Diabetes and Eye Disease
Are You Sure the Patient Has Diabetic Retinopathy?
What Else Could the Patient Have?
- Key Laboratory and Imaging Tests
Other Tests That May Prove Helpful Diagnostically
- Management and Treatment of the Disease
What’s the Evidence?/References
Are You Sure the Patient Has Diabetic Retinopathy?
The patient may be asymptomatic but may present with blurred vision, floaters and dark shadows in vision, and diplopia.
Difficulty focusing and reading or blurred vision is the most common symptom. Other symptoms are less frequent but may present in more advanced retinopathy.
History of diabetes or elevated hemoblobin (Hb)A1c.
What Else Could the Patient Have?
Retinal venous occlusive diseases such as central renal vein occlusion or branch retinal vein occlusion. These conditions are frequently seen in a patient with hypertension, hyperlipidemia, or diabetes. Clinical features include retinal hemorrhages that follow the vascular tree, retinal edema that may involve the fovea, "cotton wool" spots, and exudates. Retinal or iris neovascularization may also be present.
Carotid occlusive diseases may also present with retinal hemorrhages and vascular tortuosity, also known as Kearn's syndrome.
Radiation retinopathy can also show retinal hemorrhages, retinal edema, and areas of poor retinal perfusion. This usually occurs in a patient with radiation therapy, often for head and neck cancer (especially cancer involving the sinuses). Seen most commonly 5-10 years post treatment.
Inflammatory retinal disease such as sarcoidosis can also show retinal hemorrhages as well as neovascularization. There is often a history of chronic inflammation.
Key Laboratory and Imaging Tests
Diabetic retinopathy is the most common cause of blindness in the working population aged 21 to 64 years. The disease is caused by poor retinal circulation involved with the microcirculation. Cogan and Kuwabara demonstrated vasodilatation of the capillary bed as well as pericyte dropout, loss of endothelial cells, and microaneurysm formation. More recently, the upregulation of vascular endothelial growth factor has been demonstrated to be a key factor in the development of capillary leakage and the development of neovascularization. Poor perfusion is sometimes seen due to leukocyte plugging of the capillaries or degeneration of the retinal microcirculation.
The most common cause of visual loss is macula edema, which is swelling that involves the macula area, especially swelling involving the center of the fovea. This is called "center involved macular edema." Several factors are associated with the risk for the development of retinopathy and its severity; the most important is the duration of diabetes. Another is the degree of retinopathy control. There may also be racial and genetic factors (e.g., Hispanics and African Americans tend to have more severe retinal disease than whites). Laboratory data are not very helpful in managing retinopathy.
However, one should strive for good control of blood sugar levels, so the HbA1c is important to document. The patient should be encouraged to maintain an HbA1C level of 7 or less. The eye physician should be in good communication with the internist or endocrinologist about the state of the patient's retina and follow-up intervals that are recommended. As a team, they are better able to ensure good patient outcomes.
The Diabetic Control and Complication Trial and the United Kingdom Prospective Diabetes Study confirmed the reduction of microvascular complications of diabetes including diabetic retinopathy in patients who have good sugar control. This occurred in type 1 diabetics in the former study and type 2 diabetes in the latter. This reduction affected both the occurrence and the progression of diabetic retinopathy. Significant worsening of the patient's health status, such as blood pressure control, renal failure, or hyperlipidemia, should be communicated to the eye care practitioner, as the patient may require an earlier follow-up retinal examination.
A dilated ocular examination of the retina is important to determine the level of retinopathy and the clinical investigations needed for further patient evaluation. Dilated ocular examination should be done 5 years after diagnosis or at puberty in type 1 diabetics. After puberty, there is evidence of the increase in insulin-like growth factor 1 and other growth factors that may enhance the development of diabetic retinopathy. Ocular examination should be done on diagnosis in patients who are type 2 diabetics. Thereafter, examinations should be done at least on an annual basis. Following appropriate screening guidelines for retinopathy can reduce the risk of blindness from retinopathy by 50%.
The clinical features seen in retinopathy include:
Intraretinal hemorrhages -- these may be superficial in the nerve fiber layer, seen as striate or flame hemorrhages, or dot and blot hemorrhages, seen deep in the outer plexiform layer of the retina
Cotton wool spots -- these are infarcts in the nerve fiber layer
Lipid (hard) exudates
Retinal edema -- this may or may not involve the macula
Intraretinal microvascular abnormalities -- these are dilated capillaries that may be a sign of increasing retinal ischemia
These findings are seen in nonproliferative diabetic retinopathy (NPDR). NPDR is classified as mild, moderate, or severe. Examination results should be recorded as:
Mild retinopathy: Occasional microaneurysms and rare intraretinal hemorrhages
Moderate retinopathy: More scattered retinal hemorrhages, cotton wool spots, and exudates
Severe nonproliferative retinopathy. This is associated with increased risk of progression to proliferative retinopathy. Defined as any of the following: intraretinal hemorrhages in all 4 quadrants, venous tortuosity and beading in two quadrants, and intraretinal microvascular abnormalities in 1 quadrant. Very severe nonproliferative retinopathy will have two or more of these characteristics and have more of a grave prognosis for progression to proliferative diabetic retinopathy. According to the ETDRS study, 50% of patients with severe NPDR will progress to proliferative diabetic retinopathy (PDR). Of this group, 15% will have high-risk findings for visual loss. Patients with very severe NPDR have a 75% risk of developing PDR within 1 year, with 45% showing high-risk characteristics for visual loss.
PDR: Neovascularization from the retinal vessels and/or vitreous hemorrhage or pre-retinal hemorrhage in a patient with findings listed as seen in NPDR. One may also see pre-retinal or pre-papillary fibrosis and areas of retinal traction that are severe enough to can cause tractional retinal detachment.
Patients who develop proliferative retinopathy may also have iris neovascularization; this is called rubeosis iridis. This can progress to involve the anterior chamber angle structures, causing scarring and a severe form of angle appositional fibrotic closure. This results in a severe form of glaucoma: neovascular glaucoma. This has a grave prognosis for visual loss. These eyes are usually very sick due to severe ischemia and upregulation of vascular endothelial growth factor (VEGF).
Clinical evaluation of the presence of macular edema, and this is clinically significant. The Early treatment Diabetic Retinopathy Study defined clinically significant macular edema (CSDME) as macular thickening within 500 microns of the center of the fovea; macular thickening contiguous with hard exudates that are within 500 microns of the center of the fovea, and macular thickening that is 1 disk diameter in size if within 1 disk diameter of the center of the fovea.
The Diabetic Retinopathy Ocular Examination
Initial Exam History (Key Elements)
Duration of diabetes
Glycemic control (HbA1c)
Medications both systemic and ocular
General medical history (e.g., other complications of diabetes, hypertension, hyperlipidemia, renal disease, sleep apnea, obesity, exercise, smoking history, pregnancy in female of child-bearing age)
Past ocular history of surgery or disease
Assessing ocular alignment and ocular motility
Intraocular pressure (IOP) measurement
Gonioscopy if iris neovascularization is present or the IOP is elevated
Slitlamp biomicroscopy of the anterior and posterior segment
Dilated fundus evaluation with stereoscopic examination of the posterior pole
Indirect ophthalmoscopy of the vitreous, posterior, and peripheral retina.
Diagnostic tests are not as useful in determining whether a patient has retinopathy but are helpful in determining severity, following progress and treatment response.
Seven-field fundus photography: Useful to stage the retinopathy and for following the patient. Stereophoto pairs with slitlamp biomicroscopy are useful in determining the existence of and severity of diabetic macular edema.
Ocular coherence tomography (OCT) is useful in documenting the severity of diabetic macular edema. The latest concepts in diabetic macular edema therapy include "center involved" macular edema, where the center of the fovea has a thickness at or above 250 microns on the time domain OCT or 310 microns on the Fourier (spectral) domain OCT. OCT is also very useful for following response to therapy. It has partially replaced the fluorescein angiogram in following these patients.
Fluorescein angiography (FA) is useful in evaluating the extent of areas of nonperfusion, especially in the macula. It also is used as a guide for laser therapy in the treatment of macular edema. Note that patients may be effectively managed without this diagnostic modality, but FA may prove invaluable in retreatments and following patients.
Other Tests That May Prove Helpful Diagnostically
Widefield fundus imaging and widefield FA may be performed with new testing modalities like the Optos widefield imaging system or the Heidelberg Spectralis system. These systems are very useful in demonstrating the level of peripheral retinal disease. They are very useful in demonstrating peripheral nonperfusion, which often is a precursor to neovascularization or that may feed severe or persistent macular edema.
B-mode ultrasonography is useful in patients with opaque media where there is limited or no visualization of the posterior segment. This occurs in patients with severe vitreous hemorrhaging or opaque cataracts.
Management and Treatment of the Disease
The screening for retinopathy through dilated retinal exams is the most important recommendation for preserving vision and preventing blindness from diabetes. The Diabetic Control and Complications Trial showed that intensive glycemic control was associated with decreased incidence of the development of retinopathy and reduction in the progression of existing retinopathy in type 1 diabetics. Subjects in the primary prevention cohort experienced a 76% reduction in the risk of developing retinopathy and 54% reduction of the risk of retinopathy progression in the secondary intervention cohort. Thus control of blood sugar is important in reducing the risk of microvascular complications.
This finding was confirmed in the United Kingdom Prospective Diabetes Study in type 2 diabetics. This study demonstrated a 25% risk reduction in microvascular complications seen in the intensive treatment group compared to conventional therapy. In these patients, both blood pressure and glycemic control were associated with reduction of visual loss at 4.5 to 6 years after randomization.
Managing Diabetic Macular Edema
The ETDRS study demonstrated the benefit of laser photocoagulation in the treatment of patients with CSDME. Laser may be performed in a grid pattern over areas of diffuse leakage and focally to microaneurysms and IRMA.
Treatment papameters are yellow or green laser wavelength 50-100 microns, 0.05-0.10 second, medium to light gray burn, place 2 burn widths apart.
Grid/focal laser photocoagulation reduces the incidence of severe visual loss by 50% in patients with CSDME. Severe visual loss is defined as the loss of 3 lines (15 letters) on the ETDRS visual acuity chart. This level of visual loss is equivalent to doubling of the visual angle.
Laser therapy by itself seldom improves the vision in patients with CSDME; 40% of patients will continue to lose vision despite laser therapy.
Diabetic Retinopathy Research Network (DRCR net) protocol B looked at a comparative trial using triamcinolone acetonide gel intravitreal injection versus focal/grid laser for center involved CSDME. There was very short-term benefit (3 months) associated with the use of steroids. This benefit was not seen at 1 year and beyond; thus, there was no significant advantage for steroid over laser therapy. A interesting finding in this study was that despite previous laser therapy in patients randomized, following a careful retreatment protocol resulted in improvement in macular leakage.
With the advent of intraocular use of anti--vascular endothlial growth factors (anti-VEGFs), clinical trials in diabetic retinopathy treatment have been shown to result in improved outcomes including improved visual acuity in patients with center involved CSDME.
The DRCR net protocol I evaluated the use of intravitreal ranibizumab with either immediate or delayed laser therapy for center involved CSDME. The study also looked at triamcinolone combined with immediate focal laser therapy. Both ranibizumab arms demonstrated significantly improved visual acuity letter scores at 1 and 2 years compared with laser alone or triamcinolone combined with laser. There was a +9 letter gain in the ranibizumab groups compared with +3 letters in the laser only group and compared with +3 letters in the triamcinolone plus laser group. This benefit was also seen in the RISE and RIDE studies. These studies showed improved visual outcomes at 24 weeks using intravitreal ranibizumab versus sham injection. In both arms, laser was allowed. Both doses (0.3 mg and 0.5 mg) of ranibizumab were equally efficatious in reducing macular edema and improving vision. The 0.3-mg dose of ranibizumab is therefore the recommended dosage for treating CSDME and the dosage approved by the FDA. In the DRCR net protocol I study, there was a median of nine injections done in the first year and three in the second year.
There are numerous smaller studies that have also demonstrated the benefit of bevaczumab injected intravitreally for the treatment of CSDME. In the PACORES study, there was a mean number of 5.8 injections over the 2 years of the study. There was improvement in vision and normalization of retinal edema and macular anatomy; 64% of patients gained at least 10 letters of vision in the 1.25 mg group. The BOLT study compared the use of bevacizumab with focal/grid laser therapy. the bevacizumab recipients gained a median of 9 letters (cf 2.5 letters) in the laser group through 2 years with a mean on four injections.
Current studies are under way evaluating bevacizumab, ranibizuman, and aflibercept. The DRCR net protocol T is conducting a randomized trial comparing all three agents for DME. The DaVINCI study is evaluating the use of aflibercept (soluble VEGF decoy receptor protein). Visual acuity improved 8.5 to 11.4 letters over 24 weeks. This compared to 2.5 letters in the laser group.
My current recommendation for center involved CSDME is initial anti-VEGF therapy, followed by later laser photocoagulation.
Managing Proliferative Diabetic retinopathy (PDR)
The DRS and ETDRS trials made recommendations regarding therapy for PDR; these recommendations are still important and relevant today.
Pan-retinal laser photocoagulation is the treatment for patients with proliferative diabetic retinopathy. Studies have shown that use of anti-VEGF therapy may also be used as adjunctive therapy for patients with proliferative retinopathy. In some of these patients, one can see propagation of rpe-retinal fibrosis requiring early vitrectomy in these patients; however, the majority will see amelioration of their proliferative disease. We therefore recommend close follow-up for patients with proliferative disease, especially patients with existing preretinal fibrosis.
Pan-retinal laser photocoagulation is helpful in patients with chronic macular edema, where widefield angiography show extensive mid peripheral capillary nonperfusion.
Vitrectomy is useful in patients with vitreomacular traction and taut posterior hyaloid syndrome, chronic or recurrent vitreous hemorrhage, and tractional retinal detachment.
What’s the Evidence?/References
"Grading diabetic retinopathy from stereoscopic color fundus photocoagulation -- an extension of the modified Airlie House classification. ETDRS report number 10". Ophthalmology. vol. 98. 1991. pp. 786-806.(This paper shows the relevant staging of diabetic retinopathy.)
"The effect of intensive diabetes treatment on the progression of diabetic retinopathy in insulin-dependent diabetes melitus". Arch Ophthalmol. vol. 113. 1995. pp. 36-51.
"Photocoagulation for diabetic macular edema. Early Treatment Diabetic Retinopathy Study report number 1". Arch Ophthalmol. vol. 103. 1985. pp. 1796-1806.
"Progression of retinopathy with intensive versus conventional treatment in the Diabetes Control and Complications Trial". Ophthalmology. vol. 102. 1995. pp. 647-661.
"Intensive blood-glucose control with sulphonylureas or insulin compared with convential treatment and risk of complications in patients with type 2 diabetes (UKPDS 33)". Lancet. vol. 352. 1998. pp. 837-853.
Kohner, EM, Stratton, IM, Aldington, SJ. " Relationship between the severity of retinopathy and progression to photocoagulation in patients with type 2 diabetus melitus in the UKPDS (UPPDS 52)". Diabet Med. vol. 18. 2001. pp. 178-184.
"Tight blood pressure control and the risk of macrovasculr and microvascular complications in type 2 diabetes; UKPDS 38". BMJ. vol. 317. 1998. pp. 703-713.
McDonald, HR, Williams, GA, Scott, IU. " Laser scanning imaging for macular disease: A report by the American Academy of Ophthalmology". Ophthalmology. vol. 114. 2007. pp. 1221-12218.
Elman, MJ, Bressler, NM, Qin, H. "Diabetic Retinopathy Research Network. Expanded 2 year follow-up of ranibizumab plus prompt or deferred laser or triamcinolone plus prompt laser for diabetic macular edema". Ophthalmology. vol. 118. 2011. pp. 609-614.
Nguyen, QD, Brown, DM, Marcus, DM. "Ranibizumab for diabetic macular edema: Results from 2 phase III randmized trials: RISE and RIDE". Ophthalmology. vol. 119. 2012. pp. 789-801.
Elamn, MJ, Aello, LP, Beck, RW. "Diabetic Retinopathy Research Network. Randomized trial evaluating ranibizumab plus prompt or deferred laser or traimcinolone plus prompt laser for diabetic macular edema". Ophthalmology. vol. 117. 2010. pp. 1064-1077.
Ho, AC, Scott, IU, Kim, SJ. " Anti-vascular endothelial growth factor pharmacotherapy for diabetic macular edema: A report by the American Academy of Ophthalmology". Ophthalmology. vol. 119. 2012. pp. 2179-2188.
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