Chorioretinal Toxicities




Introduction


Numerous exogenous molecules may cause toxic chorioretinitic effects. Some agents cause disruption of the retinal pigment epithelium (RPE), while others produce vascular damage within the retina. Certain agents may also produce edema of the retina, particularly in the macular region, while other agents produce crystalline deposits in the retina from derivatives of their metabolites or even direct deposits as a function of embolic phenomena. An increasing number of drugs are used for the treatment of uveitis or systemic disease and may be associated with toxic effects in the fundus.




Disruption of The Retinal Pigment Epithelium


Chloroquine Derivatives


Chloroquine


Chloroquine is a 4-aminoquinoline derivative used originally as an antimalarial agent, but subsequently for a variety of other diseases, including amebiasis, rheumatoid arthritis, and systemic lupus erythematosus. Its toxicity begins with a very mild, asymptomatic perifoveal granularity at the level of the RPE, followed by progressive loss of pigment epithelium cells and photoreceptors with a peculiar predilection for the inferior perifoveal and paramacular areas, and eventually the entire macula itself. The retinopathy is rarely reported with a total dosage less than 300 g or a daily dosage of less than 250 mg/day. The pigment epithelial degeneration may, in severe cases, extend to involve the near and far peripheral fundus. Following discontinuation of the drug, the retinopathy may still progress as it is slowly metabolized and released by the liver.




This patient has a typical area of perifoveal atrophy in the inferior portion of the macula from chloroquine toxicity. There is a peculiar predilection for the inferior perifoveal and paramacular region in this disorder.





Light microscopy reveals a ring of photoreceptor loss and an aggregation of pigmented cells corresponding to the clinically evident toxicity.





This patient has typical bilateral disease, which is asymmetric with more advanced disease in the left eye and forms a ring or “bull’s-eye” appearance.

Courtesy of Dr. Keye Wong





These two patients reveal chloroquine toxicity with a “bull’s-eye” atrophy (left) and more diffuse pathology through the papillomacular bundle and the paramacular region ( right ) .





Chloroquine toxicity can progress to involve the periphery, which shows a retinitis pigmentosa-like fundus. Note the bony spicule appearance with pigment epithelial cell migration into the retina.





Chloroquine toxicity is typically bilateral. This patient illustrates the variation in the atrophy that may evolve in the course of the toxic response. The fluorescein angiograms show “window defect” or choroidal hyperfluorescence through atrophic defects in the RPE.





In this patient the area of atrophy forms an ovoid configuration, which is quite typical, again with a more pronounced effect in the inferior juxtafoveal and paramacular areas.





These patients demonstrate the nature of RPE disease in severe chloroquine toxicity. Progressive toxicity extends from the perifoveal area in early cases to more diffuse atrophy in severe toxicity, as above. Again, these patients demonstrate the inferior predilection of the toxic effect. Light exposure may be an explanation for this asymmetric feature.




Hydroxychloroquine


Hydroxychloroquine (Plaquenil) is a derivative of chloroquine and causes similar pathology, but generally less severe than chloroquine. Hydroxychloroquine appears to be significantly safer to use compared to chloroquine, yet it still may be toxic to the retina, producing a similar clinical presentation. Doses up to 5.0 mg/kg/day are typically considered safe. Concurrent tamoxifen therapy or chronic kidney disease may hasten onset of retinopathy. Asian patients may demonstrate a perifoveal pattern of toxicity.




This patient has bilateral hydroxychloroquine toxicity with a “bull’s-eye” appearance that is indistinguishable from chloroquine toxicity.





The pathology shows irregular pigment epithelial cell loss and photoreceptor damage.





These two patients demonstrate the variation in the atrophic pattern of hydroxychloroquine toxicity with early changes in the inferior juxtafoveal area (left) and more prominent disease surrounding the fovea (middle), with advanced toxicity (right).





In this more advanced hydroxychloroquine toxicity, there is total involvement of the perifoveal region, forming a “bull’s-eye” appearance that is indistinguishable from chloroquine toxicity.

Left image courtesy of Dr. Keye Wong





Color photographs (top left) showing mild macular pigment mottling in a patient on hydroxychloroquine with corresponding hyperfluorescence on fluorescein angiography (top right) in the pattern of a bull’s eye. Fundus autofluorescence shows a perifoveal hypoautofluorescence with a border of hyperautofluorescence (middle left) . OCT shows atrophy of the outer nuclear layer and disruption of the ellipsoid segment (middle right) . Multifocal electroretinogram (mfERG) shows diminished paracentral waveforms (bottom row) .

Courtesy of Dr. David Sarraf




Phenothiazines


Thioridazine


A piperidine initially introduced for treatment of psychoses, thioridazine (Mellaril) is a phenothiazine derivative that may cause damaging effects to the RPE, which can result, in some cases, in a “salt and pepper” appearance of the fundus with zonal atrophy and pigment epithelial clumping. Retinal toxicity is usually seen in doses in excess of 1000 mg/day with a total accumulation of 85-100 g over a 30-50-day period. Severe retinal toxicity may progress even after the drug is discontinued. It is believed that the toxic mechanism is mediated through a piperidyl side chain, which inhibits retinal enzymes and produces subsequent toxicity. Other explanations have been conceptualized, which include a dopamine and oxidative phosphorylation with derangement of rhodopsin. There is no treatment for the disintegration of the outer segments and the accumulation of lipofuscin in the RPE.




This is a patient with early but diffuse manifestations of thioridazine (Mellaril) toxicity. There is a granular or “salt and pepper”-like appearance to the fundus. The effect on the pigment epithelium is accentuated on the fluorescein angiogram.





This patient has more advanced thioridazine toxicity with irregular atrophy in the central macula and pigment epithelial hyperplastic clumping.





These two patients have progressive atrophy and pigment epithelial hyperplasia. The atrophy is not only in the macula and paramacular area (left two images), but also extends out to the periphery (right two images). The fluorescein angiogram shows pigment epithelial and choriocapillaris atrophy.





These two patients with thioridazine toxicity have extensive pigment epithelial zonal hyperplasia (left) and atrophy (right).





In this case of thioridazine toxicity the montage photos show multizonal areas of atrophy in the mid-peripheral retina with areas of relatively sparse toxicity in the periphery.





A montage fluorescein angiogram shows a “window defect” through the atrophic pigment epithelium, which is indicative of good perfusion of the choriocapillaris, with the exception of a few zonal areas of pigment aggregation and/or choriocapillaris atrophy that appear hypofluorescent.





Fundus photographs and fluorescein angiograms show extensive nummular pigmentary changes with atrophy of the choriocapillaris in intermediate thioridazine toxicity.

Courtesy of Dr. David Sarraf





This montage illustrates widespread atrophy and pigment epithelial hyperplastic change in a patient with severe thioridazine toxicity.





The gross appearance of thioridazine retinal toxicity reveals widespread atrophy of the RPE. There is an area of intact RPE near the macula (arrow), as well as only partial atrophy of the photoreceptors. The histology shows photoreceptor and RPE degeneration.




Chlorpromazine


Chlorpromazine is a piperidine similar to thioridazine, but lacks a piperidyl side chain. It is also used in the treatment of psychomotor disorders. The drug itself binds strongly to melanin and very infrequently causes retinal toxicity. The toxic changes include retinal granularity, pigment clumping, and some RPE atrophy. Reversal of the toxic effect may occur with discontinuation of the drug. Crystalline deposits have been described in the lens as cortical opacities.




These images show a granular and patchy atrophic effect to the RPE in the central macula and beyond. The fluorescein angiogram reveals pronounced window defect because the choriocapillaris is intact and hyperfluorescent through the atrophic RPE.





These patients demonstrate early toxicity of the macula (left) and more extensive toxicity throughout the posterior pole ( right) due to chlorpromazine .





Chlorpromazine toxicity may also produce granular opacities in the lens, as evident in this patient.




Dideoxyinosine (DDI)


A mid-peripheral pigmentary retinopathy has been noted in HIV patients receiving high-dose therapy with the antiviral 2′, 3′-dideoxyinosine. Chorioretinal atrophy is typically noted anterior to the vascular arcades.




Fundus photograph and fluorescein angiogram exhibiting mid-peripheral retinal pigmentary changes in a patient previously treated with DDI. Fundus autofluorescence demonstrates patches of peripheral hypoautofluorescence. OCT shows outer retinal and RPE atrophy.

Courtesy of Dr. Scott Sneed




Clofazimine


Clofazimine is a phenazine dye that has been used to treat mycobacteria, psoriasis, pyoderma gangrenosum, and discoid lupus. Toxicity may cause crystal accumulation in the cornea or pigmentary retinopathy.




Clofazimine toxicity resembles that of thioridazine toxicity. In this patient, there is peripapillary and posterior polar atrophy with relative sparing of the pigmented perifoveolar zone.




Deferoxamine


Deferoxamine is a drug used for the treatment of excess iron overload generally from chronic transfusions for anemias. Patients may experience reduced vision from RPE atrophy and hyperpigmentation accumulation, a pseudovitelliform detachment, optic neuritis, or cataract.




This patient with deferoxamine toxicity has a multifocal pattern dystrophy interspaced with irregular atrophy in the central macula. The fundus autofluorescent photographs shows accumulation of lipofuscin in the darkly pigmented areas, evident clinically. This indicates that the dark, nummular areas actually represent lipofuscin and melanin. The OCT image shows an elevation to the pigment epithelium in the areas where there is excess lipofuscin accumulation and thinning of the pigment epithelium in atrophic zones. There is also photoreceptor loss.





Patients with deferoxamine toxicity may develop a pseudovitelliform detachment like a patient with basal laminar cuticular drusen and/or a pattern dystrophy. The subretinal staining evident on the fluorescein angiogram does not represent underlying choroidal neovascularization.

Courtesy of Dr. Nicole Gross




Chemotherapeutic Agents


Denileukin Diftitox


This drug is a recombinant protein composed of human interleukin-2 (IL-2) fused to diphtheria toxin. It has a selective cytotoxicity against activated lymphocytes with a high expressivity of the IL-2 receptor. Reports of retinal toxicity have been in patients who were given this drug for steroid-resistant graft-versus-host disease. Vascular leakage producing edema and direct toxicity of selective tissues has been reported with the use of this drug. Extensive RPE mottling and photoreceptor damage may suppress ERG recordings. It may also simulate a cancer-associated retinopathy with diffuse photoreceptor and RPE changes that may not be clearly evident clinically.




This patient has a generalized, early toxicity to the RPE secondary to denileukin use. Faintly evident atrophy is seen on the fluorescein angiogram as a “window defect” from RPE atrophy.





Follow-up of this patient shows more advanced stages of RPE atrophy on fundus photography and fluorescein angiography.




MEK Inhibitors


A new class of chemotherapy agents selectively inhibiting the mitogen-activated protein kinase/extracellular signal-regulated kinase (MAPK/ERK), also referred to as the MEK enzyme, has shown promising results for systemic malignancies including metastatic melanoma. The typical ocular side-effect described is multifocal serous retinal detachment.


However, pigment epithelial detachment, optic neuropathy, retinal vein occlusion, retinal hemorrhage, cystoid macular edema, and anterior chamber inflammation may also be seen.




Color photograph, infrared, and OCT demonstrating multiple pigment epithelial detachments while on the MEK inhibitor pimasertib.

Courtesy of Michael Chilov






Vascular Damage or Occlusion


Quinine Sulfate


Quinine has been used medically for centuries for a variety of diseases, including the treatment of malaria and muscle spasms. Symptoms of toxicity include blurred vision, visual field loss, nyctalopia, photophobia, and, rarely, transient blindness. Retinal vessel attenuation and disc pallor are early manifestations of toxicity. All layers of the fundus including the pigment epithelium, photoreceptors, and ganglion cell layer, will exhibit secondary adverse effects from damage to the vasculature.




These patients with quinine toxicity developed ischemia of the retina, photoreceptor damage, and optic atrophy. The manifestations are less pronounced in the patient on the left and very severe in the patient on the right.





This patient has quinine toxicity with peripapillary retinal vascular ischemia and optic atrophy bilaterally.




Oral Contraceptives


Systemic thromboembolic diseases are known to be associated with the use of oral contraceptives. Retinal adverse effects include arteriolar occlusion, central vein occlusion, retinal hemorrhages, and macular edema. Given this retinal vascular occlusive risk, patients with pre-existing systemic or retinal vascular disease should be extremely cautious about using oral contraceptives.




This patient was using oral contraceptives. She experienced a venous stasis retinopathy with marked tortuosity, scattered hemorrhages (middle), segmental venular staining, and macular edema that progressed to a more severe non-ischemic vein occlusion.




Ergot Alkaloids


Ergot alkaloids are adrenergic blockers used to prevent migraine headaches and to control postpartum hemorrhage. Ocular complications have been reported including vasoconstriction of retinal vessels, cystoid macular edema, venous occlusive disease, and optic neuritis.




This patient was using ergotamine and experienced a central retinal vein thrombosis and severe macular edema.




Procainamide


Procainamide is an anti-arrhythmic drug used to decrease the incidence of sudden cardiac death. Procainamide depresses the excitability of cardiac muscle to electrical stimulation and slows electrical conduction. It is considered to be a sodium channel blocker. Cases of acute anterior uveitis have been reported, as well as secondary manifestations that may involve the retinal circulation with permeability and ischemic abnormalities. Optic atrophy may also be a rare association.




Procainamide toxicity produced zonal areas of retinal whitening secondary to vascular ischemic disease in these two patients. The vascular occlusive disease and optic atrophy can be very severe as in the patient in the image to the right.




Cocaine Abuse


Cocaine is a crystalline tropane alkaloid that is obtained from the leaves of the coca plant. Adverse effects in the eye relate to a carrier substance, which may be used to administer the drug intravenously. The result is a catecholamine systemic hypertensive response that could lead to hypertensive retinal vascular changes and embolic phenomena.




Cocaine use can induce an immediate rise in blood pressure, particularly when inhaled or smoked. This patient noted a sudden change in vision and a focal area of axoplasmic debris (arrow) was present. A medical work-up was unrevealing and the cotton-wool spot resolved spontaneously after discontinuation of this illicit drug (middle). More severe ischemia can be seen in some patients using cocaine at higher doses for longer periods, which can result in chorioretinal infarctions. Note the multiple areas of axoplasmic debris (right).





The hemorrhages are intermingled with scattered axoplasmic debris (left) and ischemia as seen on fluorescein angiography (right). Some of these changes may be the result of severe, concomitant, systemic hypertension, resulting from drug use. Some of these eyes may also reveal choroidal ischemia.

Left image courtesy of Dr. Matthew Benz





Color fundus photographs and fluorescein angiograms demonstrate areas of choroidal ischemia in a patient abusing cocaine.





This patient had a history of cocaine abuse and presented with significant choroidal ischemia as seen in the fundus photograph and fluorescein angiogram. The triangular region of infarction is suggestive of the sign of amalric.

Courtesy of Dr. David Sarraf

Jul 30, 2019 | Posted by in OPHTHALMOLOGY | Comments Off on Chorioretinal Toxicities

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