DIAGNOSIS
Physical Examination
Nonproliferative diabetic retinopathy (NPDR) is also known as background diabetic retinopathy in the internal medicine literature. While the term, “nonproliferative” suggests a nonprogressive condition to the diabetic patients and the nonophthalmic physicians, NPDR is not a benign or safe condition. As we are all aware, diabetic retinopathy is progressive and can be relentless in its course. Thus, it is vitally important that patients and the medical community understand that blindness can still occur if the patient is noncompliant with his diabetic treatment plan.
The pathologic processes of NPDR include the formation of capillary microaneurysms, vascular permeability, and capillary closure.
Microaneurysms are red, round dots, measuring 15 to 60 μm, most commonly found in the posterior pole. The mechanism for the formation of microaneurysms is unknown. It may be that there is a release of vasoproliferative factor with endothelial cell proliferation.
NPDR is classified into four levels of severity: mild, moderate, severe, and very severe. The extent of IRMA (intraretinal microvascular abnormalities), venous abnormalities, and retinal hemorrhages are the determining factors of mild, moderate, severe, and very severe NPDR.
Mild to moderate NPDR (also formerly known as background diabetic retinopathy) has few intraretinal hemorrhages and microaneurysms and minimal venous changes.
Severe NPDR (formerly known as preproliferative diabetic retinopathy) shows increasing ischemia and can be seen by examining the four quadrants for these characteristics: (i) severe intraretinal hemorrhages and microaneurysms in four quadrants, greater or equal to standard photograph 2A, (Fig. 7-1); (ii) venous beading in two or more quadrants; or (iii) moderate IRMA in at least one quadrant, greater than or equal to standard photograph 8A, (Fig. 7-2). This is the 4–2–1 rule.
FIGURE 7-1. Standard photograph 2A intraretinal hemorrhages and microaneurysms.
(Courtesy of the Fundus Reading Center, Madison, WI.)
FIGURE 7-2. Standard photograph 8A IRMA.
(Courtesy of the Fundus Reading Center, Madison, WI.)
Very severe NPDR is defined when two of the above characteristics are present. The retinopathy level of “very severe NPDR” is associated with rapid worsening of diabetic retinopathy to proliferative diabetic retinopathy (PDR).
Chief Complaint
The patient may complain of minimally decreased vision or may not have any visual complaints. The patient may be referred to the ophthalmologist for routine “screening” examination for diabetic retinopathy.
Patient History and Review of Systems
In taking the patient history, one can assess if the patient is knowledgeable or cognizant of the consequences of his diabetes. His responses to simple questions about duration of diabetes, history of postprandial blood sugar readings, fasting blood sugar (FBS) readings, and knowledge of blood sugar medications demonstrate his health literacy and compliance. Many times, the patient is referred to a specialist, but the patient thinks that he is there for a “baseline examination.” However, in reality, the patient has significant diabetic retinopathy or systemic manifestations of diabetes.1 Thus, the ophthalmologist and retinal specialist play the role of an educator who educates patients about diabetic retinopathy and diabetic eye disease.
If the patient cannot remember the name of his medication or how long he has had the disease, he must be newly diagnosed or his diabetes has not affected his activities of daily living. Or he could be in denial. In any case, the ophthalmologist is the diplomatic educator who tells the patient about the need for compliance in diabetes.2 In addition, the patient must understand the need for a “team” approach to diabetes: the patient and the medical doctors are a “team.” If the patient follows the instructions of his team of doctors, he will have a good treatment outcome. However, if the patient does not follow the treatment regimen for his diabetes, the treatment outcome may be disappointing.3 Consequently, the patient may suffer accelerated and severe vision loss along with systemic complications involving the heart and kidneys.3
Similarly, in asking about the review of systems, the ophthalmologist gains an understanding of the patient’s level of cardiovascular health, hypertension, and lipid metabolism.4 All these factors play a role in taking care of the patient. Weight issues and obesity play a role in diabetes and cardiovascular disease. It is estimated that 33.3% of men and 35.3% of women are obese.5,6 Smoking plays an adverse role in the development of diabetes.7 Smoking has been associated in the development of NPDR.8
Lastly, excessive alcohol intake can hamper the compliance of an ADA diet unless the patient takes into account that each glass of wine is 150 cal. Alcoholism in diabetic patients can result in loss of optic nerve function and thus, loss of vision over time.9,10
It is thought that the increase of obesity in the United States parallels the increase in cases of diabetes. Roughly, one third of adults in the United States are obese. In patients with diabetes, cardiovascular disease is a comorbid risk factor: the diagnosis of cardiovascular disease has been reported by 38.1% of adults with diabetes.11–13 Heart disease and stroke are responsible for 68% of deaths in diabetic patients. Diabetic adults have a two- to fourfold increase in heart disease death rates compared to nondiabetic adults.13
The metabolic syndrome is a constellation of interrelated risk factors of metabolic origins that appear to promote the development of atherosclerotic cardiovascular disease and increased risk of developing Type 2 diabetes mellitus.
The metabolic risk factors are atherogenic dyslipidemia, elevated blood pressure and elevated plasma glucose, or FBS. Thus, patients with the metabolic syndrome are at increased risk of developing diabetes. The history and physical examination will reveal these risk factors since they will play a role in the patient’s diabetes and diabetic retinopathy. The systemic risk factors, such as heart disease and elevated blood pressure, all are a part of the metabolic syndrome. These risk factors play a role in the development of retinal abnormalities such as “copper wiring” or “silver wiring” changes in hypertension, decreased blood flow in cardiovascular disease, or embolic phenomena in cardiovascular disease. While these retinal lesions are unrelated to diabetic retinopathy, they can decrease retinal function and cause visual disturbances, as well.
Family History
Patients with family history of severe diabetic retinopathy serve as a red flag for all ophthalmologists. Family history of death related to diabetes implies that the patient may have a genetic predisposition to severe diabetes and its complications.
Epidemiology
Certain ethnic groups are more prone to an accelerated course of diabetic retinopathy such as Pima Indians, Asians, and Native Americans. African Americans are more liable for hypertensive complications. When African Americans are diagnosed with diabetes, it may rapidly progress to severe diabetic retinopathy. Poor health literacy of chronic diseases such as diabetes is common among racial and ethnic minorities which may affect clinical diabetes outcomes2 (see Chapter 1). Similarly, obese individuals, who are Type 2 diabetics, may be at risk for rapid worsening of their diabetic retinopathy, as well. Certain ethnic groups, Asian Americans and Pacific Islanders are at a higher risk for diabetes than their Caucasian counterparts (Table 7-1).
TABLE 7-1 Nonproliferative Diabetic Retinopathy
1. Ask about comorbid associations: obesity, hypertension, cardiovascular disease, hyperlipidemia, and metabolic syndrome.
2. If comorbid conditions exist, diabetic retinopathy can be more severe and deteriorate quickly.
3. Ask that the patient’s laboratory results be sent to your office as well.
Examination
Patients with Visual Acuity of 20/20 to 20/40
Visual acuity, slit lamp examination and retinal examination are the standard examination techniques. These patients with NPDR usually present with visual acuity of 20/20 to the 20/40 range. These patients may or may not have abnormalities on Amsler grid testing. However, upon closer questioning, they will notice problems with driving at night more frequently than their nondiabetic counterparts with similar visual acuity. These patients note loss of visual acuity with reading or at the computer terminal.
If the visual acuity is <20/20, the ophthalmic exam will most likely reveal macular edema upon slit lamp biomicroscopy and some microaneurysms in the posterior pole. These patients may or may not need fluorescein angiography depending on their level of visual loss. Small changes in the internal limiting membrane at the fovea will lead to minor changes in visual acuity.
If the patient has background diabetic retinopathy with <30 microaneurysms, monitor the patient and tell him to continue to be vigilant with diet and medications. Follow the patient’s lipid profiles, FBS, and hemoglobin A1c (HbA1c). See the patient twice a year if he is compliant; otherwise, see him more frequently if patient experiences unexpected visual loss (Tables 7-2 and 7-3).
TABLE 7-2 Mild NPDR
Visual acuity: 20/20 to 20/40
1. If compliant and no comorbid conditions, see an ophthalmologist once a year.
2. Ask that the patient’s laboratory results be sent to your office as well.
3. If noncompliant, no comorbid conditions, see twice a year.
4. Ask that the patient’s laboratory results be sent to your office as well.
5. If noncompliant and with comorbid conditions, see three times a year or more if Amsler grid changes occur with home monitoring.
6. Ask that the patient’s laboratory results be sent to your office as well.
7. Be sure to emphasize to the patient that if visual loss occurs, he should come see the retinal specialist before their scheduled 4-month visit
TABLE 7-3 Moderate to Severe NPDR
Visual acuity: 20/20 to 20/40
1. Ask that the patient’s laboratory results be sent to your office as well.
2. See ophthalmologist twice a year if diabetes is the only disease and the patient has no comorbid conditions.
Patients with Visual Acuity of 20/50 to 20/80
These patients will probably have macular edema, dot blot hemorrhages, hard exudates, and cotton-wool spots. Their macular edema can present as mild or moderate, and the cotton-wool spots can occur in the area of the equator. Fluorescein angiography is needed for further evaluation and management of their macular edema. The Early Treatment Diabetic Retinopathy Study (ETDRS) classification can be used for treatment guidelines.14 Laser photocoagulation can be offered to these patients with clinically significant macular edema (CSME). OCT monitoring of the macular edema is useful for follow-up in these patients.
Patients with Visual Acuity of 20/100 to 20/400
While these NPDR patients do not have neovascularization, these patients can present with either severe macular edema with associated hard exudate rings or severe capillary nonperfusion at the retina. This type of patient is at a higher risk for developing PDR if he has risk factors such as obesity, dyslipidemia, hypertension, poor eating habits, and poorly controlled diabetes.
These patients’ prognosis for full recovery of vision to the 20/20 or 20/30 level will be guarded. However, recovery to the 20/40 level can be attained with laser treatment, treatment with anti-VEGF monoclonal antibodies such as bevacizumab, and medical treatment of their systemic disease of diabetes and hypertension. If obesity is an issue, diet and exercise must be addressed in the medical and ophthalmic rehabilitation of the patient.
Documentation
Fundus Photography, Fluorescein Angiography, or OCT
Documentation of the retinal findings is important not only for medicolegal reasons but for the patient education process. Fundus photography and fluorescein angiography are part of the standard of care for the diabetic eye patient. The fluorescein angiogram would reveal capillary nonperfusion to the clinician and thus enable more precise classification of the patient’s diabetic retinopathy. Neovascularization elsewhere can be difficult to see in the periphery in an uncooperative or anxious retinal patient, but fluorescein angiography can show areas of severe capillary nonperfusion in the equatorial region. The angiographic picture of neovascularization would lead the clinician to be more concerned about rapid acceleration to PDR. The subsequent treatment plans would be different if the patient had neovascularization versus no neovascularization. There would be a need for closer follow-up appointments in the person with areas of severe capillary nonperfusion.
The OCT can record the thickness of the macular retina with a scan of the retina’s anatomy in that region. In addition, the OCT provides a numerical reading of the actual thickness of the macula which can be followed over time. Lastly, there is a documentation of the change in Henle layer with the evolution of the patient’s macular edema.
SEVERE NONPROLIFERATIVE DIABETIC RETINOPATHY
Patients with Visual Acuity of 20/50 and Worse Vision
These patients with severe NPDR require monitoring of their FBS and HbA1c with an internal medicine and endocrinology colleague. By the time the patient reaches this stage of retinopathy, the patient will have an abnormal HbA1c and fasting blood glucose in the mid 150 to 200 range. Or in some instances, these patients have been lost to follow-up with their internist for several years. To rehabilitate a patient with severe NPDR requires a team approach. The team would include an internist, endocrinologist, nutritionist, and a nephrologist.
This type of patient will have more obvious macular edema in that he will complain about loss of vision at near. It is at this visual acuity threshold of 20/50 and beyond that the patient needs to be seen more frequently. Home monitoring of the Amsler grid is suggested to the patient. At the first sign of change or deterioration of vision, the patient should return for an ophthalmic examination.
If the patient has hypertension, cardiovascular issues, and hyperlipidemia, his macular edema may be difficult to treat if he is noncompliant. However, with laser treatment, the patient’s vision can be restored to a level of 20/40 or better vision.
Cotton-wool spots and areas of capillary nonperfusion and macular edema may require close monitoring. The patient can be seen at 1-month intervals especially in a patient with a history of noncompliance with diabetic medications.
In NPDR patients with only cotton-wool spots, watch the patient and tell him to continue to be vigilant with diet and medications. Follow patient’s lipid profiles, FBS, and HbA1c. See the patient every 4 months a year if he is compliant; otherwise, see him more frequently if the patient experiences unexpected visual loss (Table 7-4).
TABLE 7-4 Moderate to Severe NPDR
Visual acuity: 20/50 and worse + good glycemic control
Compliant with medications, diet, and exercise.
Ask that the patient’s laboratory results be sent to your office as well.
No comorbid conditions, see ophthalmologist three times a year.
Visual acuity: 20/50 and worse + poor glycemic control
Noncompliant.
Cardiovascular disease, hypertension, obesity, and lipid abnormalities.
Ask that the patient’s laboratory results be sent to your office as well.
See ophthalmologist three times a year or more if noncompliant and with comorbid conditions.
MACULAR EDEMA
Depending on the severity of macular edema, there can be a choice of monitoring the progress versus laser photocoagulation (Tables 7-5 and 7-6).
TABLE 7-5 Clinically Significant Macular Edema
1. Usually comorbid conditions exist at this point.
2. Ask that the patient’s laboratory results be sent to your office as well.
3. Ask that the patient’s laboratory results be sent to your office as well.
4. Use Amsler grid home testing.
TABLE 7-6 Metabolic Syndrome
Diagnosis by any three of the following characteristics:
1. Men: waist circumference ≥102 cm (≥40 in.) in men; >90 cm in Asian men.
2. Women: waist circumference ≥88 cm (≥35 in.) in women; ≥80 cm in Asian women.
3. Triglycerides ≥150 mg/dL.
4. HDL cholesterol (HDL-C) <40 mg/dL (men).
HDL-C <50 mg/dL (women).
5. Systolic blood pressure ≥130 mm Hg or diastolic blood pressure ≥85 mm Hg.
6. Fasting plasma glucose or FBS ≥100 mg/dL.
7. Patients receiving drug therapy to reduce triglycerides, raise HDL-C, lower blood pressure, or decrease glucose levels are considered to have a corresponding component of the metabolic syndrome.
Source: Grundy SM, Cleeman JI, Daniels SR, et al. Diagnosis and management of the metabolic syndrome: An American Heart Association/National Heart, Lung, and Blood Institute Scientific Statement. Circulation. 2005;112:2735–2752.
Patients with Visual Acuity of 20/20 to 20/30
In asymptomatic patients with the visual acuity of 20/20 to 20/30, the ophthalmic exam may or may not show CSME according to the ETDRS guidelines.14 This patient who is asymptomatic may only need patient education if there is no CSME.
If there is CSME with good visual acuity of 20/20 to 20/30 level, the patient is a candidate for laser treatment after he understands the ramification of treatment versus no treatment using the ETDRS guidelines.14 Informed consent is important for this group of patients.
Patients with Visual Acuity of 20/40
The visual acuity of 20/40 is a threshold for treatment for many patients since 20/40 is the visual acuity level needed to pass the driving test in many states. This group of patients is very motivated to see better. However, if this 20/40 patient opts for no treatment, the clinician can monitor him and ask him to check with the Amsler grid once a week. The patient needs to understand fully that the laser will preserve his vision in the long term, but in the short term, results may be some minor and immediate changes of vision as can be seen on Amsler grid testing. Informed consent is extremely important in this group of patients with relatively good visual acuity of 20/20 to 20/40.
Patients with Visual Acuity of 20/50 to 20/80
However, if the macular edema is 20/50 or worse and there is CSME on slit lamp biomicroscopy, laser photocoagulation can be offered. OCT and fluorescein angiogram are usually helpful to see the abnormal foveal net or areas of microaneurysms not seen by slit lamp biomicroscopy. With these patients, it is important that the clinician understands the ramification of treatment versus no treatment using the ETDRS guidelines.14 In addition, in patients who have 20/40 vision but are “asymptomatic,” or feel that they “see fine,” be careful in doing laser because they may see the scotoma postlaser and may be very unhappy postoperatively. For these patients who need to have macular laser, a preoperative visual field may be useful to map the central scotoma, and careful informed consent is necessary. The demonstration of macular edema on OCT and/or fluorescein angiography may be necessary in the informed consent stage.
Patients with Visual Acuity of 20/100 or Worse
These patients usually present with poor vision and have associated poor compliance with their medical treatment and/or obesity. Typically, these patients have the metabolic syndrome, have abnormal FBSs in the 150 range, and have HbA1c levels of >6.5%.
Previous Laser
These patients who have had previous macular laser will have residual macular edema. They need fluorescein angiography and OCT evaluations of their macula. From the fluorescein angiogram, the clinician will be looking for areas of capillary nonperfusion and areas of abnormal foveal capillary net. From the OCT, the ophthalmologist will be looking at the macular thickness measurement and the abnormalities of Henle layer.
These previously treated eyes are candidates for additional laser or bevacizumab intravitreal injection. It is important to warn these patients about a prolonged course of recovery. It must be emphasized that their diabetes must be under control during this time of visual rehabilitation.
No Previous Laser
In those patients who present for the first time to the ophthalmologist’s office with diabetic macular edema at the visual acuity level of 20/100 or worse, fluorescein angiography and OCT are needed to determine if there is focal or diffuse leakage. They are a candidate for macular laser using the ETDRS guidelines.15 The fluorescein angiogram will identify hundreds of additional microaneurysms not seen on regular fundus photography of the macular region. If this is the case, focal laser treatment can be performed. If upon OCT testing there are large foveal cysts, grid laser and bevacizumab may be offered together.
Glaucoma
Glaucoma is a blood flow problem for the optic nerve in some diabetic patients. Low-tension glaucoma can be seen in diabetic patients. In addition, glaucoma is difficult to diagnose in patients who have had previous panretinal photocoagulation, and therefore, their visual field will be abnormal. These patients will need more sophisticated testing such as Heidelberg retinal tomography or OCT documentation of the optic nerve. Gonioscopy is essential to look for rubeosis iridis at each follow-up visit. Central corneal thickness measurement can be used to calibrate Goldmann tonometry readings. They may have to come back for a few readings of the intraocular pressure in the mornings and in the late afternoons to establish the diurnal curve of their intraocular pressure. These patients may need provocative testing as well. Lastly, if the patient complains of visual disturbance not related to macular edema seen on OCT or fluorescein angiography, he may need a consultation with a glaucoma specialist.
MANAGEMENT OF NONPROLIFERATIVE DIABETIC RETINOPATHY
The treatment strategies for NPDR are based on the results of the Diabetic Retinopathy Study (DRS) and the ETDRS. The treatment of NPDR depends on the severity of retinopathy and the presence or absence of CSME which can be present at any stage of diabetic retinopathy.
The DRS has evaluated patients with severe NPDR or PDR and visual acuity of 20/100 or better. The DRS shows 50% reduction in severe visual loss in eyes that have received photocoagulation compared with eyes that have not received photocoagulation. Laser photocoagulation is designated as scatter or focal photocoagulation. Severe visual loss is defined as visual acuity of 5/200 or worse at two or more consecutively completed follow-up visits scheduled at 4-month intervals.
The ETDRS shows that for severe or very severe NPDR or early PDR, early scatter photocoagulation is effective in reducing severe visual loss in patients with Type 2 diabetes.16 For mild to moderate NPDR, the rates of severe visual loss between the early treatment group and deferred treatment groups were insignificant; thus, any reductions in severe visual loss do not seem sufficient to compensate for the unwanted side effects of scatter photocoagulation.17
Scatter Photocoagulation
The technique of a standard “full scatter” laser photocoagulation is 1,200 to 1,600 burns of moderate intensity. The spot size is approximately 500 μm. Green laser can be used with a Goldmann type contact lens. For the Goldmann contact lens, the power density is usually 300 to 500 MW for a 500 μm spot size. The different intensity strengths are proportional to the lens’ changes or pigmentation of the fundus.
There are a variety of lenses which allow for full scatter. In using a Rodenstock contact lens where the lens optics provide a wide-field view which is minified, the laser settings would be a 200-µm spot size with an appropriate power density. One could start with 200 MW power and increase the power until a yellow-white burn is achieved.
CLINICAL CORRELATIONS: Nonproliferative Diabetic Retinopathy 20/20 to 20/40
Patient complaints: Occasional difficulty in reading.
Caveats:This may be a screening examination only. The patient may need patient education and work toward attaining “health literacy.”
Case Study (Figs. 7-3 and 7-4)
FIGURE 7-3. Forty-three-year-old South Asian male with borderline Type 2 diabetes and 30 lb overweight.He has a family history of Type 2 diabetes in his mother, father, and both paternal and maternal grandparents. V 20/20 OD; V 20/30 NIPH OS. Fundus photographs were requested by the patient to send to his ophthalmologist in India, where he travels several months each year. Photo OD, NDR.
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