Medications or other substances that find their way into the eye may cause visual dysfunction by virtue of a toxic effect on the sensory retina, the retinal pigment epithelium (RPE), and the optic nerve. In some instances (e.g., digitalis toxicity) visual symptoms may be unassociated with ophthalmoscopic changes in the fundus. In other instances the ophthalmoscopic changes may involve any one or a combination of the RPE, retina, and optic nerve head. Fluorescein angiography is particularly valuable in detecting mild toxic alterations of the RPE before they are apparent ophthalmoscopically. Optical coherence tomography (OCT), autofluorescence imaging, full-field, and multifocal electroretinography help localize the defect in many instances.
Chloroquine (Aralen) and Hydroxychloroquine (Plaquenil) Retinopathy
Chloroquine initially was used as an antimalarial agent in World War II, but since 1959 it has been used in the treatment of amebiasis, rheumatoid arthritis, scleroderma, and systemic lupus erythematosus. Hydroxychloroquine has largely replaced chloroquine due to lower incidence of toxicity. Degeneration of the RPE and sensory retina caused by prolonged use of chloroquine or hydroxychloroquine is one of the most important of the retinotoxic diseases. Most patients who have developed retinopathy have received daily doses of chloroquine in excess of 250 mg or hydroxychloroquine in excess of 750 mg for at least a total dose of between 100 and 300 g. There is evidence that the incidence of retinotoxic effects is lower following hydroxychloroquine than following chloroquine therapy. Four unequivocal cases of hydroxychloroquine retinopathy were reported prior to 1991. All had normal or reduced visual acuity, paracentral scotomata, and bull’s-eye maculopathy. Some have evidence of peripheral retinopathy. Although it has been suggested that patients receiving daily dosages of hydroxychloroquine up to 400 mg or 6.5 mg/kg of body weight per day may tolerate massive cumulative doses (for example 3923 g) without developing retinopathy, such did occur in one patient who received 400 mg/day and a total dose of less than 2920 g. Gass has seen another woman who, after taking a total of 146 g (200 mg/day×730 days) of hydroxychloroquine, experienced rapid development of paracentral visual field loss and early bull’s-eye maculopathy. The retinopathy caused by both drugs is probably a general toxic effect but some eyes have developed toxicity after minimal exposure while others with long usage show no ill effects. This implies that some eyes may be predisposed to toxicity sooner than others by unknown factors. A study of eight patients with chloroquine and hydroxychloroquine retinopathy for ABCA4 mutations revealed two patients with heterozygous ABCR missense mutations, but none in 80 controls, suggesting some patients with ABCR mutations may be predisposed to retinal toxicity. Vitreous fluorophotometry has demonstrated a breakdown in the blood–retinal barrier in patients receiving chloroquine but not hydroxychloroquine. The earliest sign of toxicity, which may occur before development of any other ophthalmoscopic or electrophysiologic abnormality, is a paracentral visual field loss. The patient’s use of the Amsler grid may be helpful in detecting these early field defects.
The earliest ophthalmoscopic and angiographic alterations in the RPE occur in the parafoveal area ( Figure 9.01A–C and E–K ). At this stage a paracentral scotoma and minimal or no loss of visual acuity are characteristic. An enlarging ring of atrophy of the RPE surrounding the fovea produces a bull’s-eye-like lesion that is indistinguishable ophthalmoscopically from other causes of this lesion (see Chapter 5 ). As the RPE alterations extend into the foveolar area, the patient loses central vision. Weiter et al. have suggested that the retinal xanthophyll in the foveolar area may exert a photoprotective effect in the various causes of bull’s-eye maculopathy. In addition to changes in the posterior pole, continued use of the drug may cause extensive alterations in the RPE and retina peripherally ( Figure 9.01D, J–L ). These changes, together with narrowing of the retinal vessels and optic disc pallor, may resemble primary tapetoretinal dystrophies. Severe visual loss and blindness may eventually occur. Other ocular changes caused by chloroquine include whitening of the lashes, a whorl-like pattern of subepithelial corneal deposits, decreased corneal sensitivity, and extraocular muscle palsies.
Fluorescein angiography and fundus autofluorescence imaging ( Figure 9.02C–E, K, and L ) are helpful in demonstrating the faint bull’s-eye pattern of hyperfluorescence before its detection biomicroscopically, particularly in patients with blond fundi. In patients with darkly pigmented fundi, biomicroscopic evidence of RPE changes may precede angiographic changes. The area of RPE depigmentation ( Figure 9.01B, F, H, and I ) in general corresponds to the area of field loss. There is minimal angiographic evidence of damage to the choriocapillaris in the areas of RPE depigmentation ( Figure 9.01B, G, J, and K ) (see discussion in Chapter 2 ). The detection of small paracentral scotomata to red light is one of the earliest findings in chloroquine toxicity. Use of static perimetry through the vertical meridian may be the most sensitive means of detecting the early visual field damage. Multifocal electroretinogram (ERG) may be able to detect early drop in receptor amplitudes in the parafoveolar region. OCT is often able to detect loss of photoreceptors before angiographic changes ( Figure 9.02G and H ). The electro-oculogram (EOG) may initially be supernormal (200–350%).
Ideally patients requiring more than 200 mg chloroquine or 350 mg hydroxychloroquine daily should have a baseline complete eye examination, including visual acuity, visual fields, and fundus photography. If there is any biomicroscopic evidence of abnormality of the RPE or other signs of retinal degeneration or a family history of retinal degeneration, fluorescein angiography, multifocal ERG, full-field ERG and EOG should be considered as part of the baseline workup.
In the first 5 years of chloroquine or hydroxychloroquine therapy the American Academy of Ophthalmology recommendations suggest exams at periods appropriate for the patient’s age. After 5 years of therapy annual exam including central 10° visual field optical coherence tomography (OCT), color vision, and dilated fundus exam is recommended. However any suggestion of early field defects, changes in color perception, and other degenerative changes at the RPE/outer retina should warrant a prompt evaluation with autofluorescence, central visual field testing, fluorescein angiography, and discontinuation of the drug. At the present time, multifocal ERG may be the most useful means to detect early changes, even before visual field and angiographic changes appear. OCT can show loss of perifoveolar receptors much earlier than discernible changes on fundus examination or fluorescein angiography. Most of all, attention should be paid to the patient’s symptoms – variously described as changes in color perception, areas of their face missing when looking into the mirror, or parts of the TV image missing, and difficulty with dark adaptation.
Histopathologically, depigmentation of the RPE, loss of the rod and cone receptor elements, and subretinal clumping of pigment occur in the macular area ( Figure 9.01L ). Electron microscopic studies have revealed widespread changes in the retina, with the most severe occurring in the ganglion cells in spite of their relatively normal appearance by light microscopy. There is experimental evidence that chloroquine is concentrated in the RPE and remains there long after cessation of treatment. In experimental mice given intraperitoneal chloroquine, there was marked abnormality of the outer retinal layers with complete loss of the outer plexiform layer, photoreceptors, and photoreceptor nuclei. The RPE demonstrated focal atrophy, loss of nuclei, and pigment irregularity. The inner retina showed loss of Müller cells and the presence of membranous cytoplasmic bodies. In contrast, those experimental animals given the drug orally have shown much less damage with most changes limited to the RPE and photoreceptors. This suggests that the appearance of toxicity at variable durations of treatment and at variable cumulative doses in some patients may be related to the difference in absorption and bioavailability of the drug. Although there is some evidence that the early electrophysiologic changes may be reversible, in most cases, once visual loss has occurred, it is irreversible and may progress long after cessation of treatment ( Figure 9.01E–L ). There may be an interval of 7 years or longer after cessation of chloroquine and the development of the first signs of retinopathy. Some patients with disease attributed to late onset and progression of chloroquine retinopathy may in fact have had a genetically determined disease that can cause fundus changes identical to chloroquine retinopathy (e.g., cone dystrophy, rod–cone dystrophy, ceroid lipofuscinosis, and Stargardt’s disease).
Thioridazine (Mellaril) Retinopathy
Patients with acute thioridazine retinopathy typically experience blurred vision, dyschromatopsia (brownish coloration), or nyctalopia 3–8 weeks after receiving the drug in excess of 800 mg/day and less frequently in lower doses. Maximum daily dose seems more critical than cumulative dose. The fundus may be normal initially. Later a mild, fine, then coarse granular salt-and-pepper pigmentary retinopathy with a relatively uniform distribution involving the macula and sometimes the midperiphery as well, may occur ( Figure 9.03A ). In some patients this may progress to include patchy or nummular areas of loss of the RPE and choriocapillaris ( Figure 9.03D–L ) and may eventually progress to a severe diffuse tapetoretinal degeneration. Progression of the pigmentary changes but not necessarily functional changes may occur after the medication is discontinued. Visual function may occasionally improve after cessation of toxic levels of the drug. Other patients, however, may experience a late, slow progression of functional as well as anatomic changes. The progressive enlargement and confluence of patches of extrafoveal geographic atrophy of the RPE and choriocapillaris are similar to those seen in gyrate atrophy, Bietti’s crystalline dystrophy, and choroideremia. Fluorescein angiography may be helpful in detecting mild RPE alterations ( Figure 9.03B and C ). The ERG responses may be normal early but become attenuated later in more severe cases.
Histopathologically, thioridazine retinopathy is associated with atrophy and disorganization of the photoreceptor outer segments followed by loss of the RPE and choriocapillaris.
Retinotoxicity has been attributed to concentration of the drug within melanin granules in the uveal melanocytes and RPE. The drug inhibits oxidative phosphorylation, resulting in abnormal rhodopsin synthesis, which causes disintegration of rod outer segments. The RPE is overtaxed with accumulation of lipofuscin as abnormal pigment granules. In addition it is believed that thioridazine and other phenothiazines block the D4 dopamine receptors with subsequent increase in retinal melatonin synthesis and activity. This occurs in the photoreceptors and RPE where the D4 subtype of the D2-receptor family is predominant. Thioridazine has a structure similar to NP-207, an experimental drug that was never marketed because of severe retinotoxicity. There is no specific treatment other than stopping the medication.
Chlorpromazine (Thorazine) Retinopathy
Chlorpromazine rarely causes retinal toxicity. When taken in large doses in the range of 2400 mg/day over 12 months it may cause mild pigmentary changes in the retina ( Figure 9.04A and B ). These rarely are associated with visual or functional deficits. Because patients receiving chlorpromazine have often received other medications that may have included potentially retinotoxic drugs, assignment of the exact cause of the retinopathy may be difficult. White and yellow-white granular deposits may occur in the axial part of the anterior subcapsular region of the lens, and in the posterior layers of the cornea in patients receiving 300 mg/day of chlorpromazine for 3 years or more. The usual dosage of chlorpromazine is 40–75 mg/day, although dosages up to 800 mg/day are not uncommon.
Clofazimine Retinopathy
Clofazimine is a red iminophenazine dye used concurrently with dapsone and rifampin as the treatment of choice for lepromatous leprosy, for treatment of dapsone-resistant leprosy, and for Mycobacterium avium complex infections in patients with acquired immunodeficiency syndrome (AIDS). After several months of treatment, clofazimine crystals may accumulate in the ocular tissues. Reversible side-effects include a superficial whorl pattern of anterior corneal pigmented lines, brownish discoloration of the conjunctiva and tears, and crystals in the iris and sclera. A large bull’s-eye pattern of pigment epithelial atrophy ( Figure 9.04C and D ) has occurred in two patients following 200 mg/day (total dose of approximately 48 g) and after 300 mg/day (total dose of approximately 40 g). This was associated with reduced ERG b-waves and full-field photopic and scotopic as well as flicker amplitudes.
Deferoxamine Maculopathy
Intravenous administration of deferoxamine mesylate (DFO), 3–12 g/24 hours, for the treatment of transfusional hemosiderosis has produced rapid onset of visual loss; color vision abnormalities; nyctalopia; a ring scotoma; reduced electroretinographic, electro-oculographic, dark adaptation, and visual evoked responses; and mid- to high-frequency hearing loss of cochlear type. The fundi may be normal initially or there may be a slight graying of the macula ( Figure 9.05A ). Both eyes are affected. Visual symptoms usually begin 7–10 days after the last treatment. Development of maculopathy may occur after chronic subcutaneous injection of deferoxamine. Fluorescein angiography soon after the onset of visual symptoms in the presence of a normal-appearing fundus may show progressive staining at the level of the RPE in the macular areas, and in some cases leakage of dye from the optic disc vessels ( Figure 9.05B and C ). Pigmentary changes usually appear within several weeks ( Figure 9.05D ). After cessation of treatment, return of visual function occurs over 3–4 months and approximately 70% of patients recover normal acuity. Two 70-year-old patients developed pseudovitelliform lesions in the macula of both eyes while on low-dose deferoxamine. Reversible EOG changes have been noted, and a drop in the Arden ratio to less than 1.5 was seen in another patient on DFO for 2 years. On cessation of DFO following splenectomy her EOG and visual acuity returned to normal, hence EOG at regular intervals may be used as a monitor for toxicity. Some patients show increase in both rod and cone implicit times and reduction of a- and b-wave amplitudes. The mechanism of retinal toxicity is unknown. Although chelation of iron is unlikely to be the explanation, removal of other metals, particularly copper, from the RPE may be important. Copper fluxes may cause oxidative cell membrane resulting in lipid peroxidation products that are toxic to the RPE. Copper movement into extracellular fluids may interrupt monoaminergic neurotransmission in the retina. Light microscopic and ultrastructural changes in the RPE in an eye of a patient studied after recovery of visual function included patchy depigmentation and thinning, loss of microvilli from the apical surface, vacuolization of the cytoplasm, swelling and calcification of mitochondria, disorganization of the plasma membrane, and thickening of Bruch’s membrane.
More recently an oral agent Exjade is being used as a chelating agent in patients receiving repeated blood transfusions. Figure 9.05E–L shows a patient who continued to develop macular and extramacular pigmentary changes even after being switched to Exjade. High-frequency sensorineural loss and bone dysplasia are other features of deferoxamine toxicity.
Siderotic Retinopathy
If iron-containing foreign bodies enter the eye, the iron may become oxidized and be bound to the ocular tissues, producing either localized siderosis or, particularly when the foreign body lodges in the vitreoretinal region, diffuse ocular siderosis ( Figure 9.06A–E ). Evidence of ocular siderosis includes pupillary mydriasis, darkening of the iris ( Figure 9.06D ), and orange deposits in the anterior subcapsular region of the lens. Posteriorly, hazy ocular media may preclude visualization of the fundus. Early optic disc hyperemia and fluorescein angiographic evidence of leakage may be present. Later a picture simulating pigmentary degeneration of the retina and progressive loss of peripheral visual fields may occur ( Figure 9.06A and B ). These changes may be associated with optic disc hyperemia. Retinal vascular narrowing, and occasionally microangiopathy with vascular occlusion and leakage are seen. Abnormalities in the ERG eventually occur ( Figure 9.06E ) and may be reversible following early removal of the intraocular iron foreign body. Histopathologically, the iron is initially deposited primarily in the inner retina and RPE. Eventually, however, degeneration may affect all layers of the retina.
The natural course of a retained intraocular iron foreign body is variable. In some cases the foreign body may be absorbed or become encapsulated and the siderosis may stabilize or regress. In some cases the hyperpigmentation of the encapsulated mass may simulate a choroidal melanoma ( Figure 8.11B–E ). In general, intraocular iron foreign bodies should be removed, particularly from an eye showing evidence of siderosis. Removal of foreign bodies deeply embedded in the ocular wall or of largely oxidized foreign bodies may be difficult or impossible.
An acute pigment epitheliopathy, serous retinal detachment, and transient visual loss occurred in a patient with systemic hypertension and chronic glomerulonephritis after intravenous administration of iron dextran.
Experimental injection of iron powder or iron-containing solutions into the vitreous may produce acute geographic areas of retinal whitening ( Figure 9.06F–K ), fluorescein angiographic evidence of severe disruption of the RPE ( Figure 9.06G ), and a diminished or nonrecordable ERG within the first 24 hours of the injection. A zone of focal atrophy of the RPE surrounded by a zone of pigment epithelial clumping develops within a few weeks ( Figure 9.06H and I ). Histologically, the primary damage is to the receptor cells and RPE ( Figure 9.06J and K ). Retinal damage is much more severe with ferrous than with ferric compounds.
Chalcosis Maculopathy
Patients with an intraocular copper foreign body may show a wide spectrum of reactions to its presence. In the case of a copper alloy, the inflammatory reaction may be minimal and a slow diffusion of copper occurs and impregnates limiting membranes of the eye to produce the picture of chalcosis that may include peripheral corneal ring, sunflower cataract (see Figure 8.11I ), and heterochromia of the iris. In addition, irregular yellowish-golden flakes may be deposited in the macular area away from the site of the foreign body ( Figure 9.07A and B ). It is presumed that these apparently inert deposits are either copper carbonates or oxides. They appear to have little effect on visual acuity. Their location is uncertain, but they appear to be deep to the retinal vessels. These flakes disappear after removal of the foreign body ( Figure 9.07C ). The ERG is subnormal in approximately 50% of patients with chalcosis.
Experimentally, copper has been found in the macrophages within the retina, in Müller cells, and in granular clumps scattered throughout the retina. Clinicopathologic study in eyes with retained copper foreign bodies show copper deposits in Descemet’s membrane, vitreous, internal limiting membrane of the retina, and fibrous capsule around the foreign bodies. Eyes with foreign bodies containing more than 85% copper show more disseminated copper deposits and eyes with alloy containing less than 85% copper show more localized deposits. Retinal structures are usually well preserved, even in eyes with an intraocular copper foreign body retained for 22 years.
Argyrosis
Argyrosis may be associated with discoloration of the skin, mucous membranes, and many of the body organs occurring with application of colloidal silver-containing eye drops, eyelash tint, in photographers, photochemists, miners, silversmiths and industrial workers using silver-containing compounds. When this discoloration is confined to the eye following topical application of silver compounds to the eye, the blue-gray discoloration of the conjunctiva and cornea ( Figure 9.07D ) is referred to as argyria. The discoloration is caused by deposition of silver in the basement membrane of the conjunctiva and cornea, as well as in Descemet’s membrane. Occupational exposure in a silversmith from Italy was found to deposit the metal in the endothelial basement membranes of the conjunctiva and deep corneal stroma just anterior to the endothelium. Peripheral and central or diffuse corneal deposition has been noted, with the central involvement occurring with longer exposure. Patients with argyrosis caused by chronic ingestion of silver-containing compounds may develop discoloration of the skin and body organs, as well as loss of the normal choroidal markings in the ocular fundus, a “dark” choroid fluorescein angiographically, and a leopard-spot mottling of the ocular fundus when viewed with red-free light ( Figure 9.07E–G ). These fundus changes are probably caused by loss of transparency of Bruch’s membrane as a result of deposition of silver in the membrane ( Figure 9.07H ). The discoloration is permanent and chelation therapy is ineffective.
Cisplatinum and BCNU (Carmustine) Retinopathy
Intracarotid arterial chemotherapy with BCNU (1,3- bis -(9,2-chlorethyl)-1-nitrosourea), 300–400 mg, and cisplatinum ( cis -diammine dichloroplatinum(II)), 200 mg, is used for treatment of recurrent malignant gliomas of the brain. This may cause precipitous ipsilateral visual loss and fundus changes of two different types. Patients receiving BCNU either alone or in combination with cisplatinum may develop visual loss associated with ophthalmoscopic signs of retinal infarction, retinal periarteritis and phlebitis, and papillitis. A retinopathy similar to interferon retinopathy with severe bilateral retinal ischemia leading to retinal neovascularization has been described ( Figure 9.08G–J ). The mechanism of the vasculopathy is believed to be from increased platelet reactivity to nonaggregating concentration of the agonists involved in the arachidonic acid metabolism (increased thromboxane synthesis and early onset of platelet aggregation wave). The retinopathy was found to be reversible or stable; however the field defect and vision loss from optic neuropathy progressed even after discontinuation of the drug. Other findings may include cavernous sinus syndrome, partial sixth- and third-nerve palsies, severe conjunctival injection and chemosis, pain, and secondary glaucoma. Approximately 65% of patients treated develop these findings accompanied by visual loss about 6 weeks after the start of treatment. Once visual loss begins it is usually progressive and severe.
Intracarotid injection above the level of the ophthalmic artery does not protect from development of ocular complications. Those treated with cisplatinum alone or in combination with BCNU may develop visual loss associated with a pigmentary retinopathy, with a central scotoma, and later diffuse constriction of the visual field. The ERG may be nonrecordable in some patients. The visual symptoms and pigmentary changes are usually mild following administration of cisplatinum alone and appear to be potentiated with the addition of BCNU. Figure 9.08A–F shows pigmentary retinopathy in two patients treated with cisplatinum and bleomycin. A similar pigmentary maculopathy has been reported after a combination of intracarotid injection of mannitol and methotrexate together with intravenous administration of cyclophosphamide. Mannitol disruption of the blood–ocular barrier was thought to be instrumental in the macular changes, which typically do not occur with use of the two drugs alone (see Chapter 13 ).
Tamoxifen Retinopathy
Tamoxifen citrate, a nonsteroidal antiestrogen, is used to treat patients with breast carcinoma and more recently as high-dose therapy for brain tumors. Patients who receive high doses of tamoxifen (total amount of drug in excess of 90 g) may develop loss of central vision, macular edema, and superficial white refractile deposits that are located primarily in the inner layers of the retina ( Figure 9.09A, B, D, and E ). There may be punctate gray lesions at the level of the outer retina and RPE that appear nonfluorescent (hypofluorescent) angiographically ( Figure 9.09F ). Refractile lesions are more numerous and larger in the paramacular area, are more heavily concentrated temporal to the macula, and show some tendency to clump. Peripheral crystals can occur in some cases. OCT confirms the inner retinal loation. The number and size of the lesions do not change after cessation of tamoxifen. Light microscopy and electron microscopy show that the retractile lesions are located in the nerve fiber and inner plexiform layers. They are intracellular and stain positively for glycosaminoglycans. The lesions appear to represent products of axonal degeneration. Histopathologically they are similar to corpora amylacea but are larger and more numerous in the paramacular area than the peripapillary area.
There is evidence that long-term low-dosage tamoxifen may cause retinopathy. In a prospective study of 63 patients receiving a median dose of 20 mg/day tamoxifen for a median duration of 25 months, four patients developed retinopathy and/or keratopathy 10, 27, 31, and 35 months after commencement of treatment. The mean total dose in these four patients was 14.4 g. Decreased acuity, bilateral macular edema, and yellow-white dots in the paramacular and foveal areas occurred in all four patients and corneal opacities occurred in one patient. After withdrawal of drug, almost all ocular complications were reversible.
Heier and coworkers found mild deposition of intraretinal crystals in only two of 135 visually asymptomatic tamoxifen-treated patients (mean cumulative dose 17.2 g). The two patients with crystals had a cumulative dose of 10.9 and 21.9 g, respectively. In severe cases OCT shows intraretinal pseudocyst formation similar to those seen in idiopathic type 2 juxtafoveolar telangiectasia, likely from axonal degeneration of Müller cells and photo-receptors. The pseudocyst gradually enlarges with rupture of the inner layer to result in a macular hole. Transient bilateral optic disc edema, retinal hemorrhages, and macular edema may occasionally occur after starting low-dose tamoxifen daily. Multifocal ERG done prospectively to monitor for macular toxicity is not useful even in patients who develop crystals.
Oxalosis
Oxalosis is the deposition of calcium oxalate in various tissues of the body. The eye may be solely involved or may be involved as part of systemic oxalosis. Systemic oxalosis may be the result of: (1) a primary hyperoxaluria secondary to an inborn error of metabolism types 1 and 2 (see Chapter 5 ); (2) a toxic reaction to ethylene glycol or methoxyflurane general anesthesia; or (3) chronic renal failure and hemodialysis. Ocular involvement in secondary systemic oxalosis has been observed after use of methoxyflurane, which is a nonflammable anesthetic. When administered to patients with renal dysfunction and particularly if administered over a prolonged period of time, it may cause irreversible renal failure secondary to the metabolic breakdown of the anesthetic to oxalic acid and fluoride ions ( Figure 9.09K ). These patients, as well as those with primary hyperoxaluria, may develop numerous yellow-white, punctate, crystalline lesions diffusely scattered throughout the posterior pole and midperiphery of the eyes (see Figures 5.67 and 9.09G and H ). In some, the crystals appear to be most prominent in the pigment epithelium with surrounding areas of hypertrophic and hyperplastic RPE ( Figure 9.09I ), and in others, along the retinal arteries ( Figure 9.09G ). Less commonly the crystals are intraretinal, and optic atrophy is seen occasionally. In patients with methoxyflurane toxicity the retinal and pigment epithelial crystals may occur in the absence of changes in the optic disc, the macula, and the caliber of the retinal vessels seen in primary hyperoxaluria (see Figure 5.67 ). Histopathologically, the flecks seen ophthalmoscopically are calcium oxalate crystals in the RPE, neurosensory retina, and ciliary epithelium ( Figure 9.09J and K ).
The differential diagnosis includes the other forms of so-called flecked retina, including Bietti’s crystalline dystrophy, nephropathic cystinosis, canthaxanthine retinopathy, West African crystalline maculopathy, Sjögren–Larsson’s syndrome, talc retinopathy, fundus albi punctatus, retinitis punctata albescens, Stargardt’s disease, Alport’s syndrome, bilateral acquired juxtafoveolar telangiectasis, and vitamin A deficiency.
Calcium oxalate crystals may be found within the retina as an incidental finding in patients with long-standing retinal detachment (see Chapter 7, Figure 7.31A and B ) and with morgagnian cataracts unassociated with evidence of systemic oxalosis.
Canthaxanthine Maculopathy
Canthaxanthine is a carotenoid dye used in food and drug coloration. Some patients who use it orally (usually a total dose of 19 g or more within 24 months) as a tanning agent may develop a symmetric distribution of golden particles in a doughnut pattern in the superficial retina in the macular areas ( Figure 9.10 ). The retinal crystals may be exaggerated in eyes with other diseases of the fundus ( Figure 9.10D–I ). A few patients may develop similar crystals in the cornea at the level of Descemet’s membrane. Retrospective studies of pure canthaxanthine (Orobronze) consumers revealed an incidence of retinal deposits varying from 12% to 14%. The occurrence of the deposits correlates with the total dose ingested. In two studies 37 g canthaxanthine induced retinal deposits in 50% of the patients and 60 g induced deposits in 100% of patients. Predisposing factors that lead to onset of retinopathy at much lower dosage include focal disease of the RPE, ocular hypertension, and concurrent use of beta carotene ( Figure 9.10D–I ). Hennekes reported the development of canthaxanthine retinopathy in a patient with retinitis pigmentosa after ingestion of 12–14 g over a period of 4 months. The maculopathy is usually associated with normal visual acuity but reduced retinal sensitivity. Some patients may demonstrate subnormal dark adaptation and electroretinographic responses. The ERG changes in most patients are reversible after the ingestion of canthaxanthine is stopped. EOG responses are normal. Fluorescein angiography is typically normal but may show a bull’s-eye pattern of faint hyperfluorescence ( Figure 9.10C ). Morphologically these red, birefringent, and lipid-soluble carotenoid crystals are located in the inner layers of the entire retina and the ciliary body. They are particularly large and numerous perifoveally, where they are clinically visible. They are located in a spongy degeneration of the inner neuropil and are associated with atrophy of the inner parts of Müller cells. They presumably represent a canthaxanthine–lipoprotein complex.
The retinal crystals may gradually disappear a year or more after ingestion of canthaxanthine is discontinued, and some may remain for at least 7 years. The delay in reversibility is in keeping with the observation that the plasma concentration of canthaxanthine takes at least 9 months to recover to normal levels in patients having received daily oral dosage of 100 mg for 3 months. The return to normal values of static perimetry threshold in some patients suggests that the abnormality is not the result of an irreversible anatomic alteration, as suggested in experimental studies in rabbits.
Retinopathy identical to that of canthaxanthine retinopathy may occur in some patients without a history of extradietary intake of canthaxanthine ( Figure 9.08J and K ). Similar retinopathy has developed in one patient receiving long-term nitrofurantoin therapy.
Administration of amounts of canthaxanthine comparable to those ingested by patients developing canthaxanthine retinopathy produced morphologic changes in the retina of rabbits and cats, but no retinal crystals. The cats developed a progressive orange sheen to the ocular fundus that morphologically was associated with increased RPE cell height and vacuolization caused by enlargement and disruption of phagosomes. Dose-dependent ingestion of canthaxanthine in cynomolgus monkeys has shown accumulation of the crystals in nests and rods within ganglion cells near the ora serrata and in the macula. An ultrahigh-frequency OCT showed the crystals to be in superficial retina.
West African Crystalline Maculopathy
Elderly patients from the Igbo tribe in Southeastern Nigeria in West Africa have been found to deposit green or yellow, refractile, foveal crystals that are bilateral and asymmetric in distribution. Subsequent reports have found the crystals in several West African tribes, including those in Liberia, Ghana, and Sierra Leone. These crystals are found in the inner retina, mostly in the foveal inner plexiform layer, and do not affect vision or electrophysiology of the eyes ( Figure 9.11A–E ). OCT can demonstrate the location of the crystals, seen in the superficial retina in Figure 9.11L . Most patients are older than 50 years of age. The original description of the condition attributed the crystals to ingestion of kola nuts. However, only one of three patients had a history of ingestion of kola nuts more than 20 years previously. Fifteen of the 20 patients reported so far and two others ( Figure 9.11A–I ) had diabetic retinopathy, one sickle-cell retinopathy, one branch retinal vein occlusion (BRVO), one familial exudative vitreoretinopathy (FEVR), and one other patient of Dr. Edwin Ryan had a branch retinal vein occlusion; it is conceivable that the hyperpermeability of their retinal vessels may have facilitated the deposition of the crystals. All reported cases thus far have found crystals in the macula; however Figure 9.11F–H illustrates extramacular deposition of crystals in the vicinity of the flat new vessels in this patient with proliferative diabetic retinopathy. Her brother with nonproliferative diabetic retinopathy has macular crystals only.
Nitrofurantoin Crystalline Retinopathy
Nitrofurantoin macrocrystal used for a prolonged period (19 years) in a patient resulted in deposition of the shiny crystals in and around the disc and macula in both eyes. The antimicrobial is used to treat urinary tract infections. Its chemical structure delays dissolution and hence remains in a crystalline form and may become deposited on prolonged use.
Flecked Retina Associated with Vitamin a Deficiency
Patients with vitamin A deficiency secondary to inadequate dietary intake, malabsorption states resulting from celiac sprue, regional enteritis, jejunal bypass surgery, chronic liver disease, hepatic transplantation and more recently with bariatric surgery may develop night blindness, corneal xerosis, and a peculiar peripheral retinal change characterized by the presence of multiple, yellow-white, somewhat granular spots in the outer retina Figure 9.12A, C, D, F, and K ) (fundus xerophthalmicus; Uyemura’s syndrome). These flecks are of various sizes and shapes and simulate drusen. The retinal changes have been associated with marked constriction of the visual fields ( Figure 9.12H and I ), abnormal dark adaptation, and electroretinographic changes, including disappearance of the a-wave followed by loss of the b-wave and greater reduction of the scotopic than the photopic responses. Following administration of vitamin A, there may be either complete or partial ( Figure 9.12A and J–L ) reversal of the fundus and electrophysiologic changes, depending on the chronicity of the deficiency. The fundus changes are more likely to occur in those patients with vitamin A deficiency who develop evidence of corneal xerosis.
Fluorescein angiography shows only a mild variable fluorescence of the flecks ( Figure 9.12G ), suggesting the location of the flecks to be primarily at the photoreceptor layer; only some of these may cause secondary RPE change, accounting for the patchy hyperfluorescence.
Animals with vitamin A deficiency histopathologically develop disorganization of the rod outer segments and eventual loss of the visual cells. It is probable that the transient yellow-white spots occurring in humans are related to the macrophagic response to loss of rod outer segments and RPE cell disruption similar to that which has been demonstrated histopathologically to account for the peculiar yellow-white spots that may be seen in patients with Leber’s congenital amaurosis soon after birth. Malabsorption syndromes, including gluten enteropathy or celiac disease ( Figure 9.12J and K ), nutritional and other causes of malabsorption, liver dysfunction such as cirrhosis ( Figure 9.12K and L ), and most recently gastric bypass surgery are common clinical settings for vitamin A deficiency. Concomitant zinc deficiency has also been implicated in the pathogenesis of xerophthalmia.
One 50-year-old man with acquired night blindness associated with steatorrhea was noted to have the typical changes of fundus albipunctatus. His abnormal dark adaptation curves improved after vitamin A administration, but the fundus remained unchanged. Although it was postulated that the albipunctate spots may have resulted from photoreceptor damage after chronic vitamin A deficiency, this seems unlikely since other investigators who have studied this disease have not noted persistence of the white spots following therapy.
Aminoglycoside Maculopathy
The inadvertent injection of large doses of gentamicin into either the anterior chamber after cataract extraction or the vitreous during a sub-Tenon’s injection may produce a rapid and severe visual loss associated with a peculiar retinopathy that is most marked in the macular area ( Figure 9.13 ). The patient is usually aware of profound loss of vision on the first postoperative day. Initially the fundus picture may simulate that seen in central retinal artery occlusion. There is marked whitening and swelling of the retina in the macular area associated with a cherry-red spot ( Figure 9.13D, F, and I ). Other surrounding areas of patchy retinal whitening may be evident. Retinal hemorrhages develop and become more numerous ( Figure 9.13A, F, and I ). Although intravitreal injection of levels of gentamicin up to 200 μg were previously considered safe for the treatment of endophthalmitis, macular infarction may occur in some patients after intravitreal injection of 0.1 or 0.2 mg gentamicin sulfate. Repetitive injections of nontoxic doses may produce retinal damage. Fluorescein angiography typically shows a sharply defined zone of retinal vascular nonperfusion in the macular area associated with dye leakage from the neighboring retinal vessels ( Figure 9.13B, C, E, G, H, K, and L ). The retinal whitening and hemorrhages may persist for many weeks or several months ( Figure 9.13J ). Optic atrophy and retinal pigmentary changes develop later and may be accompanied by rubeosis irides and hemorrhagic glaucoma. The visual prognosis is poor.
It is probable that gentamicin and not the preservatives is the primary cause of the retinal infarction. Although experimentally the presence or absence of the lens or vitreous does not change the toxic threshold to injected aminoglycosides, there is concern clinically that nontoxic doses of aminoglycosides may be toxic if injected intravitreally into vitrectomized eyes. Although tobramycin and amikacin are less toxic than gentamicin, both have produced fundus findings similar to those caused by gentamicin. The retinopathy has been observed most frequently following intravitreal injections of 0.4 mg gentamicin after vitrectomy, but also in some cases after injection of 0.1 or 0.2 mg, doses that had previously been considered safe. Prophylactic use of subconjunctival injection of gentamicin after routine surgery was the second most frequent cause of macular infarction. The retinopathy has been observed following the inadvertent intraocular injection of tobramycin after cataract extraction. In one case this apparently resulted from diffusion of the subconjunctivally injected drug through the cataract wound. The same maculopathy has occurred after intravitreal injections of amikacin. With the advent of sutureless vitrectomy, surgery using subconjunctival gentamicin is fraught with the same risk. Because of the frequency and severity of the complication, Campochiaro and Lim recommended: (1) abandonment of prophylactic use of subconjunctival aminoglycosides after routine surgery, and (2) avoidance of intravitreal aminoglycosides in the prophylaxis of penetrating ocular trauma. Ceftazidime has replaced intravitreal amikacin for treatment of endophthalmitis.
Experimentally, retinal toxicity to gentamicin may occur at levels as low as 100 μg injected into the vitreous. In the rabbit model D’Amico et al. found lamellar storage material in the liposomes of RPE and macrophages after injection of 100 μg into the vitreous; disruption of pigment epithelial cell organelles and loss of photoreceptors after 400 μg; and full-thickness retinal necrosis after 800 μg. These findings implicate the RPE as the primary site of toxicity. Aminoglycoside maculopathy similar to that seen in humans has been produced in subhuman primates following intravitreal injection of 1000–10 000 μg gentamicin. Evidence suggests that the retinal whitening and the isoelectric electroretinographic findings that occur within minutes or hours of the injection are caused by direct damage to the inner retina by the drug before development of occlusion of the retinal vasculature. Rabbit and rat retinas both in vitro and in vivo, exposed to escalating small doses of gentamicin, showed reversible loss of b-waves but preserved a-waves. The reduced b-wave may be from metabolic effect on the bipolar cells or secondarily via effect on glutamate transport by the Müller cells. It is possible that aminoglyocosides induce metabolic change in the inner neurons that secondarily affect vascular perfusion. Alternately or in addition the toxic metabolic effects may occur at the vascular endothelial cells. Histology of the retina showed diffuse vacuolization of the nerve fiber, ganglion cell, and inner plexiform layers. The latter is accompanied by retinal hemorrhages, damage to retinal pericytes and endothelial cells, and thrombosis. A possible mechanism to explain the retinal vascular occlusion was granulocytic plugging of the retinal capillary bed.
In some patients aminoglycoside macular toxicity may be difficult to differentiate from that produced as a complication of intraneural injection during retrobulbar anesthesia or that resulting from spontaneous occlusion of the central retinal artery and vein. The vitreous inflammatory cell reaction, shallow retinal detachment, and delayed onset of retinal hemorrhages, as well as the characteristic angiographic pattern and prolonged retinal whitening associated with aminoglycoside toxicity are helpful in this regard.
Interferon-Associated Retinopathy
Patients receiving interferon alfa 2-a subcutaneously or interferon alfa 2-b intravenously ( Figure 9.14A–C ) may develop multiple cotton-wool ischemic patches in the retina associated with retinal hemorrhages. The pattern of the retinopathy may simulate Purtscher’s retinopathy and be associated with decreased visual acuity. The fundus changes are reversible after discontinuing the interferon therapy. Mild diabetes and systemic hypertension were present in 50% of patients developing the retinopathy. Similar fundus changes with retinal hemorrhages and cotton-wool spots with visual field changes have been seen, though less frequently, in patients receiving interferon beta-1b for multiple sclerosis. The fundus changes and field defects reverse once the drug is discontinued. These observations suggest that patients with moderately severe diabetic, hypertensive, or other retinopathy associated with retinal capillary nonperfusion may be at greater risk of progression of the retinopathy and permanent visual loss following the administration of large amounts of interferon such as might be used in the treatment of patients with malignancies. Circulating C5a levels have been found to be elevated in some patients developing retinopathy on interferon alpha; whether this is the cause or the result of the vasculopathy is undetermined.
