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One-Year Follow-up of Blood-Retinal Barrier and Retinal Thickness Alterations in Patients With Type 2 Diabetes Mellitus and Mild Nonproliferative Retinopathy
Conceição L. Lobo, MD, MSc;
Rui C. Bernardes, MSc;
J. R. Faria de Abreu, MD, PhD;
José G. Cunha-Vaz, MD, PhD
Arch Ophthalmol. 2001;119:1469-1474.
ABSTRACT
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Objective To examine the 1-year alterations of the blood-retinal barrier and changes
in retinal thickness occurring in the macular region in patients with type
2 diabetes mellitus and mild nonproliferative retinopathy.
Methods We classified 12 eyes of 12 patients with type 2 diabetes mellitus and
mild nonproliferative retinopathy by 7-field stereoscopic fundus photography,
levels 20 and 35 of Wisconsin grading, and examined them 3 times, at 6-month
intervals, by fluorescein angiography, retinal leakage analyzer (RLA) (modified
confocal scanning laser ophthalmoscope), and retinal thickness analyzer. The
maps of retinal leakage and retinal thickness were aligned and integrated
into one image. Data from the group of individuals with diabetes were compared
with those from a healthy control population (n = 14; mean age, 48 years;
age range, 42-55 years) to establish reference maps for the RLA and the retinal
thickness analyzer.
Results Areas of abnormally increased fluorescein sodium leakage and increased
thickness were detected in all eyes examined at baseline. The sites of increased
fluorescein leakage reached values as high as 483% above normal, but in 10
of the total 36 examinations performed, fluorescein leakage returned to normal
levels. A statistically significant correlation was found between changes
in hemoglobin A1c values and variations in percentage of abnormal
fluorescein leakage between the 6- and 12-month examinations (P<.001). When comparing the RLA-leaking sites among the 3 examinations,
a good correlation was seen among the location of these sites of maximum leakage,
but there was a clear fluctuation in the percentage of increases. A correlation
was noted between the location of the RLA-leaking sites and the location of
areas of increased retinal thickness in subsequent examinations, either 6
or 12 months later. Microaneurysms showed relatively little leakage and leaked
progressively less in successive examinations.
Conclusions The dominant alteration in the retina of patients with type 2 diabetes
mellitus and mild nonproliferative retinopathy is the presence of RLA-leaking
sites, indicating spotty retinal vascular damage characterized by alteration
of the blood-retinal barrier. This damage appears to be reversible and directly
associated with variations in glycemic metabolic control. Retinal edema appears
to develop mainly as a result of retinal vascular leakage.
INTRODUCTION
RETINOPATHY IS the most frequent microvascular complication of diabetes
mellitus. It is estimated to be the most common cause of new cases of blindness
among adults aged 20 to 74 years.1 The magnitude
of the problem becomes apparent when one realizes the projected growth of
the incidence of diabetes mellitus and the limitations of photocoagulation,
the only tested form of therapy, which is performed when disease progress
is already irreversible.2
To prevent and improve the treatment of diabetic retinopathy, it is
fundamental to know the evolution of the earliest changes that occur in the
diabetic retina and how they relate to the progression of the retinopathy.
The accepted methods to assess retinopathy are based on visual acuity
changes and findings noted on fundus photography.3
Both provide information on late changes but are not useful for identifying
initial alterations. The only features that are visible on fundus photography
are microaneurysms, hemorrhages, cotton-wool spots, hard exudates, venous
abnormalities, and neovascularization. Examination of the initial alterations
in diabetic retinal disease must involve other methods, such as measuring
alterations of the blood-retinal barrier (BRB) and changes in retinal thickness.
Methods of multimodal imaging of the ocular fundus have recently been developed
by combining information obtained from different sources, such as fundus photography
and fluorescein angiography, with measurements obtained with instrumentation,
such as the retinal leakage analyzer (RLA) and the retinal thickness analyzer
(RTA).4-6 To our
knowledge, we provide the results of the first 1-year follow-up study of changes
occurring in the macular region of eyes from patients with type 2 diabetes
mellitus and mild nonproliferative retinopathy.
PATIENTS AND METHODS
PATIENTS
Twelve eyes from 12 patients (4 men and 8 women), aged 44 to 63 years
(mean ± SD, 55 ± 5 years), with type 2 diabetes mellitus and
mild nonproliferative retinopathy characterized on 7-field stereoscopic fundus
photography (SFP), levels 20 and 35 of Wisconsin grading,2
were examined 3 times by SFP, fluorescein angiography, RLA (Zeiss, Oberkochen,
Germany), and RTA (Talia Technology, Ltd, Mevaseret Zion, Israel) at 6-month
intervals during a 1-year period. All patients had a corrected visual acuity
of 20/20. The study eye was chosen as the one fulfilling the inclusion criteria
(levels 20 and 35 of Wisconsin grading). When both eyes met the inclusion
criteria, the right eye was chosen.
The patients were followed up by the same diabetologist and remained
within limits of acceptable good medical control. Their hemoglobin A1c (HbA1c) values ranged from 5.4% to 9.7% (given as the
percentage of total hemoglobin), and their duration of diabetes ranged from
2 to 15 years (Table 1).
The tenets of the Declaration of Helsinki were followed, and approval
of the institutional review board was obtained for this study. Informed consent
was obtained from the patients before they were enrolled in the study.
METHODS
Stereoscopic Fundus Photography
Stereoscopic fundus photography was performed according to the Early
Treatment Diabetic Retinopathy Study (ETDRS) protocol.
Stereoscopic pairs of fields were obtained using a 30° fundus camera
to classify levels 20 and 35 of Wisconsin grading, but only field 2 was used
to examine and correlate with other data (leakage and thickness).
Fundus Fluorescein Angiography (FFA)
Fluorescein angiography was performed using a fundus camera with a 45°
field after patients received an injection of fluorescein sodium, 14 mg/kg
of body weight. Early- and late-phase (5 minutes) studies were analyzed.
Retinal Leakage Analyzer
The RLA is a new method that quantifies localized fluorescein leakage
in humans from the retina into the vitreous across the BRB. The instrumentation
and all the image processing have been previously described.4
The RLA obtains images of the fundus with real 3-dimensional information.
Two types of information are obtained simultaneously, one for optical imaging
and one representing fluorescence measurements being scanned. Axial graphics
of the fluorescein measurements obtained from the vitreous representing a
volume of 75 x 75 x 2550 µm were converted into retinal
leakage maps. Multiple measurements of retinal leakage can be graphically
assembled in a false-color retinal leakage map that represents the distribution
of alterations in the BRB in any chosen area of the total area of the posterior
pole under examination. Intravisit and intervisit reproducibility values of
the method are ±10.2% and ±13%, respectively.4
Retinal Thickness Analyzer
The RTA is a quantitative and reproducible method for evaluating retinal
thickness.6 The system acquires optical images
of the retina in sections by projecting the laser into the retina at an angle,
allowing the reflection or scattering of the laser light from the vitreoretinal
and chorioretinal interfaces to be viewed. The separation between the reflections
(and scatter) from these 2 interfaces is a measure of retinal thickness. The
data are analyzed, and the retinal thickness is given as a numerical value
and a color-coded map.
Data Analysis
Data from the group of individuals with diabetes were compared with
those from a healthy control population (N = 14; mean age, 48 years; age range,
42-55 years) to establish reference maps for the RLA and RTA.5
Because of the differences in resolution between the 2 instruments (RLA
and RTA), a value of leakage is obtained for a 75 x 75-µm area,
while a single value of thickness covers a 200 x 200-µm area.
Therefore, the smallest area that can be constructed that contains an integer
number of leakage and thickness values is 600 x 600 µm, that is,
8 x 8 values of leakage and 3 x 3 values of thickness.
To compare information from the RLA and RTA and to use the more detailed
data from the leakage maps, we chose 300 x 300-µm areas. The maps
are, therefore, composed of 63 (9 x 7) values, each representing a 300
x 300-µm area, for a total of 2700 x 2100 µm.
For each 300 x 300-µm area, the value of leakage is the
mean and SD of 16 (4 x 4) values.
To obtain a value of thickness for an equivalent 300 x 300-µm
area, we performed a 2-step procedure. First, values of thickness were computed
as the mean and SD of 9 (3 x 3) values, corresponding to a 600 x
600-µm area. Afterward, this area was split into 4 adjacent 300 x
300-µm areas, and the mean and SD values obtained for the 600 x
600-µm area were given to each of these 4 adjacent areas.
In the healthy control population, the mean values of the 63 mean values
of leakage and thickness are 21.29 x 10- 7 cm/s and
168.13 µm, respectively; for the SD, the mean values are 6.19 x
10- 7 cm/s and 22.56 µm, respectively. The relatively
large SD for leakage, registered after averaging 14 normal retinal leakage
maps, is expected considering the high resolution of the system associated
with regional variations in vascular distribution.
By comparing values from the patients with those from the controls,
we can compute maps of increased leakage or increased thickness as percentages.
All of the increases are computed considering the reference mean plus
2 SDs of the healthy control population.
An extended description of the data analysis methods is available elsewhere.4-5
Correlations between percentages of increases in RLA and RTA values
occurring between examinations and HbA1cvalues and systolic and
diastolic blood pressure measurements were performed using the  2 test to compare proportions.
Characterization of the Fundus Lesions
The fundus lesions are first characterized by grading each eye based
on images from 7-field SFP and using ETDRS protocols.
Only eyes showing levels 20 and 35 of Wisconsin grading were included
in this study. Combined information is obtained only from field 2, using color
SFP; FFA, early and late phases; scanning laser ophthalmoscope angiography;
RLA; and RTA.
The alterations registered in field 2 with the different methods used
were as follows.
Stereoscopic Fundus Photography.
Red dots and yellowish white deposits.
Fundus Fluorescein Angiography.
Early phase: outline of the foveal avascular zone, hyperfluorescent
(bright) spots, and hypofluorescent (dark) spots; and late phase: leaking
spots (spots surrounded by diffuse hyperfluorescence).
Scanning Laser Ophthalmoscope Fluorescein Angiography (Only Late Phase).
Leaking spots.
Retinal Leakage Analyzer.
Areas of increased fluorescein leakage (300 x 300 µm) are
areas where fluorescein leakage is more than a reference made equal to the
mean plus 2 SDs of a healthy control population. The increase is expressed
as a percentage over the reference. Retinal leakage analyzer–leaking
sites are identified as the central sites (300 x 300 µm) of maximum
percentage of increased leakage occurring in each area. In many cases, there
is continuity between areas of increased fluorescein leakage. Still, it is
possible to determine these RLA-leaking sites, checking for the first- and
second-order derivatives of the leakage map.
Retinal Thickness Analyzer.
Localized measurements of retinal thickness are obtained from a 200
x 200-µm area. The findings on fundus photographs and fluorescein
angiograms were registered by 3 different observers (C.L.L., J.R.F.A., and
J.G.C.-V.) in an independent manner. Disagreements were resolved after joint
examination. Definitions for the lesions used in the text followed ETDRS definitions.
Only eyes that showed no capillary closure during the early phase of
the fluorescein angiogram were included in the study analysis. Absence of
capillary closure was accepted when a smooth and symmetrical outline of the
foveal avascular zone was observed, with defects no larger than 10% of the
entire outline.
To interpret the data, the following definitions, coinciding largely
with ETDRS definitions, were used: microaneurysms,
isolated red dots in SFP images that coincide with hyperfluorescent spots
in the early FFA; hemorrhages, round or linear red
spots in SFP images that do not fluoresce on FFA or that appear as dark spots
in FFA images; drusen, deeply located yellowish white
deposits in the SFP image that became hyperfluorescent in early FFA; and hard exudates, white or yellow-white deposits that do not
fluoresce or that appear as dark spots in FFA images.
RESULTS
The results are summarized in Table
1. Areas of abnormally increased fluorescein leakage were detected
in all eyes examined at baseline.
Retinal leakage analyzer–leaking sites,
that is, sites of maximal fluorescein leakage for each area of abnormally
increased leakage, reached values as high as 483% above normal, but in 10
of the 36 examinations performed, the fluorescein leakage returned to normal
levels. This finding occurred in 5 eyes 6 months after inclusion in the study
and in another 3 eyes at the 12-month examination.
Of the 12 patients included in the study, 8 improved in metabolic control
during the second period of follow-up, that is, between the 6- and 12-month
examinations, and the correlation between changes in HbA1c values
and decreases or increases in percentage of abnormal fluorescein leakage was
statistically significant (P<.001). A direct correlation
between these 2 variables was present in 10 of the 12 eyes. No correlations
were found between systolic or diastolic blood pressure values and changes
in percentage of abnormal fluorescein leakage, either between baseline and
the 6- and 12-month examinations or between the 6- and 12-month examinations.
When comparing the RLA-leaking sites among the 3 examinations, there
was good correlation between the location of these sites of maximum leakage
but a clear fluctuation in the percentage increases (Figure 1 and Figure 2).
In total, the eyes examined showed 51 different RLA-leaking sites unrelated
to microaneurysms or other apparently identifiable vascular abnormalities.
These RLA-leaking sites showed the larger percentage increases in fluorescein
leakage. Of 51 RLA-leaking sites, 34 were identified in the same location
in the retina in subsequent examinations. Clear fluctuation in the percentages
of abnormal fluorescein leakage between the subsequent examinations was observed
in 8 of the 12 eyes examined. The other 4 eyes showed a progressive decrease
in fluorescein leakage in the subsequent examinations.
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Figure 1. Integrated maps of patient 10,
including data from stereoscopic fundus photography (black lines and red dots),
the retinal leakage analyzer (RLA) (color-coded maps of blood-retinal barrier
permeability indexes), and the retinal thickness analyzer (RTA) (white dot
density maps of percentage increases in retinal thickness) obtained from visits
at baseline (A), 6 months (B), and 12 months (C).
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Figure 2. Integrated information for patient
10 for the 3 visits (at 0, 3, and 6 months). Each square represents data from
a 300 x 300-µm area in the fundus. The 2 black dots show the location
of 2 microaneurysms that were present at the 3 visits. An abnormal increase
in thickness at the first visit is shown as shaded squares; at the second
visit, as 45° lines (/); and at the third visit, as 135° lines (\).
For an abnormal increase in leakage, only the central retinal leakage analyzer
(RLA)–leaking sites are shown. The numbers inside the circles represent
the percentage of increase over the reference map for the first visit. For
the second and third visits, the value is shown inside squares (none for this
patient) and inside diamonds, respectively. Note the location of the RLA-leaking
sites and their fluctuation during the 1-year period. There are 3 leaking
sites common to the first and third visits. All of them decreased to within
normal values at the second visit and showed important increases at the third
visit, thus clearly demonstrating fluctuation in the percentage of fluorescein
sodium leakage at these leaking sites. The small circle in the center of each
map denotes the location of the center of the fovea; the large circle, centered
on the fovea, denotes a circle of 1500 µm in diameter; and the black
curvy lines, retinal vessels.
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There were also 29 microaneurysms in field 2 of the 12 eyes examined.
They remained in the same location during the 1-year follow-up period. Although
associated with some degree of abnormal fluorescein leakage, the percentage
increases in fluorescein leakage were relatively low (Figure 1 and Figure 2).
Furthermore, they were found to leak progressively less in successive examinations.
Only 5 of the 29 microaneurysms showed some increase in fluorescein leakage
at the 12-month examination.
Increases in retinal thickness were also detected in all eyes examined
at 1 of the 3 examinations performed in each eye. The sites of maximum percentage
thickness were generally lower than 30% above normal values, with the sole
exception of the last examination of patient 10.
Changes were found between the location of sites of maximum percentage
increase in retinal thickness when comparing examinations performed in the
same eye in 7 of the 12 eyes. The 5 eyes that had a more stable abnormal increase
in retinal thickness also showed involvement of the fovea and had higher maximum
percentage increases in retinal thickness. The changes in retinal thickness
showed no statistical correlation with changes in HbA1c values
or with systolic or diastolic blood pressure values. Finally, a correlation
was observed between the location of the RLA-leaking sites represented by
sites of maximum percentage of increased fluorescein leakage at one examination
and the location of sites of maximum percentage increase in retinal thickness
in subsequent examinations, either 6 or 12 months later (Figure 1 and Figure 2).
The coincidence between the location of sites of increased thickness
and RLA-leaking sites in previous examinations was 61% for the 6-month examination
and 71% for the 12-month examination.
COMMENT
Our method of multimodal imaging of the ocular fundus allows correlations
to be established between fundus lesions, localized alterations of the BRB
identified by mapping fluorescein leakage into the vitreous, and changes in
retinal thickness. Previous studies5, 7
have shown in the macular region of patients with type 2 diabetes mellitus
and nonproliferative retinopathy, in most eyes examined, that localized sites
of increased fluorescein leakage did not show good correlation with the zones
of increased retinal thickness. To explain this apparent lack of correlation
between sites of alteration of the BRB and zones of retinal edema in the diabetic
macula, the presence of 2 types of edema, vasogenic and cytotoxic, was put
forward.5, 7 There is a need for
studies of the natural history of these alterations occurring in the early
stages of diabetic retinal disease using these new methods and performed in
a prospective fashion.
In the present study, a 1-year follow-up of patients with type 2 diabetes
mellitus and mild nonproliferative retinopathy, we performed 3 examinations,
at baseline and 6 and 12 months later.
The most frequent alterations observed were, in decreasing order of
frequency, RLA-leaking sites, areas of increased retinal thickness, microaneurysms,
and drusen. Hemorrhages and hard exudates were relatively rare in the macular
region (photographic field 2 of the ETDRS) in these eyes with mild nonproliferative
diabetic retinopathy (levels 20 and 35 of Wisconsin grading).
Retinal leakage analyzer–leaking sites reached permeability indexes
of the BRB as high as 483% above normal. These sites of alteration of the
BRB, well identified in the RLA maps, varied little in their location on successive
examinations at 6-month intervals, but their BRB permeability indexes fluctuated
greatly when comparing subsequent examinations. In 10 of the 36 examinations,
RLA maps returned to normal levels. Most of the RLA-leaking sites were not
associated with any visible morphologic alteration of the retina, such as
microaneurysms, hemorrhages, or other vascular abnormalities.
The intensity of fluorescein leakage, represented by the BRB permeability
indexes in these RLA-leaking sites, correlated well with the changes in HbA1c levels, when comparing the 6- and 12-month examinations. Decreases
in HbA1c levels, indicating improved metabolic control, were associated
with decreasing fluorescein leakage, and increases in HbA1c levels
with increasing fluorescein leakage. No correlation was found, however, between
variations in fluorescein leakage and blood pressure changes, either systolic
or diastolic, but this may be because of the small number of patients involved
and the fact that the blood pressure levels remained relatively stable during
the study, in each patient. These findings confirmed and expanded previous
reports using slitlamp vitreous fluorometry8
and vitreous fluorometry,9 showing that an
increase in permeability of the BRB to fluorescein is an early finding in
patients with diabetic retinal disease.10-11
The RLA, based on scanning laser ophthalmoscope methods, goes a step further
by identifying the actual sites of increased fluorescein leakage.
A particularly interesting observation in this study is the widespread
presence of increased retinal thickness, ie, retinal edema. Our findings offer
some insight into the mechanisms of development of retinal edema in the initial
stages of diabetic retinopathy. The location of RLA-leaking sites appears
to be predictive of the later development in the same location of areas of
increased retinal thickness. An alteration of the BRB appears, therefore,
to be associated with the development of diabetic retinal edema, at least
in this stage of retinopathy.
Another interesting observation was the variation found between subsequent
examinations in the location and extent of the areas of increased retinal
thickness. These variations give support to the view that the retinal edema
observed in these eyes is extracellular and not intracellular. We have, therefore,
retinal edema that fulfills the criteria for being classified as vasogenic edema, that is, it is associated with an alteration of the
BRB and appears to be predominantly extracellular. This follow-up study, allowing
comparisons to be made between 3 subsequent examinations, performed at 6-month
intervals, indicates that vasogenic edema is the predominant type of retinal
edema occurring in these initial stages of nonproliferative diabetic retinopathy.
The extent and percentage increases in retinal thickness did not show
any clear correlation with HbA1c levels or blood pressure variations.
They appeared, however, to be a late result of an alteration of the BRB identified
in previous examinations.
Longer follow-up studies are, therefore, needed to examine relationships
between the occurrence of retinal edema and changes in metabolic control or
blood pressure levels.
During the 1-year follow-up period, microaneuryms leaked progressively
less at successive examinations. This observation suggests that these vascular
lesions are in the process of progressive occlusion and gives support to the
view that they are sites of localized thrombosis.12
In conclusion, our observations suggest that the dominant alteration
in the retina of patients with type 2 diabetes mellitus and mild nonproliferative
retinopathy is the presence of RLA-leaking sites, indicating spotty retinal
vascular damage characterized by alteration of the BRB. This spotty retinal
vascular damage appears to be reversible and directly associated with variations
in metabolic glycemic control. These findings offer particularly exciting
perspectives for medical therapy of diabetic retinopathy.
The methods of examination we used could not show, however, if these
leaking sites are associated with or preceded by dynamic changes in the retinal
vasculature, such as localized vasodilation or vasoconstriction.
Retinal edema, also a frequent finding, appears to develop as a result
of retinal vascular leakage.
Longer follow-up studies, using new methods of examination, such as
the RLA and the RTA, ideally combined with blood flow studies at the capillary
level, integrated in multimodal imaging of the ocular fundus, are expected
to clarify many of the remaining questions.
AUTHOR INFORMATION
Accepted for publication February 23, 2001.
Corresponding author and reprints: Conceição L. Lobo,
MD, MSc, Center of Ophthalmology, University Hospital and Institute of Biomedical
Research on Light and Image, Faculty of Medicine, University of Coimbra, Azinhaga
de Santa Comba, 3000-354 Coimbra, Portugal (e-mail: clobo{at}aibili.pt).
From the Center of Ophthalmology, University Hospital and Institute
of Biomedical Research on Light and Image, Faculty of Medicine, University
of Coimbra (Drs Lobo, Faria de Abreu, and Cunha-Vaz), and the Center of New
Technologies for Medicine, Association for Biomedical Research and Innovation
on Light and Image (Mr Bernardes), Coimbra, Portugal.
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