Report

Spectral-Domain Optical Coherence

Tomography in Hydroxychloroquine
Retinopathy
In 2011, revised guidelines for screening chloroquine and
hydroxychloroquine (HCQ) retinopathy recommended spectraldomain optical coherence tomography (SD OCT), fundus autouorescence, or multifocal electroretinogram in addition to
ophthalmologic examination and 10-2 perimetry.1 To date, the
qualitative features of SD OCT in chloroquine and HCQ
retinopathy have been reported in <60 patients, most of whom
had established retinopathy. Also, thinning of parafoveal retina
has been documented,2,3 occurring even when cross-sectional
scans are equivocal.4
The sensitivity, specicity, and predictive value of SD OCT
abnormalities compared with other markers of HCQ retinopathy
are unknown. We undertook a point-prevalence study to evaluate
SD OCT in a cohort of patients on HCQ therapy for various
rheumatologic conditions. Medical records of 192 patients
receiving HCQ were reviewed with the approval of the CIADS
Research institutional review board; 126 patients met criteria for
inclusion having taken HCQ for
2 years and undergone
1 SD
OCT. Mean age was 55 years (range, 22e83). Median duration of
therapy was 9.8 years (range, 2e24). Median cumulative dosage
was 14.4 g/kg (range, 1.4e44.4).
Although there are no established criteria for reliably predicting
HCQ retinal toxicity, a combination of visual acuity, qualitative
and quantitative perimetric visual elds, and fundus examination
was used as the standard ophthalmologic examination for comparison with changes in SD OCT using Fisher exact test. Humphreys 10-2 threshold perimetry (Carl Zeiss Meditec, Dublin, CA)
was considered qualitatively abnormal if pericentral defects
developed after previously normal studies. Quantitative evaluation
of visual elds was based on mean deviation. The fundus was
judged abnormal when there were parafoveal pigmentary changes
consistent with HCQ retinopathy evolving over time. Each eye was
evaluated separately and considered affected if
2 of these 4 tests
were abnormal. High-denition 5-line raster SD OCT of the
parafoveal retina (Cirrus HD, Carl Zeiss Meditec) was abnormal
when there was loss of the inner/outer segment line, thinning of the
outer nuclear layer, or downward displacement of inner retinal
layers.1 Retinal thickness (mm) between inner limiting membrane
(ILM) and retinal pigment epithelium (RPE) was measured using
a 512128 scan pattern centered on the fovea generating 360
inner and outer subelds divided into superior, temporal, inferior,
and nasal quadrants. The ILM-RPE quadrant thicknesses and
cube average thickness (CAT) were generated automatically by the
Cirrus HD program. The relationships between cumulative dosages
and quadrant ILM-RPE thicknesses and CAT were determined by
linear regression with 95% prediction bands encompassing all
experimental points with 95% probability and were used to predict
minimum retinal thicknesses before HCQ therapy at dose X 0 for
each quadrant and CAT.
Two patients had established HCQ retinopathy in both eyes
based on abnormal standard ophthalmologic testing and qualitative

SD OCT. Eight eyes in 6 patients had
2 abnormal standard

ophthalmologic tests, but qualitatively normal SD OCT. Two
further patients had normal standard examinations, but qualitatively abnormal SD OCT in both eyes. The sensitivity of a
qualitatively abnormal SD OCT compared with standard ophthalmologic testing was 0.33 and specicity was 0.98. Positive predictive value was 0.50 and negative predictive value was 0.97.
When viewed as a survival curve showing the percentage of
patients maintaining normal examinations and qualitatively normal
SD OCT with increasing cumulative HCQ dosages (Fig 1), there
was no difference between SD OCT and standard testing
(P 0.3606 by log-rank [Mantel Cox] test).
There were signicant inverse relationships between each
quadrant of both inner and outer subelds and cumulative HCQ
dosage (Table 1, available at www.aaojournal.org). Because
temporal and nasal quadrants of the inner subeld lost ILM-RPE
thickness at signicantly greater rates than inferior and superior
quadrants (P < 0.0001 by 1-way analysis of variance with Bonferroni multiple comparison test), hypothetical initial values of 282
mm temporally and 294 mm nasally based on the 95% prediction
bands were considered as possible markers of risk for HCQ retinopathy. These values represent the minimum ILM-RPE thicknesses of inner temporal and nasal quadrants before HCQ therapy.
Likewise, there was a signicant inverse relationship between CAT
and cumulative dosage (P 0.0042; Fig 2, available at
www.aaojournal.org) yielding a minimum CAT of 258 mm.
Compared with values for temporal and nasal inner quadrants,
the hypothetical initial CAT value is a marker of overall macular
cube thickness.
For evaluation of quantitative SD OCT, we used minimal ILMRPE thicknesses of 285 mm temporal inner quadrant, 295 mm nasal
inner quadrant, and 260 mm CAT. If 2 of these 3 values were
subnormal, the sensitivity of quantitative SD OCT was 0.62 and
specicity was 0.94 compared with standard tests. Positive predictive value was 0.35 and negative predictive value was 0.98. The
survival curve showed no difference between the development of
abnormalities in quantitative SD OCT and standard ophthalmologic tests (P 0.1080; Fig 1). However, over the same dosage
range, quantitative SD OCT identied 21 abnormal eyes
compared with 8 identied by qualitative SD OCT assessment
(P 0.0143). Likewise, receiver operating curve analyses
yielded area under the curve results of 0.855 ( 0.021) for
quantitative SD OCT compared with standard testing and 0.947
( 0.020) compared with qualitative SD OCT. This indicates
that our quantitative SD OCT measures enhance standard
ophthalmologic tests and qualitative SD OCT in distinguishing
patients with HCQ retinopathy.
As per revised guidelines,1 SD OCT is a valuable adjunct to
standard ophthalmologic examination in evaluating patients on
long-term HCQ therapy. In the presence of an abnormal clinical
examination, a qualitatively abnormal SD OCT is pathognomonic
of HCQ retinopathy. With a normal ophthalmologic examination, it
is reassuring that SD OCT has a high negative predictive value and
a qualitatively normal study. However, a qualitatively normal SD
OCT cannot exclude HCQ retinopathy when visual elds or fundus
examination are abnormal because of low sensitivity. Retinal

Ophthalmology Volume -, Number -, Month 2015

JANINE L. JOHNSTON, MD, FRCPC1,2
PATTY DARVILL, COA, OMT3
GLEN T.D. THOMSON, MD, FRCPC4
1

Department of Medicine, University of Manitoba, Winnipeg,

Manitoba, Canada; 2Department of Ophthalmology, University of
Manitoba, Winnipeg, Manitoba, Canada; 3Misericordia Health Center,
Winnipeg, Manitoba, Canada; 4Department of Family Medicine,
University of Manitoba, Winnipeg, Manitoba, Canada
Presented at: the North American Neuro-ophthalmology Society
(NANOS) Annual Meeting, February 9-14, 2013.

Figure 1. Survival curve for patients maintaining normal examination and

spectral-domain optical coherence tomography (SD OCT) shows no difference between patients who have abnormal qualitative SD OCT (dashed
line; P 0.3606 by log-rank [Mantel Cox] test), abnormal quantitative SD
OCT (dotted line; P 0.1080) and those who have abnormalities on
2
standard ophthalmic tests (solid line). There is a signicant difference
between the development of abnormalities in SD OCT quantitatively
compared with the onset of qualitative SD OCT abnormalities (P
0.0143). Over the same dosage range, quantitative assessment of SD OCT
identied 21 abnormal eyes compared with 8 identied by qualitative SD
OCT and 12 identied by standard ophthalmological testing.

thickness measurements available on standard SD OCT increase

the sensitivity of qualitative SD OCT assessments. Abnormalities
in quantitative SD OCT occur before changes in conventional
ophthalmologic testing and qualitative SD OCT. Since observers
do not always agree on the presence of retinopathy, the minimal
ILM-RPE thicknesses that we propose can provide additional
guidance in evaluating patients with equivocal ophthalmologic
examinations or qualitative SD OCT.5 Nonetheless, in the absence
of other clinical abnormalities, SD OCT has poor positive
predictive value and cannot reliably predict incipient HCQ retinal
toxicity. Further prospective studies are required to validate the
quantitative measurements that we have recommended.

Financial Disclosure(s): The authors have no proprietary or commercial

interest in any materials discussed in this article.
Correspondence:
Janine L. Johnston, MD, FRCPC, 1835 Corydon Avenue, Winnipeg,
Manitoba Canada R3N 0K6. E-mail: novl@shaw.ca.

References
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optical coherence tomography for early detection of retinal alterations in patients using hydroxychloroquine. Indian J Ophthalmol 2013;61:16871.
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spectral domain optical coherence tomography and multifocal electroretinography ndings in hydroxychloroquine
retinopathy. Invest Ophthalmol Vis Sci 2013;54. E-Abstract
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4. Marmor MF. Comparison of screening procedures in hydroxychloroquine toxicity. Arch Ophthalmol 2012;130:4619.
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ndings in hydroxychloroquine retinopathy. Arch Ophthalmol
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