Medications topical and Systemic of Toxicity• 16Retinalchapter
Figure 16.17 Color photograph of right eye of a patient with hepatitis C, receiving interferon therapy. The patient developed multiple cotton-wool spots, though the retinopathy did not progress beyond this stage, and vision remained normal.
CYSTOID MACULAR EDEMA AND RETINAL EDEMA/FOLDS
CYSTOID MACULAR EDEMA
Epinephrine and dipivefrin
The use of epinephrine compounds in glaucoma has decreased with the advent of newer, more efficacious agents. Topical epinephrine can cause macular edema in aphakic eyes, indistinguishable clinically and angiographically from postoperative aphakic CME. In the largest controlled study, 28% of aphakic eyes treated with epinephrine and 13% of untreated aphakic eyes had macular edema, a difference that was statistically significant.127 Most cases of CME resolve with cessation of epinephrine usage. These medications should be avoided in the treatment of the glaucomatous aphakic and pseudophakic eyes.
human and animal studies did not show an association between latanoprost and CME, recent case reports and studies have documented that approximately 2–5% of susceptible patients with glaucoma may develop CME and anterior uveitis, which resolves after discontinuation of the drug. Subsequently, CME has been shown to develop with the use of all the prostaglandin analogues.133,134 The preservative used in the drug formulation may also contribute to macular edema.135 Patients with CME who are taking latanoprost should undergo a trial off the medication before initiating further therapy for the edema. High-risk CME patients, such as those with a history of recent surgery or uveitis, should be managed with other agents.
Retinal edema/folds
Sulfa antibiotics, acetazolamide, ethoxyzolamide, chlorthalidone, hydrochlorothiazide, triamterene, metronidazole
Several medications, most with a structure similar to sulfanilamide (as those listed above), can cause a syndrome of transient acute myopia and anterior-chamber shallowing. This is thought to occur as a result of ciliary body swelling or choroidal effusion, or both, with subsequent forward rotation of the lens-iris diaphragm.136–138 Retinal folds in the macula are seen in young patients with this syndrome (Figure 16.19A), but FA does not reveal retinal leakage. The folds presumably develop as a result of vitreous traction on the macula that is caused by the forward shift of the lens and iris. The syndrome is generally reversible after discontinuation of the offending medication (Figure 16.19B).
Topiramate
Topiramate is a sulfamate-substituted monosaccharide approved for the treatment of seizures as well as prophylaxis against migraine headaches. This medication was first reported to cause acute myopia and retinal striae in 2001.139 Subsequently, over 115 cases of myopia, narrow angles, or retinal striae attributable to topiramate have been reported.140 Signs and symptoms typically occur within 1 month of initiating topiramate therapy, and are usually reversible without any treatment other than discontinuation of the medication. Again, the mechanism is thought to involve ciliochoroidal effusion, forward movement of the lens-iris diaphragm, and vitreous traction on the macula.
Nicotinic acid
High doses of niacin have been used in the past to reduce serum lipid and cholesterol levels; however, better-tolerated 3-hydroxy-3-methyl- glutaryl-coenzyme A (HMG-CoA) reductase inhibitor agents, have largely curtailed its use. At doses greater than 1.5 g/day, a minority of patients will report blurred central vision, sometimes associated with a paracentral scotoma or metamorphopsia.128 FA fails to demonstrate vascular leakage despite the typical clinical appearance of CME (Figure 16.18A, B).129,130 This has led to speculation of a direct toxic effect on Müller cells, resulting in intracellular edema.131 Optical coherence tomography reveals cystoid spaces in the inner nuclear and outer plexiform layers (Figure 16.18C).132 With cessation of treatment, the CME resolves, and vision generally returns to normal. Today, an occasional case patient will be seen who is using self-prescribed high doses of niacin, as part of mega-vitamin therapy. Given the rarity of this condition, only patients who are taking high-dose niacin and who have visual symptoms should be evaluated.
Prostaglandin analogues
Latanoprost, bimatoprost, and travoprost are prostaglandin analogues that are used topically to lower intraocular pressure. Although initial
CRYSTALLINE RETINOPATHY
TAMOXIFEN
Tamoxifen is an antiestrogen agent used in the treatment of advanced breast carcinoma and as adjuvant therapy after surgical resection of early disease; it has also been tested in clinical trials (at higher dosages) for the treatment of glioblastoma multiforme. Retinal toxicity consisting of decreased visual acuity and color vision, with white intraretinal crystalline deposits, macular edema, and punctate retinal pigmentary changes, can occur.141 The intraretinal deposits appear to reside in the inner retina and are most numerous in paramacular areas (Figure 16.20), although peripheral crystals can also be seen. Early reports involved patients who had received high doses (60–100 mg/day, total dosage >100 g) of the drug over a period of 1 year.142 More recent studies have demonstrated that chronic low-dose administration (10–20 mg/ day) with as little as 7.7 g total also can cause ocular toxicity.143–146 Even asymptomatic patients may exhibit intraretinal crystalline formation.147 Visual function and edema improve after discontinuation of the drug, but the refractile deposits remain.
FA demonstrates late focal hyperfluorescence in the macula consistent with CME. Decreased photopic and scotopic a- and b-wave
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C1 C2
Figure 16.18 (A) Color photograph of left eye of a patient taking a megadose of self-prescribed niacin. There is diminution of the foveal reflex and macular thickening on clinical examination. (B) Fluorescein angiography reveals no evidence of macular leakage, though (C) ocular coherence tomography reveals prominent macular edema. The edema resolved following discontinuation of the niacin, and vision returned to normal.
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Figure 16.19 (A) Color photograph of left eye showing subtle retinal folds in a patient recently started on chlorthalidone. Vision had dropped to 20/60 left eye with mild metamorphopsia. (B) Once the condition was recognized, the medication was discontinued, and within 2 weeks, the folds had dissipated, and vision returned to normal.
delivery drug retinal for routes and models Animal • 2 section
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Medications topical and Systemic of Toxicity• 16Retinalchapter
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Figure 16.20 (A) Color photograph of right eye, and (B) left eye of a patient on tamoxifen therapy for treatment of metastatic breast carcinoma. Note the prominent ring of perifoveal crystals, though there was no macular edema, and the vision was normal. Since the patient needed the medication as part of her treatment regimen, she was left on it, and did well without loss of vision.
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Figure 16.21 (A) Color photograph of right eye, and (B) left eye, of a patient ingesting canthaxanthine for sun-tanning purposes. The patient was visually asymptomatic. Since the agent was not being utilized for medicinal purposes, the canthaxanthine was discontinued. The crystals gradually faded away over a several-year timeframe. (Courtesy of Scott R. Sneed, MD, Traverse City, MI.)
amplitude is noted on ERG testing.148 Optical coherence tomography reveals hyperreflective inner retinal deposits and a variable amount of macular thickening and cystic spaces.149
Decreased vision with bilateral optic disc swelling and retinal hemorrhages has been reported in a patient just 3 weeks after commencement of therapy with tamoxifen. These findings resolved completely after the drug was stopped.150 It is unclear whether the findings in this patient were related to the more commonly seen toxic effects. With current low-dose therapy (10–20 mg/day), retinal lesions are rare, and routine examination of asymptomatic patients is not indicated; it is estimated that approximately 2–3% of patients on the recommended therapeutic dose of tamoxifen will develop retinal crystals.151 If a patient taking tamoxifen is noted to have intraretinal crystals, FA should be performed, primarily to rule out juxtafoveal telangiectasis, which can have similar-appearing lesions.152 Asymptomatic patients with retinal crystals may be monitored. Most patients may be continued on the medication, as it is truly needed in the treatment of their metastatic breast adenocarcinoma. However, if there is confirmed evidence of toxicity causing a visual disturbance, then the medication should be stopped.
The mechanism of tamoxifen toxicity may involve formation of drug– lipid complexes, since the tamoxifen molecule has both hydrophobic
and hydrophilic components.153 In a postmortem examination of an eye with tamoxifen toxicity, light microscopy revealed lesions confined to the nerve fiber and inner plexiform layers, which stained positively for glycosaminoglycans. Small (3–10 m) intracellular and large (30–35 m) extracellular lesions were noted on electron microscopy. The lesions appeared to represent products of axonal degeneration.154
CANTHAXANTHINE
Canthaxanthine is a naturally occurring carotenoid. It is used as a foodcoloring agent, for skin pigmentation in the treatment of vitiligo, and for the treatment of photosensitivity disorders such as erythropoietic protoporphyria, psoriasis, and photosensitive eczema. It also has been used over-the-counter in high doses as an oral tanning agent. Many reports have described a characteristic ring-shaped deposition of yel- low-orange crystals in the superficial retina with high doses (usually a total dose greater than 19 g over 2 years) (Figure 16.21).155–157 The crystals appear more prominently in eyes with preexisting retinal disease and with concurrent use of beta-carotene.158
Patients usually are asymptomatic, and FA usually is normal. There have been published reports of both normal and abnormal ERG,
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