Chapter 143 – Toxic Retinopathies
DAVID V. WEINBERG
• Retinal injury resulting from systemically administered drugs.
• Retinal pigmentary epithelial irregularities.
• Atrophy of the retina, retinal pigment epithelium, and/or choroid.
• Bull’s-eye maculopathy.
• Crystalline deposition.
• Rheumatoid arthritis.
• Collagen vascular diseases.
• Psychiatric illness.
• Acquired immunodeficiency syndrome.
• Breast cancer.
The toxic retinopathies form a diverse group of conditions that result from retinal damage caused by a systemically administered drug. Although they are relatively rare, these conditions should be considered whenever an “unknown” retinopathy is evaluated, particularly when features of macular pigmentary disturbance or retinal crystal deposition are present. Recognition of a toxic retinopathy may spare the patient from future exposure to the noxious agent.
CHLOROQUINE AND HYDROXYCHLOROQUINE
Chloroquine was popularized first for the prophylaxis and treatment of malaria. Later, chloroquine was recognized as an effective treatment for various connective tissue diseases, especially rheumatoid arthritis and systemic lupus erythematosus. Treatment of these diseases required higher doses and longer duration of therapy than employed for malaria. In the late 1950s and early 1960s, descriptions of a toxic retinopathy that resulted from chloroquine use began to appear.    Currently, hydroxychloroquine, a closely related drug, has largely replaced chloroquine for the treatment of connective tissue diseases. Chloroquine and hydroxychloroquine differ in their therapeutic and toxic dose ranges but can produce identical retinopathy.
Patients who have retinopathy may be asymptomatic. When symptoms do occur, the earliest complaints are usually difficulty with reading or with other fine visual tasks because of central or paracentral scotomas.
The earliest scotomas are subtle, usually within 10° of fixation, and are more common superiorly than inferiorly to fixation. With time, the scotomas enlarge, multiply, and may involve fixation, which reduces visual acuity.
The fundus appearance may remain entirely normal even after scotomas have developed. The earliest fundus findings are irregularity in the macular pigmentation and blunting of the foveal reflex.
Figure 143-1 Chloroquine and hydroxychloroquine maculopathy. Note the concentric zone of depigmentation, more prominent inferiorly. (From Weinberg DV, D’Amico DJ. Retinal toxicity of systemic drugs. In: Albert DM, Jakobiec FA, eds. Principles and practice of ophthalmology. Philadelphia: WB Saunders; 1994:1042–50.)
With time, the central irregular pigmentation may become surrounded by a concentric zone of hypopigmentation, usually horizontally oval and more prominent inferiorly to the fovea ( Fig. 143-1 ).  This paracentral depigmentation results in the classical bull’s-eye maculopathy. With continued exposure to the drug, there may be more generalized pigmentary changes. The end-stage appearance may be indistinguishable from that of retinitis pigmentosa, with peripheral pigment irregularity and bone spicule formation, vascular attenuation, and optic disc pallor.
Fluorescein angiography highlights the macular pigmentary changes seen in established chloroquine and hydroxychloroquine maculopathy but rarely enhances the accuracy of the diagnosis. Occasionally, it may be used to help differentiate toxic maculopathy from other macular abnormalities.
The reported incidences of retinopathy with these two drugs vary widely in the literature because of variations in the definition of retinopathy and changes in the dosages used in clinical practices. The incidence of retinopathy has consistently been reported to increase with both the dose and duration of treatment. For chloroquine, daily doses of =250?mg, cumulative doses of <100?g, and duration of treatment of less than a year are associated with a very low incidence of retinopathy. For hydroxychloroquine, a dose of 400?mg/day or less has been associated with low risk of retinopathy.
To avoid toxicity with long-term therapy, the most important factor appears to be the daily dose. If the daily dose is kept below a safe threshold, no limit seems to exist to the duration of dosage or cumulative dose that can be given safely. This threshold dose has been reported as 3.5?mg/kg/day for chloroquine and 6.5?mg/kg/day for hydroxychloroquine. These dosages are based upon lean body weight. Using these criteria, the commonly
Figure 143-2 Thioridazine retinopathy. Large areas of atrophy are seen in advanced retinopathy. (From Weinberg DV, D’Amico DJ. Retinal toxicity of systemic drugs. In: Albert DM, Jakobiec FA, eds. Principles and practice of ophthalmology. Philadelphia: WB Saunders; 1994:1042–50.)
Figure 143-3 Thioridazine retinopathy associated with chronic use (nummular retinopathy). (From Weinberg DV, D’Amico DJ. Retinal toxicity of systemic drugs. In: Albert DM, Jakobiec FA, eds. Principles and practice of ophthalmology. Philadelphia: WB Saunders; 1994:1042–50.)
administered dose of 400?mg/day of hydroxychloroquine is excessive for patients who have a lean body weight <62?kg (<136 pounds). Dose adjustment is also necessary for patients with impaired renal function. It has been demonstrated that well-documented cases of maculopathy are virtually nonexistent for patients who have normal renal function and take <6.5?mg/kg/day of hydroxychloroquine for less than 10 years.   
Because the earliest macular changes are nonspecific and may be indistinguishable from age-related changes, a baseline examination that includes measurement of the central visual field and the use of color photographs is valuable. For asymptomatic patients who take <6.5?mg/kg/day of hydroxychloroquine, annual or semiannual examinations that include detailed questions about visual symptoms, dilated fundus examination, and central visual field testing should reveal rare cases of maculopathy at a very early stage. Amsler grid testing may be useful for home monitoring between visits.
The toxicity of these drugs may be related to their affinity for pigmented structures, especially in the eye. In animal models, the ganglion cells show the earliest histological evidence of toxicity, followed by other neural elements of the retina and the retinal pigment epithelium.
Thioridazine is a phenothioridazine antipsychotic drug that became popular in the late 1950s because of a favorable side-effect profile. It was used in doses of up to several grams per day. At these doses, a subacute, dramatic form of retinopathy could appear.    After 2 weeks or more of therapy, patients complained of the development of visual symptoms, which included blurring, nyctalopia, and a brownish visual discoloration; vision was normal to profoundly reduced. At the onset of symptoms, the fundus could appear normal, but within a couple of weeks characteristic changes evolved. Pigment granularity developed posterior to the equator and became more coarse over time. Eventually, geographic areas of depigmentation and loss of choriocapillaris developed ( Fig. 143-2 ). If the drug was withdrawn early after the onset of symptoms, the patients usually reported improvement in vision; however, the pigmentary changes in the fundus often progressed.
At the lower doses used today, this dramatic type of retinopathy rarely, if ever, occurs. A variant referred to as nummular retinopathy has been described in patients taking chronic doses of thioridazine. These patients are much less likely to have symptoms. Multiple, large, round areas of depigmentation and atrophy develop posterior to the equator, with relative sparing of the macula ( Fig. 143-3 ). Over time, the areas of atrophy may enlarge and become confluent. Fluorescein angiography demonstrates loss of pigment epithelium and choriocapillaris within the areas of depigmentation.  Visual field changes are nonspecific, but most characteristically show paracentral scotomas or ring scotomas.
The manufacturers’ current recommendation is that the dose be titrated to a minimal effective dose of 300?mg/day or less, with an absolute maximum of 800?mg/day for limited periods of time. Cases of retinopathy among patients treated according to these guidelines are rare.
Niacin (nicotinic acid, vitamin B6 ) is used at pharmacological doses to lower serum cholesterol. Rarely, patients who take 1.5?g or more daily develop maculopathy.
The patients develop central visual changes weeks or months after the initial administration of the drug. Visual acuity is usually reduced mildly to moderately.  The patients develop a bilateral maculopathy that has the clinical appearance of cystoid macular edema, but there is no dye accumulation with fluorescein angiography. The subjective and objective findings are partially or wholly reversible after the drug is withdrawn.
Canthaxanthine is a carotenoid drug that, when taken orally, causes bronzing of the skin. Although it has been used for treatment of certain dermatologic disorders, its main use has been as an artificial tanning agent. The risk of retinopathy is dose related. At cumulative doses of greater than 60?g, the majority of patients are found to have retinopathy. Patients who have canthaxanthine retinopathy are usually asymptomatic. The fundus appearance is bilateral, dramatic, and distinctive. A wreath formation of highly refractile yellow crystals is found in the inner retinal layers that surround the fovea ( Fig. 143-4 ). 
Although the patients are usually asymptomatic, central perimetry demonstrates reduced sensitivity in patients who have retinopathy. After administration of the drug has been stopped, the number of visible crystals decreases slowly over many years.
Figure 143-4 Canthaxanthine retinopathy. Large yellow crystals are distributed in a prominent macular ring. (From Weinberg DV, D’Amico DJ. Retinal toxicity of systemic drugs. In: Albert DM, Jakobiec FA, eds. Principles and practice of ophthalmology. Philadelphia: WB Saunders; 1994:1042–50.)
Figure 143-5 Severe tamoxifen retinopathy. (From McKeown CA, Swartz M, Blom J, Maggiano JM. Tamoxifen retinopathy. Br J Ophthalmol. 1981;65:177–9 and the BMJ Publishing Group.)
Tamoxifen is a nonsteroidal estrogen antagonist that is used in treatment of breast cancer. Retinopathy was first described among women treated with more than 180?mg/day for longer than a year. These patients usually had a symptomatic decrease in vision. The characteristic fundus findings were small white refractile deposits in the inner retina, particularly in the perimacular area. Associated pigmentary irregularity occurred ( Fig. 143-5 ). Fluorescein angiography demonstrated macular edema in most cases.
Currently, the drug is used at much lower doses. Conflicting data exist in the literature as to the incidence and significance of retinopathy at these lower doses.    Although mild crystal deposition with or without macular edema may be possible with low doses, it is probably quite rare. This is supported by the large number of patients treated with this drug and the relative paucity of well-documented cases in the literature. The most recent study of 135 patients who took 20?mg/day found two patients with questionable, but visually insignificant, maculopathy. The authors concluded that it was not necessary to screen patients who take low doses of tamoxifen.
Figure 143-6 Deferoxamine retinopathy. (From Lakhanpal V, Schocket SS, Jiji R. Deferoxamine (Desferal)-induced toxic retinal pigmentary degeneration and presumed optic neuropathy. Ophthalmology. 1984;91:443–51.)
Methoxyflurane is an inhalation anesthesia agent. Rare reports exist of crystalline retinopathy as a result of calcium oxylate deposition following methoxyflurane inhalation after prolonged surgical procedures with methoxyflurane anesthesia or after illicit methoxyflurane abuse. 
Deferoxamine mesylate is a chelating agent used to remove toxic levels of heavy metals from the body. Its primary use is to reduce iron levels in patients who have transfusion-dependent anemias. Also, it has been used to treat aluminum toxicity in patients receiving chronic renal dialysis. The drug is given as a slow intravenous or subcutaneous infusion or by intramuscular injection. The onset of visual symptoms from deferoxamine toxicity may be relatively acute. Patients usually complain of blurred vision, nyctalopia, color vision abnormalities, or visual field restriction. At the time of onset, the fundus may appear normal or subtle pigment mottling may be found. Color vision is frequently abnormal, typically with a tritan dyschromatopsia. Visual field testing usually shows central or centrocecal scotomas and, less commonly, peripheral restriction. Electroretinography may show decreased amplitude and prolonged implicit times. Visually evoked potentials may also show low voltage and delayed conduction times. If deferoxamine is withdrawn promptly, partial or complete functional recovery is usually seen. The maculopathy may progress, however, and develop into coarse macular pigmentary changes ( Fig. 143-6 ) and, occasionally, peripheral pigmentary clumping as well.   
Whether this represents a purely retinal toxicity or has a component of optic neuropathy is somewhat unclear from the literature.
Didanosine (2′,3′-dideoxyinosine) is an antiretroviral drug used for the treatment of patients who have human immunodeficiency virus infection. A peripheral retinal degeneration has been observed in a subset of children who were treated with this drug. Of 43 children receiving didanosine followed prospectively, 3 (7%) developed an asymptomatic peripheral retinal degeneration first noted after 9–19 months of therapy. The findings consisted of small, sharply demarcated areas of retinal and
Figure 143-7 Didanosine retinopathy in a child. (Courtesy of Scott M. Whitcup.)
retinal pigment epithelial atrophy around the midperiphery ( Fig. 143-7 ). The degeneration appeared to progress with continued exposure to the drug. Visual acuity remained normal in all patients. One patient who was able to undergo reliable testing demonstrated mild restriction of the peripheral visual field.
Clofazimine is an iminophenazine dye with antimycobacterial and anti-inflammatory activity. Retinal toxicity in the form of a bull’s-eye maculopathy has been reported in patients who were given clofazimine for Mycobacterium avium complex infections associated with acquired immunodeficiency syndrome. The patients developed a bilateral pattern of parafoveal pigmentary irregularity and atrophy. This was visible clinically and appeared as an irregular parafoveal transmission defect on fluorescein angiography. In contrast to other bull’s-eye maculopathies, the pigment changes in these patients were more extensive and extended outside the major vascular arcades. 
1. Hobbs HE, Sorsby A, Freedman A. Retinopathy following chloroquine therapy. Lancet. 1959;2:478–80.
2. Hobbs HE, Eadie SP, Somerville F. Ocular lesions after treatment with chloroquine. Br J Ophthalmol. 1961;45:284–97.
3. Henkind P, Rothfield NF. Ocular abnormalities in patients treated with synthetic antimalarial drugs. N Engl J Med. 1963;269:433–9.
4. Hart WM, Burde RM, Johnston GP, Drews RC. Static perimetry in chloroquine retinopathy. Perifoveal patterns of visual field depression. Arch Ophthalmol. 1984;102:377–80.
5. Weinberg DV, D’Amico DJ. Retinal toxicity of systemic drugs. In: Albert DM, Jakobiec FA, eds. Principles and practice of ophthalmology. Philadelphia: WB Saunders; 1994:1042–50.
6. Cruess AF, Schachat AP, Nicholl J, Augsburger JJ. Chloroquine retinopathy. Is fluorescein angiography necessary? Ophthalmology. 1985;92:1127–9.
7. Scherbel AL, Mackenzie AH, Nousek JE, Atdjian M. Ocular lesions in rheumatoid arthritis and related disorders with particular reference to retinopathy. A study of 741 patients treated with and without chloroquine drugs. N Engl J Med. 1965; 273:360–6.
8. Johnson MW, Vine AK. Hydroxychloroquine therapy in massive total doses without retinal toxicity. Am J Ophthalmol. 1987;104:139–44.
9. Bernstein HN. Ocular safety of hydroxychloroquine sulfate (Plaquenil). South Med J. 1992;85:274–9.
10. Easterbrook M. The ocular safety of hydroxychloroquine. Semin Arthritis Rheum. 1993;23(Suppl):62–7.
11. Rynes RI, Bernstein HN. Ophthalmologic safety profile of antimalarial drugs. Lupus. 1993;2(Suppl):S17–S19.
12. May RH, Selymes P, Weekley RD, Potts AM. Thioridazine therapy: results and complications. J Nerv Ment Dis. 1960;130:230–4.
13. Weekley RD, Potts AM, Reboton J, May RH. Pigmentary retinopathy in patients receiving high doses of a new phenothiazine. Arch Ophthalmol. 1960;64:65–76.
14. Hagopian V, Stratton DB, Busiek RD. Five cases of pigmentary retinopathy associated with thioridazine administration. Am J Psychiatry. 1966;123:97–100.
15. Meredith TA, Aaberg TM, Willerson WD. Progressive chorioretinopathy after receiving thioridazine. Arch Ophthalmol. 1978;96:1172–6.
16. Kozy D, Doft BH, Lipkowitz J. Nummular thioridazine retinopathy. Retina. 1984; 4:253–6.
17. Gass JDM. Nicotinic acid maculopathy. Am J Ophthalmol. 1973;76:500–10.
18. Millay RH, Klein ML, Illingworth DR. Niacin maculopathy. Ophthalmology. 1988;95:930–6.
19. Ros AM, Leyon H, Wennersten G. Crystalline retinopathy in patients taking an oral drug containing canthaxanthine. Photodermatology. 1985;2:183–5.
20. Boudreault G, Cortin P, Corriveau LA, et al. La rétinopathie á la canthaxanthine. I. Etude clinique de 51 consommateurs. Can J Ophthalmol. 1983;18:325–8.
21. Harnois C, Samson J, Malenfant M, Rousseau A. Canthaxanthin retinopathy. Anatomic and functional reversibility. Arch Ophthalmol. 1989;107:538–40.
22. Kaiser-Kupfer MI, Lippman ME. Tamoxifen retinopathy. Cancer Treat Rep. 1978;62:315–20.
23. McKeown CA, Swartz M, Blom J, Maggiano JM. Tamoxifen retinopathy. Br J Ophthalmol. 1981;65:177–9.
24. Pavlidis NA, Petris C, Briassoulis E, et al. Clear evidence that long-term low-dose tamoxifen treatment can induce ocular toxicity. Cancer. 1992;69:2961–4.
25. Longstaff S, Sigurdsson H, O’Keefe M, et al. A controlled study of the ocular effects of tamoxifen in conventional dosage in the treatment of breast carcinoma. Eur J Cancer Clin Oncol. 1989;25:1805–8.
26. Heier JS, Dragoo RA, Enzenauer RW, Waterhouse WJ. Screening for ocular toxicity in asymptomatic patients treated with tamoxifen. Am J Ophthalmol. 1994;117:772–5.
27. Bullock JD, Albert DM. Flecked retina. Appearance secondary to oxalate crystals from methoxyflurane anesthesia. Arch Ophthalmol. 1975;93:26–31.
28. Novak MA, Roth AS, Levine MR. Calcium oxalate retinopathy associated with methoxyflurane abuse. Retina. 1988;8:230–6.
29. Lakhanpal V, Schocket SS, Jiji R. Deferoxamine (Desferal)-induced toxic retinal pigmentary degeneration and presumed optic neuropathy. Ophthalmology. 1984;91:443–51.
30. Olivieri NF, Buncic JR, Chew E, et al. Visual and auditory neurotoxicity in patients receiving subcutaneous deferoxamine infusions. N Engl J Med. 1986;314:869–73.
31. Cases A, Kelly J, Sabater F, et al. Ocular and auditory toxicity in hemodialyzed patients receiving desferrioxamine. Nephron. 1990;56:19–23.
32. Whitcup SM, Butler KM, Caruso R, et al. Retinal toxicity in human immunodeficiency virus–infected children treated with 2′,3′-didoxyinosine. Am J Ophthalmol. 1992;113:1–7.
33. Craythorn JM, Swartz M, Creel DJ. Clofazimine-induced bull’s-eye retinopathy. Retina. 1986;6:50–2.
34. Cunningham CA, Friedberg DN, Carr RE. Clofazimine-induced generalized retinal degeneration. Retina. 1990;10:131–4.