Liu, Catherine Y. MD, PhD*; Francis, Jasmine H. MD†; Brodie, Scott E. MD, PhD†,‡; Marr, Brian MD†; Pulido, Jose S. MD§; Marmor, Michael F. MD¶; Abramson, David H. MD†,**
The retina is among the most metabolically active tissues in the body, making it a prime target for unwanted side effects of chemotherapeutic agents. Traditional chemotherapy remains a primary mode of treatment for adult and pediatric cancers, although new, targeted agents are increasingly being used to treat the growing number of cancer patients. In the United States, approximately one of two men and one of three women have a lifetime risk of developing cancer.1
Knowledge of ocular side effects is important to help guide the appropriate treatment plan for each individual. Side effect profiles are key both for early stage disease, where the ability to complete a treatment cycle depends on a patient's ability to tolerate the chemotherapy (or its residual side effects if treatment is successful), and in the metastatic setting, where the quality of life is oftentimes as important for the patient as slowing down disease progression. Treatment plans are therefore tailored to response and to what a patient values most. For example, the overall treatment paradigm for breast cancer is moving away from traditional chemotherapies to newer targeted agents. Tumor markers and individual tolerability are key to the selection of various agents.2 Details of drug toxicity are also guiding treatment protocols. In diffuse large B-cell lymphoma (the most common form of non-Hodgkin lymphoma), adriamycin is a cornerstone of protocols such as rituximab, cyclophosphamide, hydroxydaunorubicin, oncovin, prednisone.3 The overall treatment plan, however, is shaped by the knowledge of its significant cardiotoxic side effects as the lifetime cumulative dose reaches 500 mg/m2.4 Similar knowledge of ocular effects of systemic chemotherapies would be very useful in individualized care, especially with regards to quality of life, although this level of detail is not well documented in the literature.
This review aims to describe documented retinal toxicities associated with currently used chemotherapy and includes the newer targeted agents. Traditional chemotherapies affect all actively dividing cells, including cancer and normal tissue, but some chemotherapies also affect nondividing cells (e.g., alkylating agents). Meanwhile, targeted agents inhibit specific cellular molecules in pathways implicated in cell growth and proliferation (Table 1). Targeted agents include biologics (mostly monoclonal antibodies and immune modulators) and small molecule inhibitors (mostly kinase inhibitors) (Table 1).
We have excluded drugs used specifically for intraocular disease (including notably vascular endothelial growth factor inhibitors delivered intraocularly). We found that while large clinical trials occasionally report ocular adverse events (e.g., blurry vision), the specific cause was usually not reported. We have thus elected to include reports of specific retinal findings only.
The text will outline some major drug classes and their importance, but tables list every category and drug to document currently known retinal effects (Tables 2–4). The serious risks to keep in mind are highlighted (Table 5). Because of the large number of drugs and acronyms, an alphabetical table is also provided of all agents researched (with and without toxicities) (Table 6) and abbreviations (Table 7).
In total, we reviewed 12 biologics, 20 small molecule inhibitors, and 77 traditional chemotherapy agents currently on formulary and approved for use for all general and ocular oncology services at Memorial-Sloan Kettering Cancer Center. Notable drugs currently in clinical trials were also included. Lexicomp and PubMed were used to identify retinal toxicities. We searched case reports and clinical trials using the following terms for each drug: “eye,” “ocular,” “retina,” “macula,” “optical coherence tomography,” “electroretinogram” (ERG), and “toxicity” in the title or abstract. Additional sources were obtained from previous reviews.6–8 In total, 4 biologics, 8 small molecule inhibitors, and 17 chemotherapy agents had reported retinal side effects. Results using this method are summarized in Tables 2–5. Associated complications from case reports may be circumstantial, and the type of study is described for each drug in the tables.
The main drugs with retinal toxicities are interferon alpha 2b, denileukin diftitiox, and the monoclonal antibodies, ipilimumab and trastuzumab (Table 2).
Interferon alpha 2b
This is a recombinant protein widely used in the treatment of inflammatory and infectious diseases, such as hepatitis C. In oncology, it is used in the treatment of lymphoma, multiple myeloma, hairy cell leukemia, and melanoma. Its mechanism of action against these cancers is thought to be immunomodulatory because tumors seem to suppress anticancer immunity.17 Although retinal toxicity is less commonly reported in the literature on cancer usage, interferon alpha 2b is well known to cause significant toxicity in other disease usage. Thus, it has potential danger and patients under treatment need to be monitored. The pathologic findings in cancer patients are consistent with those in hepatitis C patients, suggesting the same mode of toxicity. The main finding in both settings is ischemic retinopathy. In the hepatitis C literature, in which a large number of case reports and case series exist, the incidence of cotton wool spots and intraretinal hemorrhages (some with significant vision loss, most were reversible or mildly symptomatic) with pegylated interferon usage varies from 15% to 86%.18–24 In addition, severe toxicities have been reported, including retinal artery and vein occlusions,25,26 epiretinal membrane development,27 optic disc edema,28 and macular edema.29
In the cancer population, ischemic retinopathy has also been reported with the usage of nonpegylated interferon alpha 2b in doses ranging from 3 to 20 million units per square meter given twice a week to daily.9–11,30 Cotton wool spots and intraretinal hemorrhages have been described in ∼15 cancer cases. All appeared within 6 weeks to 12 months of interferon use and most resolved with cessation of treatment. Similar to severe findings in other usages, central retinal vein occlusion has been reported in 2 cases where high-dose interferon alpha 2b were given to patients who had failed previous alternative treatments.10 Another case reported severe bilateral retinal ischemia in a patient with hypertension and a history of branch retinal vein occlusion who had total body radiation treatment, including of the head.30 These clinical scenarios are not uncommon because many cancer patients undergo multiple treatment modalities causing medical complications that may increase their risk of severe retinal toxicities from interferon usage.
Mechanistically, increased wall shear stress was described in the retinal microcirculation in patients with hepatitis C, suggesting that interferon may induce endothelial dysfunction.31 This is consistent with fluorescein angiography showing poorly perfused areas of retina.30,31 Leukocyte capillary trapping found in rat microcirculation may also explain retinal ischemia.32
This is an immunotoxin composed of diphtheria toxin linked to interleukin-2 and is approved for treating T-cell lymphoma. Several cases of visual loss post-marketing led to an amendment in the Food and Drug Administration–approved product information. A coarse macular pigmentary retinopathy was seen after several cycles of the medication, and it was associated with paracentral scotomas and diminished amplitudes on ERG.12 In two cases, circulating anti-retinal antibodies, including anti-enolase antibodies, were also detected. Although the mechanism of these retinal findings is not fully understood, ∼20% of mice depleted of CD25-positive regulatory T cells developed autoimmune retinitis.33 Fortunately, the incidence of retinopathy is less than 1 in 4,000.13 The mice studies and the presence of anti-retinal antibodies suggest that there might be an autoimmune component to the retinopathy.
This is a cytotoxic T-lymphocyte antigen-4 (CTLA-4)-directed monoclonal antibody that binds to this surface protein, blocks its inhibitory activity, and ultimately potentiates cytotoxic T-cell activation. It has been shown to improve survival in metastatic melanoma versus first-line chemotherapy treatment.34 Rare but severe cases of uveitis and retinal findings have been reported. A case of bilateral choroidal neovascular membrane was reported in a man taking ipilimumab for metastatic melanoma. As an immunologic mechanism has been proposed with choroidal neovascular membrane involvement in wet age-related macular degeneration, it is possible that an immune reaction is also related in this case.14 Uveitis35 and granulomatous panuveitis associated with serous retinal detachment15 have also been described. The latter case developed neurologic and auditory defects associated with Vogt–Koyanagi–Harada syndrome.
The HER-2–targeted monoclonal antibody, trastuzumab, used in breast cancer treatment has been rarely associated with macular edema and ischemic maculopathy, leading to severe bilateral visual loss.16 The mechanism of retinal ischemia is unclear, and although trastuzumab does have potent anti-angiogenic properties, other targeted vascular endothelial growth factor inhibitors delivered systemically do not seem to cause significant retinal toxicity.
Although biologic agents do cause a number of anterior segment side effects,36 there seem to be fewer reports of retinal toxicity in the literature. This may be because of underreporting. Alternatively, it may be related to the ability of the blood–central nervous system barrier to prevent entry of large molecules, such as monoclonal antibodies. For example, the concentration of monoclonal antibodies is 1,000-fold less in the brain compared with the systemic concentration.37 This is in contrast to the retinotoxic agent cisplatin, which has reported central nervous system penetration from 40% to nearly identical to that of plasma concentration.38,39
Small Molecule Inhibitors
The main classes of small molecule inhibitors that cause retinal toxicity are the inhibitors of v-raf murine sarcoma viral oncogene homolog B1, also known as BRAF inhibitors, including vemurafenib and dabrafenib, the mitogen-activated protein kinase/extracellular signal-regulated kinase (MEK) inhibitors currently in clinical trials, and the tyrosine kinase inhibitors, crizotinib and imatinib (Table 3).
Vemurafenib and dabrafenib are potent kinase inhibitors that target a mutated form of the BRAF gene (V600E). BRAF mutations occur in a high percentage of primary and metastatic cutaneous melanoma. The V600E mutation occurs in the majority of BRAF mutations and causes elevated kinase activity, ultimately increasing cellular proliferation and survival. Vemurafenib is a competitive inhibitor of mutant BRAF and has been shown to increase overall survival and progression-free survival in BRAF V600E-positive metastatic melanoma patients.57 Anterior uveitis and intermediate uveitis with cystoid macular edema have been described in a case series of this population of patients (submitted).40 These side effects seem to be reversible. The majority of patients responded to local corticosteroid treatment.
Mitogen-activated protein kinase/extracellular signal-regulated kinase inhibitors
The MEK inhibitors are currently under investigation for their antiproliferative activity against melanoma, non–small cell lung cancer, colorectal cancer, and breast cancer. The MEKs are downstream factors in the mitogen-activated protein kinase pathway, which regulates cell proliferation and differentiation. About 80% of cutaneous melanomas have genetic mutations in this pathway, including mutations in MEK.58 Several inhibitors are currently in development and clinical trials. The second-generation MEK inhibitor, PD0325901, showed response and disease stabilization in Phase I and II trials in metastatic cutaneous melanoma, but significant ocular toxicity occurred, limiting further development.59 Retinal vein occlusion occurred in 3 of 66 patients in a Phase I trial,42 leading to protocol amendments to exclude predisposing factors, including glaucoma. Two additional cases of retinal vein occlusion were reported in Phase I studies of the selective MEK inhibitors, trametinib (GSK1120212) (1/206 patients)45 and MSC1936369 (1/105 patients).41 Dosing was adjusted from continuous to an intermittent schedule in a Phase II study of PD0325901, and although grade I/II visual disturbances, including blurred vision, were seen, no cases of retinal vein occlusion were reported.60 Central serous retinopathy was seen in 3 of 206 patients using trametinib, with symptom resolution after the drug was discontinued45 (Figure 1A for a case of subretinal fluid associated with MEK inhibitor use). Serous retinal detachment was seen in 1 of 105 patients41 taking MSC1936369 and 10 of 52 patients taking the combination RAF/MEK inhibitor RO5126766.44 The latter were all non–dose-limiting toxicities that resolved either spontaneously or with drug cessation. A Phase III trial of trametinib is currently underway, incorporating data on predisposing factors in the exclusion criteria, including history of retinal vein occlusion, central serous retinopathy, evidence of glaucoma, uncontrolled hypertension, and uncontrolled diabetes.61 Mechanistic information on the cause of retinal toxicity would be useful in light of additional MEK inhibitors that are currently under development.
Tyrosine kinase inhibitors
Two tyrosine kinase inhibitors have been shown to adversely affect vision. Crizotinib given at the maximal tolerated dose (250 mg 2 times a day) is associated with a 41% (34 of 82 patients) incidence of light perception abnormalities, described as trailing light behind objects.46 There were no funduscopic changes noted on examination of several of these patients. Similarly, 64% of patients reported mild visual symptoms in a study of safety and tolerability, including photopsia, exaggerated brightness sensation, visual field defect, and vitreous floaters.47
Besides the common side effects of epiphora and periorbital edema, imatinib, a BCR-ABL, c-Kit, and platelet-derived growth factor tyrosine kinase inhibitor used in the treatment of chronic myelogenous lymphoma and gastrointestinal stromal tumors, has been associated with retinal hemorrhages several months into treatment.48–51 Most cases resolved after decreasing51 or stopping50 treatment. These incidents seem to be rare.49 For example, in 1 study of 250 patients with chronic myelogenous lymphoma, 2 developed retinal hemorrhages.48 Central macular edema and optic disc edema have also been rarely reported with continued treatment.52–56 Studies of imatinib introduced by intravitreal injection in rabbits also showed retinal necrosis and retinal edema,62 suggesting that direct exposure can be toxic. A cell culture model showed that imatinib induced retinal ganglion cell apoptosis that coincided with abrogation of platelet-derived growth factor signaling.63 Although this may not necessarily explain the mechanism for retinal hemorrhage and macular edema, it does show that imatinib affects retinal cell growth and survival.
In the following sections, agents are discussed by class (Table 4).
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
Retinoic acid derivative
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
Whereas some retinal side effects are reversible, others can persist. Those agents that raise the greatest concern either because of the severity or frequency of retinal side effects are listed in Table 5. An alphabetized list of drugs and a reference list of abbreviations are included in Table 6 and Table 7 for quick reference.
Knowledge of retinal toxicities from chemotherapeutic agents benefits both the ophthalmologist in managing symptoms and the oncologist in choosing an appropriate regimen to fit a patient's needs. In addition, this knowledge can be helpful in deciding if visual symptoms or vision loss is because of disease or treatment. Continued documentation of ocular side effects will be important in optimizing cancer care, especially as newer biologics and targeted molecules become available.
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 J. 2012; 18:192–202.
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);
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 Res. 2010; 16:1924–1937.
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 Res. 2012; 18:4806–4819.
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 Res. 2010; 16:2450–2457.
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. 1991; 68:15–21.
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. 1984; 54:794–799.
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. 2010; 30:1272–1277.
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. 1994; 14:253–255.
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. 1963; 16:259
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. 1992; 69:2961–2964.
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. 1988; 61:33–35.
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. 2006; 106:505–513.
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. 1989; 43:22–26.
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. 2007; 48:238–240.
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.