1. Hard exudates within 500 microns on the fovea.

On Nov. 11, 2001, a 54-year-old male of Pacific Island descent presented for an annual diabetic visual evaluation. The patient had no visual complaints and stated that his blood sugar normally reads about 155mg/dl, with an occasional reading of 200mg/dl. His last eye exam was about two years ago.

History

Records from that visit noted a diagnosis of mild non-proliferative diabetic retinopathy (NPDR) without clinically significant macular edema (CSME). We noted hard exudates (HE) in the posterior pole, but away from foveal tissue. All other ocular history was unremarkable. No related social history was noted. This patient's medical history included renal insufficiency, depression, hyperlipidemia, hypertension, cellulitis of the leg and type II diabetes with renal and ophthalmic manifestations. Medications include insulin injections b.i.d., dressings to treat cellulitis of the leg, Zestril (Lisin-opril, AstraZeneca) and Zocor (Simvastatin, Merck).  

Exam findings

2. Scattered edema from microaneurysm formation.

Upon examination, all entrance testing was normal, other than entering acuities of 20/40-2 O.U. Best-corrected visual acuity (BCVA) was 20/25 O.U. Tonometry revealed intraocular pressure (IOP) of 12mm Hg O.D. and 15mm Hg O.S. Pertinent biomicroscopy findings included no rubeosis; mild cataract development O.U.; and, most importantly, exudates and hemorrhages within 500 microns of the fovea O.D. with retinal thickening (see figure 1). We also noted microaneurysms and hemorrhages in all four quadrants. We diagnosed the patient with type II diabetes mellitus with mild/ moderate NPDR, CSME O.D. and O.S. We also suspect glaucoma secondary to IOP asymmetry and optic nerve head appearance. However, we will not address the glaucoma aspect of this case as it had minimal impact in the ending visual acuity. We scheduled the patient for fluorescein angiography (FA) to visualize the CSME in preparation for focal grid treatment.

A fluorescein study on March 4, 2002 showed scattered perfusion from microaneurysms O.S. greater than O.D. (see figure 2). The patient was treated with focal grid argon laser, with 27 burns O.D. and 57 O.S.

Follow-up

Six months later, on September 24, 2002, this patient presented for a follow-up visit with entering acuities of 20/30 O.U. The assessment included type II DM, moderate NPDR and minimal CSME O.U. The retinal practitioner at that time believed the CSME O.S. was resolving and we scheduled the patient for a four-month follow-up visit.

3. HbA1c readings over nine years. Extremely high levels show poor prognosis for retinal health.

On January 3, 2003, approximately 3.5 months later, the patient reported that everything was now blurry and he could no longer drive. He noted a gradual change in visual acuity over the past one to two months. He reported that his glucose levels were good and measured 113mg/dl that morning. He said his vision was stable after the laser treatment, but that his glasses did not help anymore. His entering acuities for that visit were counting fingers at five feet O.D. and 20/60-2 O.S.; no improvement with pinhole. After examination, we altered his diagnosis to Type II DM with severe NPDR and diffuse CSME O.U. We performed an FA the same day (see figure 4) and observed a marked increase in retinal edema. Diffuse focal grid was applied O.D. and O.S. with an evaluation for possible intravitreal triamcinolone acetonide (kenalog, Bristol Myers Squibb) injection or pan-retinal photocoagulation (PRP) upon follow-up.  

The follow-up visit in May 2003 included PRP treatment O.D. of 1400 burns and 1450 burns O.S.

Examination in July of 2003 showed an entering acuity of bare light perception O.U. We noted proliferative changes and diagnosed type II DM with severe PDR O.U. (see figure 5). We also scheduled a pars plana vitrectomy in the left eye. Figure 6 shows the eye four months after surgery was completed.

4. Fluorescein angiography shows severity of retinal edema in the right eye with flame and dot-blot type hemorrhages.

Discussion

The question as to why this patient had such a dramatic change in vision comes to any practitioner's mind. This case illustrates why you must conduct an objective analysis of a patient's underlying medical condition. Careful review of the medical history in this case revealed several important pieces of information. The most relevant is his glucose control over the past several years. We collected data on this patient's serum glucose levels, as well as his Hemoglobin A1c counts, shown above. Further analysis of the patient's primary care practitioner's notes revealed consistently poor dietary compliance over several years.

A patient is considered a suspect for diabetes when fasting serum glucose levels reach between 100 and 140mg/dl. The diagnosis is likely when that number is over 140mg/dl. Further, the hemoglobin A1c count is also utilized. If elevated above 7.0, a positive diagnosis is likely.

Both were extremely elevated in this patient over several years. When you take into account this new information, discussion of ocular treatment options becomes moot because the disease is already out of control.

In cases such as this, despite our best efforts, it's only a matter of time before vision is permanently damaged, if not lost.

Diabetic changes

Diabetic retinopathy may present initially with many different retinal changes. One of these is likely to be the formation of microaneurysms (MA) (see figure 7). Microaneurysms are very small (50 to 100 microns in size) and very difficult to see clinically unless relatively large. However, these will become apparent with fluorescein angiography. The small out-pouchings of capillary walls form in areas of hypoxia and are a response to weakening of vessel walls. Leaking ensues, causing retinal edema. Early detection of MAs can help a you educate a patient early, before serious damage occurs.

5. Severe PDR with both NVD and NVE.

Because retinal hypoxia is an unavoidable factor in diabetic retinopathy, this may also be an early indicator of retinal changes. Retinal nerve tissue is relatively translucent in a healthy state, but as it becomes ischemic, it becomes more opaque. This opaque presentation is known as cotton-wool (see figure 8). These markers of retinal hypoxia are important to note as lack of oxygen in tissue is a precursor to neovascularization, or new retinal vessel growth, which will cause retinal edema and possible fibrosis of retinal tissues.

As diabetic retinopathy causes compromise in the retinal vasculature, it is predictable that you will see some form of hemorrhaging. While it's possible to see hemorrhages in early or less severe cases of retinopathy, these will usually only present after microaneurysm and/or cotton wool spot formation. Retinal hemorrhages come in three basic forms (see figures 4 and 5):

• Dot-blot: Appear in relatively deep retinal layers, usually emerging from bleeding within the venous circulation. Due to the columnar-oriented photoreceptors, the blood appears as blots versus smeared or flowing.

• Flame-shaped: Form from an arteriol bed, usually from the postarteriolar superficial capillary bed or the radial peripapillary capillary system. Because the arteriolar system is oriented in the laterally-placed nerve fiber layer, blood will follow this orientation and present as a streak or flame-like pattern.

6. Post-vitrectomy view of the left eye.

• Pre-retinal/vitreous: If blood is able to penetrate the internal limit- ing membrane, it may pool between the retina and posterior hyaloid face and is known as pre-retinal. If blood leaks past the posterior hyaloid face and enters the vitreous cavity, it is known as a vitreous hemorrhage.

Invasive treatment is usually indicated when edema enters into the macula area of the retina. When occurring at a damaging level, it is known as clinically significant macular edema (CSME). Along with edema comes the deposition of lipid exudates in the nerve tissues. This can be a key clinical sign of progression of diabetic retinopathy. CSME is diagnosed when any of the following occurs:

• Thickening of the retina 500 microns (1/3 disk diameters [DD]) from the center of the macula.

• Hard exudates with thickening of the adjacent retina 500 microns from the center of the macula.

• Zone of retinal thickening 1 disk area (DA) in size, in part 1DD from the center of macula.

7. Microaneurysms hyperfluoresce during FA.

If any of these criterion is met, argon laser treatment may control the retinal edema.

Critical stage

When retinal hypoxia reaches critical levels, vascular endothelial growth factor (VEGF) is released, causing a proliferation, or new arteriol vessel growth. This can present in three main forms:

• Neovascularization of the iris (NVI). This is seen due to the common choroidal vasculature between the iris and retina. Most commonly beginning at the pupillary ruff, look out for this during slit lamp examination before administering dilating drops.

• Neovascularization of the disk (NVD). New vessel growth off of the nerve head will commonly protrude into the vitreous cavity due to perforations in the internal limiting membrane. This arises due to a lack of a true internal limiting membrane (ILM) at the disk (see figure 9).

• Neovascularization elsewhere (NVE). Growth of new blood vessels elsewhere, besides the nerve head along the retinal surface, usually found within the arcades (see figure 5).  

8. Cotton-wool spots.

The primary care practitioner will need the expertise of a retinal specialist after CSME or neovascularization presents, as the next indicated course of action is argon laser treatment.

Clinical Pearls

Despite our best efforts, some patients will lose vision secondary to diabetic complications. It is crucial, however, that we remember some simple steps to help us prevent/postpone serious vision loss.

Given this case, and the way in which the patient presented himself, it is essential for all practitioners to remember how important it is to have the actual serum glucose/ A1c counts available. In practices outside a hospital setting, it is easy to be misled by patient reports of their at-home readings. Each day that this particular patient reported his glucose levels, they seemed fairly reasonable. Only after looking at current A1c counts from the lab did this patient's poor control become obvious.

9. The blur of the retina indicates NVD is protruding into the vitreous.

A useful tool is the knowledge of the relationship between serum glucose readings and A1c counts. (See table 3.) The Diabetes Control and Complications Trial (DCCT) showed a correlation between the two that can be summarized in this simple formula: mean plasma glucose (MPG) = (35.6*A1c)-77. A1c counts are an indication of a patient's plasma glucose levels over the past three to four months. Due to the rate at which red blood cells die, the last 30 days are weighed heaviest. Therefore, a current A1c gives an excellent indication of patient compliance.

Furthermore, careful clinical examination is crucial. Stereoscopic evaluation is necessary in order to diagnose CSME as one of the criterion is retinal thickening. And keep in mind that it is possible to show signs of edema without actual thickening. Also, stereoscopic views are useful when determining the activity/ presence of NVD.

Finally, we can never overstate the importance of patient education. When patients are in the early signs of retinopathy, digital fundus photography is extremely useful in helping them understand the severity of the situation. Take the time to help the patient realize and

better understand the pathophysiology behind retinopathy. It is ultimately best controlled by strict control of the diabetes itself.

References available upon request.