EMILY HOOK
Hydroxychloroquine-induced Retinopathy Progression and Detection
What is Hydroxychloroquine?
Hydroxychloroquine (HCQ), commonly known as Plaquenil, is an antimalarial and immunosuppressive drug. It is frequently used to treat autoimmune disorders such as systemic lupus erythematosus and rheumatoid arthritis (Geamanu et al., 2014). Although very rare, this drug may cause damage to the retina and eventually vision loss which is known as retinal toxicity or retinopathy. According to Ding et al. (2016), estimating the actual incidence of HCQ-induced retinopathy is difficult due to varying definitions of retinopathy and lack of large, long-term studies. However, the data does suggest that the incidence is about 0.1-0.7% of individuals taking HCQ but increases the longer the drug is taken. Despite the low incidence rate, individuals taking hydroxychloroquine must be aware of the potential to develop retinopathy and should undergo sensitive screening tests to ensure their retinal health while taking the drug.
Risk Factors and Medication Dosing
Some factors that increase an individual’s risk for developing HCQ retinopathy include liver or kidney disorders, old age, and most importantly the HCQ dosage and duration of treatment (Geamanu et al., 2014). It is unknown whether the daily dose or the cumulative dose of HCQ has a greater effect on the potential of retinopathy, resulting in the American Academy of Ophthalmology making major changes to their dosing guidelines over the years (Figure 1) (Browning et al. 2020).
Figure 1. Guidelines for HCQ dosing released by the American Academy of Ophthalmology in 2002, 2011, and 2016. Reprinted from “Rethinking the hydroxychloroquine dosing and retinopathy screening guidelines”, by Browing et al., 2020, American Journal of Ophthalmology, 219, p. 104.
There is some concern with the newest dosing guidelines of <5 mg/kg real weight, as this makes the typical dose of 400 mg/day too high for many patients. This has led to some prescribing physicians ignoring the new guidelines. These physicians are concerned about the potential impact of lowering a patient’s daily dose when their autoimmune disease is well controlled with a dose above the 5 mg/kg real weight threshold (Browning et al. 2020). It is clear that not enough research has been done to definitely determine whether the cumulative or daily dose of HCQ contributes more to retinal toxicity and a large, long-term study should be conducted.
Importance of Early Detection
HCQ retinopathy is usually asymptomatic in its early stages, with the first vision changes occurring paracentrally. These paracentral changes do not affect central vision, so patients may not notice any changes to their vision until much later in the disease progression. As the disease worsens, the paracentral scotoma (blind spot) becomes larger and extends into central vision. Other symptoms include trouble with reading, seeing flashes of light, distortion of vision, reduced color vision, and peripheral vision loss (Ding et al., 2016). In cases of severe HCQ retinopathy, bull’s eye maculopathy (BEM) may form. BEM refers to damage to the center of the retina which is known as the macula. As shown in Figure 2, BEM is named because the damage looks similar to a bull’s eye, with a pale ring of depigmentation forming around a darker area of the macula. At this stage, the damage to the retinal pigment epithelium is irreversible (Geamanu et al., 2014). Figure 3 illustrates how a patient’s vision can change if they are suffering from BEM caused by HCQ. The patient will lose some of their central vision, resulting in difficulties seeing fine details or colors of the object they are looking at.
Figure 2. Retinal image showing BEM on a patient with HCQ retinopathy. The traditional look of BEM can be seen with the pale circle surrounding the dark macula. Permission to use this patient photo was given by Dr. Michael Fagin.
​Figure 3. Comparing normal vision (left) to the vision of an individual with maculopathy (right). Reprinted from “Maculopathy: Vision loss and Macular Degeneration”, by Llamas, M., (2022, Nov 11). Retrieved from https://www.drugwatch.com/health/maculopathy/
​A traditional fundus examination may remain normal until the development of BEM, which is why sensitive screening tests should be performed to catch the disease in its early stages. A baseline ophthalmological exam, including a fundus examination and a visual field test, with at least one objective test is recommended before administering HCQ. This provides a baseline for comparison and ensures that the patient does not have any disease of the retina, which could be worsened by the use of HCQ. While taking HCQ, patients should be seen at least once every two years for follow up examinations that also include visual field testing and at least one objective test, which are described below (Geamanu et al., 2014).
CENTRAL VISUAL FIELD TESTING
Central visual field testing, more specifically a 10-2 visual field test, is one of the most commonly used methods to detect HCQ retinopathy. A 10-2 visual field test can detect any vision loss in the central 10 degrees of vision, which includes both central and paracentral vision. This type of visual field test is very sensitive and can detect very early stages of HCQ retinopathy, but its effectiveness depends on the reliability of the patient. The test involves the patient looking at a screen and clicking a button when they see a stimulus appear in different locations on the screen (Figure 4). The stimulus will appear in each location a few times, sometimes clear and other times very faint to test the threshold the patient can see in these areas. The results may be inconclusive if the patient fails to maintain focus during the test or is unable to click the button in time, which could lead to false negative or positive results. A 10-2 visual field test may be the earliest mode of HCQ retinopathy detection if the patient is engaged and physically able to complete the test correctly (Ding et al., 2016). Due to the potential of unreliable results, one of the objective tests listed below should also be completed to determine whether toxicity is truly present.
Figure 4. Results from a 10-2 visual field test on a patient with HCQ retinopathy. The clear areas show where the patient was able to see all stimuli. The dark areas show locations where the stimulus was shown but the button was not clicked, the darker the color means more signals were missed. Reprinted from “Imaging in Hydroxychloroquine Toxicity”, by Sharma & Shah, (2019, April). Retrieved from https://retinatoday.com/articles/2019-apr/imaging-in-hydroxychloroquine-toxicity
OPTICAL COHERENCE TOMOGRAPHY (OCT)
OCT is a non-invasive imaging tool that uses reflected light to create an image of the retina, showing the layers of cells. This is a widely available objective test that produces accurate results that do not rely on patient compliance (Sharma & Shah 2019). The OCT can show thinning of cell layers in the retina (Figure 5) and detect toxicity before there is any loss in visual fields. It is beneficial to get a baseline OCT before or shortly after beginning to take HCQ so that any thinning or changes in the retina can be easily detected (Geamanu et al., 2014). Figure 6 shows the thinning of the retina in four patients taking HCQ. In A, the patient had stable retinal thickness throughout the course of their treatment. In B, C, and D, the patients all had some form of retinal thinning, although it varied whether the inner or outer ring thinning was more prominent. The graphs illustrate the importance of getting regular OCTs while taking HCQ because the rate and degree of retinal thinning may be unpredictable and happen rapidly.
Figure 5. OCT taken on the right eye of a patient with HCQ retinopathy. The white dots, indicated by the arrowheads, show damage to the retinal pigment epithelium. The egg shape, indicated by the arrow, is known as the “flying saucer” which is another sign of HCQ retinopathy. Reprinted from “Hydroxychloroquine-induced retinal toxicity”, by Carter & Do, 2020, The Journal of Rheumatology, 47(4), p. 632.
Figure 6. Line graphs showing the change in the retinal thickness in four patients over the course of their HCQ treatment. The y-axis shows the thickness change from their initial OCT and the x-axis indicates the number of years they’ve been taking HCQ. Reprinted from “Rapid macular thinning is an early indicator of hydroxychloroquine retinal toxicity”, by Melles & Marmor, 2022, Ophthalmology, 129(9), p. 1008.
FUNDUS AUTOFLOURESENCE (FAF)
FAF is another objective imaging tool. It uses a scanning laser to show changes in the macula present in mild and severe cases of HCQ retinopathy (Figure 7). It detects areas of hypo-autofluorescence and hyper-autofluorescence due to the loss of retinal pigment epithelium (Geamanu et al., 2014). FAF can detect the start of BEM sooner than traditional retinal images. FAF is less widely available when compared to OCT, and changes in FAF are more subtle and could potentially be missed. Due to these possible shortcomings, Ding et al. (2016) recommends that FAF be used with OCT, rather than in place of.
Figure 7. FAF taken on the right eye of a patient with HCQ retinopathy. The light area surrounding the macula, indicated by the right arrow, shows BEM that has developed due to HCQ use. Reprinted from “Hydroxychloroquine-induced retinal toxicity”, by Carter & Do, 2020, The Journal of Rheumatology, 47(4), p. 632.
MULTIFOCAL ELECTRORETINOGRAM (mfERG)
Multifocal ERG is the last objective screening test. It is considered by many to be the gold standard for detection of HCQ retinopathy, but it is not available in most ophthalmology offices (Sharma & Shah 2019). The mfERG detects electrical activity across the retina in response to light. The mfERG, which tests the central 45 degrees of vision, is used in cases of potential HCQ retinopathy instead of the full-field ERG. Patients with HCQ retinopathy may have normal full-field ERG results but decreased retinal responses are be detected when using a mfERG (So et al., 2003). This test is useful in finding toxicity in early stages of the disease and confirming bull’s eye maculopathy in late stages. The mfERG may be more sensitive to paracentral vision loss than the 10-2 visual field test (Geamanu et al., 2014). The results from this test are shown as wave forms and as 3D density plots. The results from a patient with normal vision (Figure 8) will not have the characteristic depressions in the center of the 3D density plot as seen in those with HCQ retinopathy (Figure 9). These areas of depression indicate that there was no electrical response in the retina to the light stimulus, meaning these areas have been damaged.
Figure 8. Normal mfERG results showing the 3D density plot (top) and the waveforms (bottom). Reprinted from “Evaluation of hydroxychloroquine retinopathy with multifocal electroretinography”, by So et al., 2003, Ophthalmic Surgery, Lasers and Imaging Retina, 34(3), p. 7.
Figure 9. mfERG results from a patient with HCQ retinopathy. Both the right (A) and the left (B) eyes show areas of depression in the 3D density plot when compared to the normal. Reprinted from “Evaluation of hydroxychloroquine retinopathy with multifocal electroretinography”, by So et al., 2003, Ophthalmic Surgery, Lasers and Imaging Retina, 34(3), p. 8.
References
Browning, D. J., Yokogawa, N., Greenberg, P. B., & Perlman, E. (2020). Rethinking the hydroxychloroquine dosing and retinopathy screening guidelines. American Journal of Ophthalmology, 219, 101–106. https://doi.org/10.1016/j.ajo.2020.06.030
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Carter, Kaylene L., & Do, Diana V. (2020). Hydroxychloroquine-induced retinal toxicity. The Journal of Rheumatology, 47(4), 632–632. https://doi.org/10.3899/jrheum.190538
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Ding, H. J., Denniston, A. K., Rao, V. K., & Gordon, C. (2015). Hydroxychloroquine-related retinal toxicity. Rheumatology, 55(6), 957–967. https://doi.org/10.1093/rheumatology/kev357
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Geamănu Pancă, A., Popa-Cherecheanu, A., Marinescu, B., Geamănu, C. D., & Voinea, L. M. (2014). Retinal toxicity associated with chronic exposure to hydroxychloroquine and its ocular screening. Review. Journal of medicine and life, 7(3), 322–326.
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Llamas, M. (2022). Maculopathy: Vision loss and Macular Degeneration. Drugwatch.com. Retrieved April 24, 2023, from https://www.drugwatch.com/health/maculopathy/
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Melles, R. B., & Marmor, M. F. (2022). Rapid macular thinning is an early indicator of hydroxychloroquine retinal toxicity. Ophthalmology, 129(9), 1004–1013. https://doi.org/10.1016/j.ophtha.2022.05.002
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Sharma, P., & Shah, C. P. (2019, April). Imaging in hydroxychloroquine toxicity. Retina Today. Retrieved April 16, 2023, from https://retinatoday.com/articles/2019-apr/imaging-in-hydroxychloroquine-toxicity
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So, S. C., Hedges, T. R., Schuman, J. S., & Quireza, M. L. (2003). Evaluation of hydroxychloroquine retinopathy with multifocal electroretinography. Ophthalmic Surgery, Lasers and Imaging Retina, 34(3), 251–258. https://doi.org/10.3928/1542-8877-20030501-20