dehydrogenase­ deficiency (Chakrabarti et al 1999). Darkening of skin color may be due to iatrogenic cyanosis, as a slate gray discoloration characteristic of drug-induced methemoglobinemia. Some patients under treatment with dapsone for leprosy have been known to develop lagophthalmos and posterior synechiae, but these effects are probably due to the disease rather than to the drug (Brandt et al 1984).

References and Further Reading

Alexander TA, et al. Presumed DDS ocular toxicity. Indian J Ophthalmol 37: 150–151, 1989.

Brandt F, Adiga RB, Pradhan H. Lagophthalmos and posterior synechias during treatment of leprosy with diaminodiphenylsulfone. Klin Monatsbl­ Augenheilkd 184: 28, 1984.

Chakrabarti M, Suresh PN, Namperumalsamy P. Bilateral macular infarction due to diaminodiphenyl sulfone (4,4’ DDS) toxicity. Retina 19(1): 83–84, 1999.

Daneshmend TK. The neurotoxicity of dapsone. Adverse Drug React. Acute Poisoning Rev 3: 43–58, 1984.

Daneshmend TK, Homeida M. Dapsone-induced optic atrophy and motor neuropathy. BMJ 283: 311, 1981.

Homeida M, Babikr A, Daneshmend TK. Dapsone-induced optic atrophy and motor neuropathy. BMJ 281: 1180, 1980.

Kenner DJ, et al. Permanent retinal damage following massive dapsone overdose. Br J Ophthalmol 64: 741, 1980.

Leonard JN, et al. Dapsone and the retina. Lancet 1: 453, 1982.

Seo MS, et al. Dapson maculopathy. Korean J Ophthalmol 11: 70–73, 1997.

Class: Antimalarial Agents

Generic names: 1. Chloroquine; 2. hydroxychloroquine.

Proprietary names: 1. Aralen; 2. Plaquenil.

Primary use

These aminoquinolines are used in the treatment of malaria, extraintestinal amebiasis, rheumatoid arthritis and lupus ­erythematosus.

Ocular side effects

Systemic administration

Certain

1.Decreased vision

2.Cornea

a.Punctate – yellowish to white opacities

b.Lineal – whorl-like pattern, primarily in palpebral aperture­

c.Enhanced Hudson-Stähli line

d.Transient edema

e.Decreased sensitivity

3.Retina and/or macula

a.Perifoveal granularity of retinal pigment epithelium (early)

b.Bull’s-eye appearance of the macula, with thinning and clumping of pigment epithelium (Fig. 7.1g)

c.Attenuation of vascular tree

d.Peripheral fine granular pigmentary changes

e.Prominent choroidal pattern

f.Angiography changes

4.Parafoveal retinal pigment epithithelium window defects (early)

5.Window defects in annular pattern

6.Choroidal filling defects (late)

7.Decreased or absent foveal reflex (rare)

8.Abnormal sensory testing

a.Critical flicker fusion

b.Macular recovery times

c.Decreased dark adaptation

d.EOG and ERG changes

9.Tear film

a.Drugs found in tear film

b.Aggravates sicca

c.Decreased contact lens tolerance

10.Decreased accommodation

11.Visual fields

a.Scotoma – annular, central, paracentral

b.Constriction

c.Hemianopsia

12. Eyelids and conjunctiva

a.Pigmentary changes – hyper or hypo effects

b.Yellow, bluish or blackish deposits

c.Photosensitivity reactions

d.Blepharospasm or clonus

13. Optic atrophy (late)

14. Color vision defect

a.Blue-yellow defects (early)

b.Red-green defects (late)

c.Objects have yellow, green or blue tinge

d.Colored haloes around lights

Probable

1. Oculogyric crisis

2. Myasthenia gravis (aggravates)

a.Diplopia

b.Ptosis

c.Paresis of extraocular muscle

Clinical significance

Although hydroxychloroquine is widely used in Britain, North America and Australia, chloroquine may be more common in Europe, South America and Asia. Hydroxychloroquine use has markedly increased because it has become a first-line drug for some forms of arthritis and lupus erythematosus. Probably all side effects seen with chloroquine can also be seen with hydroxychloroquine, but serious ones are primarily seen with chloroquine in long-term usage or large dose situations. Toxicity to the retina due to these drugs is dose related.

Corneal deposits due to chloroquine have no direct relationship to posterior segment disease and may be seen as early as 3 weeks after starting the medication. Corneal changes may first appear as a Hudson-Stähli line or an increase in a pre-existing Hudson-Stähli line. Probably more common is a whorl-like pattern known as ‘cornea verticillata’. It is known that a number of drugs and diseases can cause this pattern, in which morphological, histological and electron microscopic findings are identical. ‘Amphophilic’ drugs, such as chloroquine, amiodarone and chlorpromazine, form complexes with cellular phospholipids, which cannot be metabolized by lysosomal phospholipases therefore these intracellular deposits occur and are visible in the superficial portion of the cornea.

Corneal deposits due to hydroxychloroquine are of more clinical importance as an indication to hunt more aggressively for retinal toxicity. These are best seen with a dilated pupil and retroillumination. These deposits are finer and less extensive than with chloroquine. Easterbrook (1990, 1999) has found these corneal deposits to be a possible indicator of hydroxychloroquine macular toxicity. Corneal deposits occasionally cause

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haloes around lights. All corneal deposits are reversible. Hydroxy­ chloroquine crystals have been found in the tear film, which may aggravate some sicca patients and contact lens wearers.

Toxic maculopathy is usually reversible only in its earliest phases. If these drugs have caused skin, eyelid, corneal (hydroxy­ chloroquine) or hair changes, this may be an indicator of possible drug-induced retinopathy. Since the aminoquinolines are concentrated in pigmented tissue, macular changes have been thought to progress long after the drug is stopped. (This is now being questioned by some investigators as not being true for ­hydroxychloroquine.) The bull’s-eye macula is not diagnostic for aminoquinoline-induced disease since a number of other entities can cause this same clinical picture. While retinal toxicity occurs in patients taking hydroxychloroquine, the incidence is much lower than with chloroquine.

Recommendations for hydroxychloroquine

The goal for the clinician is to find early, relative scotomas. Disease in patients with early paracentral relative scotomas seldom advances when the drug is discontinued. Later findings include retinal changes, color vision loss, absolute scotoma or decreased vision. Even if the drug is stopped, once these changes occur they are often irreversible and some patients may continue to lose some vision and/or peripheral fields.

Patients at greatest risk are those who are on hydroxychloroquine for longer than 5 years and those with renal or liver disease (this drug is metabolized via kidney and liver). Elderly, thin patients may also be overdosed, as may obese patients. Editorial articles by Marmor (Marmor et al 2002; Marmor 2005) and another by Lee (2005) explain the dilemma of the diagnosis of macular toxicity and to date there is no clear-cut answer on how best to detect toxicity. The multifocal ERG may be an effective clinical screening test, but this remains to be resolved. Neubauer et al (2003, 2004) have found a computerized color vision test that is effective in screening. Disturbances on the tritan axis appear­ to occur first. How best to follow patients on hydroxy­ chloroquine was summarized in an article in the July 2002 issue of Ophthalmology (Marmor et al 2002).

1. Baseline examination: We recommend a baseline eye exam within 4–8 weeks after starting hydroxychloroquine and yearly thereafter including a dilated ophthalmic examination, including the informed consent, warning of possible permanent visual problems in rare instances. This baseline exam should include visual acuity, Amsler grids (with instructions for monthly home use) and optional color vision testing (preferably including the blue-yellow axis, such as the pseudo-isochromatic plates for color by the American Optical Corporation). If macular abnormalities are evident, it would be ideal to obtain fundus photographs. If any progressive ocular abnormality is suspected, consider a baseline Humphrey 10-2 or other automated perimetry. Multifocal ERG is optional.

2. Follow-up examinations: For patients who are not obese, frail, elderly, extremely thin, are without significant renal of hepatic disease or macular disease of any type, and who are younger than 40, exams should be completed yearly thereafter. Patients should be seen sooner if they experience any persistent visual symptoms or if their dosage exceeds 6.5 mg/kg.

3. Eye examinations more than once a year should be considered if patients have been on hydroxychloroquine therapy for longer than 5 years, if they are obese, or lean and small (especially in the case of elderly patients), or if they have ­progressive macular disease of any type, significant renal or liver disease, or their dosage exceeds 6.5 mg/kg/day.

4. Follow-up examination procedures:

a.Repeat baseline examination.

b.Fundus photography if any macular abnormality is noted.

c.Consider fluorescein angiography only in the presence of suspicious pigmentary changes.

d.Automated central visual fields (optional).

e.Multifocal ERG (selected cases).

5. Recommendations by Don C Bienfang, MD, are available on www.eyedrugregistry.com. Baseline testing consists of a complete eye exam, including HVF-10, amsler and color vision screeing. Record height and weight at baseline and on each returning visit. During baseline examination, ask

the patient if he or she is having problems with color vision, vision in dim illumination (movie theaters) or if parts of the TV screen are missing.

Toxicity can occur on low doses and once the toxicity appears, even if the drug is stopped, the toxicity can get worse. If caught early, patients tend to do better in recovery and the clinician feels often the first clue is found in the more subjective parts of the examination, i.e. asking about even minimal changes in color vision, night vision and missing parts of vision.

Recommendations for chloroquine

For patients taking chloroquine, perform the tests listed above. See patients at least annually if dosage is less than 3.0 mg/kg of ideal body weight. See every 6 months if dosage is greater than 3.0 mg/kg body weight, or if patients are short, obese or have renal and/or liver impairment.

Caution

To date, there are no data to show hydroxychloroquine toxicity worsening pre-existing macular degeneration. Common sense in a litigious society that has to find blame somewhere may make informed consent and explanation of risk-benefit ratios necessary on an individualized basis. A recent preliminary paper by Shroyer et al (2001) suggests that individuals with an ABCR mutation (Stargardt’s disease) may be predisposed to develop retinal toxicity when exposed to chloroquine or hydroxychloroquine.

References and Further Reading

Almony A, Garg S, Peters RK, et al. Threshold amsler grid as screening tool for asymptomatic patients on hydroxychloroquine therapy.

Br J Ophthalmol 89: 569–574, 2004.

Beebe WE, Abbott RL, Fung WE. Hydroxychloroquine crystals in the tear film of a patient with rheumatoid arthritis. Am J Ophthalmol 101: 377, 1986.

Easterbrook M. Is corneal decompensation of antimalarial any indication of retinal toxicity? Can J Ophthalmol 25(5): 249–251, 1990.

Easterbrook M. An ophthalmological view on the efficacy and safety of chloroquine hydroxychloroquine. (Editorial). J Rheumatol 26(9): 1866–1868, 1999.

Ehrenfeld M, Nesher R, Merin S. Delayed-onset chloroquine retinopathy. Br J Ophthalmol 70: 281, 1986.

Elder M, Rahman AM, McLay J. Early paracentral visual field loss in patients taking hydroxychloroquine. Arch Ophthalmol 124:1729–1733, 2006.

Fraunfelder FW, Fraunfelder FT. Scientific challenges in postmarketing surveillance of ocular adverse drug reactions. Am J Ophthalmol 143: 145–149, 2007.

Johnson MW, Vine AK. Hydroxychloroquine therapy in massive total doses without retinal toxicity. Am J Ophthalmol 104: 139, 1987.

Kellner U, Kraus H, Foerster MH. Multifocal ERG in chloroquine retinopathy: regional variance of retinal dysfunction. Graefe’s Arch Clin Exp Ophthalmol 238: 94–97, 2000.

Lai TYY, Chan W-M, Li H, et al: Multifocal electroretinographic changes in patients receiving hydroxychloroquine therapy. Am J Ophthalmol 140: 794–807, 2005.

Lee AG. Hydroxychloroquine screening: who needs it, when, how and why? Br J Ophthalmol 89: 521–522, 2005.