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Macular Edema and Retinal Hard Exudates in African Americans With Type 1 Diabetes
The New Jersey 725
Arch Ophthalmol. 2001;119:251-259.
ABSTRACT
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Objective To determine frequency and associated risk factors for macular edema
and retinal hard exudates in hospitalized African Americans with type 1 diabetes.
Subjects and Methods Included were 725 African Americans with type 1 diabetes who participated
in the New Jersey 725. Clinical evaluations consisted of a structured clinical
interview, ocular examination, stereoscopic fundus photographs, and blood
pressure measurements. Presence of macular edema and hard exudates was determined
via masked grading of fundus photographs. Biological evaluations included
blood and urine assays.
Results Of the 725 patients, 89 (12.3%) had macular edema and 149 (20.6%) had
retinal hard exudates in at least 1 eye. The presence of macular edema and
hard exudates was significantly associated with older age at examination,
longer duration of diabetes, and severity of diabetic retinopathy. Presence
of proteinuria, missing insulin injections at least once a week, and longer
duration of diabetes were significantly and independently associated with
macular edema. Presence of proteinuria, male sex, higher low-density lipoprotein
cholesterol levels, and longer duration of diabetes were significantly and
independently associated with severity of retinal hard exudates.
Conclusion Macular edema and hard exudates are common in African Americans with
type 1 diabetes, particularly in patients with evidence of renal disease.
INTRODUCTION
MACULAR EDEMA secondary to diabetic retinopathy is a well recognized
cause of visual loss in persons with diabetes.1-2
In the population-based Wisconsin Epidemiologic Study of Diabetic Retinopathy
(WESDR), the prevalence of macular edema among white patients with type 1
diabetes was 11.1%.3 In that study, macular
edema was significantly associated with longer duration of diabetes, male
sex, higher glycosylated hemoglobin, presence of proteinuria, and diuretic
use.3 In diabetic patients, macular edema is
often associated with retinal hard exudates.4
Severity of hard exudates has been shown to be significantly associated with
elevated serum total cholesterol and low-density lipoprotein cholesterol (LDL-C)
levels.5-6 The above studies have
been done in predominantly white patient populations. There are no published
data of frequency of, or risk factors for, macular edema and retinal hard
exudates among African Americans with type 1 diabetes.
The New Jersey 725 is a hospital-based study of a large cohort of African
Americans with type 1 diabetes.7 Patients have
been identified from lists of hospital admissions in a geographically well-defined
area surrounding the medical school in Newark, NJ, where the study is conducted.
The frequency of diabetic retinopathy (63.9%) and associated visual impairment
(3.1%) in these patients is high.7 We herein
report on the frequency of macular edema and retinal hard exudates and associated
risk factors in this patient population.
SUBJECTS AND METHODS
Since 1982, all patients discharged from the 116 New Jersey hospitals
with a diagnosis of diabetes mellitus are reported to the New Jersey Department
of Health (New Jersey Hospital Discharge Data). From these discharges, 68 455
names of African Americans, with either a primary or secondary diagnosis of
diabetes mellitus (International Classification of Diseases,
Ninth Revision codes 250.0-250.9, 648.0, and 648.8),8
were identified for the years 1982 through 1996. First, a listing of all patients
by last hospital admission was generated. This yielded a listing of 34 941
patients for the 31 hospitals located in the 7 counties within a 20-mile (32-km)
radius of Newark and that had 100 or more admissions of African Americans
with diabetes. A medical chart review was done to identify eligible patients.
African Americans with type 1 diabetes mellitus, diagnosed and treated with
insulin before 30 years of age, and currently taking insulin, were considered
eligible. Ethnicity was determined from the hospital record and later confirmed
by self-identification.
Of the 34 941 patients, medical charts of 13 615 were randomly
selected and manually reviewed. Of those, 12 489 patients were excluded
because they had either type 2 diabetes or insulin-requiring diabetes diagnosed
after 30 years of age, or type 1 diabetes and were not currently taking
insulin therapy.9-10 Also excluded
were patients with type 1 diabetes who were deceased (n = 160), resided outside
New Jersey (n = 72), had sickle cell disease (n = 4), or were currently incarcerated
(n = 15). Of the remaining 875 patients eligible for the study, 725 (82.9%)
were enrolled, 38 (4.3%) could not be traced, and 112 (12.8%) declined to
participate.
PATIENT EXAMINATION AND FUNDUS PHOTOGRAPHY
Participants were examined in the eye clinic at University Hospital,
Newark. All patients signed an informed consent before being examined. Examination
consisted of a detailed structured interview that included patients' sociodemographic
factors, medical and ophthalmologic history, family history, diet, current
medications, and lifestyle variables (ie, self-report measures of cigarette
smoking and alcohol consumption). Weight and height were recorded. Blood pressure
was measured twice using a random zero sphygmomanometer following the Hypertension
Detection and Follow-up Program protocol.11
A detailed eye examination was performed, including subjective refraction
and best-corrected visual acuity using the Early Treatment of Diabetic Retinopathy
Study (ETDRS) protocol.12-13 Intraocular
pressure was measured by applanation tonometry and slitlamp examination of
the anterior segment checked for corneal abnormalities, depth of the anterior
chamber, and presence or absence of iris neovascularization. Pupils were then
dilated and lens changes graded at the slitlamp using the Third Lens Opacification
Classification System (LOCS III).14 Fundus
examination was performed using direct and indirect ophthalmoscopy, as well
as 90-diopter slitlamp examination. Lesions of diabetic retinopathy, including
presence of clinically significant macular edema and hard exudates, were noted.
Seven standard stereoscopic fundus photographs and red reflex (lens) of each
eye were obtained using a 30° Zeiss fundus camera (Carl Zeiss, Oberkochen,
Germany).15
LABORATORY EVALUATION
A nonfasting venous blood sample was obtained for measurement of blood
glucose using the hexokinase method, total glycosylated hemoglobin (hemoglobin
A1 and A2) using high-pressure liquid chromatography
(Bio-Rad, Labcorp Laboratory, Hercules, Calif), and plasma C-peptide using
a radioimmunoassay. Plasma high-density lipoprotein cholesterol (HDL-C) and
total cholesterol levels were measured using an enzymatic assay, and LDL-C
levels using separation spectrophotometry (Genzyme Diagnostics, Cambridge,
Mass).
A morning first-voided urine specimen collected at home by the patient
and a 4-hour timed urine specimen collected in the clinic were assayed for
creatinine level using the alkaline picrate method and for albumin using a
radioimmunoassay (SmithKline Beecham Clinical Laboratory, Philadelphia, Pa).
Creatinine level in the 4-hour timed urine collection was used to determine
adequacy of collection. Leukocyte-nitrite dipstick (Boehringer Mannheim Corporation,
Indianapolis, Ind) was used to exclude patients with urinary tract infection.
FUNDUS PHOTOGRAPHY GRADING
All fundus photographs were graded by the Fundus Photograph Reading
Center in Madison, Wis. First, a detailed field-by-field, lesion-by-lesion,
grading of each photographic set for each eye was performed using the ETDRS
adaptation of the modified Airlie House classification of diabetic retinopathy.15-16 Subsequently, a computer program
was used to analyze the detailed gradings and to derive a general retinopathy
level for each eye. In addition to the retinopathy severity level for each
eye (according to the ETDRS final scale), the severity of diabetic retinopathy
for the patient was determined from the grading of the worse eye.
Macular edema was considered present if any area of the retina within
1 disc diameter from the center of the macula was thickened with or without
loss of transparency. Gradings generated for macular edema, macular thickening
size, and center macular thickening were as follows: presence or absence of
macular edema was graded as 0, if none; 10, if questionably present; 20, if
1 disc area (DA) or more within 1 disc diameter from the center of the foveal
avascular zone; 30, if 1 DA or more or hard exudates with retinal thickening
less than or equal to 500 µ from the center of the foveal avascular
zone; and 80, if it could not be graded. Macular thickening size was graded
as 0, if none; 10, if questionable; 20, if less than DA; 30, if
DA or more but less than 1 DA; 40, if at least 1 DA but less than 2 DAs; 50,
if at least 2 DAs; and 80, if could not be graded. Center macular thickening
was graded as 0, if absent; 10, if questionable; 20, if less than 1 time the
reference thickness (twice the diameter of a major retinal vein at the disc
margin); 30, if less than 2 times the reference; 40, less than DA;
50, if at least 2 DAs; 70, if cannot grade because of poor stereophotographic
quality; 80, if it could not be graded. In patients who had either questionable
or no macular edema at the time of examination, review of all previous ophthalmologic
records was done to document any history of laser photocoagulation for macular
edema due to diabetes.
DEFINITIONS
Presence or absence of macular edema in each eye was determined from
the gradings of either macular edema and/or macular thickening size and/or
center macular thickening—absent, if 0 or 10 and no history of laser
photocoagulation for macular edema, and present, if either greater than 10
but less than 70 or history of photocoagulation for macular edema. Macular
edema grading in each eye was used when examining the relationship between
macular edema and ocular characteristics.
Macular edema for each patient was defined as absent, if in both eyes
grading of either macular edema, and/or macular thickening size, and/or center
thickening size was 0 or 10 and there was no history of laser photocoagulation
for macular edema, and as present, if in either eye grading of either macular
edema, and/or macular thickening size, and/or center thickening size was either
greater than 10 but less than 70 or history of photocoagulation for macular
edema. Eyes and patients with gradings of 70 and 80 were excluded from all
analyses.
Severity of retinopathy in the worse eye was classified as follows:
level 10, none; level 15, questionable retinopathy; levels 20-53, nonproliferative
retinopathy of increasing severity; and levels 61-85, proliferative retinopathy
of increasing severity.16 For patients who
could not be graded because of media opacities or phthisis but who had a history
of panretinal photocoagulation for proliferative diabetic retinopathy or pars
plana vitrectomy for diabetic tractional retinal detachment or vitreous hemorrhage
secondary to proliferative diabetic retinopathy, the retinopathy level was
85. Proliferative diabetic retinopathy was defined as ETDRS levels equal to
or greater than 61 or less than 61 with a history of panretinal photocoagulation.
Presence of retinal hard exudates in the macula in each eye was based
on the modified Airlie House classification scheme.16
Hard exudates were considered absent if they were either absent or questionable
in both eyes, and as present, if they were levels 2, 3, 4, or 5 in either
eye.16 Severity of hard exudates was classified
as absent if hard exudates were absent, questionable in both eyes, or level
2 in either eye, and classified as present, if they were levels 3, 4, or 5
in either eye.
Visual impairment was classified as absent if the best-corrected distance
visual acuity in the better eye was better than 20/40, and as present if less
than or equal to 20/40.8
The patients' current age was defined as the age at examination or the
age at onset of diabetes when the diagnosis was first recorded by a physician
in the patient's chart, and the duration of diabetes was defined as the time
between the two. Socioeconomic factors included patients' level of education
(for those aged  25 years), marital and employment status, personal income
(for those aged 18 years), and family income. To classify patients' socioeconomic
status, we used Goldthorpe and Hope Classification of Occupations, which divides
subjects into middle (levels 1 through 22) and lower (levels 23 through 36)
class based on the occupation of the head of the household, and the Green
index.17-19 Green
index scores were divided into tertiles (low, <53; middle, 53-61.1; and
high, >61.1). Current and past history of diuretic use was noted. Smoking
history was defined as either past or current smoking and number of pack-years.
Mean systolic and diastolic blood pressures were the average of 2 systolic
and 2 diastolic blood pressure measurements. Ocular perfusion pressure (PP)
in right and left eyes was calculated using mean diastolic (D) and systolic
(S) sitting blood pressures and intraocular pressure (IOP) using the following
formula: PP =  [D + (S - D) /3] - IOP. Patients were classified as having
atherosclerotic vascular disease if they had a history of myocardial infarction,
angina pectoris, leg or toe amputation, or stroke, as confirmed by review
of the medical records.
Renal disease was considered to be present if (1) the albumin-creatinine
ratio in either morning or 4-hour timed urine specimens was greater than 0.03,
(2) the albumin excretion rate in the 4-hour timed urine specimen was equal
to or greater than 20 µg/min, and/or (3) the patient was receiving dialysis
or had a renal transplantation for diabetic renal disease. Microalbuminuria
was classified as present if the albumin excretion rate was 20 through 200
µg/min, and macroproteinuria was classified as present if (1) the albumin
excretion rate was greater than 200 µg/min and/or (2) the patient was
receiving dialysis or had a kidney transplantation.
Patients were classified as currently receiving short- or long-acting
insulin or a combination. Information regarding glucose control during the
past year was recorded as follows: missing an insulin injection was defined
as "often" if at least once a week and as "none" if less than that; frequency
of home glucose urine testing was defined as "never" or "rarely" if performed
a few times a year, as "sometimes" if done once a month or some months per
year, and as "often" if done at least a few times a month per year; frequency
of home blood glucose testing was defined as "sometimes" if done not more
than once a week, and as "often" if performed at least a few times a week.
STATISTICAL ANALYSES
Data management and statistical analyses were performed using the Windows-based
SPSS statistical software (SPSS Inc, Chicago, Ill). Estimates of the proportion
of patients (number with macular edema or hard exudates/number patients) are
reported as a function of age at examination and duration of diabetes.
Association between the presence of macular edema (or hard exudates)
and hypothesized risk factors (including age, sex, duration of diabetes, age
at diagnosis of diabetes, systemic hypertension, glycemic control, presence
of proteinuria, socioeconomic status, and behavioral factors) was estimated
and tested for significance using logistic regression analysis. For dichotomous
variables, odds ratios (ORs) and corresponding 95% confidence intervals (CIs)
were used to quantify the association between presence or absence of macular
edema (or severity of hard exudates) and each risk factor. The statistical
significance of the associations are based on Wald tests. For categorical
variables with more than 2 categories, the ORs are presented for each level
of the risk factor compared with a reference level thought to represent the
lowest risk. Overall tests of association for these categorical variables
are based on Wald tests. All tests are 2-sided and use a .05 significance
level.
Descriptive analyses, including cross-tabulations, were performed to
identify potential confounders for the relationship between macular edema
(or severe hard exudates) and the various factors. Multiple logistic regression
was used to isolate the impact of specific risk factors by controlling for
the effect of potential confounders. The dependent variable in this regression
was the presence or absence of macular edema (or severe hard exudates). Models
including and excluding proteinuria were used. The generalized estimating
equation approach to logistic regression was also used in the multivariate
analysis to evaluate ocular variables for both eyes in relation to macular
edema and severe hard exudates.
RESULTS
MACULAR EDEMA
Frequency
Of the 725 African American patients, macular edema was present in at
least 1 eye in 89 (12.3%), questionable in 15 (2.1%), and could not be graded
in 12 (1.7%). Fundus photographs were not available in 1 patient who had a
documented history of focal laser photocoagulation for macular edema. Table 1 shows the frequency of macular
edema in right and left eyes of the 725 patients. At the time of examination,
57 patients had unilateral and 16 had bilateral macular edema. There were
47 right and 42 left eyes with clinically significant macular edema; of those,
25 right (53.2%) and 30 left (71.4%) eyes had foveal involvement, and 41 right
(87.2%) and 37 left (88.1%) eyes had no evidence of focal laser photocoagulation.
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Table 1. Frequency of Macular Edema in African Americans With Type
1 Diabetes
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Compared with patients without macular edema, those with macular edema
were significantly older (mean ± SD, 35.3 ± 9.3 years vs 27.3
± 10.8 years; t712 = 6.6, P<.001) and had longer duration of diabetes (17.0 ±
7.4 years vs 10.5 ± 9.2 years; t712
= 6.4, P<.001). Frequency of macular edema increased
from 2.5% in patients aged 15 to 19 years to 33.3% in those aged 45 years
or older (Figure 1). The frequency
of macular edema also increased with duration of diabetes from 1.0% in those
with less than 5 years of diabetes to 10.3% in patients with 10 years of diabetes
and to 25.4% in those with 20 years or more (Figure 2).
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Figure 1. Frequency of macular edema by
age at examination in African Americans with type 1 diabetes.
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Figure 2. Frequency of macular edema by
duration of diabetes in African Americans with type 1 diabetes.
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Relationship With Systemic Variables
After adjusting for duration of diabetes, men were on average 1.75 times
more likely to have macular edema than women (OR, 1.75; 95% CI, 1.10-2.79)
(Table 2). Patients with body
mass index (calculated as weight in kilograms divided by the square of height
in meters) of 25 or higher were on average twice as likely to have macular
edema than those with a body mass index less than 25 (OR, 1.96; 95% CI, 1.21-3.18).
Patients who missed their insulin injection at least once a week were also
1.8 times more likely to have macular edema than those who never missed their
injections (OR, 1.81; 95% CI, 1.13-2.90).
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Table 2. Systemic Factors Associated With Macular Edema in African
Americans With Type 1 Diabetes
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Patients with hypertension were on average 3.6 times more likely to
have macular edema than those who did not have hypertension (OR, 3.59; 95%
CI, 2.13-6.05), and those in the highest quartile of either systolic or diastolic
blood pressure were 3.5 times more likely to have macular edema than those
in the lowest quartile (OR, 3.52; 95% CI, 1.77-6.97, and OR, 3.49; 95% CI,
1.90-6.42, respectively) (Table 2).
Patients with microproteinuria were on average 4.6 times more likely to have
macular edema than those without proteinuria and those with macroproteinuria
were 11 times more likely (OR, 4.61; 95% CI, 2.07-10.24, and OR, 11.0; 95%
CI, 5.27-22.97, respectively) (Table 2).
Also, patients with evidence of peripheral vascular disease were on average
twice as likely to have macular edema than those without peripheral vascular
disease (OR, 2.39; 95% CI, 1.45-3.93).
There was no association between the presence of macular edema and age
at onset of diabetes, glycosylated hemoglobin, fasting blood glucose, and
blood C-peptide levels, frequency of a diabetic diet, number of insulin injections
per day, insulin type, daily insulin dose, frequency of blood or urine glucose
testing, diuretic use, or number of hospital admission or emergency department
visits for high blood glucose levels (data not shown). There was also no association
between presence of macular edema and education, personal or family income,
socioeconomic status, smoking, or alcohol consumption after adjusting for
duration of diabetes (data not shown).
Relationship With Ocular Variables
Eyes with macular edema had significantly more visual impairment ( 22 = 6.30, P<.04 and 22 = 5.95, P<.001, for right
and left eyes, respectively), and proliferative diabetic retinopathy (21 = 77.3, P<.001).
After adjusting for duration of diabetes, patients with higher ocular
perfusion pressure were on average twice as likely to have macular edema compared
with those with lower perfusion pressure (OR, 2.11; 95% CI, 1.15-3.86, and
OR, 2.16; 95% CI, 1.20-3.88, for right and left eyes, respectively). Patients
with a myopic refractive error of at least -2 diopter spherical equivalent
were at a higher risk for macular edema compared with those with a lower refractive
error (OR, 1.19; 95% CI, 0.62-2.28, and OR, 2.07; 95% CI, 1.15-3.71), for
right and left eyes, respectively). However, the association was only significant
for left eyes. There was no association between presence of macular edema
and intraocular pressure (data not shown).
Relationship With Blood Lipid Levels
Among the 660 patients without either dialysis or renal transplantation,
the mean total cholesterol was 5.38 ± 1.46 mmol/L (208.0 ± 56.5
mg/dL), mean HDL-C was 1.43 ± 0.47 mmol/L (55.2 ± 18.1 mg/dL),
and mean LDL-C was 2.84 ± 1.09 mmol/L (109.7 ± 42.0 mg/dL).
Of the 604 patients in whom both total and HDL-C values were available, 31.3%
had a total cholesterol–HDL-C ratio equal to or greater than 4.5.
After adjusting for duration of diabetes, patients in the highest quartile
of either total or LDL-C were on average 2 to 3 times more likely to have
macular edema (OR, 2.90; 95% CI, 1.36-6.17, and OR, 2.38; 95% CI, 1.12-5.05,
respectively) than patients in the lowest quartile (Table 3). Patients with a total cholesterol–HDL-C ratio of
4.5 or more were also at higher risk of having macular edema than those with
a ratio less than 4.5 (OR, 1.70; 95% CI, 1.01-2.88). There was no significant
association between HDL-C level and macular edema.
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Table 3. Association of Serum Lipids With Macular Edema and Hard Exudates
in African Americans With Type 1 Diabetes*
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Multiple Logistic Regression
In the multivariate analyses, presence of microproteinuria or macroproteinuria,
missing insulin injections at least once a week, and longer duration of diabetes
were significantly and independently associated with the presence of macular
edema (Table 4). When proteinuria
was excluded from the model, missing insulin injections at least once a week
and longer duration of diabetes were the only 2 variables significantly and
independently associated with macular edema. Male sex and LDL-C levels were
of borderline significance. The effect of high ocular perfusion pressure (>46
mm Hg) using the generalized estimating equation approach did not significantly
enhance prediction of macular edema.
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Table 4. Multivariate Relationships Between Macular Edema and Hard
Exudates With Various Characteristics of the Population
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RETINAL HARD EXUDATES
Frequency
Among the 725 patients, 149 (20.6%; 116 right and 105 left eyes) had
retinal hard exudates. Hard exudates could not be graded in 18 patients).
Frequency of hard exudates increased significantly with age from 18.9% in
those aged 20 to 29 years to 42.4 % in patients 45 years or older (25 = 70.4, P<.001) (Figure 3). Patients with hard exudates had
a significantly longer duration of diabetes than patients without hard exudates
(17.7 ± 8.5 years vs 9.5 ± 8.6 years; t693 = 10.4, P<.001). Frequency of hard exudates
increased from 1% in patients with less than 5 years of diabetes to 22.9%
in patients with 10 years of diabetes, and 43.2% in those with 30 years or
more (22 = 47.3, P<.001)
(Figure 4).
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Figure 3. Frequency of retinal hard exudates
by age at examination in African Americans with type 1 diabetes.
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Figure 4. Frequency of retinal hard exudates
by duration of diabetes in African Americans with type 1 diabetes.
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Relationship of Severity of Hard Exudates With Systemic Variables
After adjusting for duration of diabetes, men were on average twice
as likely to have severe retinal hard exudates than women (OR, 2.04; 95% CI,
1.27-3.28) (Table 5). Patients
with hypertension were on average twice as likely to have severe hard exudates
than those who did not have hypertension (OR, 2.24; 95% CI, 1.38-3.65; P <.001), and those in the highest quartile of either
systolic or diastolic blood pressure were 2 to 3 times more likely to have
severe hard exudates than those in the lowest quartile (OR, 2.31; 95% CI,
1.18-4.51, and OR, 3.78; 95% CI, 1.98-7.23, respectively). Patients with macroproteinuria
were 5 times more likely to have severe hard exudates than those without proteinuria
(OR, 5.04; 95% CI, 2.69-9.44). Patients in the upper 2 quartiles of glycosylated
hemoglobin values were 2 to 3 times more likely to have severe hard exudates
than those in the lowest quartile (OR, 2.73; 95% CI, 1.33-5.60, and OR, 2.92;
95% CI, 1.40-6.09, respectively). Also, patients with evidence of peripheral
vascular disease were on average 2 times more likely to have severe
hard exudates than those without peripheral vascular disease (OR, 2.40; 95%
CI, 1.45-4.0).
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Table 5. Systemic Factors Associated With Hard Exudates in African
Americans With Type 1 Diabetes
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There was no association between severity of hard exudates and body
mass index, diuretic use, frequency of a diabetic diet and of missing insulin
injections, daily insulin dose, education, family income, socioeconomic status,
smoking, or alcohol consumption (data not shown).
Relationship of Severity of Hard Exudates With Ocular Variables
Severity of hard exudates was significantly associated with presence
of either proliferative diabetic retinopathy (21
= 39.23, P<.001) or macular edema (21 = 252.7, P<.001). After adjusting
for duration of diabetes, patients with higher ocular perfusion pressure were
on average twice as likely to have severe hard exudates compared with those
with lower ocular perfusion pressure (OR, 1.70; 95% CI, 0.97-3.0, and OR,
2.08; 95% CI, 1.11-3.88, for right and left eyes, respectively). There was
no association between severity of hard exudates and visual impairment, refractive
error, or intraocular pressure (data not shown).
Relationship of Severity of Hard Exudates With Blood Lipid Levels
After adjusting for duration of diabetes, patients in the highest quartile
of either total or LDL-C levels were on average 5 to 6 times more likely to
have severe retinal hard exudates than those in the lowest quartile (OR, 6.75;
95% CI, 2.67-17.07, and OR, 5.30; 95% CI, 2.17-12.95, respectively) (Table 3). Patients with a total cholesterol–HDL-C
ratio of 4.5 or more were on average twice as likely to have severe hard exudates
compared with those with a ratio less than 4.5 (OR, 2.28; 95% CI, 1.34-3.90
(Table 3). There was no significant
association between severity of hard exudates and HDL-C.
Multiple Logistic Regression
In the multivariate analyses, variables significantly and independently
associated with the severity of hard exudates included presence of macroproteinuria,
male sex, higher blood LDL-C levels, and longer duration of diabetes (Table 4). When proteinuria was excluded
from the model, male sex, higher LDL-C levels, and longer duration of diabetes
remained significantly and independently associated with the severity of hard
exudates. Including ocular perfusion pressure in both eyes in the model using
the generalized estimating equation approach did not alter the results.
COMMENT
The results of this study indicate that frequencies of macular edema
(12.3%) and retinal hard exudates (20.6%) are high in hospitalized African
Americans with type 1 diabetes. Presence of macular edema is significantly
and independently associated with presence of proteinuria, missing insulin
injections at least once a week, and longer duration of diabetes. Severity
of hard exudates is significantly and independently associated with presence
of macroproteinuria, male sex, higher LDL-C levels, and longer duration of
diabetes.
This is the first study of the frequency of macular edema and retinal
hard exudates and associated risk factors among a large (N = 725) geographically
well-defined cohort of African Americans with type 1 diabetes. In this patient
population, frequency of macular edema (12.3%) is similar to the 11.1% reported
for whites with type 1 diabetes in the WESDR.3
In the Barbados Eye Study, 41.7% of the 12 patients with younger-onset diabetes
had clinically significant macular edema.20
Higher frequencies of macular edema have also been reported in clinic-based
studies of mostly white patients with diabetes, but these may not be representative
of the diabetic population.4, 21-23
African American patients with macular edema are at a higher risk of having
other retinal lesions, including proliferative diabetic retinopathy, as previously
reported for whites with type 1 diabetes.3
They also are at a higher risk of being visually impaired, consistent with
the fact that a large proportion of eyes (53.2% of right and 71.4% of left
eyes) with clinically significant macular edema at the time of examination
have foveal involvement, and 87% to 88% of them have not received focal laser
photocoagulation. In the WESDR in 1980-1982, 54.5% of patients with macular
edema present in at least 1 eye at the baseline examination and at the follow-up
visit had not received laser photocoagulation.24
In our patient population, macular edema is not seen in those younger
than 15 years, but its frequency in patients 45 years or older (33.3%) is
higher (but not statistically so) than the 26.1% reported among whites with
type 1 diabetes of the same age.3 Macular edema
is encountered after a relatively short (4 years) duration of diabetes, peaks
to 25.7% for those with 22 to 24 years of diabetes, and then levels off. This
again differs from white patients with type 1 diabetes in whom macular edema
is rare in the first 10 years of diabetes, but then increases steadily to
reach 32% in those with at least 30 years of diabetes.3
In our patients, severity of retinal hard exudates is strongly associated
with macular edema and severity of diabetic retinopathy as previously noted.4, 24-25 This is expected since
both lesions of diabetic retinopathy are considered to be the result of a
breakdown of the blood-retinal barrier.26 Like
macular edema, retinal hard exudates are encountered in African American patients
with a short (5 years) duration of diabetes.
In African Americans, the presence of proteinuria is strongly associated
with macular edema, an association we also reported in the same group of patients
in relation to proliferative diabetic retinopathy.27
This association is also found in cross-sectional, but not incidence, data
from the WESDR.3, 24-25
It may reflect coexisting advanced microangiopathy or represent fluid overload,
since renal transplantation and dialysis have been shown to reverse macular
edema in diabetic patients with proteinuria.28-29
In our patients, proteinuria is also strongly associated with severe retinal
hard exudates. African American patients with either macular edema or severe
hard exudates should be referred for evaluation of kidney function early on
so that they may benefit from therapies directed at improving renal function.30
In the present study, male sex is a strong risk factor for severe retinal
hard exudates. Men who have proteinuria are also at a higher risk for macular
edema. This association with male sex is consistent with our previously reported
data indicating that, among African Americans with type 1 diabetes, men are
a higher risk for both hypertension and renal disease than women, as well
as with data from other studies in white patients with diabetes.3, 27, 31
In our patients, missing insulin injections at least once a week is
the only variable indicating that poor glycemic control is associated with
macular edema. Specifically, there is no "threshold" glycosylated hemoglobin
value for either macular edema or severe hard exudates. This differs from
other studies in which higher glycosylated hemoglobin values are found in
patients with macular edema and may be due to the fact that 90% of our patients
have poor glycemic control or that factors other than poor glycemic control,
such as longer duration of diabetes or presence of renal disease, are more
important determinants of macular edema in our cohort.3, 24-25,31
Among our patients, those with high LDL-C levels are at a high risk
of having macular edema and severe retinal hard exudates, as found in white
patients with type 1 diabetes.5-6,32-33
While these diabetic lesions result from leakage of plasma and lipids from
retinal capillaries, lipid abnormalities in diabetic patients are also thought
to contribute to vascular endothelial damage.34
The relationship between LDL-C values and both macular edema and hard exudates
is of practical importance since lowering lipids either through diet or pharmacological
agents has a beneficial effect not only in preventing development of hard
exudates but also in reducing hard exudates already present, although this
is not always associated with improvement in visual acuity.35-38
In our patient population, total and HDL-C levels are high compared with previous
reports in white diabetic patients, and HDL-C levels are also higher than
in African Americans without diabetes.39-40
However, neither total nor HDL-C levels are significantly associated with
either macular edema or severe hard exudates on multiple regression analysis,
as previously found in whites with type 1 diabetes in relation to hard exudates.5
In our patients, frequency of macular edema and hard exudates may have
been underestimated because these changes were graded from stereoscopic fundus
photographs, which have been shown to be less sensitive than slitlamp biomicroscopy
in evaluating macular edema.41 They may also
have been overestimated since patients were recruited from among hospital
admissions and may thus have more severe diabetes than the diabetic population
at large. Finally, results of this study may have been affected by selective
mortality of patients with renal disease, leading us not to find previously
reported associations.42
In summary, our data indicate that in African Americans with type 1
diabetes macular edema and retinal hard exudates occur early on in the disease
and are strongly associated with the presence of renal disease and longer
duration of diabetes and to a lesser degree with male sex and higher LDL-C
values. Longitudinal studies, however, are needed to further clarify the relationship
between these lesions of diabetic retinopathy and presence of renal disease
in this patient population.
AUTHOR INFORMATION
Accepted for publication June 16, 2000.
This study was supported by grant RO1 EY09860 from the National Eye
Institute, Bethesda, Md.
We thank Michael Parides, PhD, Division of Biostatistics, Joseph L.
Mailman, School of Public Health, Columbia University, New York, NY, for statistical
help; Lisa Schoenherr, study coordinator, for technical assistance; Robert
Nelson and Jim Besra, MPH, research assistants; Clara Baker for secretarial
help; the New Jersey Department of Health; and the 31 New Jersey hospitals
that participated in the study.
Corresponding author and reprints: Monique S. Roy, MD, University
of Medicine and Dentistry, New Jersey Medical School, Department of Ophthalmology,
90 Bergen St, Room 6164, Newark, NJ 07103.
Monique S. Roy, MD;
Ronald Klein, MD, MPH
From the Department of Ophthalmology, University of Medicine and Dentistry,
New Jersey Medical School, Newark (Dr Roy); and University of Wisconsin, Department
of Ophthalmology, Madison (Dr Klein).
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