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Hydraulic Conductivity of Fixed Retinal Tissue After Sequential Excimer Laser Ablation
Barriers Limiting Fluid Distribution and Implications for Cystoid Macular Edema
Richard J. Antcliff, FRCOphth;
Ali A. Hussain, PhD;
John Marshall, PhD
Arch Ophthalmol. 2001;119:539-544.
ABSTRACT
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Objectives To measure the hydraulic conductivity (HC) of human retina and to determine
the presence and location of high-resistance barriers to fluid movement through
the retina.
Methods Forty-one pairs of human eyes were investigated using an HC chamber.
Once baseline HC had been determined, the effect of ablating through varying
thickness of retina from the vitreous or photoreceptor surface using an excimer
laser (193 nm) was investigated. Tissue samples were then processed for histological
investigation.
Results The HC of fixed intact human retina was 2.54 x 10-10 m/s per pascal at 539 Pa (range, 0.6 x 10-10
to 3.3 x 10-10 m/s per pascal; SD, 0.6 x 10-10 m/s per pascal [1 mm Hg equals 133 Pa]). Ablation from either
surface resulted in little change in HC until a critical depth was reached,
at which point there was an order of magnitude increase. The critical depth
was approximately 170 µm from the inner limiting membrane when ablating
from the vitreous surface and 70 µm from the inner limiting membrane
when ablating from the photoreceptor surface. Histological specimens showed
that these barriers were the synaptic portion of the outer plexiform layer,
and the inner plexiform layer, respectively.
Conclusions The 2 high-resistance barriers to fluid flow through the retina are
the synaptic portion of the outer plexiform layer, and the inner plexiform
layer.
Clinical Relevance These observations help to explain the distribution of cystoid macular
edema seen in histological studies and with optical coherence tomography.
INTRODUCTION
CYSTOID MACULAR edema (CME) is a common sequel to many ocular conditions,
including traumatic, vascular, inherited, and inflammatory diseases of the
eye.1 Its fundoscopic appearance may vary,
but typically it may be identified as round or ovoid cysts around the fovea.
The cysts are characterized by an altered light reflex with a decreased central
reflex and a thin, highly reflective edge.2
The retina may or may not show elevation or increased thickness. Visualization
of the geometry and distribution of cysts may be enhanced by fluorescein angiography,
where the cysts become hyperfluorescent over varying times.2
The recent introduction of optical coherence tomography shows the cysts
as areas of low or no signal, with occasional high-signal elements bridging
the retinal layers.3-5
Histological studies show the cysts to be areas of retina in which the cells
have been displaced.2, 6-9
The cysts are presumed to result from the abnormal accumulation of fluid within
the retina.10 For such an accumulation to occur,
abnormalities must be present in one or both elements of the vascular supply
of the retina. The location and distribution of such fluid will depend on
the physical constraints imposed by the structure of the adjacent retina.
The retina has 2 sources of metabolic supply, the retinal capillary
system and the choriocapillaris. Both systems demonstrate barrier functions
that are referred to as the inner and outer blood-retinal barrier (BRB), respectively. The inner BRB is formed
by the endothelial cells lining the retinal capillaries and junctional complexes
between such cells. By contrast, the retinal pigment epithelium (RPE) and
similar junctional complexes between adjacent cells form the outer BRB.
To maintain retinal metabolism, there must be movement of fluid and
selected metabolites across these barriers, together with removal of catabolites.
Fluid movement may arise as a result of abnormal barrier leakage and may be
driven by a combination of active transport, diffusion, and osmosis or by
a pressure head. These systems are in equilibrium, although there is a small
net movement of fluid out of the neuroretina into the choroid.11-14
This equilibrium may be disturbed by leakage across the inner or outer BRB.
It could also be postulated that fluid could accumulate in the absence of
a leak but in the presence of a pump failure, particularly in the RPE. Failure
of the inner BRB leading to CME has been demonstrated by means of fluorescein
angiography in aphakic CME15 and of the outer
BRB in retinitis pigmentosa16; however, it
is likely that in many clinical situations both barriers are affected.16-18
Hydrodynamics ensure that fluid will accumulate at points of least resistance
and initially adjacent to the source of leakage. The pooling of fluid also
demands that the boundaries of least resistance limit the rate of fluid loss.
These boundaries can be considered resistance barriers to outflow. In the
outer retina, fluid may accumulate beneath the RPE or between the RPE and
the neuroretina, resulting in pigment epithelial detachments or serous detachments
of the retina, respectively.19-20
The location of accumulated fluid and the resultant histological abnormality
suggest a physically weak adhesion between these adjacent layers. By contrast
in the neuroretina, there are no potential horizontal cleavage planes. In
this tissue, fluid may only accumulate by displacing cells and cellular components.
A possible explanation for the distribution of fluid pooling within
the neuroretina seen in histological studies is as follows. Fluid accumulation
can occur only within the neuroretina in the presence of resistance barriers
to outflow. The morphologic appearance will be determined by the location
of the high-resistance barriers and by the physical constraints imposed by
the organization of the retina. These physical constraints may be identified
as positions where cells are joined by junctional complexes or where their
processes invaginate the surface of others or exhibit tortuousness and entwine
with processes of others. By contrast, where cell bodies or cell processes
are highly ordered, displacement may occur. In the outer retina, the Müller
fibers display junctional complexes between themselves and the photoreceptors
that collectively form the outer limiting membrane (OLM); in the inner layers,
they exhibit junctional complexes between themselves and the inner limiting
membrane (ILM).21 Thus, these cells constrain
x,y-plane displacement as a result of their junctional complexes and z-plane
displacement as a result of their processes. In the outer plexiform layer
(OPL), the invaginated synapses of the rods and cones would theoretically
limit displacement, as would the tortuousness and intertwining of the dendritic
processes in the inner plexiform layer (IPL).21
The OPL consists of 2 zones, a large outer zone containing the inner connecting
fibers of the photoreceptor cells and an inner zone of a true plexiform appearance
composed of the synaptic pedicles of these fibers and the synaptic invaginations
into the pedicle surface of the cells in the inner nuclear layer.22(p31) The outer zone is further expanded in the macula,
giving rise to the Henle fiber layer. Cell movement would then occur in the
inner and outer nuclear layers, in the Henle fiber layer, and in the nerve
fiber layers. If this concept is correct, then in the early stages of capillary
leakage, fluid would be constrained between the IPL and the synaptic portion
of the OPL, ie, in the inner nuclear layer. Similarly, with an outer BRB leak,
fluid would pool in the Henle fiber layer and may cause some displacement
of the outer nuclear layer, and, as a result, would be seen between the synaptic
portion of the OPL and the OLM.
To test this hypothesis for the presence of high-resistance barriers
to fluid movement through the retina and to determine their location, we have
undertaken a series of studies using an excimer laser to progressively ablate
retinal layers while monitoring resultant changes in the movement of fluid
through the system, using hydraulic conductivity (HC) as a means of measuring
fluid movement.
MATERIALS AND METHODS
TISSUE PREPARATION
Forty-one pairs of human donor eyes were obtained from the United Kingdom
Transplant Support Service Eye Bank at Bristol, England. Postmortem time varied
from 24 to 56 hours. The median age of the donors was 69 years (range, 18-91
years). A full-thickness circumferential incision was made 5 to 7 mm behind
the limbus. The vitreous, lens, and anterior segment were discarded. A 2-mm
trephine was used to isolate the retina from the optic disc, and the neuroretina
was gently teased away from the underlying RPE before being transferred to
phosphate-buffered saline solution containing the following antibiotic and
antimycotic agents: penicillin (100 000 U/L), streptomycin (100 mg/L),
and amphotericin B (250 µg/L) (Sigma-Aldrich Corp, Poole, England).
Pilot experiments were undertaken using 57 trephined specimens from
22 pairs of eyes to develop a reproducible system for the measurement of retinal
HC. Initial studies involved using freshly trephined retinal specimens. However,
the tissue proved too friable and broke up even at very low-pressure differentials.
A subsequent series of pilot studies established that HC could be measured
if the retina was supported on a defined artificial membrane; however, tissue
breakup still occurred in an unacceptable number of specimens. A final study
was therefore undertaken using fixed retinal tissue together with a defined
support membrane to ensure reproducible measurements in large numbers of specimens.
They also determined that fixation resulted in no significant change in HC.
In all subsequent experiments, the isolated retina was fixed by means
of immersion in 2.5% glutaraldehyde buffered with 0.1-mol/L sodium cacodylate
containing calcium chloride, 10 mg/mL (final pH, 7.4), for 1 hour. With the
use of a dissecting microscope, four 8-mm trephined specimens of neuroretina
were isolated from the macula extending to the midperiphery. These were placed
on 150-µm-thick nitrocellulose filters with 8-µm pores (Millipore
Corporation, Bedford, Mass). In individual experiments, the trephined specimens
were placed with the vitreous or photoreceptor surface against the filter,
causing exposure of the photoreceptor or vitreous surface, respectively.
HC CHAMBER AND MEASUREMENT OF FLOW
The HC chamber used in the present series of experiments was identical
to that previously described,23 except that
the tissue-mounting cassette was constructed in transparent plastic with a
central lumen of 4 mm. The retina and nitrocellulose samples were mounted
in the cassette as previously described,23
and the cassette was inserted into the chamber such that the nitrocellulose
surface was always distal to the direction of flow. Procedures for introducing
fluid into the cassette were as previously described,23
except that the phosphate-buffered saline solution was degassed with the use
of a vacuum. The assembled chamber was maintained at 37°C. Tissue was
exposed to pressures varying from 343 to 1715 Pa by altering the height of
the fluid reservoir (1 mm Hg equals 133 Pa). For each pressure at which flow
was measured, a 30-minute equilibration was first allowed, during which the
reservoir height slowly changed. The fluid height was then returned to this
pressure and the position of the meniscus was noted at 3-minute intervals
for 20 minutes.
LASER EXPOSURE PROCEDURE
An excimer laser (Apex Plus; Summit Technology, Boston, Mass) was used
in the phototherapeutic keratectomy mode with a radiant emission of 180 mJ/cm,2 but with a beam diameter of 3 mm. From each pair of eyes, up to 8
trephined specimens were obtained and mounted in the transparent plastic cassettes.
One sample was then mounted in the HC chamber with the vitreous surface exposed
and the baseline flow determined. Measurements were then repeated on a second
sample with the photoreceptor surface exposed. Subsequent samples were placed
under the operating microscope of the excimer laser. The surface of the neuroretina
was then carefully blotted using eye sponges (Visispear; Visitec, Sarasota,
Fla). The phototherapeutic keratectomy software was programmed into the laser
control system, the helium-neon aiming beams of the excimer system were focused
on the surface of the retina, and the ablation sequence was initiated. Three
specimens were ablated on the vitreous surface and 3 on the photoreceptor
surface. In early experiments, specimens received 10, 20, or 30 pulses, whereas
in the later experiments values were steadily increased up to 150, 200, and
250 pulses. After ablation, the cassettes were immersed in phosphate-buffered
saline solution before being mounted in the chamber, and measurements of flow
were undertaken. A total of 99 trephined specimens from 22 pairs of eyes were
examined. Fifty-nine trephined specimens were mounted with the vitreous surface
outward, of which 38 were ablated with excimer laser, and 40 trephined specimens
were mounted with the photoreceptor surface outward, of which 32 were ablated
with excimer laser. Finally, all specimens were removed from the cassette
and processed for light microscopy (LM) and scanning electron microscopy (SEM).
Thirteen additional samples were not included in the results because of holes
detected during flow measurement or subsequent morphologic examination.
MORPHOLOGIC FEATURES
Samples were rinsed briefly in 0.1-mol/L sodium cacodylate containing
7.5% sucrose before they were fixed for 1 hour in 2% osmium tetraoxide in
0.2-mol/L sodium cacodylate. Samples were then hemisected. Half were processed
for LM, and the other half for SEM. The LM samples were dehydrated in ethanol
and embedded in epoxy resin. Semithin (1 µm) sections were cut on an
ultramicrotome (Huxley; Leica, Milton Keynes, England) and stained with toluidine
blue. The SEM sections were dehydrated in acetone, dried in a critical point
drier, sputter coated with gold, and examined in an SEM (510S; Hitachi, Wokingham,
England).
CALCULATION OF FLOW AND HC
Flow, defined as the rate of volume change
per unit of time per unit of surface area, was calculated from F = (x x C)/(t x A), where F indicates flow; x, distance
moved by capillary column (in meters); C, manometer
calibration constant; t, time (in seconds); and A,
exposed membrane area (1.26 x 10-5 m2 for
the 4-mm-diameter tissue cassette).
The manometer calibration constant was determined by introducing a known
weight of mercury into the capillary tube of the reservoir, lowering the tube
into a horizontal position, and measuring the length of the mercury thread
with the traveling microscope.23 From the density
of mercury (13 000 kg/m2), the constant was calculated to
be 1.170 x 10-6 m3/m.
The HC was calculated from HC = F/P, where P indicates pressure (in
pascals). The units of HC are cubic meters per second x square meters
per second per pascal, which simplifies to meters per second per pascal. As
no empirical studies of the pressure reduction across the retina have been
published, it was assumed that pressure reduction would be similar to that
across the Bruch membrane and choroid (estimated at 535 Pa); therefore, the
results in the present report will be expressed at a similar pressure.24
RESULTS
The HC of fixed intact human retina was measured to be 2.54 x
10-10 m/s per pascal (range, 0.6 x 10-10 to 3.3 x 10-10 m/s per pascal; SD, 0.6 x
10-10 m/s per pascal) at 539 Pa. The average values for the
HC measured in 4 paired samples of fixed and unfixed retina were 2.75 x
10-10 m/s and 2.97 x 10-10 m/s per
pascal, respectively (ranges, 2.47 x 10-10 to 3.1 x
10-10 and 2.85 x 10-10 to 3.1 x
10-10 m/s per pascal, respectively; SDs, 0.3 x 10-10 and 0.1 x 10-10, respectively; P = .30 by t test) at 539 Pa.
For a given eye, there was no difference in HC measured when pressure was
applied to the vitreous surface or the photoreceptor surface (15 eyes; P = .64 by t test). There was
no correlation between HC and time from death to fixation or time from enucleation
to fixation (R2 = 0.013 [P = .66] and R2 = 0.117 [P = .13], respectively). There was no correlation between
HC and age (R2 = 0.055 [P = .20]). There was a logarithmic reduction in HC with increased pressure
(R2 = 0.98 [P<.001]; Figure 1).
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Figure 1. Graph of the correlation between
the hydraulic conductivity (HC) of the retinal trephined specimens and the
pressure at which the fluid was applied, showing a reduction in HC with increasing
pressure. The error bars are 1 SD. The dashed lines show an illustration of
a mean intraocular pressure (IOP) of 15 mm Hg transposed to pascals (1 mm
Hg equals 133 Pa) and an approximation of the pressure drop across the Bruch
membrane and choroid.
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Irrespective of the surface of the retina receiving ablation pulses,
there was a linear relationship between the depth of tissue removed and the
number of excimer pulses applied (R2 =
0.91 [P<.001]). The average ablation depth per
pulse was 0.5 µm.
The results of measuring HC after ablation are shown in Figure 2. Ablation from either surface resulted in little change
in HC until a critical depth was reached, at which point there was an order-of-magnitude
increase. The critical depth was approximately 170 µm from the ILM when
ablating from the vitreous surface and 70 µm from the ILM when ablating
from the photoreceptor surface.
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Figure 2. Scatterplot showing the effect
of ablating through the retina of standard macular specimens from the vitreous
surface or the photoreceptor surface on logarithmic hydraulic conductivity
(Log HC). When ablating from the photoreceptor surface, the depths ablated
are shown commencing at the outer limiting membrane. To allow for variations
in thickness, the depths have been normalized to a standard macular section.
The dashed lines show the approximate positions of the inner and outer high-resistance
barriers (HRB).
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Results of histological examination showed that these barriers were
the OPL and the IPL, respectively (Figure
3). Sections showed that the synaptic portion of the OPL was always
totally ablated such that the inner connecting fibers of the photoreceptor
cells (Henle fiber layer) were exposed. Thus, the synaptic portion of the
OPL presented the outer barrier.
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Figure 3. Photomicrographs of areas of retina
after excimer laser ablation showing tissue remaining once the resistance
barrier had been overcome. A, Trephined specimen ablated from the photoreceptor
surface showing the inner plexiform layer to be the barrier. B and C, Trephined
specimens ablated from the vitreous surface. Midperipheral retina (B) shows
the outer plexiform layer to be the barrier. Central retina with an expanded
Henle fiber layer exposed (C) shows that it was the synaptic component of
the outer plexiform layer that formed the high-resistance barrier.
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COMMENT
The measurements of HC reported in this study support the hypothesis
that the plexiform layers of the retina are regions of high resistance to
the movement of fluid under pressure. These findings identify 2 of the 3 elements
in the horizontal structural framework that would be required to produce the
distribution of cysts seen in histological specimens.2, 6-9
The remaining element is at the location of the OLM.25-26
It should be remembered that HC did not change significantly until considerable
amounts of the IPL had been ablated. This observation probably reflects a
lack of sensitivity of the measuring technique used, given an inability to
detect change as this inner barrier was traversed. This concept is further
supported by the histological findings that, in ablations from the vitreous
surface, the spatially confined synaptic portion of the OPL alone was always
completely ablated before barrier loss was detected. This layer is typically
10 µm thick. Given the 0.06-µm thickness of the OLM and the apparent
insensitivity of the present method, it is perhaps not surprising that its
demonstrable barrier properties were not elucidated by our method using a
0.5-µm ablation rate per pulse.25-26
Under normal physiological conditions, fluid must move across the entire
retina and through the high-resistance barriers; however, there is evidence
that diffusion limits for metabolic supply in the system are approximately
150 µm. This would explain the thickness of the retina within the capillary-free
zone where it rarely exceeds this value, and it would also explain cell loss
in relation to vascular closure in either the retinal or choroidal supply.
In large areas of capillary closure, all the layers internal to the OPL are
lost and replaced by gliosis,27 whereas choroidal
infarction may lead to loss of RPE and photoreceptor cells but to preservation
of all internal layers.28-30
It could be argued, therefore, that fluid leaking from a given vascular system
easily may diffuse up to 150 µm. If such fluid were leaking at an abnormal
rate and pooling within this diffusion limit, it could rapidly change the
microanatomical configuration of the tissue components and its boundaries.
Increasing pressure within the pool would lead to increasing compactness in
the surrounding tissues. Thus, in conditions leading to macular edema, fluid
leaking from retinal capillaries would result in displacement of nuclei in
the INL and, ultimately, in compression of fibers within both plexiform layers.
This concept is supported by observations in the HC studies, where resistance
increased significantly with pressure. If pressure-related barrier changes
in the OPL were slower or of less magnitude than those in the IPL, then fluid
could pass through this layer into the region of photoreceptor inner segments
and nuclei before compressing junctions in the OLM and enhancing its barrier
properties. In conditions where the outer BRB leaked, fluid would rapidly
reach the photoreceptor inner segments and outer aspect of the OLM. It could
pass through this barrier before becoming further impeded by the synaptic
portion of the OPL. Again as fluid progressively accumulated, resistance to
fluid movement through the OLM and the synaptic portion of the OPL would ultimately
govern the size of any given cyst.
Examination of cyst size in uveitic patients using optical coherence
tomography revealed a maximum z-plane dimension of approximately 460 µm
(R.J.A., unpublished data, November 1999). Beyond this size, fluid spread
laterally or accumulated in the subretinal compartment underneath the OLM.
The concept of multiple discrete cysts has developed as a result of examining
histological sections and, more recently, optical coherence tomography scans.
Both modalities give an erroneous picture in that they sample a single confined
plane through the retina. In 3-dimensional examination of cysts such as those
derived from SEM, it is clear that the cysts are a single compartment spanned
by the trunks of the Müller fibers.31
Because these trunks are some 10 to 30 µm in diameter, they are artificially
identified as apparent compartmental barriers in sectioning techniques. The
limitation in cyst size must mean that equilibrium exists between the pressures
increasing the volume of any given cyst and the forces restraining the size
of the cyst. The forces restraining the size of the cyst are the Müller
fibers themselves and the compression of the high-resistance barriers as the
cysts increase in size.
Tso6 showed in histological studies of
CME that vascular diseases were more likely to lead to cystoid spaces accumulating
in the inner retina, specifically the inner nuclear layer. By contrast, RPE
disease led to cysts accumulating in the outer retina in the Henle fiber layer.6 Tso and Shih32 also
showed with horseradish peroxidase that leakage through the RPE in monkeys
was constrained by the OPL. These observations are consistent with the evidence
of the plexiform layers being high-resistance barriers to flow, as presented
herein.
Although HC increased as the retina was ablated, there was no incremental
increase on passing through the first of the 2 plexiform layers. Ablating
through significant thickness of the retina would lead to the pressure being
dissipated across a thinner section of retina. This would be equivalent to
increasing the pressure across intact retina, which causes tissue compression.
This compression of the remaining plexiform layer would enhance its barrier
properties and thus exaggerate the increase in flow on ablating through it.
In addition, the current technique may not be sufficiently sensitive to detect
a difference in the barrier properties between the 2 plexiform layers. Hence,
if each layer confers a similar rate-limiting barrier to fluid movement, ablation
of both layers would be required before an increase in flow is detected.
There was no significant difference in HC measured at various postmortem
times up to 50 hours and no significant differences generated by time between
enucleation and death. In addition, no measurable difference was apparent
between fixed and unfixed specimens. Previous work has suggested that vacuolation
and cytoplasmic swelling occur after 10 hours post mortem but that, at least
up to 24 hours post mortem, these changes are reversible.33
The effect at a cellular level of fixation in 2.5% glutaraldehyde with its
attendant protein cross-linking is uncertain, but such fixation would arrest
any further postmortem changes. Fisher34 compared
the HC of rat lens capsule before and after fixation with glutaraldehyde.
He found the HC at low-pressure levels of fixed lens capsule to be about 0.6
times that of unfixed tissue, but he found that fixation stabilized the HC
of the lens capsule, probably by making the capsule less deformable. Similar
findings have been shown in kidney glomeruli.35
Although caution must be expressed in applying the actual measurements presented
in this article to the clinical situation, the concepts and locations of the
barriers should hold.
To our knowledge, studies of the HC of human retina have not previously
been published. Fatt and Shantinath36 investigated
rabbit retina, but it was not possible to transform their data to the units
used in this study. Pederson37 described unpublished
data showing the results of a study using dog retina with an HC of 0.38 x
10-10 m/s per pascal (converted from 0.03 µL/min per
millimeters of mercury per square centimeter), approximately 7 times less
than the HC in this study, which would be within species and technique variation
but might also reflect the freshness of their tissue. The HC of intact human
retina showed no change with age. This compares with the exponential decrease
of the HC with age in human Bruch membrane (Figure 4).38-39 In the
young, the HC of the Bruch membrane is much greater than that of retina, and
as a consequence, this would promote retinal apposition in the presence of
a flow of fluid from vitreous to choroid. Although the pressure difference,
and thus the flow, across the retina from vitreous to choroid is likely to
be small, Fatt and Shantinath36 estimated that
a pressure difference of as little as 0.52 x 10-3 mm
Hg would be sufficient to keep the retina firmly attached.
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Figure 4. Graph comparing the variation
of hydraulic conductivity (HC) with age of human retina and human Bruch membrane.
Data for human Bruch membrane are from previous publications.38-39
One mm Hg equals 133 Pa.
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In conclusion, we have demonstrated the HC of intact human retina and
have shown that 2 of the major barriers to fluid flow through the retina are
the IPL and the synaptic portion of the OPL. These observations help to provide
an explanation for the distribution of CME seen in histological studies.
AUTHOR INFORMATION
Accepted for publication Octover 18, 2000.
This study was supported by the Allerton Fund, London, England; the
Iris Fund for Prevention of Blindness, London; and the TFC Frost Fund, London.
Presented in part at the annual meeting of the Association for Research
in Vision and Ophthalmology, Fort Lauderdale, Fla, May 14, 1999.
We thank Ann Patmore and Anne Weston for their help throughout the paper
and Timothy J. ffytche, FRCS, FRCOphth, for his advice.
Corresponding author and reprints: Richard J. Antcliff, FRCOphth,
GKT Department of Ophthalmology, The Rayne Institute, Saint Thomas' Hospital,
Lambeth Palace Road, London SE1 7EH, England.
From the GKT Department of Ophthalmology, The Rayne Institute, Saint
Thomas' Hospital, London, England.
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26. Bunt-Milam AH, Saari JC, Klock IB, Garwin GG. Zonulae adherentes pore size in the external limiting membrane of the
rabbit retina. Invest Ophthalmol Vis Sci. 1985;26:1377-1380.
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27. Hamilton AM, Marshall J, Kohner EM, Bowbyes JA. Retinal new vessel formation following experimental vein occlusion. Exp Eye Res. 1975;20:493-497.
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28. Hayreh SS, Baines JAB. Occlusion of the posterior ciliary artery, II: chorio-retinal lesions. Br J Ophthalmol. 1972;56:736-753.
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29. McCleod D, Oji EO, Kohner EM, Marshall J. Fundus signs in temporal arteritis. Br J Ophthalmol. 1978;62:591-594.
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30. Parrish R, Gass JDM, Anderson DR. Outer retina ischemic infarction: a newly recognized complication of
cataract extraction and closed vitrectomy, II: an animal model. Ophthalmology. 1982;89:1472-1477.
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31. Marshall J. The effects of ultraviolet radiation and blue light on the eye. In: Marshall J, ed. The Susceptible Visual Apparatus. New York, NY: Macmillan Publishing Co Inc; 1991:54-66.
32. Tso MOM, Shih CY. Experimental macular edema after lens extraction. Invest Ophthalmol Vis Sci. 1977;16:381-392.
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33. Huang JC, Voaden MJ, Marshall J. Survival of structure and function in postmortem rat and human retinas:
rhodopsin regeneration, cGMP and the ERG. Curr Eye Res. 1990;9:151-162.
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34. Fisher RF. The deformation matrix theory of basement membrane: a study of water
flow through elastic and rigid filaments in the rat. J Physiol. 1988;406:1-14.
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35. Robinson GB, Bray J, Byrne J, Hume DA. Studies of the ultrafiltration of macromolecules across glomerular
basement membrane. In: Luker G, Hudson BG, ed. Second International
Symposium on Glomerular Basement Membrane. London, England: London
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36. Fatt I, Shantinath K. Flow conductivity of retina and its role in retinal adhesion. Exp Eye Res. 1971;12:218-226.
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37. Pederson JE. Fluid physiology of the subretinal space. In: Ryan SJ, ed. Retina. 2nd ed. St Louis,
Mo: Mosby-Year Book Inc; 1994:1955-1968.
38. Starita C, Hussein AA, Pagliarini S, Marshall J. Hydrodynamics of ageing Bruch's membrane: implications for macular
disease. Exp Eye Res. 1996;62:565-572.
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39. Moore DJ, Hussein AA, Marshall J. Age-related variation in the hydraulic conductivity of Bruch's membrane. Invest Ophthalmol Vis Sci. 1995;36:1290-1297.
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