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(Investigative Ophthalmology and Visual Science. 2007;48:3983-3987.)
© 2007 by The Association for Research in Vision and Ophthalmology, Inc.
DOI:  10.1167/iovs.06-1102
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Progression of Diabetic Macular Edema: Correlation with Blood–Retinal Barrier Permeability, Retinal Thickness, and Retinal Vessel Diameter

Birgit Sander,1 Dorte Nellemann Thornit,1 Lotte Colmorn,1 Charlotte Strøm,1 Aniz Girach,2 Larry D. Hubbard,3 Henrik Lund-Andersen,1 and Michael Larsen1

1From the Department of Ophthalmology, Glostrup Hospital, University of Copenhagen, Denmark; the 2Lilly Research Labs, Eli Lilly and Company, Surrey, United Kingdom; and the 3Department of Ophthalmology and Visual Sciences, University of Wisconsin-Madison, Madison, Wisconsin.


   Abstract
Top
 Abstract
Methods
 Results
 Discussion
 References
 
PURPOSE. To study the progression of diabetic macular edema (DME) in relation to baseline retinal thickness, retinal vascular leakage, and retinal trunk vessel diameters.

METHODS. In this single-center study, 45 patients were enrolled with 62 eligible eyes defined as having DME of a grade less than clinically significant macular edema (CSME). From the start, the patients were included in a multicenter study exploring the effect of ruboxistaurin versus placebo for 3.4 years. Subsequently, the patients were followed up for a mean of 5.7 years by optical coherence tomography, fundus photography, and vitreous fluorometry. Baseline values in eyes that progressed to photocoagulation treatment were compared with values from eyes that did not reach this endpoint.

RESULTS. In the 22 eyes of 18 patients in which CSME was diagnosed and treated, mean retinal vascular leakage at baseline was 5.6 (95% CI 4.2–7.6) nm/s, whereas eyes that did not progress to photocoagulation had a significantly lower mean leakage at baseline of 3.4 (95% CI 2.7–4.3) nm/s. No significant difference was found for measures of baseline retinal thickness or summarized retinal trunk vessel diameters. Eyes that progressed to photocoagulation treatment (mean delay to treatment, 3.6 years) had significantly higher foveal thicknesses than did nonprogressing eyes, from 18 months after study initiation.

CONCLUSIONS. Progression to photocoagulation treatment for CSME was associated with higher retinal vascular leakage at baseline, whereas baseline retinal vessel diameters and retinal thickness were comparable in progressing and nonprogressing eyes. Baseline leakage was the strongest predictor of progression from non-CSME to photocoagulation for CSME.

Diabetic macular edema (DME) usually begins as smaller areas of edema that do not involve the fovea, from which it can progress to stages that threaten or manifestly involve the center of the macula. The Early Treatment of Diabetic Macular Edema (ETDRS) defined a threshold for photocoagulation treatment, clinically significantly diabetic macular edema (CSME) that has become an important guideline for intervention in clinical practice. Retinal thickness is usually evaluated by stereoscopic biomicroscopy or fundus photography.1 2 Objective assessment of retinal thickness by optical coherence tomography (OCT) correlates with stereoscopic assessment of edema.3 Mechanistically, the relation between retinal vascular leakage of fluorescein and retinal thickening is of interest, and vitreous fluorometry has demonstrated higher leakage in CSME than in lesser grades of DME.4 5 Also of interest is the relation between changes in retinal vessel diameters and retinal thickening.6 7 The temporal relation between the various aspects of dysfunction and thickening has not been described in detail, and it remains uncertain whether increased leakage precedes, accompanies, or follows retinal thickening. In the present study, we examined retinal fluorescein leakage and retinal thickness and summarized retinal trunk vessel diameters prospectively in patients with DME of less than CSME grade at baseline. The data evaluated in this study were acquired from a placebo-controlled study of pharmacologic protein kinase C ßII inhibition using an orally administered PKC ßII-inhibitor, ruboxistaurin mesylate (LY333531).8 9


   Methods
Top
 Abstract
 Methods
Results
 Discussion
 References
 
Subjects
The study enrolled 74 eyes in 54 patients with DME in at least one eye in a randomized controlled multicenter trial of ruboxistaurin (4, 16, or 32 mg/d) versus placebo. Nine patients failed to complete the study: three patients died (one of cardiovascular disease, two of cancer), five patients withdrew their consent for reasons unrelated to the study. One patient suffered an adverse event (skin rash) and was withdrawn from the study. These withdrawals left 62 eyes in 45 patients for analysis. The study population comprised 15 women and 30 men, of whom 13 had type I and 32 had type II diabetes.

This study was a single-center extension of the multicenter trial. The patients were examined at 3-month intervals until the final visit of the study. The time to the final study visit was longer the earlier the date of enrollment and ranged from 2.8 to 4.3 years (mean, 3.4) depending on the time of inclusion. At the final visit, the study medicine was discontinued. Vitreous fluorometry, retinal thickness, and fundus photographic retinal vessel caliber measurements were performed at baseline, 12 and 18 months, and the final visit.

After the last study visit, all patients were examined clinically every 3 months until follow-up closed or, if macular edema was not found or clearly not approaching CSME grade, the patient was followed up at our fundus photographic screening unit at comparable intervals. All events of CSME were diagnosed by the same ophthalmologists. An overview of the examinations is given in Table 1 .


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  		TABLE 1. Outline of Scheduled Examinations in Study of Patients with Non-CSME at Baseline

 
Informed consent was obtained from all patients before they entered the study, which was conducted according to the ICH-Guidelines for Good Clinical Practice (ICH GCP) and the Declaration of Helsinki and was approved by the Danish Medicines Agency and regional medical ethics committee. Ocular eligibility was defined as presence of ≥1/6 disc area (DA) of definite retinal thickening within 2 disc diameters (DD) of the center of the macula and ETDRS severity of retinopathy level ≤47A, as determined by stereoscopic fundus photograph grading.2 Ocular ineligibility was defined as presence of CSME, except that retinal thickening or hard exudates adjacent to retinal thickening at/or within 500 µm but no closer than 300 µm from the fovea was allowed if visual acuity was ≥75 ETDRS letters.8

Study Design
The present study is an exploratory investigation of blood–retinal barrier permeability, retinal thickness, and retinal vessel measurements to elucidate the development of macular edema. The advent of CSME was defined as DME severe enough to necessitate macular photocoagulation, as determined by clinical evaluation based on ETDRS criteria.

Retinopathy
The level of retinopathy was graded on seven-field 40° standard color stereo fundus photographs by the Wisconsin Reading Center (University of Wisconsin, Madison, WI). The study included diabetic retinopathy of ETDRS grading levels 35, 43, and 47 at baseline.

Blood–Retinal Barrier Permeability
Using vitreous fluorometry, the leakage of fluorescein into the vitreous was measured with a fluorometer (Ocumetric, Mountain View, CA) at 30 and 60 minutes after fluorescein injection, as described earlier. In brief, the permeability of the blood–retinal barrier was calculated after correction for light loss in the lens, plasma concentration of fluorescein and the diffusion coefficient for fluorescein in the vitreous. In healthy control subjects, the permeability has been found to be ~2 nm/sec (SD 0.5).10 11 12 13 In diabetic patients, the permeability increases correlated with the level of retinopathy and edema, and in diabetic eyes with CSME the permeability in an earlier study with the same method was increased by a factor of 5 (mean, 11.3 nm/sec; 95% CI 9–15).5 Vitreous liquefaction or posterior vitreous liquefaction10 interferes with the calculation of blood–retinal barrier permeability, and in a few eyes passive permeability could not be calculated.14

Retinal Thickness
Six radial line scans of 6 mm were obtained with optical coherence tomography (model 2000, OCT2; Carl Zeiss Meditec, Inc., Dublin, CA). The software of the instrument could not produce retinal maps calculating mean thickness of specified regions. Thus, the retinal thickness from the six scans were calculated by the algorithm of the original software, and the retinal thickness was averaged off-line for three regions: the foveal region with a 500 µm radius from the center, an inner ring from 500 to 1500 µm from the center and an outer ring from 3000 to 6000 µm from the center. The outer ring was not available at baseline for eight eyes.

Calibers of Retinal Arteries and Veins
Vascular diameter was determined using computerized image analysis software enabling manual definition of the endpoints for analysis of a given retinal vascular segment.6 Vascular contour tracing was avoided near vascular crossings and branchings, near hard exudate and cotton wool spots, and near strong reflexes from the posterior hyaloid. To allow precise tracking near the ends of the selected segments, the tracking was extended beyond the target segment for a standard length of 40 pixels, so as to provide supporting extrapolation landmarks. This corresponds to about twice the diameter of a large retinal vein at the rim of the optic disc. Vessel calculation was performed in only one eye for each patient and only if image quality was of sufficient quality for the procedure. Right eyes were preferred if photographs of comparable image quality were available for both eyes.

Statistics
For the present analysis, the following visits were included: baseline, 12, 18 and ~3.4 years (all these visits within the ruboxistaurin study), 3.8 years after ruboxistaurin medication and the final follow-up with a mean of 5.7 years. A Cox regression model was used for modeling the hazard for the event of CSME with the inclusion of various covariates: baseline values of HbA1c, mean blood pressure, blood–retinal barrier permeability, retinal thickness, and vessel diameters. The Cox model includes the specific time for examinations and allows interval censoring, meaning that the assumptions for the model do not include that the exact time of the event is known. The model formulation calculates the hazard based on the log of the time variables (complementary log–log model), which is time since baseline and the interval between visits. For all results, the time since baseline, interval since last visit and treatment (placebo or active treatment) during the ruboxistaurin part of the study were included, a correction was included for the nonindependence between eyes.

Remaining covariates were entered in a forward procedure and only maintained if significant at a 5% level. The blood–retinal barrier permeability was log transformed due to a non-normal distribution or entered as a class variable; all other covariates were entered in the original scale. If no other test is mentioned, the appropriate t-tests were used to compare variables between groups. Data analysis was performed with commercial software (SAS software package, ver. 8e; SAS Institute, Cary, NC); the genmod procedure was used for the Cox model. The level of statistical significance for all tests was set at 5%.

Results for the effect of ruboxistaurin on the same study population have been presented in an earlier paper,9 for permeability data a difference of two eyes between the present paper and the previous is due to the event of early photocoagulation which were excluded in the previous paper. However, an exclusion would not be appropriate for the present study.


   Results
Top
 Abstract
 Methods
 Results
Discussion
 References
 
Of 62 eyes in 45 patients that completed follow-up, 22 eyes in 18 patients had received photocoagulation for CSME between baseline and the last follow-up examination (Tables 1 2) . Of these 22 eyes, 12 eyes in 12 patients underwent photocoagulation treatment during the 3.4-year duration of the interventional study, the treatment being performed within 18 months of baseline in four eyes in four patients. The mean follow-up in the 40 eyes that did not undergo photocoagulation was 5.5 (SD 1.1; range, 3.5–7.3) years. For treated patients, the mean period of observation between baseline and the first photocoagulation session in the first eye was at 3.6 (SD 2.0; range, 0.4–7.3) years.


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  		TABLE 2. Baseline Systemic Characteristics of Patients with Non-CSME DME in Relation to Outcome: No Photocoagulation or Photocoagulation for DME

 
HbA1c decreased during the study, from 9.3 at baseline to 8.7 at the last visit (P = 0.004) in the 28 cases with a >5-year follow-up, whereas the mean blood pressure increased, but not significantly, from 99.9 to 101.6 mm Hg (P = 0.55).

Comparison of baseline values demonstrated that the mean leakage of 5.6 (95% CI 4.2–7.6) nm/s in eyes that progressed to CSME and photocoagulation was significantly higher than the mean leakage of 3.39 (95% CI 2.7–4.3) nm/s in eyes that did not progress (P = 0.01; Table 3 ).


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  		TABLE 3. Ocular Characteristics in Eyes with Non-CSME DME at Baseline in Relation to Outcome: No Photocoagulation or Photocoagulation for DME

 
The difference was sustained at the 12- and 18-month follow-up (Table 3) . Differences at baseline between the two groups in retinal thickness, central retinal artery equivalent diameter, central retinal vein equivalent diameter, HbA1c, and mean arterial blood pressure were numerically small and did not reach statistical significance (P > 0.1; Table 3 ).

The increase in retinal thickness that led to the diagnosis of CSME and photocoagulation treatment was detectable 18 months after baseline (analysis excluding the four eyes that had undergone photocoagulation at this time; Table 3 ). The difference was modest in the foveal field (P = 0.06) and significant for the inner perifoveal ring (P = 0.04).

The statistical effects of age, gender, duration of diabetes, HbA1c, and blood pressure were evaluated with a Cox proportional hazards model. The basic model incorporated time from baseline, interval between visits, and a correction factor for the effect of ruboxistaurin treatment. Although the effect of treatment was nonsignificant, it was considered an essential explanatory variable of the statistical model because it was given for approximately half of the study period and because larger studies have shown benefit of treatment in DME. The conclusion was unaltered, whether treatment was included or excluded from the analysis. Baseline blood–retinal barrier permeability was found to be significant, both as a continuous variable and as a class variable. The hazard ratio for eyes with permeability higher than 3.6 (median of baseline value) nm/s was 6.2 times (95% CI 1.7–23.2; P = 0.0043) higher than that of eyes with baseline permeability lower than or equal to 3.6 nm/s. Setting the threshold for binary division to 2.98 nm/s, which is the upper range limit of leakage seen in healthy subjects (mean plus 2 SD), the hazard ratio was 13.7 (95% CI 1.7–111; P = 0.0022).10 No contributory value in outcome modeling was found for blood pressure, HbA1c, or retinal thickness. Not surprisingly, all measures of retinal thickness at 18 months, when significant thickening of the group of progressing eyes relative to the group of nonprogressing eyes had occurred, were found to be predictive of the outcome photocoagulation for CSME (P = 0.02 or lower).

Treatment with ruboxistaurin had no statistically significant effect on the rate of progression to photocoagulation treatment during or after the controlled intervention. Baseline ETDRS retinopathy levels ranged from 35 to 47 (27 eyes at level 35, 24 eyes at level 43, and 10 eyes at level 47). Baseline permeability was significantly correlated with baseline retinopathy level (P = 0.001, analysis of variance). Baseline retinopathy was not independently significant for the outcome of photocoagulation (P > 0.2). The lack of significance was probably due to the less sensitive semiquantitative scale of retinopathy compared with the permeability, which is measured on a quantitative scale and more closely related to the pathophysiology of macular edema.


   Discussion
Top
 Abstract
 Methods
 Results
 Discussion
References
 
Diabetic macular edema develops slowly and although systemic risk factors for development and progression of DME are known (increasing duration of diabetes, increasing HbA1c and, possibly, increasing arterial blood pressure), these factors, alone or combined, permit no certain prediction of which eyes will progress from retinopathy without edema to DME or from lesser grades of DME to CSME.

In the present study, we followed eyes with nonclinically significant DME for up to 7 years. In eyes that eventually progressed to CSME, blood–retinal barrier permeability increased significantly from baseline through month 18. In contrast, retinal thickness was comparable between nonprogressing and progressing eyes, from baseline and up to month 18. Retinal artery and vein diameters were comparable in nonprogression and progressing eyes from baseline through month 18 and up to the final study visit.

The use of fluorescein angiography and in particular the quantitative assessment of leakage with vitreous fluorometry have diminished in recent years due to the introduction of noninvasive measurement of retinal thickness and retinal vessel diameters. However, the results of the present study indicate that the initial stages of edema formation is related to basic mechanisms of the blood–retinal barrier while morphologic changes are later events and the reluctance to use invasive fluorescein angiography and related quantitative methods may lead to an incomplete understanding of the underlying mechanisms of edema progression.

Age, duration of diabetes, HbA1c and arterial blood pressure failed to reach statistical significance as predictors of progression to photocoagulation (Cox's regression model), leaving blood–retinal barrier leakage as the only significant factor, the hazard ratio being 6.3 times higher for leakage values above 3.6 nm/s than for values lower than or equal to 3.6 nm/s (median of baseline values). The present study is not ideal, as it included an intervention study in the initial stage. To correct for this, the analysis included correction for the potential effects of the experimental intervention during the first 3.4 years of the study (ruboxistaurin 4, 16, or 32 mg/d versus placebo, 25% allocated to placebo) during the first 3.4 years of the study. Half of the progressing eyes progressed within the duration of the study.

The lack of significance of ruboxistaurin is not in contrast to the positive effect of treatment found in relevant subgroups of the main study8 as the number of patients in the present substudy was small and the power thus insufficient. However, permeability seems to be a sensitive parameter, as a previous paper based on the same population as in the present substudy showed that ruboxistaurin treatment interacted significantly with baseline permeability (i.e., permeability decreased during the treatment time in eyes with high baseline permeability).9 Thus, the time to progression to photocoagulation may have been prolonged in treated eyes with high baseline permeability and, as mentioned, a correction for treatment was incorporated in the calculation of the hazard.

The observation that between-baseline leakage rather than baseline retinal thickness predicted a strongly thickness-related outcome—namely, photocoagulation for CSME—is surprising. It suggests that no simple relation exists between blood–retinal barrier leakage and retinal edema. In agreement with this, we have found indications that the rate of elimination of fluorescein from the retina is upregulated in concert with the increased retinal vascular leakage in diabetic retinopathy.4

Additional factors that need to be considered are the barrier effects of various retinal layers, and the effects of abnormalities in intraretinal hydrostatic and colloid osmotic pressure in DME. In addition, the role of aquaporins and the expansibility of the retinal layers may be relevant in the formation and localization of edema.

In conclusion, we have identified blood–retinal barrier leakage as a significant risk factor for the progression of lesser grades of DME to photocoagulation for CSME. Retinal thickening was markedly delayed in relation to the increase in leakage and first found to statistically significant 18 months after the baseline examination had revealed increased blood–retinal barrier permeability.


   Footnotes
 
Supported by Eli Lilly and Company, the Danish Eye Health Society, The Danish Diabetes Society, the VELUX Foundation, and Patient-Oriented Diabetes Research Career Award 8-2002-130 from the Juvenile Diabetes Research Foundation (ML).

Submitted for publication September 14, 2006; revised February 5, 2007; accepted June 25, 2007.

Disclosure: B. Sander, Eli Lilly (F); D.N. Thornit, Eli Lilly (F); L. Colmorn, Eli Lilly (F); F.C. Strøm, None; A. Girach, Eli Lilly (E); L.D. Hubbard, Eli Lilly (F); H. Lund-Andersen, Eli Lilly (F, R, C); M. Larsen, Eli Lilly (C)

The publication costs of this article were defrayed in part by page charge payment. This article must therefore be marked "advertisement" in accordance with 18 U.S.C. §1734 solely to indicate this fact.

Corresponding author: Birgit Sander, Department of Ophthalmology, Glostrup Hospital, Nordre Ringvej 57, DK-2600 Glostrup, Denmark; bisan{at}glo.regionh.dk.


   References
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 Abstract
 Methods
 Results
 Discussion
 References
 

  1. Klein R, Klein BE, Moss SE, Davis MD, DeMets DL. The Wisconsin epidemiologic study of diabetic retinopathy. IV. Diabetic macular edema. Ophthalmology. 1984;91(12)1464–1474.[ISI][Medline][Order article via Infotrieve]
  2. Early Treatment Diabetic Retinopathy Study Research Group. Grading diabetic retinopathy from stereoscopic color fundus photographs-an extension of the modified Airlie House classification. ETDRS report number 10. Ophthalmology. 1991;98(suppl 5)786–806.[ISI][Medline][Order article via Infotrieve]
  3. Strom C, Sander Laren N, Larsen M, Lund-Andersen H. Diabetic macular edema assessed with optical coherence tomography and stereo fundus photography. Invest Ophthalmol Vis Sci. 2002;43(1)241–245.[Abstract/Free Full Text]
  4. Sander B, Larsen M, Moldow B, Lund-Andersen H. Diabetic macular edema: passive and active transport of fluorescein through the blood–retina barrier. Invest Ophthalmol Vis Sci. 2001;42(2)433–438.[Abstract/Free Full Text]
  5. Sander B, Larsen M, Engler C, et al. Diabetic macular oedema: a comparison of vitreous fluorometry, angiography, and retinopathy. Br J Ophthalmol. 2002;86(3)316–320.[Abstract/Free Full Text]
  6. Wong TY, Knudtson MD, Klein R, Klein BE, Meuer SM, Hubbard LD. Computer-assisted measurement of retinal vessel diameters in the Beaver Dam Eye Study: methodology, correlation between eyes, and effect of refractive errors. Ophthalmology. 2004;111:1183–1190.[CrossRef][ISI][Medline][Order article via Infotrieve]
  7. Kristinsson JK, Gottfredsdottir MS, Stefansson E. Retinal vessel dilatation and elongation precedes diabetic macular oedema. Br J Ophthalmol. 1997;81(7)274–278.[Abstract/Free Full Text]
  8. The PKC-DRS Study Group. The effect of ruboxistaurin on visual loss in patients with moderately severe to very severe nonproliferative diabetic retinopathy initial results of the Protein Kinase C ß Inhibitor Diabetic Retinopathy Study (PKC-DRS) Multicenter Randomized Clinical Trial. Diabetes. 2005;54(7)2188–2197.[Abstract/Free Full Text]
  9. Strøm C, Sander B, Klemp K, Aiello L, Lund-Andersen H, Larsen M. Effect of ruboxistaurin on blood–retinal barrier permeability in relation to severity of leakage in diabetic macular edema. Invest Ophthalmol Vis Sci. 2005;46(10)3855–3858.[Abstract/Free Full Text]
  10. van Schaik HJ, Heintz B, Larsen M, et al. European Concerted Action on Ocular Fluorometry. Permeability of the blood–retinal barrier in healthy humans. Graefes Arch Clin Exp Ophthalmol. 1997;235(10)639–646.[CrossRef][ISI][Medline][Order article via Infotrieve]
  11. Sander B, Engler C, Larsen M, Lund-Andersen H. Early changes in diabetic retinopathy: macular ischemia and blood-retina barrier permeability in relation to metabolic control. Acta Ophthalmol Scand. 1994;72(5)553–559.
  12. Moldow B, Sander B, Larsen M, Lund-Andersen H. Effects of acetazolamide on passive and active transport of fluorescein across the normal BRB. Invest Ophthalmol Vis Sci. 1999;40(8)1770–1775.[Abstract/Free Full Text]
  13. van Schaik HJ, Castillo JM, Caubergh MJ, et al. European Concerted Action on Ocular Fluorometry. Evaluation of diabetic retinopathy by fluorophotometry. Int Ophthalmol. 1999;22(2)97–104.[ISI]
  14. Moldow B, Sander B, Larsen M, et al. The effect of acetazolamide on passive and active transport of fluorescein across the blood-retina barrier in retinitis pigmentosa complicated by macular edema. Graefes Arch Clin Exp Ophthalmol. 1998;236:881–889.[CrossRef][ISI][Medline][Order article via Infotrieve]



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Retinal Vessel Diameter and Diabetic Macular Edema
Tien Y. Wong
IOVS Online, 23 May 2008 [Full text]
Author Response: Retinal Vessel Diameter and Diabetic Macular Edema
Birgit Sander
IOVS Online, 23 May 2008 [Full text]
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