INTRODUCTION
Diabetes-related
eye disease is the most common cause of loss of vision in people of the working
age (20-74 years) in developed countries1. Functional abnormalities
of the retina and vision may precede clinical signs of retinopathy in diabetes2.
Multifocal electroretinography (mfERG) is an objective and noninvasive method
to measure retinal response to visual stimulation from small, essentially
discrete patches of human retina3.
Aim of Work
The aim
of this work is to evaluate the changes of the mfERG in the preclinical stage
of diabetic retinopathy as a predictor of early onset of diabetic retinopathy
and the correlation with diabetic control using glycosylated hemoglobin
(HbA1c).
MATERIALS
AND METHODS
Fifty-one eyes of 26 (5 males and 21 females) diabetic
patients with more than five years of diagnosis of diabetes, and without
diabetic retinopathy were included
in the
study. The age range was 33 (48.1±8.137) years. The eyes were examined by
ophthalmoscopic examination (indirect ophthalmoscopy and fundus biomicroscopy)
and fluorescein angiography. Eyes with angiographic evidence of diabetic
retinopathy or significant anterior or posterior segment diseases were excluded
from the study.
Twelve
eyes (23.5%) included in the study belonged to six patients with type I
(insulin-dependent) diabetes and 39 eyes (76.5%) belonged to 20 patients with
type II (non-insulin-dependent) diabetes. The diabetic control of the patients
was tested by determination of HbA1c levels in blood. HbA1c levels were
analyzed by chromatography techniques using commercially available kits in
Cairo University Hospitals Laboratories, Faculty of Medicine, Cairo University,
Cairo, Egypt. Normal values for HbA1c are
less than 5.3%.
Thirty
seven normal eyes of 21 subjects (13 males and 8 females) without ophthalmic or
systemic abnormalities comprised the normal control group. The age range in the
normal group was 43 (33.73±11.56) years.
Multifocal
Electroretinography (mfERG) Recording Procedure
A written informed consent was obtained from all
participants to perform the procedures used and mfERG test was done according
to the International Society for Clinical Electrophysiology of Vision (ISCEV)
Standards 2011 edition4. This was done by using HK Loop electrodes,
on the RETIscan21mfERG version 07/01 (Roland Consult, Wiesbaden, Germany), after 10 minutes of light adaptation and pupil dilation
with tropicamide. The stimulus consisted of 61 hexagons, covering 25-30° of
visual field and presented on a 20-inch monitor at a viewing distance of 33 cm. Refractive errors were
corrected for the viewing distance. A ground electrode was connected to the
forehead. The fellow eye was occluded with light pressure to prevent blinking
and the electrical artifacts it can introduce.
The mfERG recordings are performed
using the ‘standard’ mfERG visual stimulus. The hexagon areas increased with
eccentricity to compensate differences in cone density across the retina (leading
to a fourfold size change). Each hexagon was temporally modulated between light
and dark (frame rate: 60 Hz; maximum luminance: 120cd.m-2). Subjects
were instructed to fixate a small black cross in the center of the stimulus.
Fixation was checked by means of online video monitoring during the 6 minutes
lasting recording sessions and high-amplitude artifacts were automatically
eliminated. To improve fixation stability, sessions were broken into 45-second
segments, and eight trials were recorded in total. Signals were amplified with
a gain of 100.000 and filtered with a band-pass filter (5–300 Hz). The surface
electrode impedance was less than 10 kOhm. For each hexagon, the amplitude of
P1 (defined as the difference between N1 trough and P1 peak) was calculated,
and the implicit time of the P1 component determined from the onset of the
stimulus till the peak of the P1 wave.
Data Output
Average responses were calculated for the fovea which
corresponds to hexagon number 31 and for four retinal quadrants as in Figure
(1). The orientation of the printout setting was set to "vertically
mirrored" which sets the display and the printouts of the results
according to the examiner (mirrored for the user who analyzes the data). The
view in the printout corresponds to the retinal view. The
responses and their measurements are plotted at corresponding retinal locations
rather than in visual field orientation. The local waveforms of the diabetics
and normal groups of the right eye responses were converted to left eye orientation
to unify the locations in both eyes. Quadrant one (upper right) corresponds to
the upper temporal retina, quadrant two (lower right) corresponds to the lower
temporal retina, quadrant three (lower left) corresponds to the lower nasal
retina and quadrant four (upper left) corresponds to the upper nasal retina.
The data was obtained from five
elements from the output (four quadrant regions and the fovea) as well as the
overall average. The amplitude and implicit time of the P1 wave of the local
mfERG responses were analyzed. The data
is described as mean and standard deviation.
The data was entered into the Microsoft Excel 2003
(Microsoft Corporation, New York, USA) and MedCalc® software (version 10.2) (MedCalc
Software, Mariakerke, Belgium) for Biomedical statistical analysis. The normality of the
data acquired was tested by the chi-square test of normality. The distribution
of data from quadrants and fovea did not appear to follow a normal distribution
(Gaussian distribution) i.e. non-parametric data, so the Mann–Whitney U test
was used to test for significance between the average traces of the diabetic
and control groups in different quadrants and the fovea. A probability value (P
value) less than 0.05 is considered statistically significant. The
correlations between the non-parametric quantitative variables were done by
Spearman’s (Rho
or r) correlation test. Graphs and scatter diagrams were developed using
Microsoft Excel and MedCalc® whenever appropriate.
RESULTS
Demographic
Data:
Table (1)
summarizes the clinical and demographic characteristics of both the diabetic
and normal groups.
Spearman's coefficient of rank correlation (r)
between the age, the amplitude and peak time (latency) of P1 is shown in Tables
(2) and (3).
From
the Tables (2) and (3) below there is a negative linear relationship between
the amplitude of P1 and the patients age (i.e. as the age advances, the
amplitude decreases); but no statistically significant relationship between age
and average amplitude of P1 in both groups. A positive relationship was found
between the peak time of P1 and age (i.e. as the age advances, the latency
increases). The only statistically significant relationship (P<0.05) that
was detected between the age and peak time in the diabetics group was in
quadrant 4 (upper nasal) (P=0.0198) as well as the overall average (P=0.0372)
(Figures 2 & 3). Quadrants 2 (lower temporal) showed a marginal
significance (P=0.0572).
Effect of HbA1c
level: The mean level of HbA1c for the diabetic patients was 8.265±1.265%. All
the patients showed poor control of diabetes with the minimum value 6.5% and
maximum value 11%. We did not find any significant correlation between HbA1c
level and the P1 wave amplitude and peak time (Table 4).
Duration
of diabetes: The mean duration of diabetes in the diabetic patients was
8.608±4.257 years (Table 5). The correlation between the duration of diabetes
and the decrease in amplitude of P1 wave was less than the correlation with
increase in peak time of P1 wave. The increase of peak time was noted more in
quadrants 2, 3 and 4 (r=0.260, 0.201 and 0.292; respectively). However, the
only statistically significant result (P<0.05) was in quadrant 4 (P=0.0391).
Quadrants data and
statistics: Tables (6) and (7) show the results of the Mann-Whitney U test to
compare the average amplitude and average peak times of both the normal and
diabetic groups. Both the z scores from the data ranks of both study groups and
the P value are reported. As for the amplitude, only the fovea showed a
statistically significant difference between both study groups (P = 0.0357)
(Figure 4). The peak time showed a difference to be statistically significant
only in quadrant 2 (P=0.0308) (Figure 5).
Comparison between
different regions in the diabetic eyes had been done and the results are
presented in tables (8 and 9) below. The mean amplitude of the fovea was higher
than other quadrants and this difference has been found to be statistically
significant in 3 quadrants with the exception of quadrant 3 (Tables 6 and 8).
On comparing the 4 quadrants with each other no statistically significant
difference was detected except between quadrant 4 and 3 (P=0.0182) as the
amplitude of quadrant 4 was much lower than quadrant 3 (Tables 6 and 8).
The
mean peak time of the fovea was longer than other quadrants and this difference
has been found to be statistically significant in all of the 4 quadrants (Tables
7 and 9). On comparing the 4 quadrants with each other no statistically
significant difference was detected between any of the quadrants (Tables 7 and
9).
Figure 1. Quadrant
orientation: Fovea corresponds to hexagon 31. All eyes were analyzed as left
eye orientation.
Figure 2. Scatter diagram
showing correlation between age and overall peak time in the normal control
group.
Figure 3. Scatter diagram showing correlation
between age and overall peak time in the
diabetics group. Notice the right skewing of the scatter plots, which
indicate higher latency in diabetics in comparison to the normal group.
Figure 5. Box & Whiskers graph showing comparison between both groups peak
time of P1 at quadrant 2 which shows the mean peak time in the diabetics group
being higher than the normal controls.
Figure 4. Box & Whiskers Graph showing
comparison between both groups amplitude of P1 at the fovea which shows the
mean amplitude in the diabetics group being lower than the normal controls. The
small dot represents a single case with large amplitude
Table 1. Clinical characteristics of the
study groups.
|
Diabetics
|
Normal
|
Number (M/F)
|
26 (5 / 21)
|
21 (13 / 8)
|
Age (year, mean
[SD])
|
48.1 [± 8.137]
|
33.73 [± 11.56]
|
Eyes in study
(OD/OS)
|
26 / 25
|
18 / 19
|
Eyes per Gender
(M/F) (%)
|
10 / 41 (19.6 / 80.4 %)
|
22 / 15 (59.5 / 40.5 %)
|
Eyes per Type of
Diabetes (I/II) (%)
|
12 / 39 (23.5 / 76.5 %)
|
NA
|
Duration of
diabetes (years, mean [SD])
|
8.608 [± 4.257]
|
NA
|
HbA1c (%, mean
[SD])
|
8.265 [± 1.265]
|
NA
|
F female, HbA1c glycosylated
hemoglobin, M male, OD right, OS left; NA non-applicable, SD standard deviation
Table 2. Spearman's correlation
coefficient (r) between age and the average amplitude of P1 wave in
diabetics and normal patients.
|
Diabetics
|
Normal
|
Quadrant 1
|
-0.217 (P=0.1252)
|
-0.163 (P=0.3278)
|
Quadrant 2
|
-0.230 (P=0.1037)
|
-0.252 (P=0.1300)
|
Quadrant 3
|
-0.141 (P=0.3185)
|
-0.285 (P=0.0875)
|
Quadrant 4
|
-0.120 (P=0.3953)
|
-0.231 (P=0.1652)
|
Fovea
|
-0.108 (P=0.4442)
|
-0.283 (P=0.0899)
|
Overall Average
|
-0.184 (P=0.1939)
|
-0.325 (P=0.0508)
|
Table 3. Spearman's correlation
coefficient (r) between age and the average peak time of P1 wave in
diabetics and normal patients.
|
Diabetics
|
Normal
|
Quadrant 1
|
0.0709 (P=0.6163)
|
0.208 (P=0.2122)
|
Quadrant 2
|
0.269 (P=0.0572)
|
-0.0394 (P=0.8130)
|
Quadrant 3
|
0.261 (P=0.0645)
|
0.193 (P=0.2458)
|
Quadrant 4
|
0.330 (P=0.0198)
|
0.0128 (P=0.9387)
|
Fovea
|
0.168 (P=0.2344)
|
0.0473 (P=0.7764)
|
Overall Average
|
0.295 (P=0.0372)
|
0.119 (P=0.4758)
|
Table 4. Spearman's correlation
coefficient (r) between HbA1c and the amplitude and peak time of P1 wave
in diabetics.
|
Amplitude
|
Peak time
|
Quadrant 1
|
-0.077 (P=0.5861)
|
-0.199 (P=0.1602)
|
Quadrant 2
|
-0.0519
(P=0.7139)
|
-0.229 (P=0.1054)
|
Quadrant 3
|
-0.0539
(P=0.7031)
|
-0.0356 (P=0.8011)
|
Quadrant 4
|
-0.0697
(P=0.6219)
|
-0.0377 (P=0.7896)
|
Fovea
|
0.00798
(P=0.9550)
|
-0.144 (P=0.3098)
|
Overall average
|
-0.0428
(P=0.7623)
|
-0.240 (P=0.0890)
|
Table 5. Spearman's correlation coefficient
(r) between duration of diabetes and the amplitude and peak time of P1
wave in diabetics.
|
Amplitude
|
Peak time
|
Quadrant 1
|
0.118 (P=0.4056)
|
0.174 (P=0.2191)
|
Quadrant 2
|
0.00511 (P=0.9712)
|
0.260 (P=0.0662)
|
Quadrant 3
|
-0.0271 (P=0.8483)
|
0.201 (P=0.1549)
|
Quadrant 4
|
-0.0297 (P=0.8335)
|
0.292 (P=0.0391)
|
Fovea
|
-0.145 (P=0.3052)
|
0.0313 (P=0.8249)
|
Overall average
|
-0.022 (P=0.8763)
|
0.159 (P=0.2622)
|
Table 6.
The amplitude of P1 in both study groups (Mean±SD) and Mann-Whitney U test
results (z score and P value).
|
average amplitude of P1 wave in
diabetic and normal subjects (µV)
|
Diabetics
(Mean±SD)
|
Normal
(Mean±SD)
|
z Score
|
P value
|
Quadrant 1
|
0.5073 ± 0.2653
|
0.5438 ± 0.2318
|
0.524085
|
0.6002
|
Quadrant 2
|
0.5237 ± 0.2583
|
0.6105 ± 0.2314
|
1.715954
|
0.0862
|
Quadrant 3
|
0.5781 ± 0.2443
|
0.6269 ± 0.2628
|
0.612841
|
0.5400
|
Quadrant 4
|
0.4608 ± 0.2534
|
0.4694 ± 0.2190
|
0.409969
|
0.6818
|
Fovea
|
0.7144 ± 0.3758
|
0.8987 ± 0.3702
|
2.100565
|
0.0357
|
Overall average
|
0.5569 ± 0.2461
|
0.6299 ± 0.1978
|
1.398968
|
0.1618
|
SD standard deviation; µV microvolt
Table 7. The peak time of P1 in both study
groups (Mean±SD) and Mann-Whitney U test results (z score and P value).
|
Average peak time of P1 wave in
diabetic and normal subjects (ms)
|
Diabetics
(Mean±SD)
|
Normal
(Mean±SD)
|
z Score
|
P value
|
Quadrant 1
|
44.4667 ± 2.4055
|
44.1514 ± 2.0978
|
1.145378
|
0.2521
|
Quadrant 2
|
44.7020 ± 2.1190
|
43.6649 ± 1.5305
|
2.159736
|
0.0308
|
Quadrant 3
|
44.0765 ± 2.9090
|
43.7459 ± 1.4132
|
1.411647
|
0.0885
|
Quadrant 4
|
44.6039 ± 2.2893
|
43.8270 ± 2.7738
|
1.508856
|
0.1313
|
Fovea
|
45.0804 ± 6.8775
|
46.8270 ± 3.1224
|
1.018584
|
0.3084
|
Overall average
|
44.5349 ± 2.1039
|
44.4432 ± 1.2755
|
0.908695
|
0.3635
|
SD standard deviation, ms millisecond
Table 8. Mann-Whitney U test results of
quadrants comparison in the amplitude of P1 in diabetics.
|
Average
amplitude of P1 wave in diabetic (quadrants comparison)
( z score and P value)
|
Quadrant 1
|
Quadrant 2
|
Quadrant 3
|
Quadrant 4
|
Fovea
|
Quadrant 1
|
--------
|
0.334635
(P = 0.7379)
|
1.459010
(P = 0.1446)
|
0.829896
(P = 0.4066)
|
2.847747
(P = 0.0044)
|
Quadrant 2
|
0.334635
(P = 0.7379)
|
--------
|
1.174570
(P = 0.2402)
|
1.318463
(P = 0.1873)
|
2.690468
(P = 0.0071)
|
Quadrant 3
|
1.459010
(P = 0.1446)
|
1.174570
(P = 0.2402)
|
--------
|
2.362526
(P = 0.0182)
|
1.800338
(P = 0.0718)
|
Quadrant 4
|
0.829896
(P = 0.4066)
|
1.318463
(P = 0.1873)
|
2.362526
(P = 0.0182)
|
--------
|
3.490247
(P = 0.0005**)
|
Fovea
|
2.847747
(P = 0.0044*)
|
2.690468
(P = 0.0071)
|
1.800338
(P = 0.0718)
|
3.490247
(P = 0.0005**)
|
--------
|
* Significant at P<0.05 ** Significant at P<0.01
Table 9. Mann-Whitney U test results of
quadrants comparison in the Peak time of P1 in diabetics.
|
Average peak
time of P1 wave in diabetic (quadrant comparison)
( z score and P value)
|
Quadrant 1
|
Quadrant 2
|
Quadrant 3
|
Quadrant 4
|
Fovea
|
Quadrant 1
|
--------
|
0.0435026
(P = 0.9653)
|
0.351367
(P = 0.7253)
|
0.348021
(P = 0.7278)
|
3.430013
(P = 0.0006**)
|
Quadrant 2
|
0.0435026
(P = 0.9653)
|
--------
|
0.294479
(P = 0.7684)
|
0.301172
(P = 0.7633)
|
3.336315
(P = 0.0008**)
|
Quadrant 3
|
0.351367
(P = 0.7253)
|
0.294479
(P = 0.7684)
|
--------
|
0.632461
(P = 0.5271)
|
3.871731
(P = 0.0001**)
|
Quadrant 4
|
0.348021
(P = 0.7278)
|
0.301172
(P = 0.7633)
|
0.632461
(P = 0.5271)
|
--------
|
3.262695
(P = 0.0011*)
|
Fovea
|
3.430013
(P = 0.0006**)
|
3.336315
(P = 0.0008**)
|
3.871731
(P = 0.0001**)
|
3.262695
(P = 0.0011*)
|
--------
|
* Significant at P<0.05 ** Significant at P<0.01
DISCUSSION
In this
study, we focused on detection of abnormalities in mfERG in 51 eyes of diabetic
patients with no diabetic retinopathy and compare it to 37 normal control eyes.
The quadrant group analysis and the fovea has been used to be more relevant
clinically more than individual hexagons or ring analysis. The most important component of mfERG in diabetics is the P1
wave as P1 is most often abnormal in the eyes of individuals with diabetes5.
The
amplitude and peak time of the P1 wave in the diabetic group was compared to
those of the normal controls, and correlated with age, duration of diabetes and
HbA1c levels. The mfERG in particular is a
sensitive test for identifying neuronal deficits before the onset of vascular
change. Functional abnormalities within the retina in diabetes can be caused by
a variety of factors that lead to changes in one or more of the biochemical
pathways altered during diabetes, or alternatively, hyperglycemia-induced
changes in glial cell function6.
It has
been established that mfERG peak time delays indicate areas of functional
abnormalities in diabetes at different stages including the preclinical stage
more than does the amplitude1,3,7-10. A factor
that is likely playing an important role is the type of pathology underlying
the retinal dysfunction. Given that the early diabetic retinal disease first
affects the microvasculature supplying inner retinal neurons including
ganglion, amacrine and bipolar cells (and the Müller cells to some degree),
then the time of signal generation and signal propagation through the retinal
circuitry will be abnormally prolonged but the responses will not be extinguished11.
It is reasonable to expect that the local retinal responses would be abnormally
delayed but not necessarily reduced in amplitude1.
In a longitudinal study, Han and colleagues12
studied the value of mfERG in predicting the development of diabetic
retinopathy. They found that the main predictive parameter of the mfERG was the
peak time of P1, and it was used with the combination of other risk factors;
namely the duration of diabetes and state of diabetic retinopathy at
presentation, to develop a predictive model for the development of diabetic
retinopathy. In another study, it has been shown that abnormal mfERG peak times
were associated with an almost eight times greater risk of development of
recurring retinopathy over 3 years and combined with other risk factors for
diabetes it can predict the development of diabetic retinopathy later on10.
In this
study, we conducted; the amplitude of P1 wave showed a decrease in the diabetic
group than in normal controls. This was statistically significant only in the
fovea. However, the more important peak time was prolonged in the diabetics
than normal group, and this was statistically significant in one quadrant only;
quadrant 2 (lower temporal quadrant). On comparing the quadrants and fovea with
each other, the mean peak time of the fovea was
longer than other quadrants and this difference has been found to be
statistically significant in all of the 4 quadrants. On comparing the 4
quadrants with each other no statistically significant difference was detected
between any of the quadrants. From the above, the area that is more likely to
develop diabetic retinopathy in the macular area later is the lower temporal
quadrant. The fovea shows more peak time delay than all other regions in the
diabetic retina, however the delay at the fovea was not found to be
statistically different from the normal group.
In the review of Lai and colleagues13, the
authors reported that the reductions in mfERG response amplitudes and delays in
peak times with increasing age were found in most of the studies. Seiple and
colleagues14 found that the P1 amplitude decreases with age about
ten times more than the implicit times (P1 amplitude decreases by 10.5% per
decade versus an increase in peak time of P1 by about 1% per decade). These
results showed the importance to develop an age-matched normative data for
mfERG analysis or corrections for age to be developed for the mfERG users to
use by each laboratory.
In our
study, the age of patients affected the output of mfERG. We have found that as
the age advances, the amplitude of P1 decreases in both the diabetics and
normal control groups. No statistically significant relationship was detected
between age and average amplitude of P1 in the diabetics group. This runs in context with the results
of Shimada and colleagues15, who found that age
affected the amplitudes of P1 wave in both normal and diabetic groups but did
not find any significant difference between both groups. In case of the peak time of P1, as the age
advances, a delay in both diabetic and normal groups is noted. The effect of
age on mfERG peak time and amplitude measurement was more pronounced in the
diabetic group of subjects, which could be the result of either a combined
effect of both aging and diabetes or a delay in diagnosis that prolonged the
actual duration of the disease.
The duration of diabetes was correlated with the diabetic
mfERG amplitude and peak time. We have found that there is a positive linear
correlation between duration and peak time in all quadrants that was
statistically significant in quadrant 4 (upper nasal). This correlation was not
found between the duration of diabetes and the amplitude. It is logical that
with the increase of the duration of diabetes, the severity of the changes of
mfERG increases. This is supported by the study of Bronson-Castain and colleagues16 who have found that after a sufficient duration of the disease and the start of
appearance of early NPDR, the functional integrity of the retina is compromised
to the extent that there is a profound delay of the peak time first-order
Kernel of the mfERG.
All of the diabetic patients had uncontrolled diabetes with
high HbA1c levels. However, we did not find any significant correlation between
the mfERG and HbA1c levels. This is consistent with the findings of Tyrberg8,
Kim9, Holm17and their colleagues. These studies did not find any correlation
between HbA1c and the increased amplitude or the peak time in the first-order
component of the mfERG in diabetic patients.
Few clinical studies were conducted on the distribution of
the diabetic retinopathy changes in the retina. They have reported that
neovascularization and other changes in the form of microaneurysms and loss of
pericytes were more on the temporal retina than the nasal retina18,19.
Feman and colleagues’ study reported a higher incidence of neovascularization
in the supero-temporal quadrant of the retina than other quadrants18.
Tang and coauthors studied the distribution of biochemical disturbances that
occur in diabetic retinas, and found that the distribution of the changes in
diabetic retinopathy follows the distribution of the biochemical disturbance;
that occurred more on the temporal side of the retina19. These
reports support and give strength to the findings of our study.
To our knowledge no previous study has reported the
topographic incidence of diabetic retinopathy changes by retinal quadrants
using the mfERG peak time delays. This study is the first to report that mfERG
peak time delays are more in the lower temporal quadrant of the retina in
patients with no retinopathy, which may have an impact later on the appearance
of the diabetic changes afterwards.
[Disclosure: Authors report no
conflict of interest]
REFERENCES
1. Bearse
MA, Adams AJ, Han Y, Schneck ME, Ng J, Bronson-Castain K, et al. A multifocal
electroretinogram model predicting the development of diabetic retinopathy.
ProgRetin Eye Res.2004; 25: 425–48.
2. Bearse
MA, Han Y, Schneck ME, Adams AJ. Retinal Function in Normal and Diabetic Eyes Mapped with the Slow
Flash Multifocal Electroretinogram. Invest Ophthalmol Vis Sci. 2004; 45:
296–304.
3. Fortune
B, Schneck ME, Adams AJ. Multifocal Electroretinogram Delays Reveal Local
Retinal Dysfunction in Early Diabetic Retinopathy. Invest Ophthalmol Vis Sci. 1999;
40: 2638–51.
4. Donald
CH, Michael B, Mitchell B, David K, Mineo K, Jonathan SL, et al. ISCEV standard for
clinical multifocal electroretinography 2011 edition. Doc Ophthalmol. 2012; 124: 1–13.
5. Schneck
ME, Bearse MA Jr, Han Y, Barez S, Jacobsen C, Adams AJ. Comparison of mfERG
waveform components and implicit time measurement techniques for detecting
functional change in early diabetic eye disease. Doc Ophthalmol. 2004; 108:
223–30.
6. Fletcher
EL, Phipps JA, Ward MM, Puthussery T, Wilkinson-Berka JL. Neuronal and Glial
Cell Abnormality as Predictors of Progression of Diabetic Retinopathy. Curr
Pharm Des. 2007; 13: 2699-712.
7. Han Y, Bearse MA, Schneck ME, Barez S, Jacobsen C, Adams AJ.
Towards optimal filtering of ‘‘standard’’ Multifocal electroretinogram (mfERG)
recordings: findings in normal and diabetic subjects. Br J Ophthalmol.2004; 88:
543–50.
8. Tyrberg
M, Ponjavic V, Lövestam-Adrian M. Multifocal electroretinography (mfERG) in
insulin dependent diabetics with and without clinically apparent retinopathy.
Doc Ophthalmol. 2005; 110: 137–43.
9. Kim SJ,
Song S, Yu HG. Multifocal Electroretinogram Responses of the Clinically Normal Retinal Areas in Diabetes’. Ophthalmic Res.2007;
39: 282–8.
10. Ng JS,
Bearse MA Jr, Schneck ME, Barez S, Adams AJ. Local Diabetic Retinopathy
Prediction by Multifocal ERG Delays over 3 Years. Invest Ophthalmol Vis Sci.
2008; 49: 1622–28.
11. Hood DC,
Frishman LJ, Saszik S,Viswanathan S. Retinal Origins of the Primate Multifocal
ERG: Implications for the Human Response. Invest Ophthalmol Vis Sci. 2002; 43:
1673–85.
12. Han Y,
Schneck ME, Bearse MA Jr, Barez S, Jacobsen CH, Jewell NP, et al. Formulation
and Evaluation of a Predictive Model to Identify the Sites of Future Diabetic
Retinopathy. Invest Ophthalmol Vis Sci.2004; 45: 4106–12.
13. Lai TYY,
Chan W, Lai RYK, Ngai JWS, Li H, Lam DSC. The Clinical Applications of
Multifocal Electroretinography: A Systematic Review. SurvOphthalmol.2007; 52: 61-96.
14. Seiple W,
Vajaranant TS, Szlyk JP, Clemens C, Holopigian K, PaligaJ, et al. Multifocal
Electroretinography as a Function of Age: The Importance of Normative Values
for Older Adults. Invest Ophthalmol Vis Sci. 2003; 44: 1783–92.
15. Shimada Y, Li Y, Brease MA,
Sutter EE, Fung W. Assessment of early retinal changes in diabetes using a new
Multifocal ERG protocol. Br J Ophthalmol. 2001; 85: 414-9.
16. Bronson-Castain
KW, Bearse MA Jr, Han Y, Schneck ME, Barez S, Adams AJ. Association between
Multifocal ERG Implicit Time Delays and Adaptation in Patients with Diabetes. Invest
Ophthalmol Vis Sci. 2007; 48: 5250–6.
17. Holm K,
Larsson J, Lövestam-Adrian M. In diabetic retinopathy, foveal thickness of 300
µm seems to correlate with functionally significant loss of vision. Doc
Ophthalmol.2007; 114: 117–24.
18. Feman SS,
Leonard-Martin TC, Semchyshyn TM. The Topographic Distribution of the First
Sites of Diabetic Retinal Neovascularization. Am J Ophthalmol. 1998; 125:
704–706.
19. Tang J, Mohr
S, Du YP, Kern
TS. Non-uniform distribution of lesions and biochemical abnormalities within
the retina of diabetic humans. Curr Eye Res. 2003; 27: 7-13.