OPTOMETRY

I CASEREPORT I
Sub-retinal neovascular membrane in exudative
macular degeneration
Clin Exp Optom 2003; 86: 1: 51-56
Sandra Harris B Optom PgDipAdvClinOpt
Victorian College of Optometry, The
University of Melbourne
Age-related macular degeneration is a major cause of serious vision loss. The earliest
stages of age-related maculopathy may be defined by the size of the drusen present in
the macula and the effects on vision. Further manifestations may include soft drusen,
Received: 18 March 2002
Revised: 28 October 2002
choroidal neovascularisation, macular haemorrhage and cicatricial or disciform degen-
eration of the macula.
This report describes a patient with a macular haemorrhage, a choroidal neovascular
Accepted for publication: 18 November
2002
membrane and serious loss of vision. In addition, the pathogenesis, diagnosis and treat-
ment options of macular degeneration are reviewed.
Keywords: age-related maculopathy, macular degeneration, neovascular membrane
Age-related macular degeneration (AMD)
is the leading cause of vision loss in the
developed world and it is predicted that
the incidence of this condition will rise as
the population ages.l Studies show a fur-
ther increase in the incidence and preva-
lence of AMD independent of the aging
factor.2 The Blue Mountains Eye Study
showed the prevalence of AMD in an Aus-
tralian population to be 1.9 per cent. The
overall prevalence of AMD is estimated to
be approximately two per cent, depend-
ing on the classification systemused, with
a significant increase in prevalence over
65 years of age. Wolffsohn4 studied a Mel-
bourne low-vision population and found
that AMD was by far the most common
cause of visual impairment in those over
the age of 60 years. The percentage of this
age group whose visual impairment was
primarily due to AMD rose from about 40
per cent in 1976 to 70 per cent in 1998.
The initial form of AMD, prior to signifi-
cant vision loss, is termed age-related
maculopathy (ARM). It is defined as a
degenerative disorder in patients older
than 50 years of age with abnormalities in
the macular region, including one or more
drusen greater than 63 microns in diam-
eter.5 The grading circle of 63 microns is
used in the Wisconsin grading system6 to
differentiate the small hard drusen that are
associated with the normal aging process
from the larger soft drusen that are indica-
tiveof ARM. It can be compared to the
average optic disc diameter, which is esti-
mated to be between 1,500 and 1,900
microns.6
Retinal pigment epithelium (WE) dis-
ruption also may be evident as atrophy,
hyperpigmentation, or hypopigmentation
with associated neurosensory detachment.
The prevalence ofARM in the Blue Moun-
tains EyeStudy population, based on the
Wisconsin classification system, was7.2 per
cent and rose with age from 1.3 per cent
in those under 55 years to 28 per cent in
those aged 85 years or older. AMD is the
progression of ARM and has two clinical
forms, commonly known as dry (atrophic)
AMD and wet (exudative) AMD. The divi-
sion of the disease into dry and wet forms
is representative of the presence or ab-
sence of choroidal neovascularisation
(CNV). Subfoveal choroidal neovascular-
isation provokes sudden, severe central
vision loss. Only 10 to 15 per cent of
affected patients progress to exudative
AMD, however, this form of the condition
is responsible for up to 90 per cent of the
associated severe vision loss. In more than
40 per cent of patients with exudative
AMD, the condition becomes bilateral
within five yeax8
Currently, there are no available thera-
pies for exudative AMD that aimto restore
the patients visual acuity. The two estab-
lished treatments that stabilise vision and
limit severe vision loss in selected patients
Clinical and Experimental Optometry 86.1 January 2003
51
Sub-retinal neovascular membrane Hum's
Figure 1. A 50 degree digital fundus photograph of the patient's
right eye in April 1999. Evident at the macula is a dark, slightly
raised area of approximately onequarter disc diameter.
are laser photocoagulation, which was
widely used in the 199Os, and verteporfin
photodynamic treatment, which has been
introduced in the past two years.
Fluorescein angiography is used to diag-
nose CNV and to direct treatment. The
composition of a choroidal neovascular
lesion is classified as either classic (show-
ing a well-demarcated hyperfluorescence
in the early phase) or occult (poorly de-
marcated boundaries) depending on the
fluorescein angiography appearance, and
this has implications for ~eatment. ~ Other
imaging techniques such as Indocyanine
Green angiography are not required to
decide whether treatment is needed, but
may further assist the retinal specialist to
localise the lesion.9 It is estimated that only
13 to 26 per cent of patients would benefit
from laser photocoagulation compared
with no treatment.'" The recent introduc-
tion of verteporfin photodynamic treat-
ment (PDT) has the potential to increase
the proportion of patients eligible for treat-
ment to between 25 and 40 per cent."
However, even with treatment, there is a
high risk of the recurrence of membrane
growth and the need for retreatments.
This report illustrates the natural course
of exudative AMD with ocular fundus pho-
tographs and fluorescein angiography at
several stages. It discusses the identifica-
Figure 2. Fluorescein angiography of the patient's right eye in
May 1999 revealed a classic subfoveal choroidal neovascular
membrane. Image courtesy of Dr A Harper (Fitzroy, Victoria,
Australia).
tion of early symptoms and retinal signs
that may suggest the need for fluorescein
angiography and risk factors that may
prompt more frequent review of the sus-
ceptible patient.
CASE REPORT
A 73-year-old man presented for optomet-
ric examination to the Melbourne Optom-
etry Clinic of the Victorian College of
Optometry on 30 April 1999, having noted
for about two months reduced vision in
his right eye compared with the left. He
reported that straight edges appeared wavy
when viewed with his right eye only. Apart
from having high cholesterol, he was in
good health and was not taking any medi-
cations.
Visual acuities were R 6/12 and L 6/7.5
with R t1.00 DS and L -0.25/-0.50 x 90.
Testing with an Amsler chart showed cen-
tral distortion in the right eye. Slitlamp
examination showed early crystalline lens
changes in both eyes consistent with age.
Intraocular pressures were within normal
limits. Mydriatic ocular fundus examina-
tion showed a dark, slightly raised area at
the macula in the right eye(Figure 1) and
a faint 'dot' haemorrhage was evident one
quarter of a disc diameter superior to the
right macula. Scattered hard drusen were
present in right and left eyes. No soft
drusen were noted. Exudative AMD was
suspected in the right eye and the patient
was referred for assessment and possible
treatmen t.
At a previous examination in the clinic in
March 1998, visual acuities had been R 6/6
and L 6/7.5 with R +0.25 DS and L -0.25/
-0.50 x 135. Both internal mydriatic and
external eye examinations had appeared
unremarkable, with some subtle macular
pigment changes noted in the left eye.
At ophthalmological examination on 19
May 1999, right eye visual acuity was 6/18.
Fluorescein angiography showed a classic
choroidal neovascular membrane approxi-
mately 500 microns in diameter extend-
ing beneath the fovea (Figure 2), with
overlying subretinal fluid. Fluorescein
angiography for the left eye was relatively
normal with some macular hard drusen
but no soft drusen evident. The option of
immediate laser treatment of the right eye
was discussed with the patient, however,
the probability of further reduction in
central visual acuity with therapy was con-
sidered unacceptable. The ophthalmolo-
gist recommended observation over a
period of weeks with the possibility of
subfoveal laser treatment at a later date to
limit final scotoma size.
In March 2000, ophthalmological review
Clinical and Experimental Optometry 86.1 January 2003
52
Sub-retinal neovascular membrane Harris
Figure 3a. A red-free fundus photograph of the patients right
eye in March 2000 shows sensory retinal detachment.
Haemorrhages are indicated by arrowheads. Image courtesy of
Dr A Harper (Fitmoy, Victoria, Australia).
Figure 3b. Fluorescein angiography in March 2000 illustrates the
underlying choroidal neovascular membrane. Image courtesy of
Dr A Harper (Fitzroy, Victoria, Australia).
Figure 5. The photograph of October 2001 shows resolution of
the superior haemorrhage. Flame haemorrhages are evident along
the inferior arcade (arrowheads).
Figure 4. Red-free fundus photograph in April 2001. A macular
choroidal scar is noted, with superior haemorrhage and exudate.
Clinical and Experimental Optometry 86.1 J anuary 2003
53
Subretinal neovascular membrane Hums
gavea visual acuity of 6/60 in the right
eye. The left eye wasunchanged at 6/7.5.
Ophthalmoscopy and fluorescein angiog-
raphy showed a classic choroidal neovas-
cular membrane of at least four disc
diameters in size with minimal late leak-
age (Figure 3a, 3b). Options including
central laser photocoagulation were dis-
cussed with the patient, however, given the
further loss of acuity associated with treat-
ment, observation alone was the chosen
course of action. With the expectation of
further deterioration in the right eye, the
patient was asked to report any changes
in the vision of the left eye.
Regular optometric review was insti-
gated and in November 2000, the patient
could define a black scotoma centrally in
the right eye. Visual acuities were R less
than 6/120 and L 6/9. A large superior
subretinal haemorrhage wasnoted in the
right eye. In April 2001, visual acuities were
R 6/380 part and L6/7.5 with refraction
unchanged from 1999. There was a
chorioretinal scar at the right macula and
a one disc diameter flame haemorrhage
along the superior arcade (Figure 4). Hard
exudate wasnoted in the inferior arcade.
At review in October 2001, the patient
reported a recent diagnosis of diabetes
mellitus. Visual acuities were still R 6/380
part and L 6/7.5. Right fundus assessment
showed small flame haemorrhages along
the inferior arcade (Figure 5). The appear-
ance of the left fundus was relatively nor-
mal, with hard drusen at the macula but
no soft drusen or significant RPE changes
evident. Optometric review was scheduled
for six months. An Amsler chart waspro-
vided for home monitoring and the pa-
tient wasasked to report immediately any
signs of distortion with the left eye.
COMMENT
This case illustrates the natural course of
exudative AMD over a two and a half year
period in an older man. He was able to
observe monocular vision disruption,
which prompted presentation and diagno-
sis. The signs displayed were typical of this
condition, along with the severe monocu-
lar vision loss, which is often a portent of
devastating binocular loss. Up to 70 per
cent of eyes with subfoveal CNV second-
ary to AMD have visual acuity of 6/60 or
worse within two years of diagnosisI2 and
12 per cent of patients who present with
the unilateral form of the disease are
legally blind within two years1
The patient had reported reduced
vision in one eye and metamorphopsia of
relatively recent onset. These symptoms of
painless vision loss are typical of early
AMD. Other conditions that display uni-
lateral painless vision loss include cataract,
glaucoma, ischaemic optic neuropathy,
central serous retinopathy, retinal artery
or vein occlusion and retinal detachment.
The majority of these conditions can be
ruled out following initial optometric
assessment. The exception is central
serous retinopathy, which can be excluded
with fluorescein angiography, although it
typically occurs in younger patients, and
would be expected to display a pale rather
than dark raised macula as only the sen-
sory retina is detached.I3 In addition to re-
duced or distorted vision in AMD, patients
may describe the visual disruption as a
shadow, discolouration or loss of contrast.
Rarely, floaters may be experienced if pre-
retinal haemorrhage occurs. Given the age
group of patients with AMD, it is possible
for early symptoms to be masked by cata-
ract or posterior vitreous detachment.
Because people rarely compare the vision
between their two eyes in everyday life,
unilateral AMD often escapes detection
initially and although the patient is more
sensitive to vision changes in the fellow
eye, there may be a delay in presenting if
the patient is unaware that earlier assess-
ment maximises treatment options.
The role of the eye care practitioner is
vital in emphasising to patients who are
observed to have signs of early ARM, that
same-day presentation is important with
symptoms of visual disturbance. Without
this caution, many patients seem content
to wait for an appointment across a few
weeks, if the waiting list demands. The
patient in this case waited up to two
months after noticing the initial visual
disruption before attending for an eye
examination. An Amsler grid used at home
can be a valuable patient education tool
for patients at risk. Unfortunately, some
patients such as the above case show few
ocular warning signs to alert the practi-
tioner. As more effective treatments for
AMD become available, public awareness
campaigns may be of advantage in encour-
aging patients to attend an eyecare practi-
tioner immediately when symptoms occur.
Histopathologic evaluation of the retina
has shown that deterioration occurs in all
eyes with advancing age and AMD is the
acceleration of this process to a level where
vision loss OCCU~S. ~ The degenerative proc-
ess is manifested primarily as damage to
the RPE cells. It is thought that the
affected RPE cells are unable to digest
some elements of damaged photorecep-
tor membranes, resulting in the formation
of lipofuscin or bodies within the RPE cells
that are filled with debris. The accumula-
tion of these bodies is associated with ex-
trusion by the WE cells of a waste prod-
uct between the plasma membrane and
the basement membrane of the RPE (ba-
sal laminar deposit) .I5 These deposits may
further impair the function of the RPE by
blocking nutrient intake from the chorio-
capillaris. Formation of soft drusen occurs
with localised detachments when larger
areas of the RPE become dysfunctional
and secrete debris in vesicles through the
basal lamina to coalesce on Bruchs mem-
brane (basal linear deposits). Loss of vision
in AMD occurs with the atrophy of the
photoreceptor cells associated with the
damaged WE or by neovascular invasion
of the region, A neovascular membrane
forms when choroidal vessels are able to
breach Bruchs membrane and spread
beneath the basal laminar and basal lin-
ear deposits within the soft drusen. Haem-
orrhaging from the new vessels can cause
RPE detachment from Bruchs membrane
and subsequent neural retinal detachment
as serous exudate leaks through the dam-
aged RPE (Figure 6).
The early clinical appearance of a
subretinal choroidal neovascular mem-
brane is illustrated in Figure 1. Ophthalm-
oscopy at this stage shows subtle darken-
ing of the affected macular region that can
be seen more distinctly with a red-free fil-
ter. Although it wasdifficult to determine
the extent to which the retina waselevated
with ophthalmoscopy alone, a hyperopic
Clinical and Experimental Optometry 86.1 January 2003
54
Sub-retinal neovascular membrane Harris
Figure 6. Redrawn after Young RW." Schematic diagram of a disciform lesion. Choroidal
vessels have penetrated Bruch's membrane (BM) and have spread laterally in the plane of a
large, soft druse (D). One of the peripheral arcades of the neovascular membrane (NV) has
ruptured, producing a haemorrhagic detachment (H) of the retinal pigment epithelium (WE)
from Bruch's membrane. The haemorrhage is located in the same plane as the new vessels,
that is, between the basal lamina (BL) of the RPE and the remainder of Bruch's membrane.
Fluid has penetrated the damaged WE, producing a serous detachment (S) of the overlying
neural retina (of which only the inner and outer segments of the vi sual cells are shown).
shift of t0.75 D was noted in the right eye
across the period March 1998 to April 1999
and this gives an objective indication of
retinal elevation. Other conditions such
as myopic degeneration, angioid streaks
and ocular histoplasmosis syndrome need
to be ruled out where neovascularisation
is suspected, particularly in the absence
of other obvious signs of AMD, as in this
case.13 Of interest in the later stages of the
observation period (Figures 4 and 5) is the
fact that despite the central chorioretinal
scar, retinal haemorrhages were noted up
to two years following the initial detection
of the neovascular membrane. Given their
peripheral location, it is possible that the
haemorrhages seen in Figure 5 were a
result of the patient's diabetes rather than
AMD.
Established risk factors for ARM include
age, systemic hypertension, a history of
smoking, coronary artery disease, race,
light exposure, genetic predisposition and
iris col o~r.~~'"'~ A recent study found that
cigarette smoking for longer than 40 years
caused 14 per cent of AMD cases and that
smoking was the primary modifiable risk
factor for ARM and AMD.I6 The only risk
factors displayed by the patient in this case
at the time of diagnosis were a high cho-
lesterol level and the fact that he was 73
years of age. The patient did not display
any ocular risk factors in the right eye prior
to diagnosis of the subfoveal neovascular
membrane in 1999. It is likely that basal
laminar and basal linear deposits were
present in 1998 and contributed to the
process of neovascularisation in this pa-
tient. Ocular risk factors for the fellow eye
include presence of large drusen, soft
drusen and focal hyperpigmentation of
the RPE (Table 1). The Macular Photoco-
agulation Study Group (MPS)* reported
that where all of these ocular risk factors
are evident, the risk to the fellow eye across
five years is 87 per cent compared with
seven per cent, where none of them is
present. In this case the fellow eye re-
mained free of these ocular risk factors
throughout the period of observation, with
both ophthalmoscopy and fluorescein
angiography. Some mild pigment mottling
was noted at the left macula in 1998 that
may account for the reduction of visual
acuity to 6/7.5, although the fluorescein
angiography was normal. However, this
slight reduction may be accredited also to
early crystalline lens changes or patient
motivation. Although no specific ocular
risk factors were identified in the fellow
eye, regular review was indicated. As well
as ocular fundus assessment, regular re-
view provides an opportunity to reinforce
patient instruction in the use of an Amsler
chart and in prompt attendance for assess-
ment on noticing symptoms.
Of patients who fit the MPS criteria for
laser photocoagulation, treatment reduces
the risk of severe vision loss by ha1f.I The
MPS data show that the patients who do
best with this treatment have poor initial
visual acuity or a CNV membrane that
appears on fluorescein angiography to
cover an area less than one disc diameter.
Laser photocoagulation is applicable to
about 13 to 26 per cent of cases'O and many
experience persistent or recurrent CNV
following treatment.
Verteporfin photodynamic treatment
(PDT) is relatively new and has been avail-
able in Australia only since early 2000. It
was not available when this patient initially
presented. It involves the treatment of
CNV through a two-step process. A photo-
sensitive dye that binds selectively on new
blood vessels is injected intravenously and
later activated with a 689 nm (non-
thermal) laser. It appears to cause less
damage to the overlying retina than laser
photocoagulation, allowing the treatment
of more central lesions. The percentage
of patients who may be suitable for PDT is
limited by the classification of CNV based
on the fluorescein angiography appear-
Ocular risk factors for the fellow eye
One or more large drusen at the macula
Soft drusen at the macula
Focal hyperpigmentation of the RPE
Five or more drusen
Confluent drusen
Table 1. Risk factors for the fellow eye in
exudative AMD. The Macular Photocoag-
ulation Study Group' reports that a
combination of these risk factors in the
fellow eye increases the risk of progression
to AMD to 87 per cent across five years
compared to seven per cent, where none is
present.
Clinical and Experimental Optometry 86.1 J anuary 2003
55
Sub-retinal neovascular membrane Harris
ance. Currently, the greatest benefit occurs
for membranes with a predominantly clas-
sic profile (as above). The percentage of
AMD patients matching the treatment cri-
teria who will benefit from PDT remains
unclear. Estimates range from 20 to 30 per
cent to as few as five per cent.'" There may
be a substantial cost involved to the pa-
tient and it is necessary to reinforce the
fact that visual improvement is unlikely
and that the therapy needs to be repeated.
Finel' estimates that at least 75 per cent
of pati ents recei vi ng PDT requi re
retreatment in the first year alone. The
cost of the treatments and side effects in-
cluding transient visual disturbances and
transient photosensitivity reactions need
to be taken into account.
Other therapy options currently under-
going trials include submacular surgery
and external beam radiation. A recent
study proposes that a high-dose vitamin
supplement including antioxidants and
zinc may be protective for patients with
intermediate and advanced AMD. Patients
given a combination of both antioxidants
and zinc had a probability of progression
to advanced AMD of 20 per cent across
five years compared with 28 per cent in
the placebo group.lyJ ampolzo cautions that
one of the antioxidants, beta carotene,
should not be used in smokers or recent
former-smokers, as it may be associated
with a greater risk of lung cancer. Preven-
tion of the condition is another research
goal, however, evidence remains inconclu-
sive with respect to the benefits of such
treatments as angioinhibitory drugs."
~
CONCLUSION
The earliest signs of exudative AMD may
be detected with routine retinal examina-
tion of patients with environmental and
ocular risk factors. These patients need to
be impressed with the importance of home
monitoring and prompt attendance fol-
lowing the appearance of symptoms. Be-
cause current treatment options aim to
prevent vision loss rather than restore
vision, expedience of referral to a retinal
specialist while visual acuity is high allows
maximisation of treatment options and
reduction of severe visual acuity loss. More
patients are potentially treatable if the
symptoms have been present less than two
weeks.g Knowledge of risk factors, likely
progression and prognosis allows appro-
priate scheduling of reviews following oph-
thalmological assessment. Provision of
appropriate low vision rehabilitation is
often required once a stable level of vision
is reached.
10. Ciulla TA, Danis RP, Harris A. Age-related
macular degeneration: A review of experi-
mental treatments. Sun, Ophthalmol 1998;
43: 134146.
11. Fine SL. Editorial. Photodynamic therapy
with verteporfin is effective for selected
patients with neovascular age-related macu-
lar degeneration. Arch Ophthalmol 1999;
117: 1400-1402.
12. Bressler SB, Bressler NM, Fine SL, Hillis A,
Murphy RP, Olk RJ et al. Natural course of
choroidal neovascular membrdnes within
the foveal avascular zone in senile macular
degneration. AmJOphthalmol1982; 93: 157-
ACKNOWLEDGEMENTS
I would like to thank Dr Adrian Bruce for
editorial comment and assistance with
photographs. I would also like to thank Dr
Alex Harper for contributing Figures 2,3a
and 3b.
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Author's address:
Sandra Harris
Victorian College of Optometry
374 Cardigan Street
Carlton VIC 3053
AUSTRALIA
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56