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Clinical Variations in Assessment of Bull's-eye Maculopathy
Malaika M. Kurz-Levin, MD;
Anthony S. Halfyard, PhD;
Catey Bunce, MSc;
Alan C. Bird, MD;
Graham E. Holder, PhD
Arch Ophthalmol. 2002;120:567-575.
ABSTRACT
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Objectives To evaluate the phenotypic variation in bull's-eye maculopathy and seek
possible correlations between functional loss and clinical appearance.
Methods From January 1, 1999, to September 30, 2000, we prospectively examined
patients with bull's-eye lesions. Age of onset, duration of symptoms, visual
acuity, clinical appearance, and autofluorescence images were recorded, the
area of atrophy measured, and electrophysiologic investigations performed.
Results Forty-seven patients, including 6 sibling pairs, met the study entry
criteria. On the basis of autofluorescence imaging, 3 distinct groups were
identified. Group 1 showed a distinct ring of increased autofluorescence surrounding
an area of decreased autofluorescence. In group 2, the ring of increased autofluorescence
was not present. Group 3 displayed a speckled appearance within the affected
area. All patients had evidence of central sparing in an area of centrally
increased autofluorescence. There was significant correlation with the age
of onset, visual acuity, and duration of disease. Electrophysiologic tests
revealed that 28 patients had macular dysfunction only, 14 had cone-rod dystrophy,
3 had rod-cone dystrophy, and only 2 (monozygotic twins) had cone dystrophy.
The correlation between electrophysiologic and autofluorescence data was poor.
The sibling pairs had concordant autofluorescence appearance, but electrophysiologic
grouping differed in 2 pairs.
Conclusions Bull's-eye maculopathy represents a heterogeneous group of disorders.
The clinical appearance was not helpful in assessing the degree of retinal
dysfunction. The difference in qualitative characteristics of functional loss
between siblings implies that these attributes do not necessarily reflect
the influence of the primary mutation.
INTRODUCTION
KEARNS AND HOLLENHORST1 introduced the
term bull's-eye maculopathy (BEM) in 1966 to describe
the characteristic clinical appearance of chloroquine retinopathy. In 1971,
Deutman2 used the term to describe similar
lesions in patients with inherited retinal dystrophies initially characterized
by a central red spot surrounded by a ring of atrophic pigment epithelium
or pigment epithelial mottling. The ring of atrophy may vary in degrees of
eccentricity from the fovea. It is considered distinct from Stargardt maculopathy
in which the atrophy is physically discontinuous, as best demonstrated by
autofluorescence imaging.3 Bull's-eye lesions
in retinal dystrophies have since been reported in cone dystrophy (CD), cone-rod
dystrophy (CRD),4-7
and rod-cone dystrophy (RCD).8-9
Furthermore, Deutman6 described simplex cases
of BEM with loss of central vision but a normal full-field electroretinogram
(ERG). Similar changes have been described in dominant pedigrees.6, 10-11
The mechanisms by which the degeneration occurs in this striking distribution
are not well understood. The appearance may correspond to the pattern of lipofuscin
accumulation in the cells of the retinal pigment epithelium (RPE), which in
healthy subjects is highest at the posterior pole and shows a depression at
the fovea,12-13 thus explaining
the annular pattern and central sparing.14
Furthermore, the small area of central sparing was postulated as being due
to a photoprotective effect of the high foveal concentration of luteal pigment.14 The initially spared center usually becomes involved
during the disease, at which point the diagnosis of BEM can no longer be made.4, 15 This study aims to describe the phenotype
of patients with BEM to determine whether the nature of functional loss can
be correlated with the clinical appearance of the fundus.
PATIENTS AND METHODS
All patients with a bull's-eye lesion at the macula examined from January
1, 1999, to September 30, 2000, were included in this prospective study after
providing informed consent. Patients were excluded if any evidence of additional
retinal abnormalities were present, such as intraretinal pigmentation in a
bone-spicule pattern or white-yellow deep retinal flecks and discontinuous
atrophy suggestive of Stargardt macular dystrophy–fundus flavimaculatus
(SMD-FFM). The possibility of toxicity was ruled out in all patients. The
diagnosis of BEM was based on the presence of a ring of RPE pallor or pigment
epithelial mottling around the fovea. The diagnosis was sustained only if
there appeared to be central sparing. These changes were initially identified
by ophthalmoscopy and confirmed by autofluorescence imaging with the confocal
scanning laser ophthalmoscope (cSLO) (Zeiss Prototype; Carl Zeiss Inc, Oberkochen,
Germany) (Figure 1), using previously
published techniques.16 Patients in whom a
mutation in a gene known to cause retinal dystrophy was identified were not
included; reports of these patients have been previously published.10-11
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Figure 1. Color photographs and autofluorescence
images of patient 20, aged 31 years, with a bilateral bull's-eye lesion; visual
acuity with each eye was 6/9. The confocal scanning laser ophthalmoscope images
show decreased perifoveal autofluorescence, corresponding to the retinal pigment
epithelial atrophy bordered centrally and peripherally by increased autofluorescence.
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Patient demographics (age, sex, age of onset, age at initial examination,
duration of disease, best-corrected visual acuity, fundus appearance on slitlamp
biomicroscopy) were recorded and the mode of inheritance noted. Visual acuity
was measured using a Snellen chart. Color fundus photographs and fundus autofluorescence
images were obtained and electrophysiologic investigations undertaken. The
area of pigment epithelial atrophy, defined as the area of decreased autofluorescence
as assessed on the cSLO, was measured on computer image using Adobe Photoshop
(Adobe Systems Inc, San Jose, Calif), the number of square pixels being converted
into square degrees. Age of onset was defined as the age at which the first
symptoms were noticed. Duration of the disease was calculated as the difference
between the age of onset of symptoms and the age at examination.
All patients underwent electrophysiologic investigation according to
the protocols recommended by the International Society for Clinical Electrophysiology
of Vision.17-19
Full-field ERGs, electro-oculogram, pattern ERG (PERG), focal ERG, and color-contrast
sensitivity measurement were performed. The patients were classified as having
macular dystrophy (MD) if the results of PERG were abnormal but there was
no ERG evidence of generalized photoreceptor dysfunction. Additionally, if
the cone ERG was exclusively affected, the condition was designated as CD;
if cone ERGs were more affected than rod ERGs compared with normal, the diagnosis
of CRD was made, but if rod ERGs were more affected than cone ERGs, the diagnosis
of RCD was made, thus categorizing them into 4 groups (MD, CD, CRD, and RCD).
The patients were divided into 3 cSLO groups. Group 1 showed a distinct
ring of increased autofluorescence surrounding an area of decreased autofluorescence.
In group 2, the ring of increased autofluorescence was not present. Group
3 displayed a speckled appearance within the affected area. All patients had
an area of centrally increased autofluorescence as evidence of central sparing.
Patients were categorized as having mild (visual acuity, 6/6-6/12), moderate
(6/18-6/36), or severe visual loss (vision worse than 6/36). We subdivided
the patients into mild PERG P50 amplitude abnormality (>1.2 µV), moderate
(0.5-1.2 µV), severe (<0.5 µV), and undetectable. The ethics
committee of Moorfields Eye Hospital, London, England, approved the study.
Each patient gave informed consent.
Because of nonnormality, the Kruskal-Wallis test was used to assess
whether the patients in the 3 different cSLO image groups and those in the
4 electrophysiology groups differed significantly with regard to age of onset
and duration of disease. If the Kruskal-Wallis test was statistically significant
for cSLO groups, we used the rank sum tests to determine differences among
groups. Because of the small numbers of patients in some of the categories,
this was not repeated for the electrophysiology groupings and descriptive
results are presented. The Kruskal-Wallis test was also used when testing
for an association between visual acuity and area of atrophy. The Fisher exact
test was applied when comparing categorical variables between the cSLO groups
and the electrophysiology groups, such as the distribution of the electrophysiologic
findings and visual acuity, and when assessing any association between visual
acuity and PERG P50 component amplitude. The Spearman rank sum correlation
coefficient was applied when assessing the association between duration of
illness and area of atrophy.
RESULTS
Forty-seven patients (30 women and 17 men) fulfilled the study entry
criteria. In all but 1, who had corneal scarring owing to a perforating injury
precluding examination, the macular changes were present bilaterally. All
subjects underwent electrophysiologic investigations, whereas autofluorescence
imaging was not undertaken in 1 patient, and in 1 other patient no right eye
image was obtained because of technical problems. The results from both eyes
were concordant in all variables, unless otherwise stated, and the right eye
data were arbitrarily chosen for presentation.
The median age of onset was 26 years (range, 5-54 years), the median
best-corrected visual acuity was 6/36 (range, 6/5-1/60), and the median duration
of symptoms was 6 years (range, 0-36 years). No patient had a refractive error
of more than 2 diopters. The inheritance pattern was autosomal recessive in
43 patients and autosomal dominant in 4 (patients 1, 33, 34, and 47), including
a mother and son. There were 6 sibling pairs, including 1 set of monozygotic
twins.
The findings concerning age of onset, duration of disease, and visual
acuity were grouped according to the 3 different cSLO appearances and the
4 different electrophysiologic results (Table 1) (Figure 2 and Figure 3). There was strong evidence of a
difference between cSLO groups concerning the age of onset (P = .01). The difference was most pronounced when comparing patients
in group 1 with those in group 3 (P = .002), whereas
the age of onset of subjects in group 1 was not statistically significantly
different from those in group 2 (P = .19) or between
group 2 and group 3 (P = .09). There was strong evidence
of an association between the duration of disease and the cSLO groups (P = .03). Rank sum testing revealed that the patients in
cSLO group 3 had a statistically significantly shorter duration of disease
(P = .008) then those in cSLO group 1. There was
strong evidence of an association between visual acuity and cSLO grouping
(P = .006), with patients in cSLO group 3 tending
to have better visual acuity (P = .001 for group
1 and group 2). There was no evidence of an association between the area of
pigment epithelial atrophy and either visual acuity or duration of disease.
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Table 1. Age of Onset, Duration of Disease, and Visual Acuity OD of
All Patients With Bull's-eye Maculopathy*
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Figure 2. Autofluorescence images of patients
in the 3 different confocal scanning laser ophthalmoscope (cSLO) groups: A,
cSLO group 1. Patient 8, aged 32 years; visual acuity, 6/9 OU. This patient
demonstrates a distinct ring of increased autofluorescence surrounding decreased
autofluorescence. B, cSLO group 2. Patient 29, aged 18 years; visual acuity,
6/60 OD and 6/24 OS. The ring of increased autofluorescence is absent. C,
cSLO group 3. Patient 41, aged 35 years; visual acuity, 6/5 OU. This patient
demonstrates the speckled appearance within the lesion.
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Figure 3. Examples of the 4 different electrophysiologic
phenotypes. Note that the pattern electroretinogram (PERG) is markedly abnormal
in all 4 patients, with patient B showing the least number of PERG abnormalities.
A, Disease confined to the macula; normal electroretinograms but undetectable
PERG P50 component. B, Generalized retinal dysfunction involving both rod
and cone systems; the rod system is more affected than the cone system, with
the latter findings falling only just outside the normal range. C, Generalized
retinal dysfunction involving both rod and cone systems; the cone system is
more affected than the rod system showing profound amplitude and implicit
time changes. D, Dysfunction confined to the cone system.
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ELECTROPHYSIOLOGIC FINDINGS
The electrophysiologic findings are given in Table 2, with grouped clinical data in Table 1. Macular dystrophy (abnormal PERG, normal ERG, and normal
electro-oculogram) was present in 28 patients (60%), CRD in 14 (30%), and
RCD in 3 (6%). Only 2 patients (4%), who were monozygotic twins, had CD. Two
patients with central cone and peripheral rod involvement but normal peripheral
cone function were labeled as having CRD (patients 25 and 27). Patient 23
showed equally affected full-field cone and rod ERGs, but a nondetectable
PERG, and was also designated as having CRD. Patient 12 was labeled as having
MD since the photopic single-flash ERG was unaffected, despite a mildly subnormal
30-Hz flicker response. Three patients had a negative scotopic maximal ERG
waveform with a-wave preservation and relative b-wave loss (patients 6, 28,
and 29). The 2 patients with CD (patients 16 and 17) showed a reduced b/a
ratio in the photopic ERG. The on and off systems were separately tested in
15 patients using a 200-millisecond amber stimulus on a green background;
reduction of the on b-wave occurred in 3 cases (patients 16, 17, and 18).
These patients appear to have a postphototransduction cone on-system abnormality.
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Table 2. Results of Electrophysiologic Investigations in 47 Study Patients*
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We found strong evidence of an association between the different electrophysiology
groups and the cSLO groups (P = .02). Most patients
with CRD were in cSLO group 2, whereas no patient in the cSLO group 3 had
this diagnosis (Table 3). There
was some association between the electrophysiology groups and the age at onset
(P = .05), with a tendency for patients to develop
RCD later in life than the other categories (Table 1). There was little evidence of association between the electrophysiology
groups and the duration of disease (P = .60), visual
acuity (P = .70), or area of atrophy as measured
on the cSLO image (P = .60). However, our power to
detect any association is weak owing to the small numbers in some of the groups.
There was a strong association between the electrophysiology and the PERG
P50 component amplitude (P = .006), with almost all
CRD patients having a nondetectable PERG compared with 17 of 28 patients with
MD alone. Assessing the distribution of the PERG results among the 3 cSLO
groups, we found borderline evidence of a difference (P = .06) (Table 4). However,
there was a statistically significant association between visual acuity and
PERG: eyes with a severely reduced PERG had markedly reduced visual acuity
(Table 5).
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Table 3. Distribution of the 4 Electrophysiologic Findings Among the
3 cSLO Groups*
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Table 4. Distribution of the PERG P50 Component Among the 3 cSLO Groups*
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Table 5. Comparison of the PERG P50 Component Value With Visual Acuity
OD*
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SIBLING COMPARISON
All 6 sibling pairs were presumed to have autosomal recessive disease
(Table 2 and Table 6). When comparing their autofluorescence images, remarkable
concordance was found between the siblings, and they were assigned to the
same cSLO group. In contrast, the electrophysiologic results were dissimilar
in 2 pairs (patients 10 and 11 and patients 40 and 41). In sibling pair 2
(patients 10 and 11), the older sibling (duration of symptoms 7 years longer
than his younger sister) had CRD, whereas the sister had MD only. In sibling
pair 6 (patients 40 and 41), the older asymptomatic sister had MD and the
younger sibling had RCD on electrophysiologic examination. The PERG was similarly
affected in all sibling pairs, although in one pair (patients 26 and 27),
there was a quantitative difference with the PERG in the older patient being
undetectable, but his younger brother showing a reduced but detectable PERG.
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Table 6. Electrophysiologic Findings in Sibling Pairs*
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COMMENT
The term bull's-eye maculopathy refers to the
distinctive changes seen on fundus examination, although it may signal the
presence of a variety of disorders. This study was undertaken to analyze in
detail the phenotype in a large study population with the hope of facilitating
a more precise diagnosis. The findings might also contribute to the search
for causative genes and phenotype-genotype correlation. Apart from a functional
classification based solely on the localization of the retinal dysfunction
published by Pinckers et al,20 we are unaware
of a previous report addressing this question.
The median duration of symptoms and visual acuity in our study compares
with previously published results in BEM.4, 15
We acknowledge that the duration of symptoms may not truly reflect the duration
of disease, but this is the only viable option in the absence of longitudinal
studies.
Autofluorescence imaging of the RPE with the cSLO, as a known method
for indirectly assessing the state of the photoreceptor cells, was extremely
valuable in confirming the diagnosis but was not helpful in assessing the
degree of retinal dysfunction. In some cases, the macular abnormality was
very subtle on ophthalmoscopic examination but much more evident on the cSLO
image. That all sibling pairs showed a very similar autofluorescence pattern
suggests that this may reflect genetic influences, assuming that siblings
have the same mutations, particularly as some sibling pairs showed marked
differences in age. Given the rarity of the disorder, this is likely to be
the case. Despite this absolute concordance in the cSLO image, the electrophysiologic
results were discordant in 2 sibling pairs. This finding contrasts markedly
with previous observations on intrafamilial variation in SMD-FFM21;
although siblings with SMD-FFM showed wide variation in age of onset, visual
acuity, and clinical appearance, electrophysiologic testing revealed qualitatively
similar results. In the present study, the siblings with the longer duration
of illness had generalized retinal involvement as opposed to dysfunction confined
to the macula. This lack of concordance across sibling pairs in BEM may indicate
a progressive disorder, which is important when counseling these patients.
Unlike Stargardt disease, it cannot be concluded that normal ERGs at one stage
in the disorder imply that peripheral retinal function will remain unaffected.
Whether the disorder evolves from localized to generalized disease can be
determined by longitudinal recording and larger sibling studies.
The importance of the shorter duration of disease, significantly better
visual acuity, and the older age of onset in patients displaying a speckled
pattern of RPE atrophy within the bull's-eye lesion (cSLO group 3) is unclear.
That PERGs in this group were not better preserved than in the others, and
the fact that one case showed generalized dysfunction, argues against this
appearance merely representing earlier disease. Rather than assuming that
these patients will develop the typical confluent areas of atrophy and possibly
loss of vision, they may represent a distinct phenotype with milder disease.
Although the electrophysiologic characteristics concerning generalized
retinal dysfunction did not correlate well with variables such as duration
of symptoms, visual acuity, and area of atrophy, most patients with CRD had
the autofluorescence features of group 2, with no increased autofluorescence
around the area of atrophy. Increased autofluorescence may indicate that the
RPE is unable to cope with the metabolic demands of outer segment renewal,
either because of RPE dysfunction or phagocytosis of excess or abnormal outer
segment material.22-23 If ERG
reduction indicates a reduction in photoreceptor population, this clinical
sign may be absent as a consequence of reduced outer segment turnover. However,
the groups compared were small and therefore the power to detect differences
was low, and we cannot exclude peripheral cone and rod involvement possibly
representing a more advanced form of the disorder. In none of our cases, however,
were there any ophthalmoscopic signs of generalized retinal involvement; this
could be demonstrated only by electrophysiologic examination.
A BEM is commonly quoted as a typical feature of cone dystrophies. Previous
publications2, 4-6
have presented it in this context, although the authors acknowledged that
some cases showed some rod ERG abnormalities. They also recognized that some
might develop a variable degree of rod system involvement as the disease progresses.
To our surprise, however, only 2 patients, who were monozygotic twins, had
electrophysiologic findings compatible with the diagnosis of cone dystrophy,
whereas most cases had dysfunction confined to the macula. All the remaining
subjects with peripheral cone dysfunction had some degree of additional rod
involvement, which in some was the predominant ERG abnormality. Rather than
ascribing this discrepancy to a truly different patient population from previous
studies, we may have applied stricter criteria when diagnosing CD, not allowing
any rod system abnormality.
The striking feature of a negative waveform in the photopic ERG found
in 2 cases suggests that the dysfunction here was not localized in the cone
photoreceptors but rather in the postphototransduction system as has previously
been noted in some patients with BEM.24 A negative
scotopic ERG waveform is a recognized finding in certain cases.6, 25
There is no good explanation for this phenomenon, although synaptic changes
have been described in photoreceptor dysfunction.26
Several reports4, 6, 20
described patients with dysfunction confined to the macula, but those studies
were performed in preselected groups, precluding comparison with our study.
Our patients with only MD did not significantly differ from those with generalized
retinal involvement with regard to age of onset, duration, or visual acuity.
Thus, the differences cannot easily be explained as different disease stages.
Pattern ERG and focal ERG recordings were abnormal in all patients, including
those in whom the diagnosis was made as an incidental finding and some cases
with good vision. However, in contrast to SMD-FFM in which good visual acuity
may be associated with severely reduced PERG,21
our study population showed a highly significant correlation between the level
of visual acuity and electrophysiologic response.
Delineating the area of RPE atrophy was difficult for some patients
in the cSLO group 3, since the speckled pattern did not allow clear distinction
between affected and unaffected RPE and retina. Because no patient had a refractive
error of more than 2 diopters, image size was not corrected for any magnification
factor when measuring the area of atrophy.27-28
Whether or not the extent of atrophy in the bull's-eye lesion represents different
disorders is doubtful. It may reflect the duration of disease, although we
found no correlation with the duration of symptoms.
Unlike SMD-FFM, in which a single gene is involved, BEM seems to represent
a heterogeneous group of disorders.29 The fact
that the disorder can be present in autosomal recessive and autosomal dominant
patterns supports this view. Furthermore, although 2 genes have been implicated
in transmitting dominant disease,10-11
mutations in these genes do not explain all the dominant bull's-eye dystrophies.
AUTHOR INFORMATION
Submitted for publication May 31, 2001; final revision received December
10, 2001; accepted December 21, 2001.
This study was supported by the Macular Disease Society, London, England;
the Zürcher Hochschulverein and the EMDO-Stiftung, Zürich, Switzerland
(Dr Kurz-Levin); and the Foundation for Fighting Blindness, Baltimore, Md
(Dr Halfyard).
Corresponding author and reprints: Graham E. Holder, PhD, Moorfields
Eye Hospital, City Road, London EC1V 2PD, England (e-mail: graham.holder{at}moorfields.nhs.uk).
From the Medical Retina Service (Drs Kurz-Levin and Bird) and Departments
of Epidemiology (Dr Bunce) and Electrophysiology (Dr Holder), Moorfields Eye
Hospital, and Department of Visual Science, Institute of Ophthalmology (Dr
Halfyard), London, England.
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Pattern ERG Correlates of Abnormal Fundus Autofluorescence in Patients with Retinitis Pigmentosa and Normal Visual Acuity
Robson et al.
IOVS 2003;44:3544-3550.
ABSTRACT
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