https://ontariorheum.ca/images/uploads/content_documents/OPHTHA_2011_MarmorMarmor2011dj_AAO_plaquenil.pdf

Revised Recommendations on Screening for Chloroquine and Hydroxychloroquine Retinopathy

This review starts with a brief history and description of adaptive optics (AO) technology, followed by a showcase of the latest capabilities of AO systems for imaging the human retina and an extensive review of the literature on where AO is being used clinically. The review concludes with a discussion on future directions and guidance on usage and interpretation of images from AO systems for the eye.

/pdf/adaptive-optics-ophthalmoscopy-3gpzqoe4h5.pdf

Adaptive optics ophthalmoscopy

Objectives To compare different screening procedures for hydroxychloroquine sulfate (Plaquenil) toxicity at different stages of damage. Methods Ten patients were studied using 10-2 automated fields, multifocal electroretinography, spectral domain optical coherence tomography (SD-OCT), and fundus autofluorescence. Results All 10 patients used hydroxychloroquine for more than 6 years, and those with severe toxicity had been overdosed. Fundus examination findings were normal except for the patients with severe toxicity. All the patients showed parafoveal field loss, but this was sometimes subtle. Multifocal electroretinography demonstrated parafoveal weakness in the milder cases. The SD-OCT subfield thickness plots showed a ring of parafoveal thinning in all the patients. The SD-OCT cross-sections showed parafoveal loss of the inner segment–outer segment and cone outer segment tip lines at early stages of toxicity, progressing to parafoveal thinning of the outer nuclear layer and eventually to retinal pigment epithelium damage. There was a ring of autofluorescence in most patients. Conclusions Overdosage with hydroxychloroquine seemed a significant risk factor for toxicity. Different individuals were more or less sensitive to different tests. Fields can be sensitive but only if read with a low threshold for change. Hydroxychloroquine causes early parafoveal loss of the outer segment lines on SD-OCT, with the first changes often evident in the inferotemporal quadrant. Parafoveal thinning of the outer nuclear layer follows, before retinal pigment epithelium damage is visible. Careful screening with multiple tests can detect toxic damage before prominent loss of the outer nuclear layer.

https://jamanetwork.com/journals/jamaophthalmology/articlepdf/1150902/ecs110026_461_469.pdf

Comparison of screening procedures in hydroxychloroquine toxicity.

Congenital achromatopsia is a genetically heterogeneous, predominantly autosomal recessive, retinal disorder with a prevalence of approximately 1 in 30,000 in the general population.1 It is characterized by a lack of color discrimination, poor visual acuity, photophobia, pendular nystagmus, and abnormal photopic electroretinographic (ERG) recordings with preservation of the rod-mediated ERG. A prior report by Khan and colleagues2 showed that the rod ERG function can be modestly subnormal. The disease has been categorized into complete and incomplete achromatopsia subtypes. The incomplete (atypical) form is defined as dyschromatopsia, in which the symptoms are similar to those of the complete achromatopsia (typical) form but with less visual dysfunction.3 Patients with the complete form have nondetectable cone function on ERG testing, whereas those with the incomplete form retain some residual cone function on ERG, and often more preserved color vision and a higher level of visual acuity (up to 0.20).3–5 Funduscopy is usually normal in both forms, although not infrequently macular pigmentary mottling and even occasionally atrophic changes have been described.6

The known causes of congenital achromatopsia are all due to malfunction of the retinal phototransduction pathway. Specifically, recessive forms of achromatopsia result from the inability of cone photoreceptors to properly respond to a light stimulus by hyperpolarizing. To date, mutations in four genes have been identified to cause achromatopsia in human patients, including the α- and β-subunits of the cone cyclic nucleotide-gated ion channels, CNGA3 (ACHM2, OMIM600053) and CNGB3 (ACHM3, OMIM605080), which are located in the plasma membrane of the cone outer segments, the α-subunit of the cone photoreceptor transducin, GNAT2 (ACHM4, OMIM139340), and the catalytic α-subunit of the cone cyclic nucleotide phosphodiesterase, PDE6C (OMIM600827). The vast majority of human cases of achromatopsia are caused by mutations in either CNGA3 or CNGB3.7–11 Prior recent reports of animal studies showed that CNGB3, CNGA3, or GNAT2 knockout mice and naturally occurring dog models of achromatopsia responded well to adenoassociated virus (AAV) gene therapy. In animal models of human achromatopsia, cone ERG amplitudes recovered to nearly normal levels.12–14 These results from proof-of-principle experiments in animals with cone-directed gene therapy offer promise for eventual translation to human patients. Identifying and then targeting retinal locations with retained photoreceptors will be a prerequisite for successful gene therapy in achromatopsia patients.

Previous observations regarding photoreceptor structure in achromatopsia have been limited primarily to histologic reports. In a previous report by Galezowski,15 the retinal cones were described as entirely absent. Larsen16 reported malformed foveal cones with normal cones in the peripheral retina, whereas Harrison et al.17 found misshaped and reduced numbers of retinal cones. In another report by Falls et al.,18 normal numbers of odd-shaped foveal cones and isolated numbers of cones in the peripheral retina were described. Glickstein and Heath19 found no evidence of foveal cones and reduced numbers of peripheral cones. Although genetic testing was not available at the time of these studies, they nevertheless highlight the fact that the picture of photoreceptor structure in achromatopsia is likely to be complex. Some clarity on this issue has begun to come from the use of noninvasive imaging techniques to assess photoreceptor structure in patients with achromatopsia. Optical coherence tomography (OCT), which provides excellent axial resolution, has been used to show a highly variable phenotype at the level of the photoreceptor inner segment (IS) and outer segment (OS),4,6,20,21 although the general interpretation has been that there is an absence or reduction of healthy cone structure. Adaptive optics (AO) provides high lateral resolution,22–24 and was used in a single case to examine photoreceptor structure on the single-cell level.25 The authors visualized a normal rod photoreceptor mosaic, but did not report any evidence of cone structure. These findings only confirm the complexity of the photoreceptor phenotype in achromatopsia, thus warranting further investigation.

Here we used noninvasive high-resolution imaging tools (spectral domain [SD]- OCT and AO scanning laser ophthalmoscopy [SLO]) together with functional measures of vision (ERG, microperimetry [MP], and color vision) to assess photoreceptor structure and function in patients with congenital achromatopsia. We sought to correlate these findings with genetic information from the same subjects. Not only is this approach expected to provide a better understanding of the disease, but also should prove useful in identifying which patients may be most likely to benefit from participating in future gene-targeted treatment trials to rescue or restore cone photoreceptors in this group of patients. Moreover, the structural and functional assays used here would be useful for evaluating the therapeutic efficacy in patients who in fact go on to receive intervention.

Photoreceptor structure and function in patients with congenital achromatopsia

Purpose While the long-term incidence of hydroxychloroquine (HCQ) retinopathy is low, there remains no definitive clinical screening test to recognize HCQ toxicity before ophthalmoscopic fundus changes or visual symptoms. Patients receiving HCQ were evaluated with spectral domain optical coherence tomography (SD OCT) to assess the feasibility of identifying HCQ retinopathy at an early stage. Methods Twenty-five patients referred for the evaluation of hydroxychloroquine toxicity underwent a comprehensive ocular examination, Humphrey visual field (HVF) perimetry, time domain OCT, and SD OCT. Some patients with screening abnormalities also underwent further diagnostic testing at the discretion of the treating providers. Results Five patients were found to have SD OCT findings corresponding to HCQ toxicity and retinal damage as seen by clinical exam and/or HVF perimetry. Two patients with advanced toxicity were found to have significant outer retina disruption in the macula on SD OCT. Three patients with early HCQ toxicity and HVF 10-2 perifoveal defects were found to have loss of the perifoveal photoreceptor inner segment/outer segment (IS/OS) junction with intact outer retina directly under the fovea, creating the "flying saucer" sign. While two of these three patients had early ophthalmoscopic fundus changes, one had none. Conclusion Outer retinal abnormalities including perifoveal photoreceptor IS/OS junction disruption can be identified by SD OCT in early HCQ toxicity, sometimes even before ophthalmoscopic fundus changes are apparent. SD OCT may have a potential complementary role in screening for HCQ retinopathy due to its quick acquisition and because it is more objective than automated perimetry.

/pdf/spectral-domain-optical-coherence-tomography-as-an-effective-1y4t7zoeck.pdf

Spectral domain optical coherence tomography as an effective screening test for hydroxychloroquine retinopathy (the “flying saucer” sign)

Purpose:
To describe spectral-domain optical coherence tomography (SD-OCT) and adaptive optics (AO) imaging in hydroxychloroquine retinal toxicity.

Spectral-domain optical coherence tomography and adaptive optics may detect hydroxychloroquine retinal toxicity before symptomatic vision loss.

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Spectral-domain optical coherence tomography and adaptive optics may detect hydroxychloroquine retinal toxicity before symptomatic vision loss.

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