon.67 There are no specific guidelines for treat­
considerable microaneurysm turnover and attempts at ment and the primary goal in most cases remains visual
revascularisation of ischaemic areas, can be seen.62 stabilization or prevention of vision loss. Due to simila­
Although the changes seen in RR are irreversible, attempts rities in pathogenesis and natural history, treatment of
to recanalize nonperfused capillary beds have occasionally radiation retinopathy follows closely to that of diabetic
been observed.62 retinopathy. The type of retinopathy determines the man­
Post-treatment angiography usually shows some agement protocol.
deformed and collapsed telangiectatic vessels that fail to
perfuse with dye, adjacent to photocoagulation burns. Laser Photocoagulation
Micro aneurysms either decrease in size, disappear or Chaudhuri et al described therapeutic success with the use
become less permeable to dye after treatment.62 of argon laser photocoagulation for proliferative retinopa­
On the basis of clinical and angiographic findings, thy and vitreous hemorrhage and reported angiographic
Finger and Kurli proposed another classification in 2005.63 evidence regression of neovascularisation 2 weeks post-
Stage 1 extramacular ischemic changes, treatment.68 Kinyoun et al published similar results and
Stage 2 macular ischemic changes, and also suggested that fewer spots should be used during

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treatment in order to reduce the degree of field loss and agents was attributed to a combination of multiple factors
consecutive optic atrophy that may be added to radiation- including long-standing macular edema or when direct
related optic atrophy.49 In spite of the regression of neo­ irradiation was received by the fovea.
vascularisation, these eyes usually keep having deteriora­ Therapeutic agents like ranibizumab and aflibercept
tion in vision due to several factors such as radiation optic have been FDA approved for a multitude of retinal dis­
neuropathy, macular ischemia, macular edema, radiation eases. However, there has been no approved anti-VEGF
cataract, vitreous hemorrhage, tractional retinal detach­ for use in radiation maculopathy to date. Finger et al
ment, and neovascular glaucoma. Vitreous hemorrhage showed that ranibizumab is safe, tolerable with as many
often requires vitrectomy with endolaser or cryotherapy. as 80% of eyes having improvement in vision and all eyes
Finger and Kurli also reported the use of laser photocoa­ in the study having a reduction in macular edema.73 Since
gulation to ablate the ischemic zone after radiotherapy.63 then, several retrospective and prospective studies demon­
Their findings suggested that laser photocoagulation of the strating the efficacy of these agents have been
irradiated extramacular zones was effective in preventing published.7,74 Maximum improvement in vision appears
or regressing radiation retinopathy.63 to occur in the initial few months of treatment with
Before the era of anti-VEGF, most of the published a gradual stabilization thereafter. Schefler et al studied
literature recommended focal or grid lasers for the treat­ the efficacy of three different ranibizumab regimens in
ment of macular edema. Several studies have demon­ RR: patients either received monthly injections; monthly
strated its efficacy in the reduction of macular thickness. injection with targeted retinal photocoagulation (TRP); or
Kinyoun et al used argon laser to ablate microaneurysms/ 3 monthly doses followed by PRN injections and TRP.74
leaking vessels and capillary non-perfusion areas and After 52 weeks, all subjects entered the treat-and-extend
demonstrated a reduction in macular thickness and preven­ protocol. The authors demonstrated that ranibizumab
tion of vision loss.49 Similar results were obtained by improves vision and central macular thickness (CMT),
Amaoku and Archer who showed visual improvement and prevents vision loss through 48 weeks. Also, monthly
within 2–3 months of macular laser that was maintained injections were more effective than PRN regimen, and the
at one-year post-treatment.69 Despite the early encoura­ addition of TRP showed no additional benefits.
ging results, it was soon realized that the visual improve­ Similar results were also obtained from few recent
ment post-laser was ill-maintained. Hykin et al showed prospective trials on aflibercept. Fallico et al treated radia­
that although there was a statistically significant improve­ tion-related macular edema with a monthly 2.0 mg intra­
ment in visual acuity at 6 months post laser with reduced vitreal aflibercept followed by PRN through month 24 and
risk of vision loss at 12 months, little benefit was seen by 2 found significant improvement in vision and CMT with an
years, with almost 16% of treated eyes developing halving average number of 4.4 injections.75 Another study by
of visual angle.70 Murray et al compared a fixed treatment regimen of 6
weeks with a treat and adjust regiment centered around 6
Anti-VEGF Agents weeks and found that only 5% of eyes had a BCVA worse
Like diabetic retinopathy, VEGF has been considered as than 20/200 with nearly half of eyes maintaining BCVA
the primary pathogenic stimulus in radiation retinopathy. 20/50 or better.76
Thus, the introduction of anti-VEGF agents has opened
many doors to the treatment of radiation maculopathy. Steroids in RM
Bevacizumab is a full-length humanized monoclonal anti­ Anti-VEGF therapy reduces macular edema by control­
body that binds to all types of VEGF, which acts by ling vascular permeability and the formation of new
inhibiting the formation of abnormal blood vessels, blood vessels via direct inhibition of VEGF.77 However,
thereby decreasing vascular permeability. By the time its it has also been shown to cause upregulation of intrao­
use started in radiation retinopathy, it had already estab­ cular cytokines.78 Steroids, with their anti-cytokine prop­
lished its efficacy in the treatment of several retinal dis­ erties, are thought to act in such situations.79 It also
eases like diabetic retinopathy, retinal vein occlusion, and restores the integrity of the inner retinal barrier by
age-related macular degeneration. Initial reports on the use increasing tight junction protein and upregulates adeno­
of Bevacizumab provided encouraging results in a small sine, which reduces the osmotic swelling of Muller
subset of eyes.71,72 The variable response to anti-VEGF cells.80,81 Initial reports on the use of steroids in RM

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did not yield encouraging results. Horgan et al used safety of intravitreal 2.0 mg aflibercept is also ongoing and
40 mg periocular triamcinolone at plaque application has finished patient enrolment.93 Use of pars plana vitrect­
and again 4 and 8 months later and showed a reduced omy and silicone oil injection at the time of plaque appli­
risk of macular edema.82 However, the intervention did cation has also been tried in few studies to reduce radiation
not benefit the long-term visual outcome with similar damage to the healthy retina, and has been shown to
rates of moderate and severe vision loss compared to decrease the rates of abnormal macula and lower macular
control groups. In another study, Shields et al studied thickness in treated eyes.94
RM secondary to plaque therapy treated with primary The encouraging results from the previous studies favor
IVTA and found that while 91% of patients’ vision sta­ the role of intravitreal anti-VEGF and steroids for the treat­
bilized or improved at 1 month.83 However, this benefit ment of radiation maculopathy, and thus can be considered as
was reduced to 45% at 6 months. Thus, none of these a first-line treatment.95 The results appear to be better if treat­
studies advocated continuous periodic treatment with ment is continued for a longer duration with injection intervals
steroids. Treatment with intravitreal dexamethasone shorter than 90 days. A more intensive treatment regimen,
implant as a primary treatment has also been tried with with the help of combination therapy, may be required in more
satisfactory results.84,85 aggressive forms of the disease. Increasing the dose of the anti-
VEGF agent can be considered as a viable option in cases of
Recalcitrant Edema recalcitrant macular edema. Caution is advised during the use
Despite improvements in vision in these modalities, dis­ of intravitreal or periocular steroids due to the risk of glaucoma
continuation of treatment with anti-VEGF often results in and cataract formation. However, dexamethasone implants, in
recurrence of macular edema and a drop in visual acuity. general, have a lower risk of these complications and have the
Finger et al conducted a prospective trial that showed added benefit of slow release of the drug that can act for up to 6
stabilization of visual acuity in 70% eyes treated with months (resulting in a lesser number of injections).95
2 mg ranibizumab, with 80% of eyes having a significant Nonetheless, studies comparing intravitreal anti-VEGF agents
reduction in the central macular thickness of recalcitrant with steroids have found no difference in efficacy.96 Focal or
RM by 12 months.73 In 2016, Finger et al reported the use grid laser, although rarely performed in the current era, can be
of escalating doses of intravitreal anti-VEGF therapy (bev­ used in selective cases of recalcitrant macular edema.
acizumab, ranibizumab) and showed that it can preserve However, for the treatment of proliferative radiation retino­
vision (for 80% of patients for a mean of 38 months).86,87 pathy, peripheral laser photocoagulation continues to play
Similar therapeutic benefit was later shown in several a vital role.
other studies, suggesting that RM is a progressive disease
requiring increased dosage of the anti-VEGF agent with Prophylaxis
continuous periodic administration in order to preserve Prophylaxis with anti-VEGF agents, steroids or laser, is
vision.73,88 In another study, Kaplan et al showed that the another extensively studied aspect of RM.95 Finger and
use of intravitreal triamcinolone in edema, not responding Kurli reported the use of prophylactic pan-retinal photocoa­
to high-dose bevacizumab, can help preserve vision and gulation and reported that only (19%) of the patients devel­
reduce macular edema.89 This response was different from oped retinopathy at the end of follow-up.97 Reports by Shah
the initial reports on the use of intravitreal steroids in that et al98 and Shields et al99 showed significant benefits in eyes
a higher percentage of patients had stable or improved VA that received intravitreal bevacizumab at the time of plaque
at 6 months. Thus, prior treatment with anti-VEGF agents removal and every 4 months for 2 years. In both studies,
seems to have a better outcome than using IVTA in treat­ treated eyes had less evidence of radiation maculopathy
ment-naive eyes. Isolated case reports on the use of compared to no treatment at each time point. Kim et al also
aflibercept90 and brolucizumab91 in recalcitrant edema demonstrated the beneficial effect of 2 monthly injections of
have also been recently published. Intravitreal dexametha­ ranibizumab on the prevention of retinopathy.7 The RadiRet
sone implant is another effective treatment option, trial demonstrated a similar role in radiation retinopathy,
although Seibel et al demonstrated no difference in VA where the authors suggested similar efficacy of PRP and
or central foveal thickness when comparing it with intra­ ranibizumab in its prevention.100 Thus, treatment with rani­
vitreal bevacizumab and IVTA.92 An open-label, rando­ bizumab every 2 months and bevacizumab every 4 months
mized, prospective study by Schefler et al, studying the after plaque radiotherapy can be administered for the

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prevention of retinopathy and macular edema. Peri-ocular 7. Kim IK, Lane AM, Jain P, Awh C, Gragoudas ES. Ranibizumab
for the prevention of radiation complications in patients treated
steroids as a prophylactic agent have also been studied.95
with proton beam irradiation for choroidal melanoma (an
Patients treated with prophylactic sub-tenon triamcinolone American Ophthalmological Society thesis). Trans Am
acetonide with or without laser photocoagulation have been Ophthalmol Soc. 2016;2:114.
8. Krema H, Somani S, Sahgal A, et al. Stereotactic radiotherapy for
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However, the authors also demonstrated ocular hypertension doi:10.1136/bjo.2008.153429
9. Gragoudas ES, Seddon JM, Egan K, et al. Long-term results of
rates of around 7–15% following treatment.82,101 Thus, it is proton beam irradiated uveal melanomas. Ophthalmology.
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10. Haas A, Pinter O, Papaefthymiou G, et al. Incidence of radiation
treatment for prophylaxis in eyes with glaucoma.
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11. Shields CL, Naseripour M, Cater J, et al. Plaque radiotherapy for
Radiation retinopathy is a potentially blinding condition. large posterior uveal melanomas (≥ 8-mm thick) in 354 consecu­
Unlike patients undergoing treatment with plaque bra­ tive patients. Ophthalmology. 2002;109(10):1838–1849.
doi:10.1016/S0161-6420(02)01181-8
chytherapy, who routinely undergo evaluation by retina 12. Gündüz K, Shields CL, Shields JA, Cater J, Freire JE, Brady LW.
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The material has not been previously presented at any J Ophthalmol. 1991;75(10):629–632. doi:10.1136/bjo.75.10.629
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Funding 16. Max Conway R, Poothullil AM, Daftari IK, Weinberg V,
Chung JE. Estimates of ocular and visual retention following
There is no funding to report.
treatment of extra-large uveal melanomas by proton beam
radiotherapy. Arch Ophthalmol. 2006;124(6):838–843.
Disclosure doi:10.1001/archopht.124.6.838
17. Rudoler SB, Corn BW, Shields CL, et al. External beam irradia­
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