Ophthalmic Genetics

ISSN: 1381-6810 (Print) 1744-5094 (Online) Journal homepage: http://www.tandfonline.com/loi/iopg20

Progressive expansion of the

hyperautofluorescent ring in cone-rod dystrophy
patients

Luiz H. Lima, Claudio Zett, Vinícius Kniggendorf, Bruna Marianelli, Ricardo A.

P. de Carvalho, Michel E. Farah & Juliana M. F. Sallum

To cite this article: Luiz H. Lima, Claudio Zett, Vinícius Kniggendorf, Bruna Marianelli, Ricardo
A. P. de Carvalho, Michel E. Farah & Juliana M. F. Sallum (2018): Progressive expansion
of the hyperautofluorescent ring in cone-rod dystrophy patients, Ophthalmic Genetics, DOI:
10.1080/13816810.2018.1461911

To link to this article: https://doi.org/10.1080/13816810.2018.1461911

Published online: 19 Apr 2018.

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OPHTHALMIC GENETICS
https://doi.org/10.1080/13816810.2018.1461911

CASE REPORT

Progressive expansion of the hyperautofluorescent ring in cone-rod dystrophy

patients
Luiz H. Limaa, Claudio Zetta,b, Vinícius Kniggendorfa, Bruna Marianellia, Ricardo A. P. de Carvalhoa, Michel E. Faraha,
and Juliana M. F. Salluma
a
Department of Ophthalmology, Federal University of Sao Paulo (UNIFESP), São Paulo, Brazil; bDepartment of Ophthalmology, Pontificia
Universidad Católica de Valparaíso, Valparaíso, Chile

ABSTRACT ARTICLE HISTORY

Purpose: To evaluate the expansion of the hyperautofluorescent ring and the retinal structure changes Received 1 August 2017
over time in cone-rod dystrophy (CRD) patients, using fundus autofluorescence (FAF) and spectral- Revised 24 March 2018
domain optical coherence tomography (SD-OCT). Accepted 1 April 2018
Methods: Retrospective case series study. Six eyes of three CRD patients with a parafoveal hyperauto- KEYWORDS
fluorescent ring were studied. The diagnosis of CRD was established by the presence of the implicit time Cone-rod dystrophy; fundus
shift at 30-Hz flicker and prevalent decrease of photopic over scotopic responses on electroretinography. autofluorescence;
External and internal ring expansion was evaluated by measurements of its area at baseline and at 24- hyperautofluorescent ring;
month follow-up using FAF. SD-OCT analyzed the retinal structure of the ring and the length of devoid spectral-domain optical
ellipsoid zone (EZ) was measured over time. coherence tomography
Results: The mean age of study patients was 21 years old and the mean baseline visual acuity was 20/
200. The external and internal FAF rings involving the fovea were identified in all study eyes. SD-OCT
showed a normal retinal structure outside the ring. At the transitional zone of the ring, disorganization
of both EZ and external limiting membrane (ELM) was observed. Inside the hyperautofluorescent ring,
EZ and ELM were not identified. At 24-month follow-up examination, the mean % area increase of
external and internal rings were 18.32% and 20.42%, respectively, and was concordant with the EZ band
defect length enlargement.
Conclusion: Progressive expansion of hyperautofluorescent macular ring with a correspondent EZ band
defect enlargement was observed over time in CRD patients.

Cone-rod dystrophy (CRD) is an inherited retinal dystrophy
that primarily involves cones or causes concomitant loss of
both cone and rod photoreceptor (1).CRD patients usually
present decreased visual acuity, color vision defects, and
photophobia as predominant symptoms. Although milder
cases are not diagnosed until later in life, the age of symptoms
onset is typically in the first decade of life. There are approxi-
mately 20 genes (ABCA4, CRX, GUCY2D, and RPGR repre-
sent the main causative genes) and three inheritance patterns
(autosomal dominant, autosomal recessive, and X-linked)
involved in nonsyndromic CRD cases (2–4).Cellular interac-
tion, protein transport along the cilium, phototransduction,
and defective outer segment morphogenesis represent the
most common mechanisms of loss of cone function in CRD
patients (5,6).
Perifoveal hyperautofluorescent rings have been reported
in diseases such as retinitis pigmentosa (RP), CRD, X-linked
retinoschisis, autoimmune retinopathy, and Leber congenital
amaurosis and may represent an abnormal perifoveal accu-
mulation of lipofuscin in the RPE as a result of an increased
outer segment degeneration as a precursor of apoptosis (7–9).
The disorganization of EZ in the transition zone of the hyper-
autofluorescent ring indicates an ongoing degenerative
process involving photoreceptors, possibly evolving with
apoptosis and culminating with photoreceptor death. The
presence and extent of EZ loss has been used as a morpholo-
gic marker for photoreceptor damage in animal models and
human diseases (10,11).
Although the presence of a hyperautofluorescent ring has
already been reported in CRD patients (8,10), the optical
coherence tomography (OCT) ring structure and the fundus
autofluorescence (FAF) area change over time have not been
described yet. The purpose of this study is to demonstrate the
progressive expansion of the hyperautofluorescent ring and
the changes in retinal structure in patients with CRD, using
both the FAF and B-scan OCT imaging.
Methods
Subjects
This case series study included six eyes of three patients with a
clinical diagnosis of CRD and hyperautofluorescent rings of
different diameters on FAF where expansion, constriction or
no change of the ring diameter was documented at follow-up.
The clinical findings of the study patients were evaluated by

CONTACT Luiz H. Lima luizlima9@gmail.com Federal University of São Paulo (UNIFESP), Rua Botucatu, 821, Vila Clementino, São Paulo, Brazil.
Color versions of one or more of the figures in the article can be found online at www.tandfonline.com/iopg.
© 2018 Taylor & Francis
2 L. H. LIMA ET AL.
one retina specialist and the full-field scotopic and photopic
electroretinograms (ERGs) were performed according to the
International Society for Clinical Electrophysiology of Vision
standards (12). Both clinical features and ERGs tracings were
consistent with the diagnosis of CRD in all patients. Two
study patients had CRD consequent upon mutation in
ABCA4 gene and one had RPGR mutation. All eyes in the
study had clear media facilitating FAF and spectral-domain
optical coherence tomography (SD-OCT) imaging. Eyes were
excluded if there was a refractive error greater than ±6.0
diopters spherical or ±2.0 diopters cylindrical, evidence of
cystoid macular edema (outer retinal degenerative cystoid
spaces), an epiretinal membrane, and evidence or a history
of other ocular diseases (e.g. glaucoma, diabetes). Four
patients were excluded due to outer retinal degenerative
cystoid spaces (3 patients) and epiretinal membrane (1
patient) on SD-OCT. These SD-OCT scans presented with
disorganization of outer retinal layers, therefore precluding a
precise measurement analysis.
Fundus autofluorescence
FAF imaging was performed using the Spectralis HRA+OCT
(Heidelberg Engineering, Dossenheim, Germany) after pupil
dilation with topical 0.5% tropicamide and 2.5% phenylephrine
eye drops. FAF imaging was performed using a 30° field of view
at a resolution of 1536 × 1536 pixels. An optically pumped
solid-state laser (488 nm) was used for excitation and a 495 nm
barrier filter was used to modulate the blue argon excitation
light. A standard procedure was followed for the acquisition of
FAF images, including focus of the retinal image in the infrared
reflection mode at 820 nm, sensitivity adjustment at 488 nm,
and acquisition of 9 single 30° × 30° FAF images encompassing
the entire macular area with at least a portion of the optic disc.
The 9 single images were computationally averaged to produce
a single frame with improved signal-to-noise ratio.
The external and internal boundaries of the hyperauto-
fluorescent ring in both horizontal and vertical axes were
defined as the visible limits seen on FAF. The external and
internal diameters of the hyperautofluorescent ring were iden-
tified along the horizontal and vertical axes that passed
through the fovea. The baseline and follow-up FAF images
were registered using commercial software (MatLab R2006;
The MathWorks, Inc., Natick, MA). We tested the accuracy of
each registration by superimposing the baseline and follow-up
image as a layered image in Photoshop CS2 (Adobe Systems
Inc., San Jose, CA) and flickering the superficial layer on and
off (13). The requirements for accuracy were that constant
features, i.e., the retinal vasculature, and corresponding vessels
should remain stationary. If registration was inaccurate, a new
registration was performed until the result was satisfactory.
Because they were precisely superimposed, both image scales
were identical and exact spatial relations between FAF
abnormalities in the initial and follow-up images could be
determined.
The total area of external and internal rings, i.e., the area
comprised within the limits of external and internal hyperau-
tofluorescent rings, were measured using commercial software
(Image J, National Institute of Health, Bethesda, MD) (14).
Figure 1. The horizontal length of devoid ellipsoid zone (EZ) band was measured
using the horizontal foveal scan at the same precise landmark and the caliper
available on the spectral-domain optical coherence tomography (SD-OCT) soft-
ware at baseline (A) and 24-month follow-up (B) examinations.
This area was measured at baseline and 24-month follow-up
examination, and the percentage change in area of the ring on
FAF at each follow-up examination was compared to the
baseline measurement in all subjects and calculated. The
increase in the area of the hyperautofluorescent ring was
defined as the value at the baseline subtracted from the
value obtained at 24-month follow-up visit.
Spectral-domain optical coherence tomography
SD-OCT was obtained at baseline and at 24-month follow-up,
and was performed with the Spectralis HRA+OCT (Heidelberg
Retina Angiograph, HRA2, Heidelberg Engineering, Heidelberg,
Germany). The simultaneous acquisition of OCT and FAF
images facilitates point-to-point correlation between the en-
face and cross-sectional images. Spectralis SD-OCT imaging
was acquired by a broadband 870 nm superluminescent diode
that scanned the retina at 40,000 A-scans per second with an
optical depth resolution of 7 µm. The standard protocol included
25 OCT scans averaged to improve the signal-to-noise ratio. The
AutoRescan feature of Spectralis SD-OCT was used to automa-
tically put the follow-up scans in exactly the same location as the
baseline scan.
The EZ defect was determined by measuring the length of
the region devoid of the EZ band at the foveal SD-OCT
B-scan. The horizontal length of the EZ defect was measured
using the horizontal foveal scan at the same precise landmark
and the caliper available on the SD-OCT software at baseline
and 24-month follow-up examination. This measurement at
baseline was compared to that at 24-month follow-up exam-
ination, and the percentage change was calculated (Figure 1).
The area of the hyperautofluorescent ring and the length of
the EZ defect were measured independently by two of the
authors (BM and VK) who were masked to the other findings
and data of the patients. In the event of disagreement, a third
investigator (LL) was consulted for the final determination.
Results
We analyzed six eyes of three CRD patients. All study patients
were white, and the patients (1 female, 2 males) ranged in age
 OPHTHALMIC GENETICS 3

from 18 to 25 years (mean age: 21 years). The most common
visual complaints noted were progressive decrease in visual
acuity, photophobia, dyschromatopsia, and central scotoma
on visual field test. The best-corrected visual acuity (BCVA)
ranged from 20/100 to 20/400 (mean visual acuity: 20/200).
Full-field photopic ERG responses were diminished in ampli-
tude (13.6 µV ± 10.5 at baseline and 13.1 ± 10.1 at 24-months
follow-up) for all 6 eyes compared with normal control values.
The CRD lesions occurred in the central macula and
involved the fovea. A hyperautofluorescent ring surrounding
the foveal area and presenting in an ovoid configuration
oriented horizontally occurred in all study eyes, and its exter-
nal and internal boundaries were also identified on FAF. The
FAF depicted a normal FAF outside the hyperautofluorescent
ring, and hypo and hyperFAF inside the ring and at ring
transitional zone, respectively. In all study eyes, the SD-OCT
structural analysis of the hyperautofluorescent ring demon-
strated a normal retinal structure with intact EZ and ELM
outside the ring. At the transitional zone of the ring, disorga-
nization of both the EZ and ELM was observed. Inside the
hyperautofluorescent ring, the EZ and ELM were not identi-
fied (Figures 2, 3 and 4).
An increase in area of both the external and internal
hyperautofluorescent rings was observed at the follow-up
examination in all patients (Figures 1, 2 and 3). At baseline,
the external ring had an area that ranged from 107.55 to
180.24 µm2. At the 24-month follow-up, the area of the
external ring had increased compared to the baseline mea-
surement. The change ranged from 12.57 to 47.12 µm2. The
mean % increase in area of the external ring was compared to
baseline. The mean % increase in area compared to baseline
was 18.32% at 24-month follow-up examination. The internal
ring had an area that ranged from 96.77 to 164.38 µm2 at
baseline. At the 24-month follow-up, the area of the external
ring had increased compared to the baseline measurement.
The change ranged from 20.33 to 36.61 µm2.The mean %

Figure 2. Progressive expansion of the hyperautofluorescent ring and concurrent EZ lamina enlargement in Case #1. A, B, C1, and D1. Baseline fundus
autofluorescence (FAF) and SD-OCT images of both eyes. All four images illustrate that across the ring, there is disorganization and loss of both the EZ band and
external limiting membrane (ELM). Outside the hyperautofluoresecent ring, all outer retinal layers are visible and have normal structure. Inside the ring, no EZ band
or ELM is observed. E, F, G1, and H1. Two-year follow-up FAF and SD-OCT of both eyes showed the expansion of the ring along with the enlargement of the EZ
defect. The length of the EZ defect in the right eye of Patient #1 measured 2095 μm at baseline and 2879 μm at 24-month follow-up. In the left eye, the length of
the EZ defect measured 2564 and 2845 μm at baseline and 24-month follow-up, respectively. C2, G2, D2, and H2. In a magnified view of SD-OCT, note the
progressive increase of EZ lamina disorganization nasally to the fovea two years later.
4 L. H. LIMA ET AL.

Figure 3. Progressive expansion of the hyperautofluorescent ring and concurrent enlargement of the EZ defect in Case #2. A, B, C1, and D1. Baseline FAF and
corresponding SD-OCT images of both eyes. All four images illustrate that across the ring, there is disorganization and loss of both the EZ band and ELM. Outside the
hyperautofluoresecent ring, all outer retinal layers are visible and have normal structure. Inside the ring, no EZ band or ELM is observed. E, F, G1, and H1. Two-year
follow-up FAF and SD-OCT of both eyes showed the expansion of the ring along with the enlargement of the length of the EZ defect. The EZ defect length in the
right eye of Patient #2 measured 2338 μm at baseline and 2776 μm at 24-month follow-up. In the left eye, the EZ defect length measured 2474 and 2674 μm at
baseline and 24-month follow-up, respectively. C2, G2, D2, and H2. In a magnified view of SD-OCT, note the progressive increase of EZ lamina disorganization nasally
to the fovea two years later.

increase in area of the internal ring was compared to baseline.
The mean % increase in area compared to baseline was
20.42% at 24-month follow-up examination (Table 1).
The measurements of the length of the EZ defect within
the central 3-mm zone were determined in all study eyes with
SD-OCT follow-up examination. At baseline, this length ran-
ged from1136 to 2564 µm. At the 24-month follow-up, the
minimal increase in comparison to the baseline was 64 µm
and the maximum increase was 784 µm. At 24-month follow-
up, the mean % increase of the length of the EZ defect was
17.16% (range: 5.63–37.42%) in comparison with baseline.
Table 2 shows the progressive increase of the length of devoid
EZ, and Figures 5, 6 and 7 demonstrate the progression of
internal and external ring areas and the length of the EZ
defect and its relationship with BCVA over a 24-month fol-
low-up period.
Discussion
This report describes a case series of hyperautofluorescent
macular rings in patients presenting with predominant cone
dysfunction on ERG that was consistent with CRD. The
increased FAF within the central macular area is a nonspecific
presentation of CRD that may appear in other forms of retinal
degenerations, such as bull’s eye maculopathy, cone dystrophy
with supernormal rod response, and rod-cone dystrophy
(15,16). Increased fundus autofluorescence is related to a
localized accretion of lipofuscin, a waste product from RPE
metabolism and photoreceptor outer segments turnover. In
histopathological examination, the excessive quantity of lipo-
fuscin in the retina has been associated with photoreceptor
cells impairment indicating the peculiar toxicity of lipofuscin
on these cells (17).
In RP, the macular hyperautofluorescent ring is presumed
to represent a transition between abnormal paracentral and
normal central cone function, outlining a retinal area with
visual field preservation (18–20). The SD-OCT structural
analysis of hyperautofluorescent rings is already reported in
RP patients. In this setting, the retina outside the ring depicts
absence of the EZ and ELM. At the edge of the ring, disorga-
nization of both EZ and ELM is observed. Within the hyper-
autofluorescent ring, the retina is totally normal (10).
Progressive over time constriction of the hyperautofluorescent
rings has also been described in RP patients (11). In our CRD
series, similarly to RP, disorganization of both the EZ and
ELM was observed at the edge of the ring. Conversely, the
retina outside the ring was intact and there was absence of the
EZ and ELM within the hyperautofluorescent ring. At 24-
 OPHTHALMIC GENETICS 5

Figure 4. Progressive expansion of the hyperautofluorescent ring and concurrent enlargement of the EZ defect in Case #3. A, B, C1, and D1. Baseline fundus FAF and
corresponding SD-OCT images of both eyes. All four images illustrate that across the ring, there is disorganization and loss of both the EZ band and ELM. Outside the
hyperautofluoresecent ring, all outer retinal layers are visible and have normal structure. Inside the ring, no EZ band or ELM is observed. E, F, G1, and H1. Two-year
follow-up FAF and SD-OCT of both eyes showed the expansion of the ring along with the enlargement of the EZ defect length. The EZ defect length in the right eye
of Patient #3 measured 1181 μm at baseline and 1443 μm at 24-month follow-up. In the left eye, the EZ defect length measured 1136 and 1200 μm at baseline and
24-month follow-up, respectively. C2, G2, D2, and H2. In a magnified view of SD-OCT, note the progressive increase of EZ lamina disorganization nasally to the fovea
two years later.

Table 1. Measurements of external and internal rings area at baseline and 24-month follow-up.
Right eye Left eye
External ring Internal ring External ring Internal ring
Baseline 24-month Follow-up Baseline (µm2) 24-month follow-up Baseline (µm2) 24-month follow-up Baseline (µm2) 24-month follow-up
2
Case #1 177.64 µm 190.21 (7.08%) 162.91 183.24 (12.48%) 180.24 195.76 (8.61%) 164.38 190.94 (16.16%)
Case #2 107.55 µm2 154.67 (43.81%) 96.77 133.38 (37.83%) 115.02 136.49 (18.67%) 97.80 121.34 (24.07%)
2
Case #3 157.78 µm 179.98 (14.07%) 134.09 155.98 (16.32%) 150.20 176.80 (17.71%) 135.16 156.35 (15.68%)
(%) = % increase in area compared to baseline.

Table 2. Measurements of lenght of devoid ellipsoid zone on SD-OCT at baseline and 24-month follow-up.
Right eye Left eye
Baseline (µm) 24-month follow-up Baseline (µm) 24-month follow-up
Case #1 2095 2879 µm (22.18%) 2564 2845 µm (5.63%)
Case #2 2338 2776 µm (18.73%) 2474 2674 µm (8.08%)
Case #3 1181 1 443 µm (37.42%) 1136 1200 µm (10.96%)

month follow-up, an expansion of the FAF ring area along Robson et al. (7) demonstrated that the radius of the parafoveal
with enlargement of EZ loss was observed in all study cases. ring of high density correlated with pattern electroretinography
The changes observed in this case series indicate a centrifugal P50 and encircled areas of central atrophy in CRD patients. Wang
progression of retinal structural changes in CRD. et al. (9) showed that hyperautofluorescence in the foveola is a
6 L. H. LIMA ET AL.

Figure 5. Progression of external ring area and its relationship with best-corrected visual acuity (BCVA) over 24-month follow-up period.

µm2 = square micrometers

( ) = best-corrected visual acuity (BCVA)

Figure 6. Progression of internal ring area and its relationship with best-corrected visual acuity (BCVA) over 24-month follow-up period.

µm2 = square micrometers

( ) = best-corrected visual acuity (BCVA)
OD = right eye
OS = left eye

nonspecific manifestation of photoreceptor-RPE dysfunction in suggesting CRD disease progression over time. Although these
CRD. Nong et al. (21) found in three family members with recent publications have described the presence of hyperauto-
mutation in GUCA1A gene that enlarging hypoautofluorescent fluorescent rings in CRD patients, none of them analyzed the
lesions over three years were consistent with macular atrophy, SD-OCT ring structure or the rate of ring progression over

Figure 7. Progression of the length of devoid ellipsoid zone and its relationship with best-corrected visual acuity (BCVA) over 24-month
follow-up period.
µm = micrometers
( ) = best-corrected visual acuity (BCVA)
OD = right eye
OS = left eye
time. Our data support the hypothesis that expansion of the
hyperautofluorescent ring may reflect the structural disorganiza-
tion of photoreceptors during the progression of CRD. In all study
eyes, BCVA did not show significant change and did not correlate
with progression of internal and external rings and EZ band loss
over the follow-up period. It may be probably related to the fact
that the central visual acuity corresponds to the central 3 degrees
of visual field that represents the fovea on retinal fundus (22). As
the foveal area is typically atrophic in CRD patients, central visual
acuity may not attain the sensitivity and precision required to
measure subtle foveal changes in the visual function associated
with micrometric changes in the studied parameters as measured
by OCT. Despite the maintenance of good visual acuity, disrup-
tions of the EZ band are associated with reduced differential light
sensitivity In this setting, these fine changes would be identified by
additional visual function tests such as perimetry and microperi-
metry (23,24).
In this current study, two CRD patients had mutation in
ABCA4 gene and one patient had RPGR mutation. Robson
et al. (16) reported the first CRD cases associated with macular
annuli of high density on FAF in RPGR and RIMS1 patients
specifically. In this report, the FAF ring size correlated with a
gradient of scotopic and photopic sensitivity loss and expanded
with time in two subjects. Hyperautofluorescent rings have not
been described in CRD patients with ABCA4 mutation, but one
ABCA4 Stargardt’s patient presenting with this type of ring was
reported recently (25). Although Robson et al. (16) showed
progressive ring expansion, these two previous studies on
CRD and Stargardt’s patients with hyperautofluorecent ring
did not demonstrate the structural ring assessment or the
ring area change over time (16,25).
Similarly to RP, the anomalous FAF observed in CRD patients
is represented by the hyperautofluorescent ring and may indicate
OPHTHALMIC GENETICS 7
an abnormal high rate of photoreceptors phagocytosis (26,27) and
the RPE dysfunction of increased metabolic load on the RPE due
to photoreceptor apoptosis (28,29). The great amount of lipofuscin
that causes the hyperintensity of FAF would result in RPE atrophy
followed by lipofuscin granules loss. Differently from RP, visual
fields are more preserved in eyes with small hyperautofluorescent
rings as retinal degeneration in CRD progresses centrifugally from
the macular area. The hypoautofluorescence observed within the
ring is probably related to photoreceptor loss in conjunction with
RPE atrophy. Although expanding centrifugally in CRD in con-
trast to centripetally in RP, the hyperautofluorescent ring may also
have a role as a surrogate marker for disease progression and,
therefore, be used as a measurable outcome of in clinical trials.
Other factors are likely implicated in the size and rate of expansion
of the hyperautofluorescent ring in CRD patients, including the
underlying genotype.
This report has some limitations, including its limited popula-
tion, follow-up period, and limited visual function assessment.
Furthermore, our findings are limited to phenotypes of the disease
presenting with the hyperautofluorescent rings. Other phenotypes
were excluded and, therefore, no inference can be made about
changes or progression related to other patterns of abnormal FAF
present in CRD patients. In summary, the present study showed
evidence of ring expansion associated with an enlargement of the
EZ band loss in CRD patients that present with hyperautofluor-
escent ring. Therefore, FAF and SD-OCT may be valuable non-
invasive imaging techniques to follow CRD patients and may help
in monitoring or measuring disease progression based on struc-
tural retinal changes. Larger series with long-term follow-up of
CRD patients presenting with hyperautofluorescent ring, includ-
ing more comprehensive visual function assessments, are needed
to validate the use of hyperautofluorescent ring expansion and loss
of EZ band as secondary outcomes for therapeutic trials.
8 L. H. LIMA ET AL.
Declaration of interest
The authors report no conflicts of interest.
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