14th Annual Diabetes Report
Contemporary Care Protocols for DR and DME
New treatment paradigms for diabetic eye disease are enabling our patients to enjoy improved visual function and sustained visual acuity gains.
Diabetic retinopathy (DR) is the leading cause of blindness in the working-aged population of the western world. As the number of people living with type 2 diabetes mellitus continues to rise, eye care providers are seeing more cases of DR than ever before. Traditional treatment of DR still is an effective management approach. But, with newer, more effective options, such as MPLT and pharmacotherapy, the outcome profile for affected patients is changing for the better.
Carlo J. Pelino, O.D., and Joseph J. Pizzimenti, O.D.
This course is COPE-approved for 2 hours of CE credit. COPE ID is 35278-PS. Please check your state licensing board to see if this approval counts toward your CE requirement for relicensure.
This continuing education course is joint-sponsored by the Pennsylvania College of Optometry.
Drs. Pelino and Pizzimenti have no relationships to disclose.
Diabetic retinopathy (DR) is the leading cause of blindness in the working-age population of the western world. As the number of people living with type 2 diabetes mellitus (DM) continues to rise, eye care providers are seeing more cases of DR than ever before. In general, lethargy and obesity in children, adolescents and adults have widely contributed to this increased prevalence in type 2 DM.
DR is a microvascular disease. Proliferative DR is characterized by new vessel formation in the retina and optic disc as a result of hypoxia, microangiopathy and capillary occlusion. Tractional retinal detachment, diabetic macula edema (DME) and neovascular glaucoma are associated complications that may result in severe vision loss.
In 2005, we experienced a sea change in the preferred treatment of exudative age-related macular degeneration (AMD)—a shift from ablative therapy to pharmacotherapy. Now, another sweeping transition is occurring in the treatment of DR and DME, with thousands of patients achieving improved visual outcomes with fewer complications.
The Burden of Disease
People with DM are at an increased risk for a multitude of ocular complications. Common ocular symptoms in patients with DM include blurred or fluctuating vision, diplopia and ocular surface dryness. These individuals are 40% more likely to develop glaucoma and 60% more likely to develop cataracts than those without DM, according to the American Diabetes Association (ADA).1 More specifically, cataracts develop earlier and progress faster in patients with DM, and the risk of glaucoma increases with advanced age and longer disease duration.2,3
Other ocular anomalies associated with DM include decreased corneal sensitivity, iris neovascularization, pupillary abnormalities secondary to autonomic neuropathy, fluctuating refractive error associated with sorbitol in the lens, a "snowflake" cataract in patients with type 1 DM, optic nerve abnormalities and other cranial nerve neuropathies.4,5
Both the prevalence and the economic burden of DM and DR are on the rise.6 Patients with DR represent a large and growing segment of the American population with vision impairment. The Centers for Disease Control and Prevention estimates that DR causes 12,000 to 24,000 new cases of blindness each year.6 In fact, patients with DM are 29 times more likely to become blind than individuals of similar age and gender without diabetes.7,8
A loss of fine detail in central vision typically is one of the first and most common symptoms in patients with DR. Night vision problems, flashes and floaters are other, less common complaints. Severe and moderate levels of vision loss secondary to DR often are preventable with timely detection and treatment.9-14
Patients with DM may not understand the importance of dilated retinal examinations or recognize the benefits of early disease detection. Survey data published by the National Eye Institute indicated that just about half of all patients with DM obtained an annual dilated retinal exam.15
Pathophysiology of DR
Most individuals with DM ultimately develop some degree of retinopathy.13,16 DR results from an alteration in retinal blood flow that degrades the retina's performance. DR affects the retinal capillaries before it impacts the larger vessels.17-19 However, the exact cause of microvascular complications in DM is unknown.17,18
An early finding in DR is the loss of pericytes, which may cause leakage and dysfunction of capillary endothelial cells.17,18 Pericytes are the modified smooth muscle cells of capillaries that regulate retinal vascular flow via dilation and contraction. These mural cells provide structural support for the capillaries' endothelium and help constitute the inner blood-retinal barrier.
Excess glucose within the retinal capillary is thought to stimulate production of vascular endothelial growth factor (VEGF), protein kinase C and advanced glycation end-product.17,20 These biochemicals alter the capillary pericyte integrity. Over time, non-perfusion weakens the capillary walls, resulting in bulging, leaking or scarring. Outpouchings of the capillaries (microaneurysms) frequently are the earliest clinically detectable sign of DR. With tissue ischemia, angiogenic growth factors (such as VEGF) are upregulated and released, causing neovascularization and increased vascular permeability—both of which lead to retinal edema.18,21,22
Leakage from the perifoveal vessels may cause DME, which manifests as swelling or thickening of the central retina. DME continues to be a common cause of central vision loss and decreased quality of life in working-aged Americans.23,24 Results from the Wisconsin Epi-demiologic Study of Diabetic Retinopathy indicated that, after 15 years of known diabetes, the prevalence of DME is approximately 20% in patients with type 1 DM, 25% in patients with type 2 DM who take insulin and 14% in patients with type 2 DM who do not take insulin.25 In the United States, the incidence of DME approaches 30% in adults who have had DM for 20 years or more.
Also of note: The prevalence of DME in mild non-proliferative diabetic retinopathy (NPDR) is just 3%. However, this statistic balloons to 38% in eyes with moderate to severe NPDR, and 71% in eyes with proliferative reti-nopathy (PDR).25
DME occurs as a consequence of both vascular abnormalities and inflammatory processes. Both components interact with each other to promote disease progression. The vascular abnormalities stimulate the inflammatory processes that eventually lead to further vascular compromise and leakage. Hypoxia, altered blood flow, ischemia, toxicity and inflammation are processes that cause macular edema formation. Compromise to the inner blood-retinal barrier causes increased vascular permeability as well as extravasation of lipoproteins and other macromolecules. Over time, accumulation of intraretinal fluid in combination with macular thickening causes decreased visual acuity.19
Much more is now understood about the origins of diabetic inflammation. Leukocytes are recruited to the retinal vasculature after the retinal tissue has been stressed. Intracellular adhesion molecules eventually are expressed on the luminal surface of the vascular endothelial cells, which allows the adhesion of leukocytes and possible blockage of the capillary (known as leukostasis). In DR, the white blood cells no longer flow freely within the retinal vessels. Eventually, they damage and kill the cells that line the blood vessel wall. After adhesion occurs, several chemotactic molecules, such as monocyte chemo-attractive protein-1 (MCP-1), are secreted by the vascular lumen. MCP-1 influences the migration of leukocytes into the retinal tissues.
Once the leukocyte is inside the retina, a variety of inflammatory cytokine mediators, such as interleukin-1 beta, interleukin-6, tumor necrosis factor-alpha (TNF-alpha), insulin-like growth factor 1, stromal-cell derived factor-1 and VEGF-A, are secreted and propagate the vascular permeability process.19
Also, the insulin-sensitizing agents Avandia (rosiglitazone, GlaxoSmithKline) and Actos (pioglitazone, Takeda Pharmaceuticals) may increase the risk of DME in patients with type 2 DM who experience peripheral edema and weight gain.26 So, if your patients are using either agent, you may wish to switch them to an entirely different category of diabetes medications.
Clinical Features and Classification of DR
The classic clinical features of NPDR include dot- and blot-shaped hemorrhages, microaneu-rysms, intraretinal microvascular abnormalities (IRMA), venous beading, hard exudates (lipid), cotton-wool spots and retinal edema (figure 1).
Cotton-wool spots represent focal infarcts of the retinal nerve fiber layer (figure 2). IRMA are dilated and tortuous capillaries, and are good indicators of progressive DR. Venous beading is a focal irregularity in the caliber of retinal veins that serves as a strong predictor for the development of neovas-cularization.27
Ruptured microaneurysms, leaking capillaries and IRMA may result in intraretinal hemorrhages. The ophthalmoscopic appearance of these hemorrhages is consistent with the retinal level in which they occur.
Hemorrhages in the retinal nerve fiber layer have a flame-shaped appearance that is consistent with the layer's structure. (Also, note that flame-shaped hemorrhages typically occur in patients with hypertension.27) Hemorrhages located deeper in the retina assume a pinpoint, blot or dot shape and are more characteristic of DR.
While NPDR is characterized by a microangiopathy that involves intraluminal, intramural and extravascular damage, PDR is an entirely different disease entity. The hallmark of PDR is the formation of new blood vessels at the vitreoretinal interface and in the vitreous itself. Fibrovascular tissue proliferates on the surface of the retina, optic nerve and/or iris. After 15 to 20 years of DM, this proliferative form affects about 50% of patients with type 1 DM; 5% to 10% of patients with non-insulin- dependent type 2 DM; and 30% of patients with insulin-dependent type 2 DM.28
For an eye to be classified as having PDR, it must exhibit one or more of the following characteristics: neovascularization of the optic nerve head or disc (NVD); neovas-cularization elsewhere (NVE); or vitreous or pre-retinal hemorrhage associated with NVE (figure 3).29
Leakage from perifoveal vessels causes DME, which could result in permanent central vision loss if left untreated. This edema can occur at any stage of retinopathy, whether proliferative or non-proliferative. For macular edema to be classified as clinically significant (CSME), an eye must exhibit one or more of the following characteristics: thickening of the retina within 500µm of the center of the macula; hard exudates within 500µm of the center of the macula with associated thickening of the adjacent retina; or at least one zone of retinal thickening that is greater than one optic disc diameter in size.27,29
Is "tomographically significant" macular edema—visible on OCT but not on fundoscopy—changing the definition of what constitutes CSME? Clinical evidence certainly suggests so, because OCT yields both qualitative and quantitative information about retinal thickness and edema.
Thus, OCT can be helpful, in a non-invasive manner, to support a diagnosis of CSME or to rule it out. On OCT, CSME is represented by increased retinal thickening due to intraretinal fluid leakage, which appears as hyporeflective (dark) areas on the cross-sectional image (figure 4). Additionally, OCT is valuable in monitoring the eye's response to treatment.30
Further, there is now evidence that OCT plays a defining role in determining DME treatment criteria. Researchers from the Diabetic Retinopathy Clinical Research Network (DRCR.net) have recommended OCT-measured central retinal thickness values greater than or equal to 250µm as an eligibility criterion for at least 11 study protocols. In the RISE and RIDE studies, which investigated the efficacy of intravitreal ranibizumab in treating DME, an OCT-measured central subfield thickness greater than or equal to 275µm was used as one of the two eligibility criteria for treatment.30 Subsequently, the Safety and Efficacy of Ranibizumab in Diabetic Macular Edema With Center Involvement (RESOLVE) trial used an OCT-measured central retinal thickness of greater than or equal to 300µm, as well as with visual acuity parameters, as eligibility criteria for the treatment of DME with ranibizumab.30
As these studies indicate, OCT imaging could enable closer monitoring, more intensive systemic diabetes management and more timely treatment of DME.30
Management of Concomitant Diseases
Proper management of associated systemic disorders ultimately influences the onset, progression and visual outcome of DR.
* Hypertension. Systemic hypertension is an established risk factor for the development and progression of retinopathy. In the third U.S. National Health and Nutritional Examination Survey, hypertension was documented in up to 75% of adults with diabetes.31 Research has shown that individuals with DM and hypertension are more likely to develop DR, and likely experience more rapid disease progression compared to DM patients without hypertension.9 Additionally, DM patients with concomitant hyper tension are up to three times more likely to develop DME.
Fortunately, reduced blood pressure levels have been shown to decrease the risk of DR progression.9 Several antihypertensive agents have been evaluated for their therapeutic effect on DR. Angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor blockers have been shown to reduce DR progression in nor-motensive patients with type 1 DM and mild DR.32 In multiple trials, aggressive blood pressure treatment was accompanied by improved outcomes in both retinopathy and nephropathy. As a result, the Joint British Diabetes Societies have recommended that both type 1 and type 2 DM patients should be aggressively treated to blood pressure levels of less than 130mm Hg systolic and 80mm Hg diastolic.31
If any degree of proteinuria is present, the diastolic blood pressure should be lower than 75mm Hg. This research also indicated that any individual with DM should have a diastolic blood pressure lower than 75mm Hg if there is any evidence of retinopathy.31
* Kidney disease. Because DR is also associated with renal disease (proteinuria/albuminuria), diabetes patients with renal dysfunction should be monitored closely for progressive retinopathy. Also, any patient with rapidly progressing DR should be evaluated for possible nephropathy.9 Further, most patients with type 1 DM should receive ACE inhibitors to reduce the risk of progression from micro-albuminuria to macroalbuminuria.
* Elevated cholesterol. Dyslipidemia may also play a role in the progression of DR and DME— although there is conflicting evidence. Some studies have linked elevated HDL and total cholesterol levels with a higher incidence of DR.9 A cross-sectional analysis from the Wisconsin Epidemiology Study of Diabetic Retinopathy trial, however, showed no association between elevated cholesterol levels and the severity of DME in either type 1 or type 2 diabetes patients.9,33
Nonetheless, lipid-lowering medications should be considered for any diabetes patients with high cholesterol.9 Studies of fenofibrate mono-therapy have indicated that the drug may slow DME progression.34
* Anemia. Anemia is a common finding in patients with DM due to the high systemic burden of chronic kidney disease. Reduced hemoglobin levels independently help to identify DM patients who are at an increased risk for microvascular complications (including retinopathy), cardiovascular disease and mortality.35
Anemia often accompanies diabetic kidney disease. When glomerular filtration rates are less than 60mL/minute, the most common cause of the anemia is a relative erythropoietin deficiency that reduces hemoglobin levels to less than 11g/dL.31 An ETDRS analysis found that low hematocrit was a risk factor for the development of high-risk DR. A separate cross-sectional study uncovered an increased risk of retinopathy in patients with hemoglobin levels lower than 12g/dl.9
* Sleep apnea. Obstructive sleep apnea (OSA) is a common disorder that often coexists with DM.36 The consequences of OSA include cardiovascular morbidity (coronary artery disease/myocardial ischemia), cerebrovascular accident and overall mortality.36
Obesity, a well-known risk factor for type 2 DM, is also a risk factor for OSA. Patients with OSA often have a body mass index greater than 25kg/m2 and a neck circumference larger than 17 inches in men and 16 inches in women.36 Several studies also have found a link between OSA and hypertension.36-39 OSA may aggravate DR secondary to nocturnal hypertension and hypoxemia.
* Tobacco use. The role of smoking in DR has not been clearly established. Some studies have shown a definitive association, while others have shown no relationship when controlling for additional risk factors, such as age of onset and duration of diabetes and/or associated hypertension.31 Smoking increases circulating leukocytes and platelet activation. Nicotine in tobacco smoke causes severe retinal vasoconstriction. Smokers often exhibit higher levels of LDL and lower levels of HDL. Because the link between cigarette smoking and cardiovascular disease is well established—especially among patients with DM—it is essential that doctors encourage their patients to stop smoking.31
Treatment of DR (Without CSME)
* Treatment of NPDR (without CSME). NPDR is significant because of its potential to progress to PDR. The current stage of NPDR at the initial diagnosis dictates the patient's follow-up schedule.
Mild NPDR carries a 5% chance of progression to PDR in one year, and a 15% chance of progression to high-risk PDR within five years.27,40,41 Moderate NPDR has a 12% to 27% chance of progressing to PDR in one year, and a 33% chance of progressing to high-risk PDR within five years.27,40,41 Finally, severe NPDR has a 52% chance of progressing to PDR in one year, and a 60% chance of progressing to high-risk PDR within five years.27,40,41
Both the Diabetes Control and Complications Trial (DCCT) and the United Kingdom Prospective Diabetes Study showed the therapeutic benefit of intensive glycemic control in patients with type 1 and type 2 DM. Improved glucose control significantly reduced the likelihood of vitreous hemorrhage, retinopathy that required laser pho-tocoagulation and renal failure.10,42
Management of NPDR centers on stabilizing the condition and arresting the progression to PDR. The DCCT showed that intensive glycemic control involving multiple daily blood sugar measurements, nutritional counseling, and both medical and glycosylated hemoglobin evaluations every three months decreased the risk of the development and progression of retinopathy.10
The ADA recommends an interdisciplinary approach to management of DM and its complications, with close monitoring of blood pressure, blood glucose and cholesterol, as well as smoking avoidance/cessation, exercise and weight control.1,43 Further, proper instruction from a certified diabetes educator regarding self-management techniques is a mainstay of any interdisciplinary treatment approach.
* Treatment of PDR (without CSME). In cases of PDR, retinal imaging with fluorescein angiog-raphy is needed to determine if/ when the patient has reached any treatment landmarks, as well as to document any leakage patterns.17,29 Treatment of PDR usually involves laser surgery to seal leaking vessels (indirectly) and prevent further development of neovascularization. New, weaker blood vessels can rupture, scar and cause retinal tissue necrosis.
The Diabetic Retinopathy Study (DRS) and the Early Treatment of Diabetic Retinopathy Study (ETDRS) provided evidence that laser photocoagulation significantly reduced the risk of severe vision loss in patients with DR. Results of the DRS indicated that panretinal photocoagulation reduced the risk of severe vision loss in most (60%) patients with PDR.44 Earlier and more adequate treatment is effective in more than 90% of cases.11,45-47
The inherent retinal tissue scarring associated with thermal laser photocoagulation may cause reduced contrast sensitivity, poor dark adaptation and visual field loss. Intravitreal injections of anti-VEGF agents have been shown to be effective as individual and/ or combination treatments for PDR. Several studies are still being conducted to assess the safety of repeated intravitreal injections, which frequently are needed to achieve optimum benefit.48
Because thickened posterior vitreous cortex is one of the main factors in the development of disease proliferation in patients with PDR, a consequent shrinkage of the posterior vitreous cortex often leads to hemorrhages and tractional retinal detachments. In this instance, the new vessels use the posterior vitreous face as a scaffold. Therefore, some clinicians believe that PDR should be called "proliferative diabetic vitreoretinopathy."49
In some cases of PDR, vitrectomy surgery can be beneficial. Indications for vitrectomy include vitreous hemorrhage that blocks the view of the retina, dense premacular hemorrhage, complicated retinal detachment and severe neovascular proliferation that does not respond to laser treatment. The Diabetic Retinopathy Vitrectomy Study results showed that early vitrectomy was beneficial in restoring and preserving vision in patients with PDR with or without associated vitreous hemorrhage.49
So-called pharmacologic vitreolysis has been suggested as another important consideration for future management. Diabetes induces significant biochemical and structural changes within the vitreous. Because a diabetic vitreous is different from a normal vitreous, pharmacologic vitreolysis of a normal vitreous may fail to uncover an agent that is effective for pathologic conditions.
This may explain why Vitrase (hyaluronidase, Bausch + Lomb) failed in phase III FDA clinical trials for treatment of vitreous hemorrhage in patients with DR. Hyaluronidase is a vitreous lique-factant, not a vitreous interfactant. Thus, the agent will liquefy the gel vitreous, but will not induce vitreoretinal dehiscence. In PDR, this results in persistent traction on the neovascularization, which may lead to possible recurrent vitreous hemorrhage and vision loss.
It is worth noting that Ocriplasmin (microplasmin, ThromboGenics) likely will be the first drug approved for clinical pharmacologic vitreolysis in cases of symptomatic vitreomacular adhesion. Biologically, Ocriplasmin serves as both a liquefactant and an interfactant.50
Treatment of DR (With CSME)
Although PDR is more likely to cause severe vision loss (20/200 or worse) than NPDR, the most common cause of functional visual loss (worse than 20/40) in patients with DR is DME (specifically CSME). With more than 25 million people estimated to have DM in the United States, the morbidity of CSME has a significant impact on public health.33 So, CSME needs to be treated early—before chronic disease leads to irreversible functional vision loss.
* Conventional laser treatment.
Laser photocoagulation is the standard of care in the treatment of CSME. Focal or grid laser photo-coagulation reduces macular edema by inducing coagulation necrosis. Focal laser treatment is intended to close leaky microaneurysms, while grid laser is used to treat more diffuse edema.46
The goal of laser treatment for CSME is not to improve vision, but to slow or prevent central visual loss as a result of chronic edema and secondary tissue damage. The ETDRS indicated that focal or grid laser photocoagulation reduced the risk of moderate visual loss due to CSME by 50%.51
As previously mentioned, the anatomical and visual benefits of laser photocoagulation have been shown to be effective over the long term; however, the treatment of DME is associated with risks and side effects caused by iatrogenic damage of retinal tissue.
* Micropulse laser treatment.
Micropulse laser technology (MPLT) has been shown to be as effective as conventional argon laser for DME.52 Micropulse technology with 810nm and 577nm lasers is used to produce a therapeutic effect without inducing collateral retinal damage during or after treatment.53 With MPLT, the induced temperature increase in the targeted tissue remains sublethal, and no visible lesion is produced (subvisible-threshold). Micropulse power as low as 25% of the visible threshold intensity has been shown to be have a therapeutic effect, while sparing neurosensory retinal tissue.53
MPLT is less destructive to tissue, yet achieves the desired therapeutic effect. For instance, one study showed that MPLT appears to be as effective as laser photo-coagulation for the treatment of DME, but causes far less damage to the retinal pigment epithelium.54
* Pharmaceutical options.
Although laser therapy may slow visual loss, it is not often accompanied by visual gain. This led to evaluation of other CSME management options, including potential pharmacologic therapies that may be used alone or in combination with laser therapy.
The anti-inflammatory effect of intravitreal corticosteroids contributes to a reduction of edema.55 More specifically, intravitreal triamcinolone has been shown to reduce macular edema and improve visual acuity.56,57 However, the short-term effect of steroids necessitates multiple treatments, which may increase the risk of adverse effects, including ocular hypertension, glaucoma, cataract, retinal detachment, epimacular membrane and endophthalmitis.
Sustained-release devices containing the corticosteroids dexa-methasone and fluocinolone may provide long-term therapeutic benefits, and are undergoing clinical trials. However, such devices also may increase the patient's risk for the aforementioned adverse effects.
A large, multicenter study that compared intravitreal triamcinolone with laser photocoagulation was designed to help elucidate the therapeutic role of steroids in CSME management.58 The researchers determined that, over a two-year period, focal/grid photo-coagulation was more effective and had fewer side effects than 1mg or 4mg doses of preservative-free intravitreal triamcinolone. These results also suggest that focal/grid photocoagulation should remain the benchmark against which other CSME treatments are compared in future clinical studies.58
Recently, several studies have evaluated the therapeutic effect of anti-VEGF agents on CSME.59,60 It appears that pan-VEGF-A inhibitors (which block uptake of all VEGF-A isoforms) exhibit better bioactivity than selective VEGF-A inhibitors in patients with CSME.48
Eylea (aflibercept, Regeneron Pharmaceuticals) is a recombinant fusion protein that inhibits the function of both VEGF-1 and VEGF-2 receptors. The DA VINCI study showed that aflibercept, compared to macular laser photoc-agulation, produced a statistically significant and clinically relevant visual acuity improvement in patients with DME.60
DRCR.net conducted a randomized controlled trial to assess whether an intravitreal injection of Lucentis (ranibizumab, Genen-tech/Roche) combined with either prompt or deferred laser or intra-vitreal triamcinolone acetonide combined with prompt laser could improve visual acuity outcomes for patients with DME when compared to focal/grid photocoagulation.61 This Phase III study clearly showed that intravitreal Lucentis, with either prompt or deferred laser, provided superior anatomic and functional outcomes in individuals with DME through two years of follow-up compared to laser therapy alone.61
* Surgical intervention. Vitrectomy also may aid in the resolution of DME. The initial rationale for use of vitrectomy was justified by evidence from early epidemiologic studies. Researchers observed a lower incidence of complete posterior vitreous detachment in patients with DME than in those without evidence of edema.62 This finding suggested that a partially attached vitreous is a risk factor for DME, and that vitrectomy will remove the tractional forces at the retinal surface, reduce oxygen consumption of the vitreous and reduce hypoxia at the retina.62
On the basis of currently available data, we don't know yet if prolonged ocular treatment with anti-VEGF agents will yield increased systemic side effects, such as hypertension and cardiovascular or thromboembolic events. The probable need for repeated injections also elevates the risk of visually devastating ocular side effects, such as endophthalmitis.63
Combination therapy comprised of laser and pharmacologic agents potentially can yield additional benefits, including improved visual outcome and less frequent re-treatments—which, in turn, can reduce the risk of adverse events.
The longer a patient has been living with diabetes, the more likely it is that he or she will develop DR. Diabetic retinopathy is a significant public health problem, especially among blacks and Hispanics. Fortunately, however, DR is a treatable condition.
Traditional treatment of DR still is an effective management approach. But, with newer, more effective options, such as MPLT and pharmacotherapy, the outcome profile for affected patients is changing for the better.
Dr. Pelino is an assistant professor at Pennsylvania College of Optometry at Salus University in Elkins Park, Pa. Dr. Pizzimenti is an associate professor at Nova Southeastern University College of Optometry in Fort Lauderdale, Fla. Together, they co-author our "Review of Systems" column.
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