Chloroquine and Hydroxychloroquine Toxicity Workup

Updated: Jul 30, 2020
  • Author: Manolette R Roque, MD, MBA, FPAO; Chief Editor: Andrew G Lee, MD  more...
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Approach Considerations

Given the emergence of more sensitive diagnostic techniques and the recognition that risk of toxicity from years of hydroxychloroquine use is greater than previously believed, the American Academy of Ophthalmology has released updated guidelines on screening for retinopathy associated with hydroxychloroquine toxicity. The guidelines recommend, that within the first year of treatment with chloroquine and/or hydroxychloroquine, the prescribing physician should refer the patient to an ophthalmologist for a baseline examination. [5]

The ophthalmologist should conduct a complete examination to document any preexisting conditions, the visual field, and the fundus appearance to rule out underlying diseases. The examination should include the following:

  • History (including refraction)
  • Visual acuity (uncorrected visual acuity [UCVA] and best spectacle-corrected visual acuity [BSCVA])
  • Slit-lamp biomicroscopy
  • Direct and indirect ophthalmoscopy (this is not a screening tool; it picks up relatively late toxic changes)

The examination should also include a Humphrey visual field central 10-2 white-on-white pattern (24-2 or 30-2 in Asian patients), and at least one of the following objective tests, if available (see Workup):

  • Spectral-domain optical coherence tomography (SD-OCT) or swept-source optical coherence tomography (SS-OCT)
  • Fundus autofluorescence (FAF) test
  • Multifocal electroretinogram (mfERG)

Cukras et al reported that optical coherence tomography (OCT) retinal thickness and visual field mean deviation (VFMD) are objective measures demonstrating clinically useful sensitivity and specificity for the detection of hydroxychloroquine toxicity as identified by mfERG and thus may be suitable surrogate tests. [15]

Ahn et al reported that 9-mm horizontal- and vertical-line scans and wide-volume SS-OCT scans yielded the highest sensitivity in detecting hydroxychloroquine toxicity in the Asian population. [16]

The following ancillary tests are not recommended for toxicity screening because of low sensitivity, specificity, or reliability but may be used in diagnosing toxicity:

  • Amsler grid
  • Color vision testing
  • Color fundus photography: documenting changes over time, especially in patients with preexisting retinal pathology
  • Full-field ERG or electro-oculogram
  • Fluorescein angiography: may assist in visualizing early subtle changes in the retinal pigment epithelium

Other studies include the macular dazzle (photostress) test and dark adaptometry. The photostress test is a method of subjective evaluation of the macula in which the clinician "dazzles" the macula with a light source and then measures the length of time that the subject takes to regain the previous level of visual acuity. An ophthalmoscope or a pen torch is customarily used as the light source, but a conventional electronic flash from a camera can also serve this purpose.

In dark adaptometry, the pupils are dilated and the retina is dark adapted for 30 minutes. Dark adaptation can be affected in late toxicity but may have no role in screening.


Retinal Examination and Photography

Fundus photography has low sensitivity for toxicity signs in early stages and is not recommended for regular screening. Baseline retinal photographs may be used in patients starting chloroquine/hydroxychloroquine therapy to document pre-existing age-related macular changes.

When observable, early fundus changes in chloroquine/hydroxychloroquine toxicity include the loss of foveal reflex, macular edema, and pigment mottling that is enhanced with the red-free filter. The appearance of the macula correlates poorly with visual-field testing results. [17]

Mottling or stippling of the retinal pigment epithelium is similar in appearance to early age-related macular degeneration. A bull's eye pattern of maculopathy is a late fundus finding.


Amsler Grid

An Amsler grid may be used to detect paracentral scotomas within 10° of fixation. It is not recommended as a screening method for early antimalarial retinopathy because it is inconsistent in detecting subtle scotomas. However, it may reveal defects before they can be visualized by kinetic and static visual fields. Relative scotomas may be revealed with the red Amsler grid.

Patients may find it helpful to monitor their vision at home with an Amsler grid, shown in the image below.

An Amsler grid is used to assess the central porti An Amsler grid is used to assess the central portion of the macula. This simple test is helpful for patients to monitor their vision at home.

Color Vision Testing

Color vision testing may be helpful in patients with unreliable visual field results. However, color vision testing has not been shown to be sensitive or specific for the detection of chloroquine/hydroxychloroquine retinopathy and should not be used for screening.

Male patients can have a baseline test prior to the use of chloroquine and/or hydroxychloroquine to identify any underlying congenital color vision deficiency that might be confused later with toxicity. Both the Ishihara plates and the Farnsworth D-15 test have been shown to be normal in the presence of early retinopathy. Acquired maculopathies are generally more likely to affect the blue-yellow or tritan axis of confusion than the red-green. Most patients with color vision defects also have absolute scotomas.



Baseline central visual field examination may be useful because early macular changes are nonspecific and may be indistinguishable from age-related changes. The Humphrey 10-2 program (white target) is recommended for confirming defects found by the Amsler grid. Since the pattern of toxicity often extends beyond the macula in Asian patients, 24-2 or 30-2 should be used in these patients.

The early scotomas associated with retinal toxicity are subtle and usually within 10° of fixation. They more commonly manifest as superonasal field defects. The later scotomas attributed to retinotoxicity become enlarged and may involve fixation, which reduces visual acuity. Visual fields can vary considerably between visits; uncertain results and should prompt retesting or evaluation with other objective tests. 

Preferential hyperacuity perimetry (PHP)

A pilot study conducted in 15 patients on chloroquine or hydroxychloroquine therapy found that the 10 patients with known or suspected toxicity—based on standardized visual field testing, fluorescein angiography, or both—all demonstrated significant hyperacuity defects on PHP testing. [18] None of the 5 patients on long-term therapy who had no clinical evidence of toxicity demonstrated a PHP hyperacuity defect. The researchers concluded that PHP has potential benefit as a useful adjunct for testing patients with suspected toxicity.

Microperimetry (MP-1)

Microperimetry (MP-1) has not been proven to be more revealing than automated perimetry and requires different test patterns for Asians and non-Asians. [5] However, a case report from England noted the use of MP-1 in detecting subclinical early retinal toxicity as a result of long-term use of chloroquine and in monitoring the changes in macular sensitivity. Although the patient was asymptomatic with best-corrected visual acuity of 20/20, MP-1 showed bilateral loss of sensitivity in the macular region with a dense scotoma within the central 12°. [19]


Fluorescein Angiography

Angiography may be performed in patients with preexisting macular disease. Angiography highlights the macular pigmentary changes that occur in well-established quinolone maculopathy. Fundus autofluorescence can give a topographic view of damage across the posterior fundus and extramacular patterns in Asian eyes, but the value of angiography as an early method of detection has not been established. Angiography can reveal late changes such as RPE defects and is not recommended for screening.

Most patients with relative scotomas usually have negative angiography findings, while patients with absolute scotomas usually have positive findings. Positive angiography findings show early hyperfluorescence in the macular area that corresponds to areas of attenuation of the retinal pigment epithelium (RPE) and accentuation of the underlying choroidal fluorescence. Reduced fluorescence is seen with late RPE loss. 



ERG can be full field, focal, or multifocal. Focal ERG techniques can record an ERG response from the foveal and parafoveal regions. Compared with focal ERG, mfERG is more appropriate for the evaluation of chloroquine and/or hydroxychloroquine toxicity because it generates local ERG responses topographically across the posterior pole and can document a parafoveal or extramacular depression in early retinopathy or bull's eye distribution of ERG depression in late stages. Objective evaluation of visual field can be confirmed with similarly sensitive mfERG.



The EOG as an objective test of global retinal function ("mass response") shows abnormalities in late chloroquine or hydroxychloroquine toxicity but is not sensitive to early functional changes that are predominant in the macula. This test is not recommended for screening of early hydroxychloroquine toxicity, but it may be useful in the evaluation of any patient with manifest toxicity to determine severity and geographic extent of the damage.


Computerized Acuity Mapping of the Macula

In this technique, the patient fixates on a central cross and is presented with 101 letters flashed in succession to different locations within each macula. Letters not seen or incorrectly named are considered errors and their locations are designated with black dots with respect to fixation. Patients with vision better than 20/80 are candidates for this test. Patients with reduced ERG in the foveal cone may result in abnormal acuity mapping results.


Spectral Domain Optical Coherence Tomography

Pasadhika and Fishman evaluated the peripapillary retinal nerve fiber layer (RNFL) thickness and macular inner and outer retinal thickness using spectral domain optical coherence tomography (SD-OCT) in patients with long-term exposure to hydroxychloroquine or chloroquine. They concluded that OCT is useful for the detection of peripapillary RNFL thinning in clinically evident retinopathy. [20]

Selective photoreceptor loss and macular thinning are strong indicators of toxicity and can be detected in the absence of clinically apparent fundus changes. Non-Asian eyes show localized thinning of photoreceptors in the parafoveal region, while Asian eyes show thinning near the arcades and therefore need wider-angle scans.

SD-OCT may be less sensitive than mfERG but is definitive when the characteristic regional thinning pattern is detected. [5] Uncertain results can be retested using the same or different objective tests for confirmation. 


Histologic Findings

Animal studies have shown that the first morphologic changes become visible within 1 week after initiation of chloroquine treatment and involve ganglion cells manifesting membranous cytoplasmic bodies. Other neural cells of the retina show these changes later. Changes after up to 5 months of therapy were reversible.

Prolonged therapy resulted in progressive degeneration of the ganglion cells, photoreceptor cell bodies and nuclei, and outer segment involvement. The most severe changes tended to be perifoveal, with relative foveal sparing. Abnormalities of the pigment epithelium and choroid were seen after degeneration of the ganglion cells and photoreceptors. These changes were observed before abnormalities in the fundus or on ERG were detectable.

Pathologic studies of patients with chloroquine retinopathy are few and limited to cases with advanced retinopathy. However, consistent findings in literature include degeneration of the outer retina, particularly the photoreceptors and the outer nuclear layer, with relative sparing of the photoreceptors in the fovea. Pathologic changes in the ganglion cells are common, and pigment migration into the retina is also seen. Sclerosis of the retinal arterioles is variable.