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

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.

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