Antimalarial drugs CQ and HCQ are widely used in the
treatment of various autoimmune disorders. Although
antimalarial are usually well tolerated, often retinal
toxicity which may cause vision-threatening effects is
required to change or discontinue these drugs. Thus, it
is important to detect early stages of CQ/HCQ retinopathy
and, to predict the development of retinopathy
which may be more useful
1,5.
The pathophysiologic mechanisms of CQ/HCQ
retinopathy are not exactly understood. The earliest
abnormalities in retina are detected in ganglion cells.
Paracentral photoreceptors are showed the most severe
damage whilst ganglion cells and retinal pigment epithelium
(RPE) cells are less severely affected2-6.
Histopathologic studies of human and animal retinas
with CQ/HCQ toxicity have shown loss of ganglion
cells and subsequently photoreceptors and consequently
leading to atrophy of the RPE, especially in the
perifoveal region2.
Antimalarial related maculopathy is characterized
by relative sparing of foveolar function in the presence
of parafoveolar dysfunction and subsequent photoreceptor
degeneration1,4.
Antimalarial-associated retinopathy may be classified
as premaculopathy and bull’s eye retinopathy.
The visual field defects correlate with the degree of
retinal damage and it is the first indicator of retinopathy3-5.
Antimalarials are highly concentrated in the pigmented
ocular tissues such as RPE, binds to melanin,
and may remains there for prolonged periods of time
even after cessation of therapy. The destruction of
paracentral photoreceptors with sparing of the foveal
cones explains the fundoscopic appearance of the bull’s
eye maculopathy1,2.
Premaculopathy consists of fine pigmentary stippling
of the macula and loss of foveal reflex. It may
progress to true retinopathy that usually consists of
stippled hyperpigmentation of the macula, and is surrounded
first by a clear zone of depigmentation and
then by a second ring of pigment, giving a bull’s eye
appearance. Frequent screening may be necessary to
detect reversible premaculopathy3-5.
Early CQ/HCQ retinopathy though still inadequately
described, is defined as an acquired paracentral
scotoma on threshold visual field testing, with no detectable
retinal findings, while advanced retinopathy
has associated parafoveal RPE atrophy1-3.
The ganglion cell population is the densest at the
macular region. So, antimalarials would affect firstly
ganglion cells at perifoveal region. The fact that the
first functional change is a paracentral scotoma, and the
first observable RPE changes are seen in this area supports
this assumption1-5. Therefore, the detection of perifoveal cupping or perifoveal retinal thinning may
provide more accurate and earlier predictions of antimalarial
toxicity, even before the scotoma develops
and even maybe prevent further damage by stopping
the drug at this point.
The OCT may give the information on the status
of the RPE, photoreceptors, and the retinal thickness6-9. Recently, Rodriguez et al have shown discontinuity
or loss of perifoveal photoreceptor inner segment
and outer segment (IS/OS) junctions and thinning of
the outer nuclear layer by ultra high resolution optical
coherence tomography (UHR-OCT) in patients receiving
HCQ8. However, they have not been able to
shown distinctive effects on the ganglion cells. We
present a distinctive finding on these cells and consider
that it may be termed as perifoveal cupping because of
the thinning or foveolar flattening at the retinal ganglion
cell layer.
Retinal structural abnormalities in patients receiving
antimalarial drugs have been identified prior to
ophthalmoscopically visible alterations using multifocal
electroretinography (mfERG) and UHR-OCT8-10. However, the screening for antimalarial related
maculopathy is difficult because of the vastness of
patients receiving treatment, nonspecific early symptoms
(reading difficulties, far sight difficulties), and
limited availability and the sophistication and expensiveness
of diagnostic methods above mentioned. In
addition, UHR-OCT is not available as yet for general
clinical use7.
Up to date, the reduction of retinal thickness and
disruption at IS/OS junction at perifoveal region were
demonstrated in the OCT studies concerning antimalarial
related maculopathy7-11. Kellner et al. reported
that loss of outer nuclear layer thickness detected by
OCT might be the earliest indicator of CQ retinopathy.
Also, Kellner et al demonstrated that retinal thickness
in parafoveal area by OCT was most severely reduced7-10.
Similarly, two recent case reports by Fung and
Fontaine et al. demonstrated that the detection of reduced
macular thickness with hyporeflective atrophic
retina and pigment epithelium or increased reflectance
of the choroid layer in a perifoveal region by OCT can
support a suspected diagnosis of CQ or HCQ related
retinal toxicity11,12. In addition, Korah et al reported
that loss of ganglion cell layers, causing marked
retinal thinning of the macula and parafoveal region
may be early evidence of CQ toxicity13.
In our previous case report, we had been demonstrated
the regression in the HCQ maculopathy by Sd-
OCT. However, we did not observe any foveal contour
changes such as perifoveal cupping or the flattening of
the foveal contour and foveal/perifoveal retinal thinning14.
However, none of these studies above mentioned
demonstrated the foveal cupping. The observation of
this finding in some patients without clinically and
perimetrically specific findings of antimalarial maculopathy
is spectacular. In our study, we demonstrated the
enlargement of central foveolar depression area due to
flattening foveal contour or perifoveal cupping in eighteen
patients. In these cases, central foveal thicknesses
were normal range whereas perifoveal retinal thicknesses
were reduced.