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Figure 39-11.  Note white, necrotic appearance and associated hemorrhage of entire optic disc in this example of papillitis secondary to cytomegalovirus.

Figure 39-12.  Kaposi’s sarcoma of the conjunctiva most often occurs in the inferior cul-de-sac. Flat lesions may be easily mistaken for subconjunctival hemorrhage. (Courtesy Drs. Carol and Jerry Shields.)

findings are observed in 20% of patients with visceral disease. Skin lesions are more common than conjunctival lesions. Orbital tumors are rare. Treatment is indicated in patients with cosmetic or functional problems. Local ocular treatment is reserved for lesions that persist following systemic therapy. Conjunctival lesions may be excised, and skin lesions may be treated with cryotherapy (flat lesions) or external beam radiation (nodular lesions).45,46

83.What other periocular malignancies may develop?

Squamous cell carcinoma of the conjunctiva has been reported with increasing frequency in patients with AIDS. The lesions may mimic papillomas or be more characteristic masses with associated leukoplakia. Young patients with conjunctival squamous cell carcinoma should be tested for HIV.47

84.Which medications may be associated with ocular toxicity?

Rifabutin, when used in combination with clarithromycin and fluconazole, has been reported to cause severe hypopyon iritis and, in rare instances, sterile endophthalmitis. Ethambutol may cause optic neuropathy. Side effects of cidofovir include uveitis, hypotony, and nephrotoxicity.48

References

1.Brewerton DA, Hart FD, Nicholls A, et al.: Ankylosing spondylitis and HL-A 27, Lancet 1:904–907, 1973.

2.Tay-Kearney ML, Schwam BL, Lowder C, et al.: Clinical features and associated systemic diseases of HLA-B27 uveitis, Am J Ophthalmol 121:47–56, 1996.

3.Clements DB: Juvenile xanthogranuloma treated with local steroids, Br J Ophthalmol 50:663–665, 1966.

4.Zimmerman LE: Ocular lesions of juvenile xanthogranuloma. Nevoxanthoendothelioma, Trans Am Acad Ophthalmol Otolaryngol 69:412–439, 1965.

5.Grégoire MA, Kodjikian L, Varron L, Grange JD, Broussolle C, Seve P: Characteristics of uveitis presenting for the first time in the elderly: analysis of 91 patients in a tertiary center, Ocul Imunol Inflamm 19:219–226, 2011.

6.Cupp EW, Duke BO, Mackenzie CD, et al.: The effects of long–term community level treatment with ivermectin (Mectizan) on adult Onchocerca volvulus in Latin America, Am J Trop Med Hyg 71:602–607, 2004.

7.Raja SC, Jabs DA, Dunn JP, et al.: Pars planitis: clinical features and class II HLA associations, Ophthalmology 106:594–599, 1999.

8.Zein G, Berta A, Foster CS: Multiple sclerosis-associated uveitis, Ocul Immunol Inflamm 12:137–142, 2004.

9.Smith JR, Cunningham Jr ET: Atypical presentations of ocular toxoplasmosis, Curr Opin Ophthalmol 13:387–392, 2002.

10.Weiss MJ, Velazquez N, Hofeldt AJ: Serologic tests in the diagnosis of presumed toxoplasmic retinochoroiditis, Am J Ophthalmol 109:407–411, 1990.

1.Describe the clinical features of chloroquine retinopathy.

Patients are usually asymptomatic but some may experience difficulties with reading due to paracentral scotomas or metamorphopsia. Because the initial retinal changes are in the parafoveal area, the visual acuity is typically normal in the early stages of retinopathy. Nyctalopia, color vision defects, and blurred vision occur when the retinal epithelial atrophy extends to involve the fovea. In the early stages of toxicity, mild mottling of the perifoveal retinal pigment epithelium is seen in conjunction with a reduced foveal reflex. Peripheral pigmentary changes often occur at this stage but may be overlooked. Macular pigmentary changes progress to a classic bull’s eye maculopathy (Fig. 40-1). In the later stages, generalized retinal pigmentary changes occur with vascular attenuation and optic disc pallor.

2.What doses of chloroquine and hydroxychloroquine cause retinopathy?

Retinopathy is unlikely with a daily dose of <4 mg/kg/day chloroquine (CQ) or <6.5 mg/kg/day hydroxychloroquine (HCQ). A daily dose of >8 mg/kg/day hydroxychloroquine produces retinopathy in 40% of cases. Retinopathy is extremely unlikely with a total dose <100 g of chloroquine or <300 g of hydroxychloroquine and rare with total doses of <300 and <700 g, respectively.

3.What are the risk factors for chloroquine and hydroxychloroquine retinopathy?

The cumulative dose is believed to be the most important risk factor. A cumulative dose of 1000 g of HCQ is reached in 7 years with a typical daily dose of 400 mg, and a cumulative dose of 460 g of CQ is reached in 5 years with a typical daily dose of 250 mg. With daily doses of >6.5 mg/kg for HCQ and >3.0 mg/kg for CQ accumulation of the drug may enhance the rate or degree of toxic retinopathy. CQ and HCQ are excreted by the kidney and liver. Therefore, hepatic and renal failure/disease are risk factors, because they may contribute to increased blood levels of the drug. Other risk factors are age, genetic factors, and preexisting macular disease.

4.How should patients taking chloroquine and hydroxychloroquine be monitored?

All patients starting CQ or HCQ therapy should have a baseline examination within the first year of the treatment. The baseline examination should include careful biomicroscopy, automated threshold visual-field testing with a white 10-2 protocol for the detection of paracentral scotomas, and one or more further subjective tests for screening: spectral domain optical coherence tomography (SDOCT) showing disorganization or loss of the ellipsoid layer in the parafoveal region of the macula

is an early objective sign. Similarly, the multifocal electroretinogram (mfERG) is more sensitive in documenting localized paracentral functional loss compared to the white 10-2 visual field. Fundus autofluorescence (FAF) imaging may reveal paracentral foci of hyperfluorescence due to accumulation of outer segment debris within the retinal pigment epithelium (RPE) and hypofluorescent areas in the later stages due to RPE loss. Baseline color fundus photography may be useful for documentation. Annual screening should be performed after 5 years of treatment with CQ and HCQ as described above.

5.What management is advised for chloroquine retinopathy?

If retinal toxicity is present, hydroxychloroquine or chloroquine should be stopped immediately. There is a stage of very early functional loss when the cessation of the drug will reverse the toxicity, but progression typically continues although it is not clear if it is related to low excretion of the drug or to gradual decompensation of cells that were damaged during the period of drug exposure. If suggestive findings/visual symptoms occur, subjective tests should be repeated (automated fields, mfERG, SD-OCT, FAF). If toxicity is suspected, cessation of the CQ and HCQ followed by 3- to 6-monthly review is advised. Patients with probable toxicity (bilateral bull’s eye scotoma, bilateral paracentral mfERG, SD-OCT/FAF abnormalities) should be closely monitored every 3 months.

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A

B

C

Figure 40-1.  Bull’s eye lesion due to chloroquine retinopathy: color photograph (A), autofluorescence image (B), magnified photograph of macula with associated spectral domain optical coherence tomography (C).

6.Is the pathogenesis of chloroquine and hydroxychloroquine retinopathy understood?

The earliest histopathologic changes of chloroquine retinopathy include membranous cytoplasmic bodies in ganglion cells and degenerative changes in the outer segments of the photoreceptors. However, chloroquine has a selective affinity for melanin, and it has been suggested that this affinity reduces the ability of melanin to combine with free radicals and protect visual cells from light and radiation toxicity. Other authors believe that the drug may directly damage photoreceptors.

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Figure 40-2.  Thioridazine retinopathy.

7.How may thioridazine affect the retina?

Thioridazine (Mellaril) may cause nyctalopia, dyschromatopsia, and blurred vision. The earliest retinal changes are a fine mottling or granularity to the retinal pigment epithelium posterior to the equator, which may progress to marked pigmentary atrophy and hypertrophic pigment plaques (Fig. 40-2). Vascular attenuation and optic atrophy may follow. Toxicity is said to be uncommon with daily doses <800 mg/day but may develop rapidly with doses over 1200 mg/day. Toxicity is more dependent on total daily dose than on cumulative dose. In perimetry, a nonspecific but most characteristic finding is a paracentral or ring scotoma. Fluorescein angiography reveals the loss of RPE and choriocapillaris within the areas of depigmentation.

8.What other phenothiazines cause retinopathy?

Retinal toxicity has been reported with other phenothiazines, including chlorpromazine. However, these compounds are less likely to cause retinopathy, probably because they lack the piperidinylethyl side group of thioridazine. It is thought that 1200 to 2400 g/day chlorpromazine for at least 12 months is required before toxicity occurs.

9.How may quinine sulfate cause retinopathy?

Quinine sulfate is used for nocturnal cramps and as a malarial prophylaxis. It may cause retinal toxicity after a single large ingestion (4 g). The therapeutic window is narrow, with some patients taking a daily dose of 2 g. Patients develop blurred vision, nyctalopia, nausea, tinnitus, dysacusis, and even coma within 2 to 4 hours of ingestion. The acute findings include dilated pupils, loss of retinal transparency caused by ganglion cell toxicity (Fig. 40-3), and dilated retinal vessels. As the acute phase resolves, vessel attenuation and optic disc pallor result. Visual acuity may improve after the acute phase.

10.What are the similarities and differences in electrophysiologic tests between chloroquine and phenothiazine retinopathy?

The ERG in chloroquine toxicity may show an enlarged a wave and depressed b wave, whereas it is generally depressed in phenothiazine toxicity. The electro-oculogram (EOG) is decreased in both, but only progressive disease is significant in chloroquine retinopathy because some decrease is common shortly after starting chloroquine therapy. Dark adaptation may remain normal in chloroquine toxicity even in late cases, whereas it is typically delayed in phenothiazine toxicity.

11.What are the retinal toxic effects of sildenafil (Viagra)?

Sildenafil is an effective drug for erectile dysfunction, acting to inhibit phosphodiesterase type 5 (PDE-5) isoenzyme. It can also inhibit PDE-6 isoenzyme, an important enzyme in the retinal

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Figure 40-3.  Mild loss of retinal transparency caused by quinine sulfate toxicity.

phototransduction cascade, and can cause reversible reduced amplitude of the a and b waves in an ERG. Overall 3 to 11% of patients may experience transient visual changes such as tinting of vision or photosensitivity lasting minutes to hours after the ingestion of the drug. Serious and permanent side effects have been described, including retinal hemorrhages, branch retinal vein and artery occlusion, anterior ischemic optic neuropathy, and acceleration of proliferative diabetic retinopathy.

12.How does cocaine abuse affect the retina?

Cocaine has both dopaminergic and adrenomimetic effects. Dopamine is found in high concentrations in the retina and plays an important role in color vision. Cocaine-withdrawn patients have significantly reduced blue cone b-wave amplitude responses on the electroretinogram and blue–yellow color vision defects. The adrenomimetic response and sudden increase in blood pressure associated with the intranasal use of cocaine may also cause retinal arterial occlusions.

13.What is vigabatrin retinotoxicity?

Vigabatrin (VGB) is an irreversible inhibitor of γ-aminobutyric acid transaminase and is a highly effective antiepileptic drug for treating partial-onset seizures and infantile spasms. It causes a characteristic form of peripheral retinal atrophy and nasal or “inverse” optic disc atrophy in approximately 10% of children being treated with VGB, resulting in severely constricted visual fields. Discontinuation of VGB should be strongly considered in these children.

14.How does fetal alcohol syndrome affect the retina?

Alcohol-induced malformations include hypoplastic optic discs and tortuous retinal vessels.

15.What is unusual about cystoid macular edema caused by nicotinic acid?

Nicotinic acid is used to reduce serum lipid and cholesterol levels for the treatment of hyperlipidemia. In doses of >1.5 g/day patients will report blurred vision sometimes associated with paracentral scotoma or metamorphopsia. Although typical cystoid macular edema is seen clinically, fluorescein angiography shows no leakage, suggesting that the edema is caused by a toxic effect on Müller cells resulting in intracellular edema. The incidence is low (0.67%) and dose related. The cystoid macular edema is reversible.

16.Name the substances that may cause crystalline retinopathy.

•Tamoxifen

•Canthaxanthin

•Talc (often used with intravenous drug abuse) (Fig. 40-4)

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A

B

Figure 40-4.  Talc retinopathy showing fine perifoveal talc particles (A) and extensive resultant posterior pole retinal vascular closure on fluorescein angiography (B).

•Drugs that cause secondary oxalosis

•Methoxyflurane anesthesia

•Ethylene glycol

•Salicylate ingestion in the presence of renal failure

17.What is the mechanism of the retinopathy caused by talc?

Talc is used as filler in methylphenidate hydrochloride (Ritalin) pills that drug addicts may crush and inject intravenously. Initially, the talc particles embolize the lungs, but after prolonged abuse

(=12,000 pills), pulmonary arteriovenous shunts allow talc into the systemic circulation. Emboli to the retinal arterioles may lead to marked peripheral and posterior closure, resulting in retinal neovascularization, vitreous hemorrhage, and ischemic maculopathy.

18.How should talc retinopathy be managed?

Immediate cessation of Ritalin abuse is essential. If retinal neovascularization and vitreous hemorrhage are present, peripheral panretinal photocoagulation should be considered. There is no effective treatment for ischemic maculopathy.

19.What is xanthopsia? Which drug may cause it?

Xanthopsia is the unusual symptom of yellow vision. Along with hemeralopia (reduced visual acuity in the presence of increased background illumination), blurred vision, poor color vision, and paracentral scotomas, it is caused by digitalis toxicity.

20.What are the clinical features of tamoxifen retinopathy? How much drug is necessary to cause symptoms?

Patients are typically asymptomatic, although significantly reduced visual acuity has been reported in a subset of cases. Irreversible dot-like or refractile crystals are seen deposited in the inner retina and located predominately in the paramacular region and often associated with macular edema. The cumulative dose of tamoxifen seems to be important, with retinal deposits occurring more frequently after a 100-g lifetime dose. The overall prevalence is 1 to 6%.

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Figure 40-5.  Tacrolimus-associated retinopathy.

No consistent ERG changes are seen. SD-OCT may prove to be a sensitive diagnostic tool in the future and may identify cases with macular hole, the risk of which appears to be increased in patients taking tamoxifen. Patients with documented visual loss or macular edema should

discontinue the drug. Although vision may recover and macular edema resolve after cessation of tamoxifen, the retinal deposits will persist.

21.Can intraocular injection of antibiotics cause retinopathy?

Inadvertent intraocular injection of gentamicin may result in rapid onset of retinal whitening in the macular area, superficial and intraretinal hemorrhages, retinal edema cotton-wool spots, arteriolar narrowing, and venous beading. Optic atrophy and retinal pigment epithelial changes develop later. The visual prognosis is poor and neovascular glaucoma may develop. Fluorescein

angiography will reveal severe vascular nonperfusion in the acute stages. Macular infarction has been reported after intravitreal injection of 400 μg. Similar problems may occur with tobramycin and amikacin.

22.What is interferon retinopathy?

Interferon-associated retinopathy is dose related and occurs in healthy patients 12% of the time. Sixty-five percent of diabetic patients and 50% of hypertensive patients taking interferon may develop retinopathy or have exacerbated current retinopathy. Ischemic retinopathy includes cotton-wool spots, retinal hemorrhages, cystoid macular edema, vascular occlusions, epiretinal membrane development, and optic disc edema. The mechanism may include immune complex deposition in the retinal vasculature and activated complement C5a followed by leukocyte infiltration and vascular closure. The EOG may become abnormal in early toxicity. Fluorescein angiography demonstrates poorly perfused areas of retina.

23.What is tacrolimus-associated retinopathy?

Tacrolimus is an effective immunosuppressive agent that inhibits cytokine synthesis and blocks T-cell development. Bilateral optic neuropathy and ischemic maculopathy were reported in patients after the use of tacrolimus. Rarely, tacrolimus toxicity may manifest as cotton-wool spots and superficial hemorrhages (Fig. 40-5). A direct neurotoxic effect on the RPE, cones, or rods has been hypothesized. The presentation is a gradual onset of bilateral blurred vision associated with nonspecific findings on OCT and fluorescein angiography but with a central scotoma on 10-2 threshold visual-field testing. Multifocal ERG has demonstrated foveal suppression in both eyes.

24.What effects may iron overload have on the retina?

A retained iron intraocular foreign body may lead to darkening of the iris, orange deposits in the anterior subcapsular region of the lens, anterior and posterior vitritis, pigmentary retinopathy, and progressive loss of visual field. The intraocular foreign body should be removed as soon as possible.

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Figure 40-6.  SD-OCT of poppers maculopathy.

25.What drugs can cause retinal thromboembolic events?

Oral contraceptives have been associated with central, branch, and cilioretinal artery occlusions and central retinal vein occlusion. Considerable controversy surrounds the role of oral contraceptives in causing these events, but stopping the oral contraceptive seems advisable. Talc retinal emboli are discussed in questions 17 and 18. Periorbital steroid injection with inadvertent arterial penetration may result in extensive embolization of the retinal circulation.

26.What chelating agents may cause maculopathy?

The chelating agents deferoxamine and deferasirox are used routinely for iron overload, particularly in thalassemia major. Deferoxamine is a siderophore that has been commercially available for over 30 years and may cause blurred vision, nyctalopia, and ring scotoma. The fundus may show bilateral widespread retinal pigment derangement. Deferasirox is a highly protein-bound synthetic chelator that became available in 2005. Preclinical and clinical trials of deferasirox reported it is well tolerated and does not cause toxic retinopathy, although one possible deferasirox-related retinopathy has been reported.

27.What is poppers maculopathy?

Poppers are a recreational substance of abuse belonging to the alkyl nitrite family of compounds. In the United Kingdom, the most commonly used compound is isopropyl nitrite, which can be purchased legally, but is illegal to sell for human consumption. The exact mechanism of central photorecep-

tor damage is unknown. The patient presents with the symptoms of a central scotoma, distortion of vision, and phosphenes. Clinical signs range from a normal foveal appearance to yellow, dome-shaped lesions at the fovea. Disruption or loss of the presumed ellipsoid layer on SD-OCT is the characteristic feature (Fig. 40-6).

28.Which cancer therapy drugs can cause toxic retinopathies?

The retina is among the most metabolically active tissues in the body, making it vulnerable to unwanted side effects of chemotherapeutic agents. Biologic agents, small-molecule inhibitors, and chemotherapies can all cause toxic retinopathies. Clinical findings noted with monoclonal antibodies include choroidal neovascularization (Ipilimumab) and macular edema, hemorrhages, and hard exudates (Trastuzamab). Chemotherapies such as cisplatin may cause retinal/macular pigment changes or, rarely, retinal ischemia, neovascularization, intraretinal hemorrhages, and exudates. Retinoid acid derivatives such as isotretinoin may cause nyctalopia.