Hany EL-DefrawyHany EL-DefrawyMVR fellowMVR fellow

Bristol eye hospitalBristol eye hospital

Medical retina teachingMedical retina teaching

A 68 year old lady presented to BEH in A 68 year old lady presented to BEH in 2011 Complaining watering of both eyes2011 Complaining watering of both eyes

Syringing revealed bilateral NLD Syringing revealed bilateral NLD obstructionobstruction

POH: SCC diagnosed in 2005 involving the POH: SCC diagnosed in 2005 involving the nasal cavity for which she received nasal cavity for which she received cephalic radiation over 5 monthscephalic radiation over 5 months

Anterior segment examination was Anterior segment examination was unremarkableunremarkable

Fundus examination showed retinal Fundus examination showed retinal hemorrhages ,and disc neovascularization.hemorrhages ,and disc neovascularization.

Visual field defect.Visual field defect.

Radiation retinopathyRadiation retinopathy

Radiation retinopathy is characterized by Radiation retinopathy is characterized by delayed onset of slowly progressive delayed onset of slowly progressive occlusive vasculopathy that may lead to occlusive vasculopathy that may lead to capillary non-perfusion, large-vessel capillary non-perfusion, large-vessel occlusion, retinal vascular incompetence, occlusion, retinal vascular incompetence, neovascularization, and other sequelae. neovascularization, and other sequelae. These changes may cause loss of visual These changes may cause loss of visual function. function.

First report of posterior-segment First report of posterior-segment complications following radiation therapy complications following radiation therapy appeared in 1933appeared in 1933

Studies performed on monkeys and rats treated Studies performed on monkeys and rats treated with 15-30 Gy showedwith 15-30 Gy showed

Focal loss of capillary endothelial cells and Focal loss of capillary endothelial cells and pericytes with cotton-wool spots seen clinically. pericytes with cotton-wool spots seen clinically.

large areas of retinal capillary non-perfusion.large areas of retinal capillary non-perfusion. Histopathologic studies showed that the first Histopathologic studies showed that the first

changes involved deep, small retinal vessels. changes involved deep, small retinal vessels. Larger vessels were involved laterLarger vessels were involved later

Occlusion of the choriocapillaris Occlusion of the choriocapillaris Intraretinal neovascularizationIntraretinal neovascularization   Irvine AR, Wood IS. Radiation retinopathy as an experimental model for ischemic Irvine AR, Wood IS. Radiation retinopathy as an experimental model for ischemic

proliferative retinopathy and rubeosis iridis. Am J Ophthalmol 1987; 103:790-797proliferative retinopathy and rubeosis iridis. Am J Ophthalmol 1987; 103:790-797 Archer DB, Amoaku WMK, Gardner TA. Radiation retinopathy: clinical, Archer DB, Amoaku WMK, Gardner TA. Radiation retinopathy: clinical,

histopathological, ultrastructural, and experimental correlations. Eye 1991; 5:239-histopathological, ultrastructural, and experimental correlations. Eye 1991; 5:239-

251.251.  

HistopathologyHistopathology Endothelial cell damage occurs in the arterial circulation Endothelial cell damage occurs in the arterial circulation

as a result of as a result of free radical generationfree radical generation in this high-oxygen in this high-oxygen environment. After an initial wave of cell death, the environment. After an initial wave of cell death, the remaining viable endothelial cells replicate and migrate to remaining viable endothelial cells replicate and migrate to maintain vascular architecture. Later cycles of endothelial maintain vascular architecture. Later cycles of endothelial cell death occur during mitosis as a result of radiation-cell death occur during mitosis as a result of radiation-induced damage to chromosomal DNA. induced damage to chromosomal DNA.

In contradistinction to diabetic retinopathy, in which In contradistinction to diabetic retinopathy, in which pericyte loss predominates, a predilection for pericyte loss predominates, a predilection for endothelial endothelial cell losscell loss was identified in cases with radiation injury was identified in cases with radiation injury

The vascular endothelium becomes discontinuous, The vascular endothelium becomes discontinuous, resulting in intraluminal coagulation and capillary closure resulting in intraluminal coagulation and capillary closure characteristic of radiation retinopathy. characteristic of radiation retinopathy.

  Archer DB, Amoaku WMK, Gardner TA. Radiation retinopathy: clinical, histopathological, Archer DB, Amoaku WMK, Gardner TA. Radiation retinopathy: clinical, histopathological, ultrastructural, and experimental correlations. Eye 1991; 5:239-251. ultrastructural, and experimental correlations. Eye 1991; 5:239-251. 

Archer DB. Doyne lecture: responses of retinal and choroidal vessels to ionizing radiation. Eye Archer DB. Doyne lecture: responses of retinal and choroidal vessels to ionizing radiation. Eye 1993; 7:1-131993; 7:1-13

SequaleSequale Studies in humans have shown loss of ganglion cells Studies in humans have shown loss of ganglion cells

secondary to neovascular glaucoma, cystic changes in the secondary to neovascular glaucoma, cystic changes in the outer plexiform and inner nuclear layers, and thickening of outer plexiform and inner nuclear layers, and thickening of the vessel walls from deposition of fibrillary or hyaline the vessel walls from deposition of fibrillary or hyaline material. There may be myointimal proliferation in larger material. There may be myointimal proliferation in larger vessels.vessels.

There is preferential damage to inner retinal layersThere is preferential damage to inner retinal layers Photoreceptors appear to be relatively resistant to Photoreceptors appear to be relatively resistant to

radiation damage radiation damage Subretinal and choroidal neovascularization (CNV) has Subretinal and choroidal neovascularization (CNV) has

been reported as a rare complication of ocular irradiation been reported as a rare complication of ocular irradiation

Brown GC, Shields JA, Sanborn G et al. Radiation retinopathy. Ophthalmology 1982; 89:1494-Brown GC, Shields JA, Sanborn G et al. Radiation retinopathy. Ophthalmology 1982; 89:1494-1501. 1501. 

Egbert PR, Fajardo LF, Donaldson SS et al. Posterior ocular abnormalities after irradiation for Egbert PR, Fajardo LF, Donaldson SS et al. Posterior ocular abnormalities after irradiation for retinoblastoma: a histopathological study. Br J Ophthalmol 1980; 64:660-665. retinoblastoma: a histopathological study. Br J Ophthalmol 1980; 64:660-665.

Ross HS, Rosenberg S, Friedman AH. Delayed radiation necrosis of the optic nerve. Am J Ross HS, Rosenberg S, Friedman AH. Delayed radiation necrosis of the optic nerve. Am J OphthalmolOphthalmol 1973; 76:683-686. 1973; 76:683-686.

Clinical featuresClinical features Flick, in 1948, described Flick, in 1948, described acute ocular lesionsacute ocular lesions as as

cottonwool spots, intraretinal and preretinal cottonwool spots, intraretinal and preretinal hemorrhages, Roth's spots in survivors of the atomic hemorrhages, Roth's spots in survivors of the atomic blasts at Hiroshima and Nagasaki.blasts at Hiroshima and Nagasaki.

Delayed radiation damageDelayed radiation damage to retinal blood vessels to retinal blood vessels causes vascular incompetence and occlusion. This causes vascular incompetence and occlusion. This include capillary dilation, telangiectasias, include capillary dilation, telangiectasias, microaneurysm formation, and capillary closure, microaneurysm formation, and capillary closure, retinal ischemia ,retinal , disc neovascularization, retinal ischemia ,retinal , disc neovascularization, vitreous hemorrhage, and retinal detachment . vitreous hemorrhage, and retinal detachment .

Exudative phenomenaExudative phenomena resulting from retinal vascular resulting from retinal vascular incompetence may occur with preferential incompetence may occur with preferential involvement of the macula.involvement of the macula.

Flick JJ. Ocular lesions following the atomic bombing of Hiroshima and Nagasaki. Am J Ophthalmol 1948; Flick JJ. Ocular lesions following the atomic bombing of Hiroshima and Nagasaki. Am J Ophthalmol 1948; 31:137-154.31:137-154.

Spaide and collegues reported an Spaide and collegues reported an unusual choroidal unusual choroidal vascular anomalyvascular anomaly in patients receiving external beam in patients receiving external beam radiation to treat subfoveal CNV secondary to age-radiation to treat subfoveal CNV secondary to age-related macular degeneration. In this retrospective related macular degeneration. In this retrospective analysis, 193 patients were evaluated: these patients analysis, 193 patients were evaluated: these patients underwent treatment with either 10 to 12 Gy or 20 Gy underwent treatment with either 10 to 12 Gy or 20 Gy external beam photons. Nineteen patients (9.8%) external beam photons. Nineteen patients (9.8%) developed round to oval vascular blebs along the developed round to oval vascular blebs along the periphery of the CNV that showed marked leakage of periphery of the CNV that showed marked leakage of fluorecein dye on angiography. These lesions, termed fluorecein dye on angiography. These lesions, termed radiation-induced choroidal neovasculopathy, were radiation-induced choroidal neovasculopathy, were best imaged using best imaged using indocyanineindocyanine green green  angiography.  angiography. Patients who developed this finding tended to have a Patients who developed this finding tended to have a poor visual prognosis. poor visual prognosis.

Spaide RF, Leys A, Herrmann-Delemazure B et al. Radiation-associated choroidal Spaide RF, Leys A, Herrmann-Delemazure B et al. Radiation-associated choroidal neovasculopathy. Ophthalmology 1999; 106:2254-2260. neovasculopathy. Ophthalmology 1999; 106:2254-2260.

External beam radiation vs External beam radiation vs BrachytherapyBrachytherapy

In the 1982 report by Brown and colleagues involving In the 1982 report by Brown and colleagues involving 36 eyes36 eyes with radiation with radiation retinopathyretinopathy

2020 patientspatients had received had received radioactive cobalt plaques (brachytherapy)radioactive cobalt plaques (brachytherapy) for the for the treatment of intraocular tumors. Eighty-five percent of these patients treatment of intraocular tumors. Eighty-five percent of these patients developed hard exudates, 75% showed microaneurysm formation, 65% had developed hard exudates, 75% showed microaneurysm formation, 65% had intraretinal hemorrhages, 35% had retinal vascular telangiectasia, 30% had intraretinal hemorrhages, 35% had retinal vascular telangiectasia, 30% had cottonwool spots, and 20% showed vascular sheathing. cottonwool spots, and 20% showed vascular sheathing.

The The 16 patients16 patients who received who received external beam irradiation (teletherapy)external beam irradiation (teletherapy) showed hard exudates in 38% of cases, microaneurysms in 81%, and showed hard exudates in 38% of cases, microaneurysms in 81%, and intraretinal hemorrhage in 88%. Retinal vascular telangiectasia and intraretinal hemorrhage in 88%. Retinal vascular telangiectasia and cottonwool spots were seen in 38% of these patients, and vascular sheathing cottonwool spots were seen in 38% of these patients, and vascular sheathing was apparent in 25% of cases.was apparent in 25% of cases.

Brown and co-workers postulate that the increased frequency of hard Brown and co-workers postulate that the increased frequency of hard exudate formation in patients treated with brachytherapy rather than exudate formation in patients treated with brachytherapy rather than teletherapy may have been connected with vascular leakage related to the teletherapy may have been connected with vascular leakage related to the intraocular neoplasm, and not simply the radiation therapy alone intraocular neoplasm, and not simply the radiation therapy alone

One of the 20 plaque-treated patients developed posterior-segment One of the 20 plaque-treated patients developed posterior-segment neovascularization, as compared with seven of 16 patients treated with neovascularization, as compared with seven of 16 patients treated with external beam radiation. Four of the 16 patients subsequently developed external beam radiation. Four of the 16 patients subsequently developed neovascular glaucoma. neovascular glaucoma.

Neovascularization is more frequent in patients who are treated with Neovascularization is more frequent in patients who are treated with external beam radiationexternal beam radiation, as the entire retinal area receives the dose as , as the entire retinal area receives the dose as opposed to a localized area following radioactive plaque therapy opposed to a localized area following radioactive plaque therapy

INCIDENCE AND INCIDENCE AND DOSIMETRYDOSIMETRY

It is generally accepted that the incidence of radiation It is generally accepted that the incidence of radiation retinopathy depends on both the retinopathy depends on both the total radiation dosetotal radiation dose and and fraction sizefraction size. .

Using both retrospective and prospective data, authors Using both retrospective and prospective data, authors analyzed 68 eyes of 64 patients receiving teletherapy for analyzed 68 eyes of 64 patients receiving teletherapy for extracranial tumors.extracranial tumors.

Doses in the Doses in the 45 to 55 Gy range45 to 55 Gy range delivered to half or more of the delivered to half or more of the retina produced a 53% rate of retinopathy, with the risk retina produced a 53% rate of retinopathy, with the risk increased by diabetes, chemotherapy, and high dose per increased by diabetes, chemotherapy, and high dose per fraction. fraction.

In a study of 64 patients receiving In a study of 64 patients receiving iodine-125 brachytherapyiodine-125 brachytherapy for uveal melanoma, a 23.4% incidence of radiation retinopathy for uveal melanoma, a 23.4% incidence of radiation retinopathy and a 18.8% incidence of rubeosis iridis after a mean follow-up and a 18.8% incidence of rubeosis iridis after a mean follow-up of 64.9 months. Radiation doses for the iodine-125 plaque were of 64.9 months. Radiation doses for the iodine-125 plaque were calculated at between calculated at between 80 and 100 Gy80 and 100 Gy

Parsons JT, Bova FJ, Fitzgerald CR et al. Radiation retinopathy after external beam irradiation: analysis Parsons JT, Bova FJ, Fitzgerald CR et al. Radiation retinopathy after external beam irradiation: analysis of time-dose factors. Int J Radiat Oncol Biol Phys 1994; 30:765-773.of time-dose factors. Int J Radiat Oncol Biol Phys 1994; 30:765-773.

  Packer S, Stoller S, Lesser ML et al. Long-term results of iodine 125 irradiation of uveal melanoma. Packer S, Stoller S, Lesser ML et al. Long-term results of iodine 125 irradiation of uveal melanoma. Ophthalmology 1992; 99:767-774. Ophthalmology 1992; 99:767-774.

Differential diagnosisDifferential diagnosis

Diabetic Retinopathy. Diabetic Retinopathy. Multiple-branch retinal artery Multiple-branch retinal artery

obstructionsobstructions Multiple episodes of venous Multiple episodes of venous

occlusive diseaseocclusive disease Retinal telangiectasia from other Retinal telangiectasia from other

causes causes

DiagnosisDiagnosis Questioning the patient and determining if there Questioning the patient and determining if there

has been radiation therapy in the past. has been radiation therapy in the past. A review of the treatment records will permit the A review of the treatment records will permit the

ophthalmologist to determine whether the eyes ophthalmologist to determine whether the eyes were included in the field of radiation. were included in the field of radiation.

Diagnosis of radiation retinopathy should be Diagnosis of radiation retinopathy should be considered following cephalic radiation for any considered following cephalic radiation for any reason. reason.

Radiation retinopathy has been reported after Radiation retinopathy has been reported after orbital treatment for thyroid disease and for orbital orbital treatment for thyroid disease and for orbital pseudotumor, as well as after intracranial radiation pseudotumor, as well as after intracranial radiation therapy for both primary and metastatic central therapy for both primary and metastatic central nervous system tumors, paranasal sinus radiation nervous system tumors, paranasal sinus radiation therapy and can occur after radiation therapy for therapy and can occur after radiation therapy for skin tumors of the face and lids skin tumors of the face and lids

TREATMENTTREATMENT Visual loss related to Visual loss related to macular nonperfusionmacular nonperfusion probably cannot be probably cannot be

reversed. However, several groups have applied treatment reversed. However, several groups have applied treatment guidelines of the Early Treatment Diabetic Retinopathy Study guidelines of the Early Treatment Diabetic Retinopathy Study (ETDRS) to eyes with macular edema and (ETDRS) to eyes with macular edema and posterior-segment posterior-segment neovascularizationneovascularization, with favorable results. In one study, 12 eyes , with favorable results. In one study, 12 eyes with clinically significant macular edema secondary to radiation with clinically significant macular edema secondary to radiation were treated with focal and grid photocoagulation; eight of 12 were treated with focal and grid photocoagulation; eight of 12 (67%) eyes showed improvement in macular edema after laser (67%) eyes showed improvement in macular edema after laser therapy, with six (50%) eyes having complete resolution of therapy, with six (50%) eyes having complete resolution of clinically significant edema after a mean follow-up of 39 clinically significant edema after a mean follow-up of 39 months. Vision improved from a median preoperative level of months. Vision improved from a median preoperative level of 20/100 to 20/75 at the time of final examination. Macular 20/100 to 20/75 at the time of final examination. Macular ischemia, cataract, and radiation optic neuropathy were noted ischemia, cataract, and radiation optic neuropathy were noted in all eyes and contributed to vision loss in some cases. in all eyes and contributed to vision loss in some cases.

Kinyoun JL, Chittum ME, Wells CG. Photocoagulation treatment of radiation retinopathy. Am J Ophthalmol Kinyoun JL, Chittum ME, Wells CG. Photocoagulation treatment of radiation retinopathy. Am J Ophthalmol 1988; 105:470-478.1988; 105:470-478.

Kinyoun JL, Zamber RW, Lawrence BS et al. Photocoagulation treatment for clinically significant radiation Kinyoun JL, Zamber RW, Lawrence BS et al. Photocoagulation treatment for clinically significant radiation macular oedema. Br J Ophthalmol 1995; macular oedema. Br J Ophthalmol 1995; 

45. Kinyoun JL, Zamber RW, Lawrence BS et al. Photocoagulation treatment for clinically significant radiation macular oedema. Br J Ophthalmol 1995; 

TREATMENTTREATMENT Hykin and co-workers examined the efficacy of ETDRS-type Hykin and co-workers examined the efficacy of ETDRS-type

treatment for eyes with treatment for eyes with clinically significant radiation clinically significant radiation macular edema (CSRME)macular edema (CSRME) secondary to scleral plaque secondary to scleral plaque radiotherapy for choroidal melanoma. In this retrospective radiotherapy for choroidal melanoma. In this retrospective study, 19 cases treated once with focal laser were compared study, 19 cases treated once with focal laser were compared to a matched group of 23 eyes with CSRME receiving no to a matched group of 23 eyes with CSRME receiving no treatment. Treated eyes showed significant benefit with treatment. Treated eyes showed significant benefit with respect to vision improvement at 6 months, with 8/19 (42%) respect to vision improvement at 6 months, with 8/19 (42%) gaining ≥ 1 Snellen line versus no cases in the untreated gaining ≥ 1 Snellen line versus no cases in the untreated group. A trend was noted in the treated group towards group. A trend was noted in the treated group towards resolution of macular edema at 6 months and towards less resolution of macular edema at 6 months and towards less vision loss at 12 months following focal laser. However, early vision loss at 12 months following focal laser. However, early improvement in vision and edema in the treated group was improvement in vision and edema in the treated group was not sustained not sustained

The authors concluded that a single treatment with focal The authors concluded that a single treatment with focal laser will not result in sustained benefit and that additional laser will not result in sustained benefit and that additional treatments may be indicated for persistent or recurrent treatments may be indicated for persistent or recurrent CSRME. CSRME.

Hykin PG, Shields CL, Shields JA et al. The efficacy of focal laser therapy in radiation-induced macular Hykin PG, Shields CL, Shields JA et al. The efficacy of focal laser therapy in radiation-induced macular edema. Ophthalmology 1998; 105:1425-1429.edema. Ophthalmology 1998; 105:1425-1429.

In an earlier report, Kinyoun et al.described treatment of In an earlier report, Kinyoun et al.described treatment of six eyes with six eyes with high-risk neovascularizationhigh-risk neovascularization by panretinal by panretinal photocoagulation. Three eyes had regression of new photocoagulation. Three eyes had regression of new vessels, with no recurrent vitreous hemorrhages within 19 vessels, with no recurrent vitreous hemorrhages within 19 to 66 months' follow-up. Pars plana vitrectomy was to 66 months' follow-up. Pars plana vitrectomy was performed in three eyes with nonclearing hemorrhages, performed in three eyes with nonclearing hemorrhages, with improvement in vision. Kinyoun et al. later reported a with improvement in vision. Kinyoun et al. later reported a success rate of 91% in 11 eyes treated with panretinal success rate of 91% in 11 eyes treated with panretinal photocoagulation for proliferative radiation retinopathy.photocoagulation for proliferative radiation retinopathy.2222 However, long-term visual outcome in this group was  However, long-term visual outcome in this group was poor, with few eyes retaining vision better than 20/200. poor, with few eyes retaining vision better than 20/200.

Kwok et al analyzed the occurrence of Kwok et al analyzed the occurrence of neovascular neovascular glaucomaglaucoma in a group of 50 eyes undergoing cataract in a group of 50 eyes undergoing cataract surgery after external beam radiation. Panretinal surgery after external beam radiation. Panretinal photocoagulation significantly reduced the incidence of photocoagulation significantly reduced the incidence of neovascular glaucoma after cataract surgery, with 5 of 15 neovascular glaucoma after cataract surgery, with 5 of 15 without laser and 0 of 35 eyes with laser developing without laser and 0 of 35 eyes with laser developing neovascular glaucoma. neovascular glaucoma.

PrognosisPrognosis

Three situations appear to exacerbate Three situations appear to exacerbate radiation retinopathyradiation retinopathy

1.1. Patients who have a pre-existing Patients who have a pre-existing microangiopathy appear to be more microangiopathy appear to be more prone to developing severe changesprone to developing severe changes

2.2. Diabetic patients are more likely to show Diabetic patients are more likely to show changes following lower doses of changes following lower doses of radiation than are non-diabetic patients. radiation than are non-diabetic patients.

3.3. Patients who receive certain Patients who receive certain chemotherapeutic agents. chemotherapeutic agents.

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