Diabetes is the leading cause of new blindness in Americans under age 74, the leading cause of end-stage renal disease and non-traumatic amputation, and the sixth leading cause of death in the United States. Each year, more than 200,000 U.S. deaths are reported as being caused by diabetes or its complications.1 Recent work has shown diabetes to be strongly associated with several types of cancer2 and Alzheimer’s disease.3 In 2012, diabetes care cost the U.S. economy $245 billion, a 41% increase from 2007.4 By the year 2020, Americans with diabetes or prediabetes could cost the U.S. healthcare system $3.35 trillion.5 The American Diabetes Association estimates that 25.8 million Americans have diabetes,6 and another 79 million have pre-diabetes,6 the majority of whom will develop type 2 diabetes without intervention.6 Moreover, as many as 7 million Americans have undiagnosed diabetes right now.6
Optometrists are well aware of these statistics because we see the ophthalmic manifestations of diabetes on a daily basis, often in patients who have yet to be formally diagnosed.
Diabetic eye disease refers to conditions prevalent among patients with diagnosed or undiagnosed diabetes that are attributable, either directly or indirectly, to hyperglycemia-cataracts, glaucoma, ocular surface disease, nonarteritic ischemic optic neuropathy, cranial mononeuropathy, extraocular muscle palsy, and most importantly, diabetic retinopathy. Diabetes patients are also at higher risk for other retinal-vascular disorders as a function of concomitant dyslipidemia and hypertension, including retinal vein and artery occlusion.
Diabetes and the aging eye
The quintessential ophthalmic finding in undiagnosed diabetes is fluctuating refractive error. Both myopic and hyperopic shifts have been reported due to lenticular changes caused by hyperglycemia,7 but the majority of studies show a myopic shift with subsequent reversal toward hyperopia after control of blood glucose.8-10 The mechanisms responsible for this phenomenon include changes in regional refractive index, lens curvature, and hydration. Cataract development and progression in diabetes occur at a younger age and a faster rate due to glycation of lens proteins, osmotic stress, and disorganization of collagen.11
Recently, a device (ClearPath DS-120, Freedom Meditech Inc.) for measuring advanced glycation end products (AGEs) as a function of crystalline lens autofluorescence received FDA clearance. The device gives eyecare professionals insight into long-term glycemic stress in patients with both diagnosed and undiagnosed diabetes (see Figure 1).
The association between diabetes and open-angle glaucoma is hotly debated.12 Glycation of laminar collagen, as well as poorer optic nerve perfusion, may increase risk of damage from ocular hypertension. However, it is likely that higher rates of diagnosis in diabetes patients is confounded by glucose-induced increases in corneal rigidity, resulting in over-detection of OHTN,13 as well as detection bias in a population being scrutinized for disease of the posterior segment.
There is no doubt diabetes increases the risk of both neovascular glaucoma secondary to ischemia,14 and iatrogenic glaucoma due to use of corticosteroids for the treatment of retinopathy and macular edema.15 Other optic nerve diseases more commonly seen in diabetes include non-arteritic anterior ischemic optic neuropathy16 (co-association among NAION, sleep apnea, and diabetes increases this risk) and so-called diabetic papillopathy-typically unilateral disk swelling caused by vascular leakage around the optic nerve head, with good recovery of vision in most cases.
Ocular surface disease and use of artificial tear supplements are more common in diabetes patients than in the general population.17 This phenomenon is mediated by increased glucose in tears and meibomian secretions, as well as morphologic changes in corneal nerves and hemidesmosomal attachments that increase risk of corneal erosion. Severity of keratoconjunctivitis sicca appears to correlate with glucose control and severity of retinopathy.18 A major Spanish study found that diabetes doubled the risk of asymptomatic meibomian gland dysfunction, a finding that may underscore diminished corneal sensation.19 Another retrospective study of nearly 160,000 patients over 10 years found diabetes to significantly increase the risk of herpetic eye disease,20 possibly due to impaired corneal immune response. Diabetes is also associated with reduced endothelial cell counts.21 Though the vast majority of people with diabetes can successfully wear contact lenses,22 these processes support conservative prescription and careful follow-up by optometrists.
Isolated cranial nerve palsy is about seven times more common in diabetes, presumably due to microvascular infarct.23 CN III, IV, VI, and VII are most commonly affected, and recovery of function is the rule within 6 months.24 Multiple CN palsies in diabetes rarely occur and warrant neuroimaging to rule out compressive lesion. Corneal hypoesthesia can result from sensory neuropathy of CN V, a finding that increases the risk of dry eye as well as neurotrophic keratitis.25,26 Idiopathic ptosis is associated with increased risk of insulin resistance,27 as are acanthosis nigricans26 (hyperpigmentation caused by hyperinsulinemia), skin tags, and demodex folliculorum29 of the eyelids.
Diabetic retinopathy (DR) is the single most important ocular complication of diabetes, with a wide spectrum of presentations and severity. Evidence suggests DR is a neurovascular disease, with changes in retinal nerve fiber layer thickness and ganglion cell function preceding the vascular changes identified by dilated eye examination.30 Functionally, these processes may result in abnormal color vision (acquired tritan and tetartan defects), reduced contrast sensitivity,31 and loss of perimetric sensitivity.32 Abnormalities in multifocal electroretinogram response are known to precede clinically detectable retinopathy and even predict future sites of retinal-vascular damage.33
A host of processes have been implicated in the pathobiology of DR, including hyperglycemic oxidative stress, hypertension, inflammatory dyslipidemia, and release of inflammatory cytokines that mediate blood-retinal barrier breakdown, apoptosis of retinal pericytes, capillary closure, and ischemia that triggers neovascularization.34 Optometrists are well aware of the various fundus lesions seen in DR; the key is to remember which findings presage the highest risk of sight-threatening retinopathy (extensive intra-retinal hemorrhage or microaneurysm formation; vein beading; and IRMA) and those that immediately threaten vision-retinal thickening that involves or approaches the macular center (see Figure 2); neovascularization of the optic nerve, retina, or anterior chamber angle; and pre-retinal or vitreous hemorrhage, especially with fibrovascular proliferation (see Figure 3).
The prevalence of diabetes among patients with hypertension is high, and vice versa. So it is not surprising that hypertensive retinopathy is more common in diabetes patients, may accelerate diabetic retinopathy, and may muddy the waters regarding the underlying etiology of retinopathy in patients with both conditions.35 From the standpoint of diagnostic suspicion of undiagnosed type 2 diabetes, it is interesting to note that generalized retinal arteriolar narrowing, a classic finding of mild hypertensive retinopathy, independently raises the risk of diabetes about 70%.36 It is also important to realize that diabetes is a risk factor for retinal vascular occlusive disease, more commonly venous but also arterial occlusions.37 Patients experiencing these events often have hypertension and cardiovascular disease that frequently co-mingle with diabetes.
As we have seen, diabetes affects the eye in a myriad of ways, including alterations in visual function as well as structure. These ocular changes are important because they also reflect systemic metabolic insult, are associated with other complications of diabetes including kidney and cardiovascular disease, and put the optometrist on the front line in detecting diabetes in those who have not yet been diagnosed.ODT
Facts About Diabetes. Health Library, Johns Hopkins Medicine. http://www.hopkinsmedicine.org/healthlibrary/conditions/diabetes/facts_about_diabetes_85,P00335. Accessed May 9, 2013.
Habib SL, Rojna M. Diabetes and risk of cancer. ISRN Oncol. 2013;2013:583786. doi: 10.1155/2013/583786. Epub 2013 Feb 7.
Vignini A, Giulietti A, Nanetti L, Raffaelli F et al. Alzheimer's disease and diabetes: new insights and unifying therapies. Curr Diabetes Rev. 2013 May 1;9(3):218-227.
Economic costs of diabetes in the U.S. in 2012. Diabetes Care. 2013 Apr;36(4):1033-1046.
Cost of Diabetes Will Be $3.35 Trillion by 2020. Diabetes In Control. http://www.diabetesincontrol.com/articles/53-diabetes-news/11960-cost-of-diabetes-will-be-335-trillion-by-2020. Accessed May 9, 2013.
American Diabetes Association National Diabetes Fact Sheet, 2012. http://www.diabetes.org/diabetes-basics/diabetes-statistics. Accessed May 9, 2013.
Tai MC, Lin SY, Chen JT, Liang CM, Chou PI, Lu DW. Sweet hyperopia: refractive changes in acute hyperglycemia. Eur J Ophthalmol. 2006 Sep-Oct;16(5):663-666.
Sonmez B, Bozkurt B, Atmaca A, Irkec M, Orhan M, Aslan U. Effect of glycemic control on refractive changes in diabetic patients with hyperglycemia. Cornea. 2005 Jul;24(5):531-537.
Okamoto F, Sone H, Nonoyama T, Hommura S. Refractive changes in diabetic patients during intensive glycaemic control. Br J Ophthalmol. 2000 Oct;84(10):1097-1102.
Lin SF, Lin PK, Chang FL, Tsai RK. Transient hyperopia after intensive treatment of hyperglycemia in newly diagnosed diabetes. Ophthalmologica. 2009;223(1):68-71.
Hashim Z, Zarina S. Osmotic stress induced oxidative damage: possible mechanism of cataract formation in diabetes. J Diabetes Complications. 2012 Jul-Aug;26(4):275-279.
Wong VH, Bui BV, Vingrys AJ. Clinical and experimental links between diabetes and glaucoma. Clin Exp Optom. 2011Jan;94(1):4-23.
Krueger RR, Ramos-Esteban JC. How might corneal elasticity help us understand diabetes and intraocular pressure? J Refract Surg. 2007 Jan;23(1):85-88.
Hayreh SS. Neovascular glaucoma. Prog Retin Eye Res. 2007 Sep;26(5):470-485.
Jonas JB. Intravitreal triamcinolone acetonide for diabetic retinopathy. Prog Retin Eye Res. 2007 Sep;26(5):470-485.
Hayreh SS. Ischemic optic neuropathy. Prog Retin Eye Res. 2009 Jan;28(1):34-62.
Kaiserman I, Kaiserman N, Nakar S, Vinker S. Dry eye in diabetic patients. Am J Ophthalmol. 2005 Mar;139(3):498-503.
Nepp J, Abela C, Polzer I, Derbolav A. Is there a correlation between the severity of diabetic retinopathy and keratoconjunctivitis sicca? Cornea. 2000 Jul;19(4):487-491.
Viso E, Rodríguez-Ares MT, Abelenda D, Oubiña B, Gude F. Prevalence of asymptomatic and symptomatic meibomian gland dysfunction in the general population of Spain. Invest Ophthalmol Vis Sci. 2012 May 4;53(6):2601-2606.
Kaiserman I, Kaiserman N, Nakar S, Vinker S. Herpetic eye disease in diabetic patients. Ophthalmology. 2005 Dec;112(12):2184-2188.
Sudhir RR, Raman R, Sharma T. Changes in the corneal endothelial cell density and morphology in patients with type 2 diabetes mellitus: a population-based study, Sankara Nethralaya Diabetic Retinopathy and Molecular Genetics Study (SN-DREAMS, Report 23). Cornea. 2012 Oct;31(10):1119-1122.
O'Donnell C, Efron N. Diabetes and contact lens wear. Clin Exp Optom. 2012 May;95(3):328-337.
Watanabe K, Hagura R, Akanuma Y, Takasu T, Kajinuma H, Kuzuya N, Irie M. Neuro-ophthalmic associations and complications of diabetes mellitus. Diabetes Res Clin Pract. 1990 Aug-Sep;10(1):19-27.
Burde RM. Neuro-ophthalmic associations and complications of diabetes mellitus. Am J Ophthalmol. 1992 Oct 15;114(4):498-501.
Rogell GD. Corneal hypesthesia and retinopathy in diabetes mellitus. Ophthalmology. 1980 Mar;87(3):229-233.
Messmer EM, Schmid-Tannwald C, Zapp D, Kampik A. In vivo confocal microscopy of corneal small fiber damage in diabetes mellitus. Graefes Arch Clin Exp Ophthalmol. 2010 Sep;248(9):1307-1312.
Bosco D, Costa R, Plastino M, Glucose metabolism in the idiopathic blepharoptosis: utility of the Oral Glucose Tolerance Test (OGTT) and of the Insulin Resistance Index. J Neurol Sci. 2009 Sep 15;284(1-2):24-28.
Abraham C, Rozmus CL. Is acanthosis nigricans a reliable indicator for risk of type 2 diabetes in obese children and adolescents? A systematic review. J Sch Nurs. 2012 Jun;28(3):195-205.
Yamashita LS, Cariello AJ, Geha NM. Demodex folliculorum on the eyelash follicle of diabetic patients. Arq Bras Oftalmol. 2011 Nov-Dec;74(6):422-424.
Simó R, Hernández C. Neurodegeneration is an early event in diabetic retinopathy: therapeutic implications. Br J Ophthalmol. 2012 Oct;96(10):1285-1290.
Ewing FM, Deary IJ, Strachan MW, Frier BM. Seeing beyond retinopathy in diabetes: electrophysiological and psychophysical abnormalities and alterations in vision. Endocr Rev. 1998 Aug;19(4):462-476.
Nittala MG, Gella L, Raman R, Sharma T. Measuring retinal sensitivity with the microperimeter in patients with diabetes. Retina. 2012 Jul;32(7):1302-1309.
Harrison WW, Bearse MA Jr, Ng JS et al. Multifocal electroretinograms predict onset of diabetic retinopathy in adult patients with diabetes. Invest Ophthalmol Vis Sci. 2011 Feb 9;52(2):772-777.
Ciulla TA, Amador AG, Zinman B. Diabetic retinopathy and diabetic macular edema: pathophysiology, screening, and novel therapies. Diabetes Care. 2003Sep;26(9):2653-2664.
Grosso A, Veglio F, Porta M, Grignolo FM, Wong TY. Hypertensive retinopathy revisited: some answers, more questions. Br J Ophthalmol 2005;89:1646-1654.
Wong TY, Klein R, Sharrett AR, et al. Retinal arteriolar narrowing and risk of diabetes in middle-aged persons. JAMA 2002 May 15;287(19):2528-2533.2002;287:2528–2553.
Recchia FM, Brown GC. Systemic disorders associated with retinal vascular occlusion. Curr Opin Ophthalmol. 2000 Dec;11(6):462-467.
Optometrists too often see the ophthalmic manifestations of diabetes-cataracts, glaucoma, ocular surface disease, nonarteritic ischemic optic neuropathy, cranial mononeuropathy, extraocular muscle palsy, and diabetic retinopathy. Patients with diabetes are also at high risk for other retinal-vascular disorders, including retinal vein and artery occlusion.
Dr. Chous completed his undergraduate education at Brown University and University of California, Irvine, and then received his MA and OD degrees with highest honors from University of California, Berkeley. He has a private practice specializing in diabetes eyecare and education in Tacoma, WA.
Proliferative diabetic retinopathy with vitreous hemorrhage and fibrovascular traction. (Photos courtesy of A. Paul Chous, OD.)
The Freedom Meditech ClearPath DS-120 measures lens fluorescence, a marker of long-term glycemic stress.