- 1.
Describe the clinical features of chloroquine retinopathy.
Patients are usually asymptomatic but some may experience difficulties with reading due to paracentral scotomas or metamorphopsia. Because the initial retinal changes are in the parafoveal area, the visual acuity is typically normal in the early stages of retinopathy. Nyctalopia, color vision defects, and blurred vision occur when the retinal epithelial atrophy extends to involve the fovea. In the early stages of toxicity, mild mottling of the perifoveal retinal pigment epithelium is seen in conjunction with a reduced foveal reflex. Peripheral pigmentary changes often occur at this stage but may be overlooked. Macular pigmentary changes progress to a classic bull’s eye maculopathy ( Fig. 40-1 ). In the later stages, generalized retinal pigmentary changes occur with vascular attenuation and optic disc pallor.
Figure 40-1
Bull’s eye lesion due to chloroquine retinopathy: color photograph (A), autofluorescence image (B), magnified photograph of macula with associated spectral domain optical coherence tomography (C).
- 2.
What doses of chloroquine and hydroxychloroquine cause retinopathy?
Retinopathy is unlikely with a daily dose of <4 mg/kg/day chloroquine (CQ) or <6.5 mg/kg/day hydroxychloroquine (HCQ). A daily dose of >8 mg/kg/day hydroxychloroquine produces retinopathy in 40% of cases. Retinopathy is extremely unlikely with a total dose <100 g of chloroquine or <300 g of hydroxychloroquine and rare with total doses of <300 and <700 g, respectively.
- 3.
What are the risk factors for chloroquine and hydroxychloroquine retinopathy?
The cumulative dose is believed to be the most important risk factor. A cumulative dose of 1000 g of HCQ is reached in 7 years with a typical daily dose of 400 mg, and a cumulative dose of 460 g of CQ is reached in 5 years with a typical daily dose of 250 mg. With daily doses of >6.5 mg/kg for HCQ and >3.0 mg/kg for CQ accumulation of the drug may enhance the rate or degree of toxic retinopathy. CQ and HCQ are excreted by the kidney and liver. Therefore, hepatic and renal failure/disease are risk factors, because they may contribute to increased blood levels of the drug. Other risk factors are age, genetic factors, and preexisting macular disease.
- 4.
How should patients taking chloroquine and hydroxychloroquine be monitored?
All patients starting CQ or HCQ therapy should have a baseline examination within the first year of the treatment. The baseline examination should include careful biomicroscopy, automated threshold visual-field testing with a white 10-2 protocol for the detection of paracentral scotomas, and one or more further subjective tests for screening: spectral domain optical coherence tomography (SD-OCT) showing disorganization or loss of the ellipsoid layer in the parafoveal region of the macula is an early objective sign. Similarly, the multifocal electroretinogram (mfERG) is more sensitive in documenting localized paracentral functional loss compared to the white 10-2 visual field. Fundus autofluorescence (FAF) imaging may reveal paracentral foci of hyperfluorescence due to accumulation of outer segment debris within the retinal pigment epithelium (RPE) and hypofluorescent areas in the later stages due to RPE loss. Baseline color fundus photography may be useful for documentation. Annual screening should be performed after 5 years of treatment with CQ and HCQ as described above.
- 5.
What management is advised for chloroquine retinopathy?
If retinal toxicity is present, hydroxychloroquine or chloroquine should be stopped immediately. There is a stage of very early functional loss when the cessation of the drug will reverse the toxicity, but progression typically continues although it is not clear if it is related to low excretion of the drug or to gradual decompensation of cells that were damaged during the period of drug exposure. If suggestive findings/visual symptoms occur, subjective tests should be repeated (automated fields, mfERG, SD-OCT, FAF). If toxicity is suspected, cessation of the CQ and HCQ followed by 3- to 6-monthly review is advised. Patients with probable toxicity (bilateral bull’s eye scotoma, bilateral paracentral mfERG, SD-OCT/FAF abnormalities) should be closely monitored every 3 months.
- 6.
Is the pathogenesis of chloroquine and hydroxychloroquine retinopathy understood?
The earliest histopathologic changes of chloroquine retinopathy include membranous cytoplasmic bodies in ganglion cells and degenerative changes in the outer segments of the photoreceptors. However, chloroquine has a selective affinity for melanin, and it has been suggested that this affinity reduces the ability of melanin to combine with free radicals and protect visual cells from light and radiation toxicity. Other authors believe that the drug may directly damage photoreceptors.
- 7.
How may thioridazine affect the retina?
Thioridazine (Mellaril) may cause nyctalopia, dyschromatopsia, and blurred vision. The earliest retinal changes are a fine mottling or granularity to the retinal pigment epithelium posterior to the equator, which may progress to marked pigmentary atrophy and hypertrophic pigment plaques ( Fig. 40-2 ). Vascular attenuation and optic atrophy may follow. Toxicity is said to be uncommon with daily doses <800 mg/day but may develop rapidly with doses over 1200 mg/day. Toxicity is more dependent on total daily dose than on cumulative dose. In perimetry, a nonspecific but most characteristic finding is a paracentral or ring scotoma. Fluorescein angiography reveals the loss of RPE and choriocapillaris within the areas of depigmentation.
Figure 40-2
Thioridazine retinopathy.
- 8.
What other phenothiazines cause retinopathy?
Retinal toxicity has been reported with other phenothiazines, including chlorpromazine. However, these compounds are less likely to cause retinopathy, probably because they lack the piperidinylethyl side group of thioridazine. It is thought that 1200 to 2400 g/day chlorpromazine for at least 12 months is required before toxicity occurs.
- 9.
How may quinine sulfate cause retinopathy?
Quinine sulfate is used for nocturnal cramps and as a malarial prophylaxis. It may cause retinal toxicity after a single large ingestion (4 g). The therapeutic window is narrow, with some patients taking a daily dose of 2 g. Patients develop blurred vision, nyctalopia, nausea, tinnitus, dysacusis, and even coma within 2 to 4 hours of ingestion. The acute findings include dilated pupils, loss of retinal transparency caused by ganglion cell toxicity ( Fig. 40-3 ), and dilated retinal vessels. As the acute phase resolves, vessel attenuation and optic disc pallor result. Visual acuity may improve after the acute phase.
