SURVEY OF OPHTHALMOLOGY

VOLUME 54  NUMBER 2  MARCHAPRIL 2009

AFTERIMAGES
ANDREW HARRISON AND MICHAEL LEE, EDITORS

High-resolution Spectral Domain Optical Coherence

Tomography Findings in Multifocal Vitelliform
Macular Dystrophy
Giuseppe Querques, MD,1,2 Michael Regenbogen, MD,1 Gisele Soubrane, MD, PhD,1
and Eric H. Souied, MD, PhD1
1

Department of Ophthalmology, University of Paris XI, Creteil, France; and 2Department of Ophthalmology, Policlinico
Ospedali Riuniti, University of Foggia, Italy

Abstract. We describe the abnormalities seen in the mid periphery and posterior pole of two patients
with multifocal vitelliform macular distrophy as evaluated by high-definition spectral domain optical
coherence tomography (HD-OCT). In patient 1, HD-OCT scans revealed, in the central area, a thicker
and more reflective layer compared with the normal macula, located between the retinal pigment
epitelium and the interface of the inner segment /outer segment, corresponding to the Verhoeffs
membrane. Moreover, HD-OCT macular scans, as well as C-scans, revealed a slight hyper-reflective
lesion just above an area of reduced reflectivity between the photoreceptor layer (interface of the inner
segment and outer segment) and the Verhoeffs membrane. In patient 2, on HD-OCT macular scans,
the layer corresponding to the interface of inner segment and outer segment of the photoreceptor,
and the Verhoeffs membrane, appeared disrupted, whereas the retinal pigment epithelium layer
appeared preserved. On the other hand, in both patient 1 and 2, the clinically evident vitelliform
lesions outside the macular area appeared on HD-OCT scans either as small focal hyper-reflective
lesions at the level of the retinal pigment epithelium/photoreceptor complex, either as a more
pronounced diffuse thickening of the retinal pigment epithelium/photoreceptor complex, facing the
deposition of lipofuscin reported on the histopathologic examination. These new findings would help
in a further understanding of multifocal vitelliform macular distrophy. (Surv Ophthalmol 54:311--316,
2009. 2009 Elsevier Inc. All rights reserved.)
Key words. Best disease  high definition
coherence tomography  spectral domain

multifocal vitelliform macular dystrophy

Vitelliform macular distrophy (VMD), also called

Best disease, is an autosomal dominant hereditary
disease with strong penetrance but variable expressivity, characterized by the deposition of yellowish
material (lipofuscin) at the level of the retinal
pigment epithelium (RPE) and in the macrophages
of the subretinal and choroidal space.3,9 It is

optical

associated with a mutation in the gene VMD2

(Vitelliform Macular Dystrophy-2)8 on chromosome
11q13 that codes for bestrophin,10 a Ca2-sensitive
Cl-- channel protein found on the basolateral
membrane of RPE cells.5,11 VMD is a clinically
heterogenous and pleomorphic disease. Most cases
have a solitary lesion in the macula; others have
311

2009 by Elsevier Inc.

All rights reserved.

0039-6257/09/$--see front matter

doi:10.1016/j.survophthal.2008.12.010

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Surv Ophthalmol 54 (2) March--April 2009

QUERQUES ET AL

Fig. 1. Patient 1. Color fundus photograpy, of the macula of the right eye (RE) and left eye (LE) showing no major
alterations except for a foveal granularity (A and B). Color fundus photograpy of the RE and LE showing several vitelliform
lesions outside the macular area and in mid periphery (C ). High-definition spectral domain optical coherence tomography
(HD-OCT) scan of normal macula (D), and HD-OCT scan from the patients left eye (E ), showing a thicker and more
reflective appearance of the layer between the RPE and the interface of IS and OS of the photoreceptor (the Verhoeffs
membrane) (arrowheads) in the central region compared with the normal human macula. ELM 5 external limiting
membrane; IS 5 inner segment; OS 5 outer segment; VM 5 Verhoeffs membrane; RPE 5 retinal pigment epithelium.

multifocal vitelliform lesions,3,9 most of which are

confined to the posterior pole. The exact location of
the material, whether below, above, or inside the
RPE, has not yet been conclusively determined,
either by clinical or histological assessment. Histopathologic examination shows extensive deposition
of lipofuscin in the RPE throughout the retina and
accumulation of fibrillar material under the RPE
and in the choroid.4,7,12
High-definition spectral domain optical coherence tomography (HD-OCT, OCT 4000 Cirrus,

Humphrey-Zeiss, San Leandro, California) is

a high-resolution high-speed OCT system (up to
27,000 axial scans per second) using spectral/
Fourier domain detection, with an axial image
resolution of 5 mm. In vivo visualization is possible
of detailed intraretinal structures, and especially the
RPE, the inner segment (IS) and outer segment
(OS) of the photoreceptor layer, which are often
involved in early stages of retinal disease.
We present the abnormalities seen in the mid
periphery and posterior pole of two patients with

MULTIFOCAL VITELLIFORM MACULAR DYSTROPHY

313

Fig. 2. Patient 1. High-definition spectral domain optical coherence tomography (HD-OCT) scan passing through the
foveola, as well as C-scans (en face planes reconstructed from B-scans data), reveals, in the left eye, a slight hyper-reflective
lesion (A and B, arrowheads), just above an area of reduced reflectivity involving the photoreceptor layer (interface of the
inner segments [IS] and the outer segments [OS]) and the layer between the retinal pigment epithelium (RPE) and the
interface of IS and OS of the photoreceptor (the Verhoeffs membrane) (A and C, arrows). HD-OCT scans passing
through the vitelliform lesions outside the macular area show small focal hyper-reflective lesions at the level of the RPE/
photoreceptor complex (D and E ) (open arrows), as well as a more pronounced thickening of the RPE /photoreceptor
complex (F and G) (open arrows), associated with a focal disruption of the layer corresponding to the IS/OS interface
(E and G) (enlarged views).

multifocal VMD (one of which was asymptomatic) as

evaluated by HD-OCT.

Methods
The two patients were submitted to a complete
ophthalmologic examination. HD-OCT examination included 5 Line raster (scans through five
closely spaced horizontal lines, covering 1 mm

vertically). Each line was 6 mm long and composed

of 4,096 A-scans. A Macular Cube 512  128 Combo
(a series of 128 horizontal scan lines each composed
of 512 A-scans, generating a cube of data through
a 6-mm square grid) was obtained. All scans were
positioned within the macular area, ensuring that
the cross sectional cut would go through vitelliform
lesions outside the macular area, based on color
fundus photography and fundus autofluorescence.

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Surv Ophthalmol 54 (2) March--April 2009

Fig. 3. Patient 2. Color fundus photograpy, of the macula

of the left eye (LE) showing no major alterations except
for a foveal granularity (A). Several vitelliform lesions are
localized outside the macular area (A). Fundus autofluorescence shows several autofluorescent lesions outside the
macular area, corresponding to the vitelliform lesions (B).

Case 1
A 40-year-old woman was referred to our department for clinical evaluation because of family
history of VMD (both her 63-year-old father and her
9-year-old son had been previously diagnosed with
adult-onset VMD and VMD, respectively). Blood
samples from the patient were collected and linkage
analysis on genomic DNA revealed that a mutation
was present in one allele of VMD2 (T791C),
resulting in the heterozygous change. A comprehensive consent was obtained as required by Good
Clinical Practice guidelines before proceeding with
all examinations. An electro-oculogram showed an
abnormal light peak to dark trough ratio of 0.94 in
the right eye (RE) and 1.17 in the left eye LE
(normal $ 1.85). Her best corrected visual acuity
(BCVA) was 20/32 in the RE and 20/125 in the LE.
On fundus biomicroscopy, the macula of the RE and
LE showed no major alterations except for a mild
foveal granularity (Fig. 1A and 1B). Several vitelliform lesions were seen outside the macular area and

QUERQUES ET AL

in mid periphery (Fig. 1C). The presesence of

lipofuscin within the lesions outside the macular
area as well as the apparent absence of vitelliform
lesions within the macular area were confirmed by
fundus autofluorescence. HD-OCT was then performed. On HD-OCT macular scans, in both eyes,
the layer between the RPE and the interface of IS
and OS of the photoreceptor, corresponding to
Verhoeffs membrane,13 had a thicker and more
reflective appearance in the central area compared
with the normal macula (Fig. 1D and1E). Moreover,
HD-OCT B-scans passing through the foveola, as
well as C-scans (en face planes reconstructed from Bscans data), revealed, in both eyes, a slight hyperreflective lesion (Fig. 2A and 2B), just above an area
of reduced reflectivity involving the photoreceptor
layer (interface of IS and OS) and Verhoeffs
membrane (Fig. 2A and 2C). The vitelliform lesions
outside the macular area appeared on HD-OCT
scans either as small focal hyper-reflective lesions at
the level of the RPE/photoreceptor complex
(Fig. 2D and 2E), either as a more pronounced
thickening of the RPE/photoreceptor complex
(Fig. 2F and 2G), associated with a focal disruption
of the layer corresponding to the IS/OS interface
(Fig. 2E and 2G). HD-OCT scans revealed both the
macular and the extra-macular areas, an almost
normal reflectivity of all major retinal layers from
the internal limiting membrane (ILM) to the
external limiting membrane (ELM).

Case 2
A 37-year-old man was referred to our department
for blurred vision. A comprehensive consent was
obtained as required by Good Clinical Practice
guidelines before proceeding with all examinations.
An electro-oculogram showed an abnormal light
peak to dark trough ratio of 1.54 in the RE and 1.84
in the LE (normal $ 1.85). His BCVA was 20/32 in
the RE and 20/25 in the LE. On fundus biomicroscopy, the macula of the RE and LE showed no
major alterations except for a mild foveal granularity
(Fig. 3A). Several vitelliform lesions were seen
outside the macular area and in mid periphery
(Fig. 3A). The presence of lipofuscin within the
lesions outside the macular area as well as the
apparent absence of vitelliform lesions within the
macular area were confirmed by fundus autofluorescence (Fig. 3B). HD-OCT was then performed. On
HD-OCT macular scans, in both eyes, the layer
corresponding to the interface of IS and OS of the
photoreceptor and the Verhoeffs membrane appeared disrupted (Fig. 4A). The RPE layer appeared
preserved and almost regular. The vitelliform lesions

MULTIFOCAL VITELLIFORM MACULAR DYSTROPHY

315

Fig. 4. Patient 2. High-definition spectral domain optical coherence tomography (HD-OCT) scan passing through the
macula, reveals, in the left eye, that the retinal pigment epitelium (RPE) layer is preserved and almost regular (A,
arrows), while the layer corresponding to the interface of the inner segment (IS) and the outer segment (OS) of the
photoreceptor and the layer between the RPE and the interface of IS and OS of the photoreceptor (the Verhoeffs
membrane) appear disrupted (A, arrowheads). HD-OCT scans passing through the vitelliform lesions outside the
macular area show small focal hyper-reflective lesions at the level of the RPE/photoreceptor complex (B1, B2, and B3)
(open arrows), associated with a focal disruption of the layer corresponding to the IS/OS interface (enlarged views).

outside the macular area appeared on HD-OCT

scans as small focal hyper-reflective lesions at the
level of the RPE/photoreceptor complex, associated
with focal disruption of the layer corresponding to
the IS/OS interface (Fig. 4B). HD-OCT scans
revealed for both the macular and the extra-macular
areas, an almost normal reflectivity of all major
retinal layers from the ILM to the ELM.

Discussion
The exact locations of the vitelliform material in
VMD, whether below, above, or inside the RPE, has
not yet been conclusively determined, either by
clinical or histological assessment. In most cases the
yellow lesions slowly are absorbed, progressing to
retinal atrophy. Visualizing exact intraretinal details
with the higher imaging quality and resolution are
essential to better understand macular diseases. In
a recent study, using OCT, we described in adultonset VMD the location of yellowish material as
under the sensory retina, but above the retinal
pigment epithelium.2

Histologically, attenuation of the outer nuclear

layer has been described previously as a finding in
VMD,7 and the degree of photoreceptor degeneration over a relatively intact RPE layer led some
investigators to conclude that the primary lesion in
Best disease is in the photoreceptor cells.4 Mullins et
al,6 in contrast to the normal localization of
bestrophin to the basal aspect of the RPE and in
contrast to previous studies that demonstrated
massive lipofuscin accumulation in the RPE, reported one patient in whom the RPE appeared
histologically healthy in some regions of the macula
that exhibited loss of photoreceptors. They proposed that the possible mistargeting of bestrophin,
as suggested by immunofluorescence studies, could
result in a harmful alteration of the ionic milieu of
the subretinal space and contribute to the type of
photoreceptor cell loss observed histologically.
In addition, Arnold et al1 in their clinicopathological report found that the predominant finding
was a collection of extracellular material beneath
the sensory retina, and proposed that this material
was derived internally from photoreceptor outer

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Surv Ophthalmol 54 (2) March--April 2009

segments and externally from the RPE, the latter

first undergoing hypertrophy and then disruption
and attenuation. They concluded that the vitelliform lesions lie beneath the sensory retina, and that
these lesions consist of mainly photoreceptor debris,
possibly as result of faulty phagocytosis by the RPE,
mixed with pigment granules liberated as the RPE
undergoes disruption.
We believe the macular findings in our patients,
probably due to the reported alteration of the ionic
milieu of the subretinal space,6 were the result of the
pre-clinical changes for VMD, which involved first the
layer between the RPE and the IS/OS interface, as
revealed by HD-OCT in patient 1, and then the IS/
OS interface, as revealed by HD-OCT in patient 2.
Interestingly, in both patients 1 and 2, the RPE layer
appeared, on HD-OCT, preserved and almost regular.
We could speculate that we were able to detect these
changes by means of HD-OCT, which allows images
with a resolution close to histological section, because
of the multifocal nature of VMD, in our patients,
apparently sparing the macula. On the other hand,
the clinically evident and thus more advanced vitelliform lesions outside the macular area appeared on
HD-OCT scans either as small focal hyper-reflective
lesions at the level of the RPE/photoreceptor
complex, or as a more pronounced thickening of
the RPE/photoreceptor complex facing the deposition of lipofuscin within the RPE reported on the
histopathologic examination.4,7,12

Conclusion
In conclusion, based on our findings, we hypothesize that early changes in VMD involve the layer
between the RPE and the IS/OS interface, first with
accumulation of material beneath the sensory
retina, and then with disruption and attenuation

QUERQUES ET AL

of IS and OS. On the other hand, late changes

involve the RPE, first undergoing hypertrophy and
then disruption and attenuation.

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