Toxicity with Diffuse Retinal Changes

Toxicity with Pigmentary Degeneration

Quinolines

Chloroquine (Aralen, Sanofi Winthrop Pharmaceuticals, New York, NY), a member of the quinoline family of agents, and the less toxic derivative hydroxychloroquine (Plaquenil, Sanofi Winthrop Pharmaceuticals, New York, NY) are antimalarial agents also used to treat certain rheumatologic diseases.

Quinoline retinal toxicity has been recognized for over 50 years [1–4]. Initially, the patient may be asymptomatic, and the first sign may be a loss of the foveal light reflex. Verticillata-like changes of the cornea may be noted. Nonspecific macular pigmentary alterations typically ensue, ultimately leading to the classic bull’s eye lesion (Fig. 26.1a, b). In advanced cases, diffuse retinal pigmentary changes may develop, associated with retinal vascular attenuation and optic atrophy (Fig. 26.2a–d).

In mild cases, discontinuation of the agent may cause stabilization or even amelioration of toxicity, although patients with more advanced disease may continue to progress [5]. Quinolines are associated with an exceptionally long clearance time [6], and toxicity 7 years following discontinuation of chloroquine has been reported [7].

In 2002, a task force of the American Academy of Ophthalmology (AAO) established guidelines for screening patients being treated with quinoline

antimalarials, particularly hydroxychloroquine. The task force recommended risk stratification based on a baseline examination, including assessment of daily dosage, dilated fundus examination, and either Amsler grid testing or automated macular perimetry [8]. Patients being treated with a daily dose less than 3 mg/kg of chloroquine or 6.5 mg/kg of hydroxychloroquine, with no other systemic or ocular risk factors, were considered unlikely to develop retinal toxicity and could be followed as per the AAO Preferred Practice Patterns for otherwise healthy adult patients [9]. The daily dose should be calculated based on ideal body weight, rather than actual weight, because quinolones are stored to a greater degree in lean body tissues. Obese patients may require more frequent monitoring [10].

These guidelines are well established and straightforward, but there appear to be challenges in their practical implementation. In one study, about one-third of patients being treated with hydroxychloroquine had not received an eye examination [11]. More recently, screening roles have been proposed for spectral domain optical coherence tomography (OCT) [12], fundus autofluorescence [13], and multifocal electroretinography (ERG) [14]. The precise roles of these ancillary tests are yet to be fully determined, along with microperimetry.

In early 2011, the screening guidelines for monitoring patients on hydroxychloroquine were updated by a task force from the American Academy of Ophthalmology [15]. These guidelines included recommendation of a baseline

Fig. 26.2 (a) Color photograph showing a bull’s eye pattern of maculopathy. (b) Corresponding FA highlighting the area of pigment loss. (c) Color photograph of the same patient several years later, having been off of chloroquine

in the interim, documenting progression of disease even in the absence of supplemental medication. (d) FA highlighting the expanded area of pigment loss

examination performed at the commencement of therapy. Screening examinations during the first 5 years of therapy can be performed during routine ophthalmic examination (interval to be determined by the age of the patient and the presence or absence of retinal or macular disease). Earlier recommendations emphasized dosing by weight, as most patients are given 400 mg/day of hydroxychloroquine. This dose is generally acceptable for all patients except for those of short stature (generally 5 ft 2 in. or less in height). These

patients should be given a dose based on their ideal body weight, as otherwise overdosage may occur (Fig. 26.3a, b). Furthermore, the dosage may need to be altered if the patient has renal or liver dysfunction.

After 5 years of therapy, screening should be performed at least annually. Current guidelines are centered around tests found to detect early toxicity often prior to any appreciable fundus findings. Patients should have a Humphrey 10-2 automated visual field (HVF) test with a white

Fig. 26.4 Screening tests for hydroxychloroquine toxicity. (a) Color photograph showing very minimal macular pigment mottling in a patient on hydroxychloroquine for 5 years. (b) Fundus autofluorescence shows a minimal degree of abnormality in the macular region. (c) Spectral

domain OCT shows minimal disruption of the inner segment/outer segment (IS/OS) junction. (d) Multifocal ERG (D) shows normal waveforms (Images courtesy of Michael Marmor, M.D., Stanford, CA)

test object and in addition should have one of three objective tests at each screening: spectral domain OCT (SD-OCT), multifocal electroretinogram (mfERG), and/or fundus autofluorescence (FAF) (Fig. 26.4a–d). Any abnormalities of the pattern deviation on the HVF need to be taken seriously. In most situations, SD-OCT should also be obtained. While abnormalities on FAF are generally associated with concerns for active disease, the test has not yet been shown to be reliably predictable as a screening tool for future toxicity. While mfERG is most likely the most sensitive test, it is still not uniformly available to all patients.

As noted in the preceding paragraph, it is imperative to discuss the risk of toxicity with patients and the rationale for screening (to detect, but not necessarily prevent visual loss). If ocular toxicity occurs and is recognized at an early stage, efforts should be made to communicate this directly to the prescribing physician so that

alternative treatment options can be discussed with the patient. In almost all cases, cessation of the drug should be suggested.

The related medication quinine (Quinamm, Marion Merrell Dow, Inc., Kansas City, MO) is used to treat benign nocturnal muscle cramps and may be associated with distinct toxicity. Acute overdose is associated with headache, nausea/ vomiting, tremor, hypotension, and loss of consciousness, associated with severe visual loss [16]. Acutely, there may be mild retinal edema with mild venous dilation. Over several weeks, arteriolar attenuation and optic atrophy develop (Fig. 26.5a, b). Diffuse retinal damage is indicated by abnormalities on full-field ERG and other electrophysiologic tests [17, 18]. More recently, it was reported that therapeutic doses of quinine used to treat cerebral malaria in children were associated with asymptomatic and transient evidence of photoreceptor dysfunction, as measured by full-field ERG [19].

Phenothiazines

Historically, the phenothiazines were commonly used antipsychotic medications. The piperidine phenothiazines, such as thioridazine (Mellaril, Sandoz Pharmaceuticals, East Hanover, NJ), are associated with a characteristic retinal toxicity. Symptoms include impaired vision, nyctalopia, and dyschromatopsia (red or brown) [20]. Early signs include nonspecific macular pigmentary changes, which may progress to widespread, nummular atrophy of the retinal pigment epithelium (RPE) and choriocapillaris [21] (Fig. 26.6a, b). Advanced cases may manifest diffuse retinal pigmentary alterations with vascular attenuation and optic atrophy [22] (Fig. 26.7a, b). Discontinuation of the medication in milder cases may allow for stabilization or improvement of vision. In some cases, visual loss may continue to progress due to

a continued decline of previously damaged retinal tissue [23]. For example, a recent report documented progressive visual loss 30 years after discontinuing thioridazine [24].

Deferoxamine

Deferoxamine (desferrioxamine, Desferal, Novartis, East Hanover, NJ) chelates iron and aluminum and is used to treat patients receiving repeated blood transfusions. Toxicity is unusual but generally manifests as decreased vision, nyctalopia, and visual field loss [25]. Initially, a gray discoloration of the macula may progress to diffuse pigmentary changes [26, 27] (Fig. 26.8a, b). A single dose may cause toxicity [28]. Visual loss typically resolves after discontinuation of the medication [29], but persistent visual loss has been reported [30].