2.4.1.1 Baseline Characteristics
Electronic records of 2051 appointments were screened, and 1298 unique
attendances identified. 821 patients attended for assessment of diabetic eye disease, of which, 767 patients had Type 2 diabetes. The male to female ratio was 5:4, and mean age was 64.2 years (SD: 12.6). Of the patients with Type 2 diabetes, 488 met the inclusion criteria for fluorescein angiography. In these cases, an attempt was made to grade both eyes for severity of DMI: in 401 patients, FA images were of sufficient quality to allow DMI grading in both eyes; in a further 52 patients, DMI grading was possible in a single eye only. In 35 patients, FA images were of
insufficient quality to permit grading of DMI in either eye. Forty-five patients were then excluded due to the presence of ocular co-morbidities. In total, 408 eyes from 408 patients were included in the analysis (Table 2.1). For this assessment of DMI severity, substantial inter-grader agreement was demonstrated, with a weighted kappa of 0.704. (SE: 0.087, 95% CI: 0.535 to 0.874).
2.4.1.2 Symmetry of Disease:
Within the 401 patients where both eyes were gradable, 62.1% had bilaterally symmetrical macular ischaemia. The difference in grade between the asymmetrical eyes was as follows: no more than one grade in 26.7% of patients, two grades in 8%, three grades in 3%, and four grades in 0.2%. Where there was symmetrical disease, one eye was randomized for analysis. In asymmetrical disease (37.9%), the eye with the most severe DMI grade was selected.
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2.4.1.3 Prevalence of Diabetic Macular Ischaemia:
Overall prevalence and severity of diabetic macular ischaemia by ETDRS-DMI grade:
In the 408 eyes analysed, 39.7% had none, 18.4% questionable, 25.2% mild, 11%
moderate, and 5.6% had severe ETDRS-DMI grades.
Table 2.1: Patient demographics and clinical characteristics of patients (type 2 diabetes) with and without diabetic macular ischaemia.
No DMI
Retinopathy Grades DMI:No DMI (n=408)
No Diabetic Retinopathy
DMI = Diabetic Macular Ischaemia; NPDR = Non-Proliferative Diabetic Retinopathy; PDR=
Proliferative Diabetic Retinopathy; DME = Diabetic Macular Oedema; CSME = Clinically Significant Macular Oedema; SD = Standard Deviation; IQR = Interquartile range
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Prevalence of DMI (by ETDRS grade) within different severity grades of retinopathy and maculopathy (Table 2.1): In eyes with proliferative diabetic
retinopathy (PDR) (both treated and untreated), concurrent DMI was seen in 77.2%
of cases (in 22.8% of cases, DMI was not present). The occurrence of DMI was similar across all other grades of non-proliferative diabetic retinopathy (NPDR), and in
patients without diabetic retinopathy (i.e., R0 in the NSC grading system). In eyes with clinically significant macular oedema (CSME), concurrent DMI was seen in 69.4% of cases (in 30.6% of cases, therefore, no DMI was observed). In eyes with DME, but without CSME, concurrent DMI was seen in 55.8% of cases (in 44.2% of cases, DMI was not present). An increase in the proportion of eyes with DMI in relation to eyes with no DMI, expressed as the “DMI : No DMI” ratio, was seen in patients with severe NPDR and PDR, and across all maculopathy grades. Table 2 shows the distribution of eyes between different grades of retinopathy and maculopathy in the presence or absence of DMI.
Increasing FAZ area with ETDRS-DMI severity grades (Figure 2.6): As expected, the median FAZ area increased with grade of ETDRS-DMI severity, and ranged from 0.19 mm2 (interquartile range (IQR): 0.13 to 0.25) in eyes with ETDRS-DMI grade:
none, to 0.78 mm2 (IQR: 0.60 to 1.32) in eyes with ETDRS-DMI grade: severe. (Figure 2.6) Highly significant differences in median FAZ area were seen across all subgroups of DMI, with the exception of “questionable” versus “mild” DMI. Median FAZ area was significantly correlated with ETDRS DMI severity grade (r=0.477, p<0.001). (Table 2.2)
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Figure 2.6. Distribution of diabetic macular ischaemia grades
Box-plots of FAZ Area (mm2) in different Early Diabetic Treatment Retinopathy Study (EDTRS) grades of Diabetic Macula Ischaemia (DMI) – None, Questionable, Mild, Moderate, and Severe. The top of the box represents the 75th percentile, the bottom of the box represents the 25th percentile, and the line in the middle represents the 50th percentile. The whiskers represent the highest and lowest values that are not outliers or extreme values. Outliers and extreme values are represented by circles beyond the whiskers.
Prevalence of temporal and/or papillomacular ischaemia: Temporal ischaemia was seen in 112 eyes (27.5%), while papillomacular ischaemia was seen in 34 eyes (8%). Both temporal and papillomacular ischaemia were most prevalent in higher ETDRS-DMI grades. This was most notable for temporal ischaemia, which was present in 87% of eyes in the severe subgroup, as compared to 6.2% of eyes in without DMI.
Papillomacular ischaemia was also more frequently seen in the ETDRS-DMI severe subgroup (34.8% of eyes with severe vs. 10.7% of eyes with mild ETDRS-DMI grade).
2.4.1.4 Visual Significance of Macular Ischaemia:
Relationship between visual acuity and ETDRS-DMI severity Grade (Table 2.2):
Median logMAR visual acuity (VA) was 0.2 (IQR: 0 to 0.3) (Snellen 20/32) in eyes with
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none, 0.2 (IQR: 0 to 0.5) (Snellen 20/32) in eyes with questionable, 0.2 (IQR: 0.2 to 0.5) (Snellen 20/32) in eyes with mild, 0.5 (IQR: 0.2 to 0.6) (Snellen 20/63) in eyes with moderate, and 0.6 (IQR: 0.3 to 0.8). (Snellen 20/80) in eyes with severe ETDRS-DMI grades. Significant differences in VA were observed between moderate and severe ETDRS-DMI versus all other grades (Table 2.3). Overall, VA showed a weak but highly significant correlation to ETDRS grading of DMI severity (rho=0.22, p<0.001).
Table 2.2: Comparing Median FAZ Area (mm2) between all Diabetic Macula Ischaemia subgroups.
DMI Subgroups
p-values None Questionable Mild Moderate Severe
None
Questionable <0.001**
Mild <0.001** 0.18
Moderate <0.001** <0.001** 0.002**
Severe <0.001** <0.001** <0.001** <0.001**
DMI= Diabetic Macular Ischaemia; p values significant at 5% level are indicated with (*), and (**) at 1% level.
Relationship between FAZ size and visual acuity (Table 2.3): Overall, we found no evidence any correlation between VA and FAZ area (mm2) (rho=0.061, p=0.219).
However, when the data were stratified by severity of ischaemia, quantile regression models revealed a statistically significant association between VA and FAZ area (mm2) in all quantiles for eyes with moderate and severe ETDRS-DMI grades (Table 2.4, Figure 2.7). Severe DMI showed the strongest association with quantile regression coefficient, β = 0.406; SE 0.101, (p<0.001), at the 50th percentile. In moderate DMI, the greatest association was also observed at the 50th percentile, β = 0.299; SE 0.108, (p<0.006). The effects of FAZ area on VA on moderate and severe ETDRS-DMI grades for different quantiles are summarized in Table 2.5 and Figure 2.7A and B. No
relationships were observed between VA and FAZ area for milder grades of ischaemia.
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Table 2.3: Comparing Median Visual Acuities (LogMar) between all Diabetic Macula Ischaemia subgroups.
DMI Grade None Questionable Mild Moderate Severe
P value for VA None
Questionable 0.651
Mild 0.143 0.527
Moderate <0.001** 0.02* 0.03*
Severe <0.001** <0.001** <0.001** 0.04*
DMI= Diabetic Macular Ischaemia; p values significant at 5% level are indicated with (*), and (**) at 1% level.
Relationship of temporal and papillomacular ischaemia with visual acuity (Table 2.4): We investigated whether papillomacular and temporal ischaemia had a significant impact on VA after adjustment for FAZ area. A higher than expected association was observed in papillomacular ischaemia at the 25th, 50th, 75th and 90th quantile regression lines (Table 2.5, Figure 2.7). Thus, papillomacular ischaemia has an impact on VA independent of FAZ size. This effect was maintained after adjusting for potential confounders such as DME (Table 2.6). No relationship was observed with temporal ischaemia.
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Table 2.4: Association between Visual Acuity and Foveal Avascular Zone area (mm2) stratified by EDTRS Diabetic Macular Ischaemia severity grades for five different Quantiles.
10th Quantile 25th Quantile 50th Quantile 75th Quantile 90th Quantile Adjusting for age, (continuous variable) gender, retinopathy grade, and the presence of macular
oedema (categorical variable)
Coefficient (β) and standard error (SE) are reported for 10%, 25%, 50%, 75%, and 90%. Coefficients that are significant at 5%
level are bold, and those at the 1% level are bold and underlined. p values significant at 5% level are indicated with (*), and (**) at 1% level. Standard errors are obtained using 1000 bootstrap replications.
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Table 2.5: Association between Visual Acuity and area of Papillomacular or Temporal ischaemia (mm2) for five different Quantiles after adjusting for Foveal Avascular Zone area (mm2) as a co-variate.
10th Quantile 25th Quantile 50th Quantile 75th Quantile 90th Quantile Adjusting for gender, retinopathy grade, the presence of macular oedema (categorical variables) and
age, FAZ area (mm2) (continuous variables) Area of
Coefficient (β) and standard error (SE) are reported for 10%, 25%, 50%, 75%, and 90%. Coefficients that are significant at 5%
level are bold, and those at the 1% level are bold and underlined. p values significant at 5% level are indicated with (*), and (**) at 1% level. Standard errors are obtained using 1000 bootstrap replications.
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Table 2.6: Multivariable median regression between Visual Acuity and Area of Papillomacular ischaemia (mm2) adjusting for Foveal Avascular Zone area (mm2) and other clinical co-variates.
Median Regression
coefficient
Standard Error p-value
Papillomacular ischaemia 1.123 0.341 0.004**
Foveal Avascular Zone Area 0.178 0.259 0.501
Gender 0.17 0.162 0.291
Age 0.01 0.012 0.401
Diabetic Macular Oedema
No DME 0.193 0.271 0.485
Clinically Significant DME 0.310 0.485 0.530
Treated clinically significant
DME 0.106 0.252 0.679
The median regression coefficient is reported with standard errors obtained using 1000 bootstrap replications. Coefficients that are significant at 5% level are bold, and those at the 1% level are bold and underlined. p values significant at 5% level are indicated with (*), and (**) at 1% level.
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Figure 2.7. Relationship between visual acuity and ischaemia
(a) Line plot of quantile regression coefficients (vertical dotted line represents the median regression coefficient) of Visual Acuity with Foveal Avascular Zone area (mm2) in the
moderate (dotted line) and severe (solid line) subgroups of diabetic macular ischaemia (DMI), after adjustment for age, gender, retinopathy grade and the presence of diabetic macular oedema. (b) Line plot of quantile regression coefficients (vertical dotted line represents the median regression coefficient) of Visual Acuity with Papillomacular and Temporal ischaemia area (mm2), after adjustment for age, gender, retinopathy grade, the presence of diabetic macular oedema and Foveal Avascular Zone area (mm2).