The first reports of tamoxifen-associated ocular toxicity appeared in 1978 among women with metastatic breast cancer receiving high-dose tamoxifen (usually >60–100 mg·kg−1·d−1).115 Multiple case reports and series and small cross-sectional and prospective studies have subsequently reported the presence of irreversible refractile or dot-like crystalline retinal deposits, white to yellow in color located predominantly in the paramacular region and often associated with macular edema.112,114,117,118,120,121 Significant vision loss occurred in only a subset of cases, and no consistent ERG changes were seen.119 Although these findings were first reported with high-dose tamoxifen, they were also later reported with low-dose treatment (Table 5). Ultimately, the cumulative dosage of tamoxifen seems to be important, with retinal deposits occurring more often as lifetime dosage approaches 100 g. Thus, the potential retinal toxicity associated with prolonged usage of tamoxifen is important to keep in mind as treatment protocols expand. Although macular edema and reduced acuity may resolve with cessation of tamoxifen, retinal deposits often persist. Several clinical trials involving the use of low daily dosing of tamoxifen (e.g., 20 mg/d, median cumulative dose 8 g123) showed that ocular symptoms in general and retinopathy specifically were uncommon.119,123
Tamoxifen is an amphipathic compound structurally similar to drugs with known retinal side effects, such as chloroquine, chlorpromazine, thioridazine, and tilorone, all of which can cause lamellated or crystalloid deposits in the retina.119 Histologically, crystalline deposits from tamoxifen seem to be intracellular inclusions in the nerve fiber and inner plexiform layers of the retina. Although the mechanism of the toxicity is unclear, axonal degeneration has been suggested.119 Similar crystals may appear in the anterior segment, suggesting that the crystals are composed of the drug itself or derivatives of the drug.
Alkylating agents work by alkylation and cross-linking DNA and RNA, interfering with normal function. This cross-linking may develop in dividing and nondividing cells and may form within a single chromosome or bridge distinct chromosomes. The nitrosourea, carmustine, has been used to treat brain gliomas by direct intra-arterial infusion in an effort to increase local concentration. This method has caused significant retinal toxicity, including central retinal artery occlusion,65 blindness (Phase III clinical trial),71 and retinal vasculitis.65–70,72 In addition, several case reports and case series document retinal artery occlusion and hemorrhages with high-dose systemic therapy.74,75 In a prospective trial with >100 bone marrow transplant patients receiving combination chemotherapy, including high-dose carmustine, a quarter of patients developed cotton wool spots or retinal hemorrhages.73 Several other studies in bone marrow transplant patients show similar findings.70,74
The alkylating platinum agents, cisplatin and to lesser extents carboplatin and oxaliplatin, have been shown to cause toxicity in the retina. Intracarotid infusion of cisplatin has been associated with ipsilateral vision loss in 2 of 40 patients in a clinical trial for malignant gliomas.79 Retinopathy that is vascular in origin has been described. Both retinal vascular occlusion and ischemia have been seen with intracarotid and systemic methods of delivery.65,75,82 Additionally, a granular pigmentary retinopathy with intravenous delivery has been well documented.6,84,85,88,89 A case report of inadvertent overdose revealed ERG changes to the on-pathway of the retina.89 Another showed splitting of the outer plexiform layer in the retina, which may explain ERG changes seen with cisplatin toxicity.127 Higher concentrations of cisplatin have also been associated with altered color vision, which can take months to years to return to baseline.86,87,89,90
Less toxicity has been reported with carboplatin and oxaliplatin. Although no isolated incidence of vasculopathy has been described, a case of severe acute orbital inflammation76 and pain and visual disturbance 30 hours after injection77 was seen with intracarotid infusion of carboplatin. Two cases of pigmentary maculopathy similar to cisplatin have also been described.78 A case of central retinal vein thrombosis was noted in a metastatic colon cancer patient concurrently taking oxaliplatin, capecitabine, and bevacizumab.91
Pyrimidine and purine analogs incorporate into DNA and inhibit DNA synthesis. Cytarabine (cytosine arabinoside) is a pyrimidine analog that is used in the induction phase of bone marrow transplant. Thus, most studies come from this particular population. High-dose cytosine arabinoside with total body irradiation given as induction showed a high incidence of retinal microvascular damage, including capillary nonperfusion, dilatation, neovascularization, vitreous hemorrhage, and macular edema.96 As these changes can be seen with radiation-induced retinopathy, and in light of the low dose of radiation given, it was thought that cytosine arabinoside acted as a radiosensitizer.96 A similar case was seen with low-dose brain radiation with subsequent chemotherapy, including cytosine arabinoside for T-cell acute lymphoblastic leukemia.97
The purine analog, fludarabine, has been associated with rapid vision loss in the setting of bone marrow transplant. Three cases have been reported in the literature, all with poor visual outcome.93 Fundus examination showed punctate yellow flecks in the macula. Loss of retinal bipolar and ganglion cells, gliosis within the retina and optic nerve, and optic nerve atrophy were seen on autopsy.
Outside of the setting of bone marrow transplant, pentostatin, another purine analog, has been associated with retinopathy and retinal detachment in the treatment of hairy T-cell lymphoma, although the exact nature of the retinal findings was not detailed.94,95
The antimetabolite, methotrexate, is widely used to treat inflammatory disorders and malignancies. Despite its extensive usage, only two reports of cotton wool spots have been observed, both with chronic daily use to treat rheumatoid arthritis128 and psoriatic arthritis.129 The latter case was associated with reduced rod and cone responses on ERG that resolved when the treatment was stopped.129 Although no other retinal toxicities have been reported with current standard regimens and modes of delivery (orally, intravenous, intramuscular, or intrathecal), toxicities have been reported in the past with hyperosmotic disruption of the blood–brain/blood–ocular barrier. In an attempt to achieve higher intracranial concentrations of methotrexate and cyclophosphamide to treat intracranial malignancies, mannitol was used to hyperosmotically disrupt the blood–brain barrier.92 In this setting, a case series of 11 patients showed foveal and parafoveal retinal pigmentary changes associated with mild functional vision loss.92 Awareness of this potential side effect may be helpful in future treatment regimen design.
Docetaxel and paclitaxel are antimicrotubular agents used in the treatment of breast and ovarian cancers. Both agents have been reported to cause bilateral cystoid macular edema without evidence of leakage by fluorescein angiography98–100,102,103 (Figure 1B) or with minimal leakage on late frames.101 Optical coherence tomography showed fluid accumulation in cystoid spaces in the outer and inner plexiform layers.100,101,103 Macular edema resolved with discontinuation of the chemotherapy.99,101,102 Acetazolamide has been reported to help in these eyes.98,100
This agent is used as postsurgical adjuvant therapy or as palliation for adrenocortical tumors. Adrenal suppression was first described in dogs, where a precursor drug caused markedly decreased secretion of 17-hydroxycorticosteroids in association with degeneration of the zona reticularis and zona fasciculata without affecting the zona glomerulosa.107 Its derivative, mitotane, is used for treatment in humans. Visual side effects have been occasionally reported. In 2 larger studies, toxic retinopathy with features of optic disc swelling and retinal hemorrhages was seen in several patients (2 of 138 patients and 3 of 19 patients).106,107 Dosage was titrated to the maximum tolerated, usually 8 g to 10 g daily. At these levels, most patients experienced gastrointestinal side effects (mostly nausea and vomiting) and central nervous system symptoms (such as somnolence), which were reversible.107 A pigmentary retinopathy associated with ERG changes was also reported in a patient treated with mitotane concurrently with intra-arterial cisplatin.109
Retinoids are synthetic analogs of vitamin A that inhibit binding of retinol to retinol-binding protein, lowering serum vitamin A.130 The derivative, fenretinide, has been proposed as a treatment for Stargardt disease and age-related macular degeneration. The proposed mechanism is to reduce the accumulation of toxic molecules, such as fluorophore A2E. Another derivative, isotretinoin, is commonly used in the treatment of severe recalcitrant nodular acne. Both have associated retinal toxicities. In oncology, retinoids are used to induce differentiation/maturation of the highly proliferative immature promyelocyte cells in acute promyelocytic leukemia, a subtype of acute myelogenous leukemia. This drug is successful in curing 80% to 95% of cases of acute promyelocytic leukemia.131–133
All-trans retinoic acid, or tretinoin, is the retinoic acid derivative currently used to treat acute promyelocytic leukemia. Two cases of Terson syndrome, suggested by intracranial hypertension with associated swollen optic discs and splinter and flame hemorrhages, have been described.111 Although no direct retinal toxicity has been reported, it must be taken in the context of the retinal toxicities reported with other members of this class. Night blindness134–136 and scotopic ERG changes134−137 occurred with fenretinide in past clinical trials for the treatment of multiple cancers (not currently approved for oncological use). Night blindness with abnormal dark adaptation curves and ERGs consistent with cone and rod dysfunction have also been reported in isotretinoin use for cystic acne.138–140 Awareness of abnormalities in related members of the retinoid derivatives is important as treatment regimens for hematological cancers expand.
Vincristine is a microtubule inhibitor used to treat several hematologic malignancies among others. Retinal side effects are very rare. There has been one case of night blindness following vincristine treatment in a young, previously healthy patient who received 2 cycles of multiagent chemotherapy, including vincristine (along with dacarbazine and bleomycin) for the treatment of malignant melanoma (vincristine-sulfate at dose of 0.032 mg/kg × 5 days per cycle).126 Studies of retinal function were significant for their similarity to recessively inherited stationary night blindness—dark adaptation curve was monophasic without evidence of a scotopic branch, b-wave of ERG was depressed while a-wave remained normal, rhodopsin kinetics were normal, and spectral threshold data showed residual rod-mediated vision.126 The dosage was not particularly high compared with standard treatment regimens. Although there was no evidence of night blindness by history before the start of treatment, it is difficult to tell whether these findings were related to vincristine or progression of disease. Indeed, since this report was published, the paraneoplastic syndrome, melanoma-associated retinopathy, has been recognized and validated in a number of melanoma patients. Melanoma-associated retinopathy produces a clinical picture that mimics stationary night blindness, and this vincristine case may represent melanoma-associated retinopathy rather than drug toxicity. Vincristine has also been associated with a few case reports of optic neuropathy in pediatric patients that resolved with discontinuation of treatment.141–143 Histologic sections from one adult patient showed loss of ganglion cells in the macular region and corresponding optic nerve atrophy.144
The authors thank Kevin Dai and Lira Xing for their suggestions in preparing the manuscript and Charles A. Frueauff Foundation, Rose M. Badgeley Charitable Trust, and Leo Rosner Foundation, Inc, for their support.
3. Fisher RI, Gaynor ER, Dahlberg S, et al.. Comparison of a standard regimen (CHOP) with three intensive chemotherapy
regimens for advanced non-Hodgkin's lymphoma. N Engl J Med 1993;328:1002–1006.
4. Singal PK, Iliskovic N. Doxorubicin-induced cardiomyopathy. N Engl J Med 1998;339:900–905.
5. Gerber DE. Targeted therapies: a new generation of cancer
treatments. Am Fam Physician 2008;77:311–319.
6. Schmid KE, Kornek GV, Scheithauer W, Binder S. Update on ocular complications of systemic cancer chemotherapy
. Surv Ophthalmol 2006;51:19–40.
7. Hazin R, Abuzetun JY, Daoud YJ, Abu-Khalaf MM. Ocular complications of cancer
therapy: a primer for the ophthalmologist treating cancer
patients. Curr Opin Ophthalmol 2009;20:308–317.
8. O AE, O CE. Ocular toxicity of systemic anticancer chemotherapy
. Pharm Pract 2006;4:55–59.
9. Esmaeli B, Koller C, Papadopoulos N, Romaguera J. Interferon-induced retinopathy in asymptomatic cancer
patients. Ophthalmology 2001;108:858–860.
10. Hejny C, Sternberg P, Lawson DH, et al.. Retinopathy associated with high-dose interferon alfa-2b therapy. Am J Ophthalmol 2001;131:782–787.
11. Guyer DR, Tiedeman J, Yannuzzi LA, et al.. Interferon-associated retinopathy. Arch Ophthalmol 1993;111:350–356.
12. Ruddle JB, Harper CA, Honemann D, et al.. A denileukin diftitox (Ontak) associated retinopathy? Br J Ophthalmol 2006;90:1070–1071.
13. Ruddle JB, Prince HM. Denileukin diftitox and vision loss. Leuk Lymphoma 2007;48:655–656.
14. Modjtahedi BS, Maibach H, Park S. Multifocal bilateral choroidal neovascularization in a patient on ipilimumab for metastatic melanoma. Cutan Ocul Toxicol 2013.
15. Wong R, Lee J, Huang J. Bilateral drug (ipilimumab)-induced vitritis, choroiditis, and serous retinal detachments suggestive of Vogt–Koyanagi–Harada syndrome. Retin Cases Brief Rep 2012;6:423–426.
16. Saleh M, Bourcier T, Noel G, et al.. Bilateral macular ischemia and severe visual loss following trastuzumab therapy. Acta Oncol 2011;50:477–478.
17. Davar D, Tarhini AA, Kirkwood JM. Adjuvant therapy for melanoma. Cancer
18. Jain K, Lam WC, Waheeb S, et al.. Retinopathy in chronic hepatitis C patients during interferon treatment with ribavirin. Br J Ophthalmol 2001;85:1171–1173.
19. Malik NN, Sheth HG, Ackerman N, et al.. A prospective study of change in visual function in patients treated with pegylated interferon alpha for hepatitis C in the UK. Br J Ophthalmol 2008;92:256–258.
20. Cuthbertson FM, Davies M, McKibbin M. Is screening for interferon retinopathy in hepatitis C justified? Br J Ophthalmol 2004;88:1518–1520.
21. Kim ET, Kim LH, Lee JI, Chin HS. Retinopathy in hepatitis C patients due to combination therapy with pegylated interferon and ribavirin. Jpn Journal Ophthalmology 2009;53:598–602.
22. Lim JW, Shin MC. Pegylated-interferon-associated retinopathy in chronic hepatitis patients. Ophthalmologica 2010;224:224–229.
23. Hayasaka S, Nagaki Y, Matsumoto M, Sato S. Interferon associated retinopathy. Br J Ophthalmol 1998;82:323–325.
24. Zegans ME, Anninger W, Chapman C, Gordon SR. Ocular manifestations of hepatitis C virus infection. Curr Opin Ophthalmol 2002;13:423–427.
25. Nicolo M, Artioli S, La Mattina GC, et al.. Branch retinal artery occlusion combined with branch retinal vein occlusion in a patient with hepatitis C treated with interferon and ribavirin. Eur J Ophthalmol 2005;15:811–814.
26. Kiratli H, Irkec M. Presumed interferon-associated bilateral macular arterial branch obstruction. Eye (Lond) 2000;14:920–922.
27. Kargi SH, Oz O, Ustundag Y, Firat E. Epiretinal membrane development during interferon treatment. Can J Ophthalmol 2003;38:610–612.
28. Schulman JA, Liang C, Kooragayala LM, King J. Posterior segment complications in patients with hepatitis C treated with interferon and ribavirin. Ophthalmology 2003;110:437–442.
29. Kang HY, Shin MC. Pegylated interferon-associated severe retinopathy in a patient with chronic hepatitis. Korean journal of ophthalmology. Korean J Ophthalmol 2012;26:147–150.
30. Tu KL, Bowyer J, Schofield K, Harding S. Severe interferon associated retinopathy. Br J Ophthalmol 2003;87:247–248.
31. Nagaoka T, Sato E, Takahashi A, et al.. Retinal circulatory changes associated with interferon-induced retinopathy in patients with hepatitis C. Invest Ophthalmol Vis Sci 2007;48:368–375.
32. Nishiwaki H, Ogura Y, Miyamoto K, et al.. Interferon alfa induces leukocyte capillary trapping in rat retinal microcirculation. Arch Ophthalmol 1996;114:726–730.
33. Takeuchi M, Keino H, Kezuka T, et al.. Immune responses to retinal self-antigens in CD25(+)CD4(+) regulatory T-cell-depleted mice. Invest Ophthalmol Vis Sci 2004;45:1879–1886.
34. Lemech C, Arkenau HT. Novel treatments for metastatic cutaneous melanoma and the management of emergent toxicities. Clin Med Insights Oncol 2012;6:53–66.
35. Attia P, Phan GQ, Maker AV, et al.. Autoimmunity correlates with tumor regression in patients with metastatic melanoma treated with anti-cytotoxic T-lymphocyte antigen-4. J Clin Oncol 2005;23:6043–6053.
36. Ho WL, Wong H, Yau T. The ophthalmological complications of targeted agents in cancer
therapy: what do we need to know as ophthalmologists? Acta Ophthalmol 2012.
37. Atwal JK, Chen Y, Chiu C, et al.. A therapeutic antibody targeting BACE1 inhibits amyloid-beta production in vivo. Sci Transl Med 2011;3:84ra43.
38. Khan AB, D'Souza BJ, Wharam MD, et al.. Cisplatin therapy in recurrent childhood brain tumors. Cancer
Treat Rep 1982;66:2013–2020.
39. Diamond SB, Rudolph SH, Lubicz SS, et al.. Cerebral blindness in association with cis-platinum chemotherapy
for advanced carcinoma of the fallopian tube. Obstet Gynecol 1982;59:84S–86S.
40. AR S, E C, P M, et al.. Nongranulomatous Anterior and Intermediate Uveitis secondary to selective BRAF mutation inhibitor treatment for metastatic cutaneous melanoma: a clinical case Series. Submitted 2013.
41. Houede N, Faivre SJ, Awada A. Safety and evidence of activity of MSC1936369, an oral MEK 1/2 inhibitor, in patients with advanced malignancies. J Clin Oncol 2011;29(suppl); abstr 3019.
42. LoRusso PM, Krishnamurthi SS, Rinehart JJ, et al.. Phase I pharmacokinetic and pharmacodynamic study of the oral MAPK/ERK kinase inhibitor PD-0325901 in patients with advanced cancers. Clin Cancer
43. Lorusso PM, Krishnamarthi SS, Rinehard JJ. A phase 1-2 clinical study of a second generation oral MEK inhibitor, PD 0325901, in patients with advanced cancer
. J Clin Oncol 2005;23:3011.
44. Martinez-Garcia M, Banerji U, Albanell J, et al.. First-in-Human, phase I dose-escalation study of the safety, Pharmacokinetics, and Pharmacodynamics of RO5126766, a first-in-Class Dual MEK/RAF inhibitor in patients with Solid tumors. Clin Cancer
45. Infante JR, Fecher LA, Falchook GS, et al.. Safety, pharmacokinetic, pharmacodynamic, and efficacy data for the oral MEK inhibitor trametinib: a phase 1 dose-escalation trial. Lancet Oncol 2012;13:773–781.
46. Kwak EL, Bang YJ, Camidge DR, et al.. Anaplastic lymphoma kinase inhibition in non-small-cell lung cancer
. N Engl J Med 2010;363:1693–1703.
47. Labs P. XALKORI (crizotinib) prescribing information. New York, NY: 2011.
48. Breccia M, Gentilini F, Cannella L, et al.. Ocular side effects
in chronic myeloid leukemia patients treated with imatinib. Leuk Res 2008;32:1022–1025.
49. Fraunfelder FW, Solomon J, Druker BJ, et al.. Ocular side-effects associated with imatinib mesylate (Gleevec). J Ocul Pharmacol The 2003;19:371–375.
50. Christoforidis JB, DeAngelo DJ, D'Amico DJ. Resolution of leukemic retinopathy following treatment with imatinib mesylate for chronic myelogenous leukemia. Am J Ophthalmol 2003;135:398–400.
51. Gulati AP, Saif MW. Retinal neovascularization and hemorrhage associated with the use of imatinib (Gleevec((R))) in a patient being treated for gastrointestinal stromal tumor (GIST). Anticancer Res 2012;32:1375–1377.
52. Masood I, Negi A, Dua HS. Imatinib as a cause of cystoid macular edema following uneventful phacoemulsification surgery. J Cataract Refract Surg 2005;31:2427–2428.
53. Georgalas I, Pavesio C, Ezra E. Bilateral cystoid macular edema in a patient with chronic myeloid leukaemia under treatment with imanitib mesylate: report of an unusual side effect. Graefes Arch Clin Exp Ophthalmol 2007;245:1585–1586.
54. Kusumi E, Arakawa A, Kami M, et al.. Visual disturbance due to retinal edema as a complication of imatinib. Leukemia 2004;18:1138–1139.
55. DeLuca C, Shenouda-Awad N, Haskes C, Wrzesinski S. Imatinib mesylate (Gleevec) induced unilateral optic disc edema. Optom Vis Sci 2012;89:e16–e22.
56. Kwon SI, Lee DH, Kim YJ. Optic disc edema as a possible complication of Imatinib mesylate (Gleevec). Jpn J Ophthalmol 2008;52:331–333.
57. Chapman PB, Hauschild A, Robert C, et al.. Improved survival with vemurafenib in melanoma with BRAF V600E mutation. N Engl J Med 2011;364:2507–2516.
58. Platz A, Egyhazi S, Ringborg U, Hansson J. Human cutaneous melanoma; a review of NRAS and BRAF mutation frequencies in relation to histogenetic subclass and body site. Mol Oncol 2008;1:395–405.
59. Lorusso PM, Adjei AA, Varterasian M, et al.. Phase I and pharmacodynamic study of the oral MEK inhibitor CI-1040 in patients with advanced malignancies. J Clin Oncol 2005;23:5281–5293.
60. Haura EB, Ricart AD, Larson TG, et al.. A phase II study of PD-0325901, an oral MEK inhibitor, in previously treated patients with advanced non-small cell lung cancer
. Clin Cancer
61. NCT01245062 CgI. Accessed August 1, 2013.
62. Kitzmann AS, Baratz KH, Mohney BG, et al.. Histologic studies of the intraocular toxicity of imatinib mesylate in rabbits. Eye (Lond) 2008;22:712–714.
63. Biswas SK, Zhao Y, Sandirasegarane L. Imatinib induces apoptosis by inhibiting PDGF- but not insulin-induced PI 3-kinase/Akt survival signaling in RGC-5 retinal ganglion cells. Mol Vis 2009;15:1599–1610.
64. Sigma-Tau. Matulane ® (procarbazine hydrochloride) capsules prescribing information; 2004.
65. Kupersmith MJ, Frohman LP, Choi IS, et al.. Visual system toxicity following intra-arterial chemotherapy
. Neurology 1988;38:284–289.
66. Greenberg HS, Ensminger WD, Seeger JF, et al.. Intra-arterial BCNU chemotherapy
for the treatment of malignant gliomas of the central nervous system: a preliminary report. Cancer
Treat Rep 1981;65:803–810.
67. Greenberg HS, Ensminger WD, Chandler WF, et al.. Intra-arterial BCNU chemotherapy
for treatment of malignant gliomas of the central nervous system. J Neurosurg 1984;61:423–429.
68. Grimson BS, Mahaley MS Jr, Dubey HD, Dudka L. Ophthalmic and central nervous system complications following intracarotid BCNU (Carmustine). J Clin Neuroophthalmol 1981;1:261–264.
69. Pickrell L, Purvin V. Ischemic optic neuropathy secondary to intracarotid infusion of BCNU. J Clin Neuroophthalmol 1987;7:87–92.
70. Shingleton BJ, Bienfang DC, Albert DM, et al.. Ocular toxicity associated with high-dose carmustine. Arch Ophthalmol 1982;100:1766–1772.
71. Shapiro WR. Chemotherapy
of malignant gliomas: studies of the BTCG. Rev Neurol (Paris) 1992;148:428–434.
72. Bristol-Myers Squibb. BiCNU ® (Carmustine for Injection) Prescribing Information. Princeton, NJ: Bristol-Myers Squibb; 2003.
73. Johnson DW, Cagnoni PJ, Schossau TM, et al.. Optic disc and retinal microvasculopathy after highdose chemotherapy
and autologous hematopoietic progenitor cell support. Bone Marrow Transplant 1999;24:785–792.
74. Khawly JA, Rubin P, Petros W, et al.. Retinopathy and optic neuropathy in bone marrow transplantation for breast cancer
. Ophthalmology 1996;103:87–95.
75. Wang MY, Arnold AC, Vinters HV, Glasgow BJ. Bilateral blindness and lumbosacral myelopathy associated with high-dose carmustine and cisplatin therapy. Am J Ophthalmol 2000;130:367–368.
76. Lauer AK, Wobig JL, Shults WT, et al.. Severe ocular and orbital toxicity after intracarotid etoposide phosphate and carboplatin therapy. Am J Ophthalmol 1999;127:230–233.
77. Watanabe W, Kuwabara R, Nakahara T, et al.. Severe ocular and orbital toxicity after intracarotid injection of carboplatin for recurrent glioblastomas. Graefes Arch Clin Exp Ophthalmol 2002;240:1033–1035.
78. Rankin EM, Pitts JF. Ophthalmic toxicity during carboplatin therapy. Annals of oncology. Ann Oncol 1993;4:337–338.
79. Dropcho EJ, Rosenfeld SS, Vitek J, et al.. Phase II study of intracarotid or selective intracerebral infusion of cisplatin for treatment of recurrent anaplastic gliomas. J Neurooncol 1998;36:191–198.
80. Margo CE, Murtagh FR. Ocular and orbital toxicity after intracarotid cisplatin therapy. Am J Ophthalmol 1993;116:508–509.
81. Wu HM, Lee AG, Lehane DE, et al.. Ocular and orbital complications of intraarterial cisplatin. A case report. J Neuroophthalmol 1997;17:195–198.
82. Rogers LR, Purvis JB, Lederman RJ, et al.. Alternating sequential intracarotid BCNU and cisplatin in recurrent malignant glioma. Cancer
83. Kwan AS, Sahu A, Palexes G. Retinal ischemia with neovascularization in cisplatin related retinal toxicity. Am J Ophthalmol 2006;141:196–197.
84. Kupersmith MJ, Seiple WH, Holopigian K, et al.. Maculopathy caused by intra-arterially administered cisplatin and intravenously administered carmustine. Am J Ophthalmol 1992;113:435–438.
85. Hilliard LM, Berkow RL, Watterson J, et al.. Retinal toxicity associated with cisplatin and etoposide in pediatric patients. Med Pediatr Oncol 1997;28:310–313.
86. Wilding G, Caruso R, Lawrence TS, et al.. Retinal toxicity after high-dose cisplatin therapy. J Clin Oncol 1985;3:1683–1689.
87. Feun LG, Wallace S, Stewart DJ, et al.. Intracarotid infusion of cis-diamminedichloroplatinum in the treatment of recurrent malignant brain tumors. Cancer
88. Miller DF, Bay JW, Lederman RJ, et al.. Ocular and orbital toxicity following intracarotid injection of BCNU (carmustine) and cisplatinum for malignant gliomas. Ophthalmology 1985;92:402–406.
89. Marmor MF. Negative-type electroretinogram from cisplatin toxicity. Doc Ophthalmol 1993;84:237–246.
90. Squibb B-M. Platinol ® -AQ (Cisplatin Injection) Prescribing Information. Princeton, NJ: Bristol-Myers Squibb; 2002.
91. Gilbar P, Sorour N. Retinal vein thrombosis in a patient with metastatic colon cancer
receiving XELOX chemotherapy
combined with bevacizumab pre-hepatic resection. J Oncol Pharm Pract 2012;18:152–154.
92. Millay RH, Klein ML, Shults WT, et al.. Maculopathy associated with combination chemotherapy
and osmotic opening of the blood-brain barrier. Am J Ophthalmol 1986;102:626–632.
93. Bishop RJ, Ding X, Heller CK 3rd, et al.. Rapid vision loss associated with fludarabine administration. Retina
94. Parke Davis. Nipent ® (pentostatin for injection) prescribing information. Morris Plains, NJ: Parke Davis, 1991.
95. Bedford Laboratories. Pentostatin for injection prescribing information. Bedford, OH: Bedford Laboratories; 2006.
96. Vogler WR, Winton EF, Heffner LT, et al.. Ophthalmological and other toxicities related to cytosine arabinoside and total body irradiation as preparative regimen for bone marrow transplantation. Bone Marrow Transplant 1990;6:405–409.
97. Wiznia RA, Rose A, Levy AL. Occlusive microvascular retinopathy with optic disc and retinal neovascularization in acute lymphocytic leukemia. Retina
98. Telander DG, Sarraf D. Cystoid macular edema with docetaxel chemotherapy
and the fluid retention syndrome. Semin Ophthalmol 2007;22:151–153.
99. Teitelbaum BA, Tresley DJ. Cystic maculopathy with normal capillary permeability secondary to docetaxel. Optom Vis Sci 2003;80:277–279.
100. Georgakopoulos CD, Makri OE, Vasilakis P, Exarchou A. Angiographically silent cystoid macular oedema secondary to paclitaxel therapy. Clinical & experimental optometry. Clin Exp Optom 2012;95:233–236.
101. Smith SV, Benz MS, Brown DM. Cystoid macular edema secondary to albumin-bound paclitaxel therapy. Arch Ophthalmol 2008;126:1605–1606.
102. Joshi MM, Garretson BR. Paclitaxel maculopathy. Arch Ophthalmol 2007;125:709–710.
103. Murphy CG, Walsh JB, Hudis CA, et al.. Cystoid macular edema secondary to nab-paclitaxel therapy. J Clin Oncol 2010;28:e684–e687.
104. Risard SM, Pieramici DJ, Rabena MD. Cystoid macular oedema secondary to paclitaxel (Abraxane). Retin Cases Brief Rep 2009;3:383–385.
105. Tan WW, Walsh T. Ocular toxicity secondary to paclitaxel in two lung cancer
patients. Med Pediatr Oncol 1998;31:177.
106. Hoffman DL, Mattox VR. Treatment of adrenocortical carcinoma with o,p'-DDD. Med Clin North Am 1972;56:999–1012.
107. Hutter AM Jr, Kayhoe DE. Adrenal cortical carcinoma. Results of treatment with o,p'DDD in 138 patients. Am J Med 1966;41:581–592.
108. Molnar GD, Mattox VR, Bahn RC. Observations in adrenal cancer
. A report on 7 patients treated with o'pDDD. Cancer
109. Ng WT, Toohey MG, Mulhall L, Mackey DA. Pigmentary retinopathy, macular oedema, and abnormal ERG with mitotane treatment. Br J Ophthalmol 2003;87:500–501.
110. Abu el-Asrar AM, al-Momen AK, Harakati MS. Terson's syndrome in a patient with acute promyelocytic leukemia on all-trans retinoic acid treatment. Doc Ophthalmol 1993;84:373–378.
111. Guirgis MF, Lueder GT. Intracranial hypertension secondary to all-trans retinoic acid treatment for leukemia: diagnosis and management. J AAPOS 2003;7:432–434.
112. Bourla DH, Sarraf D, Schwartz SD. Peripheral retinopathy and maculopathy in high-dose tamoxifen therapy. Am Journal Ophthalmol 2007;144:126–128.
113. Kaiser-Kupfer MI, Kupfer C, Rodrigues MM. Tamoxifen retinopathy. A clinicopathologic report. Ophthalmology 1981;88:89–93.
114. McKeown CA, Swartz M, Blom J, Maggiano JM. Tamoxifen retinopathy. Br J Ophthalmol 1981;65:177–179.
115. Kaiser-Kupfer MI, Lippman ME. Tamoxifen retinopathy. Cancer
Treat Reports 1978;62:315–320.
116. Curtis MG. Comparative tolerability of first-generation selective estrogen receptor modulators in breast cancer
treatment and prevention. Drug Saf 2001;24:1039–1053.
117. Gorin MB, Day R, Costantino JP, et al.. Long-term tamoxifen citrate use and potential ocular toxicity. Am J Ophthalmol 1998;125:493–501.
118. Tang R, Shields J, Schiffman J, et al.. Retinal changes associated with tamoxifen treatment for breast cancer
. Eye (Lond) 1997;11:295–297.
119. Nayfield SG, Gorin MB. Tamoxifen-associated eye disease. A review. J Clin Oncol 1996;14:1018–1026.
120. Pavlidis NA, Petris C, Briassoulis E, et al.. Clear evidence that long-term, low-dose tamoxifen treatment can induce ocular toxicity. A prospective study of 63 patients. Cancer
121. Yanyali AC, Freund KB, Sorenson JA, et al.. Tamoxifen retinopathy in a male patient. Am J Ophthalmol 2001;131:386–387.
122. Ashford AR, Donev I, Tiwari RP, Garrett TJ. Reversible ocular toxicity related to tamoxifen therapy. Cancer
123. Gianni L, Panzini I, Li S, et al.. Ocular toxicity during adjuvant chemoendocrine therapy for early breast cancer
: results from International Breast Cancer
Study Group trials. Cancer
124. Gualino V, Cohen SY, Delyfer MN, et al.. Optical coherence tomography findings in tamoxifen retinopathy. Am J Ophthalmol 2005;140:757–758.
125. Parkkari M, Paakkala AM, Salminen L, et al.. Ocular side-effects in breast cancer
patients treated with tamoxifen and toremifene: a randomized follow-up study. Acta Ophthalmol Scand 2003;81:495–499.
126. Ripps H, Carr RE, Siegel IM, Greenstein VC. Functional abnormalities in vincristine-induced night blindness. Invest Ophthalmol Vis Sci 1984;25:787–794.
127. Katz BJ, Ward JH, Digre KB, et al.. Persistent severe visual and electroretinographic abnormalities after intravenous Cisplatin therapy. J Neuroophthalmol 2003;23:132–135.
128. Klemencic S. Cotton wool spots as an indicator of methotrexate-induced blood dyscrasia. Optometry 2010;81:177–180.
129. Ponjavic V, Granse L, Stigmar EB, Andreasson S. Reduced full-field electroretinogram (ERG) in a patient treated with methotrexate. Acta Ophthalmol Scand 2004;82:96–99.
130. Peng YM, Dalton WS, Alberts DS, et al.. Pharmacokinetics of N-4-hydroxyphenyl-retinamide and the effect of its oral administration on plasma retinol concentrations in cancer
patients. Int J Cancer
131. Rodeghiero F, Avvisati G, Castaman G, et al.. Early deaths and anti-hemorrhagic treatments in acute promyelocytic leukemia. A GIMEMA retrospective study in 268 consecutive patients. Blood 1990;75:2112–2117.
132. Miller WH Jr, Kakizuka A, Frankel SR, et al.. Reverse transcription polymerase chain reaction for the rearranged retinoic acid receptor alpha clarifies diagnosis and detects minimal residual disease in acute promyelocytic leukemia. Proc Natl Acad Sci U S A 1992;89:2694–2698.
133. Burnett AK, Grimwade D, Solomon E, et al.. Presenting white blood cell count and kinetics of molecular remission predict prognosis in acute promyelocytic leukemia treated with all-trans retinoic acid: result of the Randomized MRC Trial. Blood 1999;93:4131–4143.
134. Modiano MR, Dalton WS, Lippman SM, et al.. Phase II study of fenretinide (N-[4-hydroxyphenyl]retinamide) in advanced breast cancer
and melanoma. Invest New Drugs 1990;8:317–319.
135. Kaiser-Kupfer MI, Peck GL, Caruso RC, et al.. Abnormal retinal function associated with fenretinide, a synthetic retinoid. Arch Ophthalmol 1986;104:69–70.
136. Costa A, Malone W, Perloff M, et al.. Tolerability of the synthetic retinoid Fenretinide (HPR). Eur J Cancer
Clin Oncol 1989;25:805–808.
137. Marmor MF, Jain A, Moshfeghi D. Total rod ERG suppression with high dose compassionate Fenretinide usage. Doc Ophthalmol 2008;117:257–261.
138. Weleber RG, Denman ST, Hanifin JM, Cunningham WJ. Abnormal retinal function associated with isotretinoin therapy for acne. Arch Ophthalmol 1986;104:831–837.
139. Denman S, Weleber R, Hanifin JM, et al.. Abnormal night vision and altered dark adaptometry in patients treated with isotretinoin for acne. J Am Acad Dermatol 1986;14:692–693.
140. Brown RD, Grattan CE. Visual toxicity of synthetic retinoids. Br J Ophthalmol 1989;73:286–288.
141. Weisfeld-Adams JD, Dutton GN, Murphy DM. Vincristine sulfate as a possible cause of optic neuropathy. Pediatr Blood Cancer
142. Shurin SB, Rekate HL, Annable W. Optic atrophy induced by vincristine. Pediatrics 1982;70:288–291.
143. Norton SW, Stockman JA III. Unilateral optic neuropathy following vincristine chemotherapy
. J Pediatr Ophthalmol Strabismus 1979;16:190–193.
144. Sanderson PA, Kuwabara T, Cogan DG. Optic neuropathy presumably caused by vincristine therapy. Am J Ophthalmol 1976;81:146–150.