Subclinical Diabetic Macular Edema Study

• To determine the incidence of progression of subclinical diabetic macular edema (DME)
• To evaluate factors predictive of the presence of subclinical macular edema
• To determine indicators of risk for progression of subclinical DME

The complications of diabetic retinopathy remain the most common cause of blindness among American adults 20-74 years of age, with nearly 4% of individuals with type 1 diabetes meeting the definition of legal blindness and many more suffering from moderate visual loss. Nearly 99% of type 1 diabetics develop diabetic retinopathy within 20 years of their initial diagnosis.

The microvascular complications of diabetic retinopathy are due to elevated blood glucose levels with selective loss of pericytes, thickening of the retinal capillary basement membrane, microaneurysm formation, and retinal capillary closure. The most common cause of visual loss in diabetes is retinal macular edema, in which there is swelling (or thickening) of the central retina (or "macula") due to excessive permeability of the retinal blood vessels.

The clinical standard for the detection of retinal edema is to view the macula with a lens at the slit lamp through a pharmacologically dilated pupil. This is a subjective process that is highly dependent on observer skill and experience, study participant cooperation, the degree of pupillary dilation, the presence of media opacity (e.g., cataract), and the pattern and degree of retinal swelling. Several years ago, a medical device entered the market that can objectively measure retinal morphology called an Optical Coherence Tomography (OCT) scanner. OCT is a noninvasive, non-contact, high resolution scan of the retina based on the light-reflecting properties of the layers of the retina. OCT creates a cross-sectional image of the retina with a resolution of 10 microns, enabling evaluation of the macular contour and retinal fluid collections.

Currently, laser photocoagulation treatment is indicated when clinically significant macular edema is present. However, when macular edema is not apparent on clinical examination but OCT demonstrates mild central thickening (center point thickness 225 to 299 microns), standard practice is observation without treatment.

At least two studies have shown that mild abnormal thickening on OCT may not correspond to edema recognized by biomicroscopy. A recently conducted masked non-randomized prospective clinical case series compared contact lens biomicroscopy with Optical Coherence Tomography (OCT) for the detection of diabetic macular edema, confirming the notion that retinal thickening detected by OCT might not be seen on contact lens examination of the fovea in subjects with diabetic retinopathy. Study participants consisted of a convenient cohort of consecutive patients with diabetes seen at the Wilmer Eye Institute's Retina Division at the Johns Hopkins University School of Medicine. Exclusion criteria included the presence of any pathology, other than diabetes, that could affect retinal thickness or preclude identification of edema involving the center of the macula. Case characteristics were recorded and eyes were examined by one of four experienced retina specialists using contact lens biomicroscopy. The presence of edema involving the center of the macula ("macular edema") was assessed as definitely present, questionably present, or definitely not present. OCT testing was performed and interpreted by trained technicians, masked to the physicians' assessment of macular edema.

If at least 25% of cases with no edema apparent on clinical examination have subclinical macular edema, subclinical macular edema may affect many patients in the United States with diabetes, and many more throughout the world.

Since OCT devices are now widely available in U.S. ophthalmic practices that specialize in the management of retinal problems, the routine detection of subclinical macular edema by including OCT scanning in routine screening paradigms of individuals with diabetes is a possibility. The detection of retinal thickening at earlier stages using this technology could lead to the earlier treatment of vision-threatening complications of diabetic retinopathy and improve visual outcomes for many patients with diabetic retinopathy. However, further studies are necessary to confirm the importance of "subclinical" thickening detected by OCT, prompting this current protocol.

It is expected that most cases of subclinical macular edema in individuals with diabetes will be in those that have at least some retinopathy; furthermore, it is expected that individuals with subclinical macular edema who progress to at least 300 microns with at least a 50 micron increase will have some retinopathy at baseline. However, it is important to confirm these expectations in this study as well as to have information on the OCT-measured thickness of the retina in individuals with diabetes who do not have retinopathy.

The study is designed as a prospective observational study consisting of both a baseline phase and follow-up phase.

Subclinical DME is defined as no edema involving the center of the fovea as determined by biomicroscopy but with center point thickness on OCT of at least 200 microns but less than or equal to 299 microns. Progression of DME is defined as increase in center point thickness of at least 50 microns to >300 microns.

Subject-level Inclusion Criteria

To be eligible, the following inclusion criteria (1-3) must be met:

1. Age >= 18 years

2. Diagnosis of diabetes mellitus (type 1 or type 2)

3. Able and willing to provide informed consent.

Exclusion

A potential study participant is not eligible if any of the following exclusion criteria (4-11) are present:

4. History of chronic renal failure requiring dialysis or kidney transplant.

5. History of pancreatic transplant.

6. A condition that, in the opinion of the investigator, would preclude participation in the study (e.g., unstable medical status including blood pressure and glycemic control).

7. Participation in an investigational ocular trial requiring follow-up at the time of study entry.

8. Any medical treatment for the retina or medication that has been proven to affect edema.

9. History of systemic (e.g., oral, IV, IM, epidural, bursal) corticosteroids within 4 months prior to enrollment or topical, rectal, or inhaled corticosteroids in current use more than 2 times per week.

10. Participant is expecting to move out of the area of the clinical center to an area not covered by another clinical center during the 2 years of the study.

11. Blood pressure > 180/110 (systolic above 180 OR diastolic above 110).

No longer recruiting. Comments: Recruitment ended April 30, 2007.

Completed, with results published. Comments:

On average, central subfield (CSF) thickness was 201 +/- 22 microm. CSF thickness was significantly greater in retinas from men than retinas from women (mean +/- standard deviation, 209 +/- 18 microm vs 194 +/- 23 microm; P < .001). After adjusting for gender, no additional factors were found to be associated significantly with CSF thickness (P > .10).

CSF thicknesses on Stratus OCT in people with diabetes and minimal or no retinopathy are similar to thicknesses reported from a normative database of people without diabetes. CSF thickness is greater in men than in women, consistent with many, but not all, previous reports. Studies involving comparisons of retinal thickness with expected norms should consider different mean values for women and men.