In the United States, the estimated prevalence of diabetes mellitus (DM) is between 4.4-17.9 %. While diabetes has a major impact on quality of life and economics, the associated vascular complications result in approximately 14 % of US health care expenses.
The complications of DM are divided into macrovascular (coronary artery disease, stroke and peripheral arterial disease) and microvascular (retinopathy, nephropathy, and neuropathy).
Diabetic retinopathy (DR) is the most common and potentially the most devastating ophthalmic complication of diabetes. DR is classified as non-proliferative and proliferative. Approximately 700,000 people in the United States have proliferative retinopathy, with an annual incidence of 65,000 cases.
Approximately 75% of the patients with retinopathy remain asymptomatic until the late stages. Recent studies have estimated a 28.5% prevalence of retinopathy amongst diabetics aged 40 years and older. DR is one of the most important preventable causes of visual loss worldwide, and a major cause of visual impairment in patients 25 to 74 years of age.
Duration of diabetes is probably the strongest predictor for development and progression of retinopathy. At the time of diagnosis, DR is unusual in patients with type 1 diabetes, but 20-40% of patients with type 2 diabetes will have some degree of retinopathy. Twenty years after the diagnosis, nearly 99% of patients with type 1 and 60% with type 2 will have retinopathy.
Intensive glucose control has decreased the prevalence of retinopathy, as demonstrated in the Diabetes Control and Complications trial (DCCT) for type 1 diabetes and the United Kingdom Prospective Diabetes Study (UKPDS) for type 2 diabetes.
Maintaining the HbA1c level below 7% can substantially reduce the incidence and delay the onset and progression of DR. Treatment of hypertension offers further substantial benefit with a goal blood pressure less than 140/90 mm Hg. Additionally, aggressive pharmacotherapy for dyslipidemia and maintaining a healthy lifestyle, i.e. physical activity and smoking cessation, may be beneficial. Progression of proliferative retinopathy to blindness can often be prevented by panretinal photocoagulation.
Worsening of DR in pregnant women with pre-existing retinopathy may occur, requiring close monitoring during pregnancy and the first year postpartum.
Diabetic retinopathy does not occur in isolation and is typically associated with other microvascular and macrovascular complications. Compared to those without retinopathy, patients with DR have a greater incidence of myocardial infarction, stroke, need for revascularization, and cardiovascular disease associated death.
Undoubtedly, these patients typically have other metabolic risk factors, such as hypertension and hyperlipidemia; however, after adjusting for hypertension and nephropathy, the risk of cardiovascular events remain two-fold higher for patients with proliferative DR (but not for those with non-proliferative retinopathy).
The diabetic foot
Diabetic foot infections are the most common skeletal and soft-tissue infections in patients with diabetes. Both types of diabetes confer a 30-fold higher risk of lower extremity amputation due to infection compared with patients without diabetes.
Diabetic foot complications can range from cellulitis to chronic osteomyelitis. These complications arise with local trauma in the setting of neuropathy, compromised vascular supply, and immunosuppression. Prevention, early recognition, and early treatment may help protect from amputations and surgical intervention.
According to the National Institutes of Health, the National Diabetes Statistics reported the lifetime incidence of diabetic foot ulcer in individuals with diabetes is about 25%. Every 30 seconds there is a limb lost somewhere in the world due to complications of diabetes. Every 24 hours there are about 230 amputations performed in the US for complications of the diabetic foot.
Diabetic nephropathy is a potentially devastating microvascular complication of both type 1 and type 2 diabetes, and it is the most common type of proteinuric kidney disease. Longstanding hyperglycemia leads to changes in the kidney, such as glomerular sclerosis, basement membrane thickening, and mesangial expansion. Diabetic nephropathy is the leading cause of kidney disease in those on chronic renal replacement therapy.
The major manifestation of diabetic nephropathy is albuminuria, which is further separated into microalbuminuria (urinary albumin excretion of 30-300mg on 24 hour urine collection or 30-300mg/g Cr on a spot urine sample) and macroalbuminuria (urinary albumin excretion over 300mg on 24 hour urine collection or over 300mg/g Cr on spot urine). Microalbuminuria is less severe but predicts high risk for future nephropathy. Untreated macroalbuminuria can lead to a decline in the glomerular filtration rate (GFR) and eventual end stage renal disease (ESRD).
Fifteen years after the diagnosis of DM, 20-30% of patients with type 1 diabetes will have microalbuminuria, which can regress, stay stable, or progress to overt nephropathy depending on glycemic control and blood pressure control. Overt nephropathy typically occurs 10-15 years after onset of type 1 diabetes. However, if there is no proteinuria after 20-25 years, the risk of developing overt renal disease is much lower.
Less than 2% of the patients treated intensively in the DCCT/EDIC trial developed chronic renal insufficiency (serum Cr >2 mg/dl or renal replacement therapy) after having DM for 30 years. Although the use of angiotensin converting enzyme inhibitors (ACEI) and angiotensin receptor blockers (ARB) can reduce the rate of progression of diabetic kidney disease, these agents alone cannot prevent diabetic nephropathy.
The United Kingdom Prospective Diabetes Study (UPKDS) showed that in type 2 diabetes, at 10 years after diagnosis, 25% of patients will have microalbuminuria, 5% will have macroalbuminuria, and 0.8% will have chronic renal insufficiency (elevated plasma creatinine concentration over 2mg/dl or requirement for renal replacement therapy).
Similar to type 1 diabetes, microalbuminuria in type 2 DM can regress, stay stable, or progress. The time from onset of diabetes to the time of proteinuria or end stage renal disease is similar in type 1 diabetes and type 2 diabetes.
II. Diagnostic Approach.
A. What is the differential diagnosis for this problem?
Acutely elevated blood pressure leads to vasoconstriction and endothelial damage leading to leakage of plasma, mural thickening, and luminal narrowing. The following findings may be evident on retinal exam: generalized or focal arterial narrowing, arterio-venous nicking, retinal hemorrhages, cotton-wool spots, hard exudates and optic disc swelling.
There are a lot of similarities between hypertensive and diabetic retinopathy, but there are some distinguishing features. Retinal vessel narrowing, tortuosity, and nicking, cotton-wool spots, and optic disc swelling are more commonly seen in hypertensive retinopathy, whereas microaneurysms, macular swelling, and new vessel formation are more often associated with diabetes and are not typical for hypertension.
Retinal venous occlusion (central retinal vein occlusion or branch retinal vein occlusion)
After diabetic retinopathy, retinal vein occlusion is the second most common cause of vision loss. This results from a thrombus forming at the central retinal vein near the lamina cribrosa. It is characterized by diffuse retinal hemorrhages, venous dilation and tortuosity, optic disc swelling, cotton wool spots and macular edema. It is a common cause of iris neovascularization, which may lead to secondary glaucoma. Branch vein occlusion occurs usually at the crossing of retinal artery and vein, and manifests as a wedge-shaped pattern of above findings with the tip pointing towards the etiologic crossing.
Sickle cell retinopathy
Most severe in HbSC disease > S Thal > SS > SA. This can have seafan-shaped retinal neovascularization, retinal hemorrhages, vitreous hemorrhage, and retinal detachment. Comma-shaped conjunctival vessels may also be seen.
Suspect in patients with a history of HIV/AIDS. Usually asymptomatic, with retinal findings of cotton-wool spots, Roth spots, and retinal hemorrhages.
Dose-dependent complication following exposure to any type of radiation. Occurs months and years after radiation treatment. Diabetes is one of the risk factors. This clinically presents as painless loss of vision. Microaneurysms, telangiectasias, neovascularization, vitreous hemorrhage, macular edema and tractional retinal detachment can be found on retinal exam. Detailed history is important in the differential diagnosis.
Retinal hemorrhages can be found; mechanism for fundus lesions is not well understood.
Idiopathic juxtafoveal retinal telangiectasia
Telangiectatic alterations of the juxtafoveolar capillary network of one or both eyes.
Ocular ischemic syndrome
An uncommon condition of chronic arterial hypoperfusion to the eye, often with gradual or sudden vision loss. This usually results from stenosis or occlusion of the common or internal carotid arteries with atherosclerosis being the most common cause. It manifests as vision loss, orbital pain, corneal edema, mild anterior uveitis, retinal hemorrhages, cotton-wool spots, and dilated retinal veins. Other signs may include iris neovascularization and secondary glaucoma, asymmetric cataract, iris atrophy, neovascularization at the optic disc and in the retina, cherry-red spot, and vitreous hemorrhage.
May involve almost all ocular structures, but on fundoscopy, may show engorged retinal veins, retinal hemorrhages, Roth spots, cotton-wool spots, optic nerve edema, and boat-shaped pre-retinal hemorrhage.
Fluid and protein deposition under the macula causing blurred vision. Multiple etiologies include diabetes, venous occlusion, Irvine-Gass syndrome (after cataract surgery), epinephrine, retinitis pigmentosa, and nicotinic acid.
The diabetic foot
Differential diagnosis for the erythematous diabetic foot:
Arthritis: inflammatory, Lyme, sarcoid.
Sickle cell crisis.
Deep vein thrombosis.
Venous insufficiency and chronic venous stasis.
Differential diagnosis for elevated urine albumin excretion:
Patients often have dysuria, fever, or other systemic signs or symptoms of infection; however, they may be asymptomatic.
Usually thought with known history of malignancy or kidney stones.
Systemic Lupus Erythematosus (SLE) or cryoglobulinemia
Patients may have a history of skin rash or arthritis.
Patients should be asked about HIV risk factors or diagnosis.
Patients may have a history of liver disease or hepatitis C risk factors.
Patients may have a history of liver disease or hepatitis B risk factors.
Patients may have a history of proteinuria and hypertension in childhood or pregnancy.
Polycystic kidney disease
There may be a family history of kidney disease.
Hypertension is a common cause of non-proteinuric kidney disease, but is usually not associated with proteinuria in the absence of other pathology.
B. Describe a diagnostic approach/method to the patient with this problem.
The diabetic foot
All diabetics should have at least one comprehensive foot exam per year, and visual inspection should be done on each follow up visit. Patients at higher risk of developing foot ulcers may require more frequent comprehensive foot exams. Basic screening includes a history of diabetic and vascular complications and examination of the feet, including skin, distal pulses, and sensation.
Increased urinary protein is the first clinical finding of diabetic nephropathy. All patients with type 2 DM should be screened annually with urine testing from the time of diagnosis, since most have had years of hyperglycemia prior to diagnosis. The American Diabetes Association recommends annual screening of all type 1 diabetics starting at 5 years from diagnosis
Abnormal results should be repeated over months because false positives can occur in cases of acute illness, infection, vigorous exercise, heart failure, short term hyperglycemia, or acutely uncontrolled hypertension. These conditions can independently lead to elevated urine albumin excretion.
1. Historical information important in the diagnosis of this problem.
Since patients are typically asymptomatic until the late stages of diabetic retinopathy, treatment options become limited. Therefore, regular screening is important for early detection, treatment, and reduction of disease progression. All newly diagnosed diabetics should undergo an initial comprehensive, dilated eye exam by an optometrist or ophthalmologist who is experienced in diagnosing and treating retinopathy. For patients who do not have the resources for comprehensive eye exams, retinal camera screens are a less expensive alternative.
For type 1 DM, the initial eye exam should be done within 5 years of diagnosis of diabetes. Once the patient is over age 10, then exams should be done annually.
For type 2 DM, the initial eye exam should be done at the time of diagnosis.
Subsequent examinations for patients with type 1 and type 2 DM should be repeated annually. Less frequent examinations (every 2-3 years) may be cost-effective after one or more normal eye exams in patients with well-controlled type 2 DM. More frequent examinations are required if retinopathy is progressing.
For gestational diabetes, pregnant women should have an eye examination in the first trimester of pregnancy and should be followed closely throughout pregnancy up until 1 year postpartum. Pregnant women with pre-existing diabetes have a much quicker progression to retinopathy and need to be counseled.
Joint contractures and neuropathy due to diabetes also increase the likelihood of a patient having diabetic retinopathy. A recent meta-analysis also shows that diabetic retinopathy is a predictor for other microvascular disease, particularly nephropathy.
Duration of DM.
Pregnancy in type 1 DM (laser photocoagulation can minimize the risk of progression and vision loss).
The diabetic foot
The two most common risk factors for developing diabetic foot ulcers are diabetic neuropathy and peripheral arterial disease. Early recognition and management of risk factors can prevent or delay the adverse outcomes.
The following are associated with an increased risk of foot ulcers and the need for amputations:
Prior foot ulceration or amputation.
Diabetic nephropathy (especially patients on dialysis).
Peripheral vascular disease: ankle brachial index <0.9.
Poor glycemic control.
Therefore, a careful history should include symptoms of numbness or tingling, decreased sensation, prior foot ulcers, cigarette smoking, claudication, a history of vessel bypass or amputations, average glycemic control, and the presence of other micro or macrovascular complications.
General foot self-care education should be provided to all patients with diabetes.
Patients with complaints of leg discomfort are recommended to be screened with the following questions to obtain a quantitative assessment of symptoms:
What is the sensation felt? – Burning, numbness, or tingling (2 points); fatigue, cramping, or aching (1 point). Maximum is 2 points.
What is the location of symptoms? – Feet (2 points); calves (1 point); elsewhere (no points). Maximum is 2 points.
Have the symptoms ever awoken you at night? – Yes (1 point).
What is the timing of symptoms? – Worse at night (2 points); present day and night (1 point); present only during the day (no points). Maximum is 2 points.
How are symptoms relieved? – Walking around (2 points); standing (1 point); sitting or lying or no relief (no points). Maximum is 2 points.
The total symptom score can then be determined:
0 to 2 – Normal.
3 to 4 – Mild.
5 to 6 – Moderate.
7 to 9 – Severe.
Diabetic retinopathy is commonly associated with other diabetic microvascular complications, namely neuropathy and retinopathy. Retinopathy often precedes nephropathy. However, in addition to diabetic nephropathy and diabetic retinopathy, there are other renal and ophthalmologic complications associated with diabetes. Patients with type 2 DM may have renal insufficiency due to glomerular causes independent of diabetes.
None of the following are predictive, but there are many factors associated with an increased risk of diabetic nephropathy.
For both types of DM, the likelihood of developing diabetic nephropathy is increased in patients with a first degree relative who has diabetic retinopathy. Many other genes are also currently being studied.
Advancing age and longer duration of the disease are associated with an increased risk of albuminuria.
Poorly controlled hypertension is associated with progression of renal disease.
Glomerular hyperfiltration has been associated with an increased risk of diabetic renal disease due to hypertrophy and increased renal size, possibly as a response to hypertension.
Poor glycemic control
Worsened glycemic control is associated with more rapid progression to diabetic retinopathy.
Higher body mass index (BMI) is associated with a higher incidence of diabetic nephropathy.
Smoking tobacco is associated with a higher incidence of diabetic nephropathy.
2. Physical Examination maneuvers that are likely to be useful in diagnosing the cause of this problem.
Direct ophthalmoscopy is reasonable for screening when performed by well-trained primary care physician. Indirect ophthalmoscopy can be done by an optometrist or ophthalmologist. However, the accuracy of ophthalmoscopy is lower when performed by primary care physicians.
The diabetic foot
The ADA, in conjunction with the American Association of Clinical Endocrinologists, asserts that while history is important, a careful foot exam is key in risk assessment. The bare feet should be examined in a well lit room, and shoes should be evaluated to ensure appropriate fit and effective barrier. The size and fit of the shoe may increase the risk of calluses, abrasions, and blisters.
The foot examination should include:
Inspection: skin color, thickness, cracking, dryness, sweating, ulcerations, calluses, blisters, fungal or nail infections.
Musculoskeletal: muscle wasting between metatarsals, deformity such as claw toes, prominent metatarsal heads, Charcot joint.
Testing for loss of protective sensation (LOPS) consists of (one or more abnormal tests suggests LOPS):
Neurologic: 10-g monofilament in addition to any one of the following:
Vibration using a 128-Hz tuning fork: Place a 128-Hz tuning fork on the bony prominence of the dorsum of the great toe proximal to the nail bed. Ask the patient to report the perception of the start of vibration sensation and the cessation of vibration on dampening. Repeat this on each first toe once.
Vibration perception threshold (VPT).
Consider obtaining ankle brachial index (ABI) as many patients with peripheral arterial disease are asymptomatic.
Venous filling time: With the patient in a supine position, identify a prominent pedal vein then elevate the leg to 45 degrees for 1 minute, causing the vein to collapse. Following this, have the patient sit up and hang the leg over the examination table. If it takes longer than 20 seconds for the vein to bulge above the skin, then significant arterial disease is likely present.
Pain and Temperature sensation.
The Neuropathy Disability score has also been validated:
Achilles tendon reflex – absent (2 points for each foot); present with reinforcement (1 point for each foot).
Vibration sense Rydel-Seiffer tuning fork – absent or reduced (1 point for each foot).
Position or sensation – absent or reduced (1 point for each foot).
What is the temperature sensation? – reduced (1 point for each foot).
The neurologic signs score can then be determined:
0 to 2 – normal
3 to 5 – mild
6 to 8 – moderate
9 to 10 – severe
Signs concerning for neuropathy include foot deformities, diminished sweating, cracked skin, decreased sensation to monofilament, decreased pain and temperature sensation, and loss of vibratory sensation.
Signs concerning for peripheral arterial disease (PAD) include absent distal pulses, femoral bruits, decreased skin temperature, pallor, lack of hair, and prolonged venous filling time. A diagnostic ABI should be performed in individuals over the age of 50 years old with DM per ADA consensus statement recommendations and should be considered in patients under 50 years old who have additional PAD risk factors (smoking, hypertension, hyperlipidemia, or duration of DM >10 years).
Signs heralding a developing foot ulcer include lesions between toes (sign of tight shoes), calluses, and painless macerated regions between toes.
Signs of diabetic nephropathy usually cannot be detected physical exam until one reaches end stage renal disease. Patients may note foamy urine from proteinuria. However, exam findings of diabetic neuropathy and diabetic retinopathy may be predictive of diabetic nephropathy.
3. Laboratory, radiographic and other tests that are likely to be useful in diagnosing the cause of this problem.
Seven-field stereoscopic fundus photography
This is comparable in yield to ophthalmoscopy, but it also requires both a trained photographer and a trained reader.
Digital stereoscopic retinal imaging
This allows remote interpretation by an ophthalmologist, which may improve retinopathy screening in areas with a shortage of eye care specialists. It does not require fundal dilation and takes 15-20 minutes. When compared to dilated fundoscopic examination, digital imaging has good sensitivity and specificity for detecting diabetic retinopathy.
This is an adjunct in the diagnosis and management of diabetic retinopathy. This can help in evaluating for macular ischemia, neovascularization, and guide treatment for macular edema.
Optical coherence tomography (OCT)
OCT uses light to generate a cross-sectional image of the retina. This is used to determine the thickness of the retina and the presence of swelling within the retina as well as vitreomacular traction. This test is particularly used for the diagnosis and management of diabetic macular edema.
Ultrasound can be used to evaluate the status of the retina if the media is obstructed by opacity (vitreous hemorrhage, cataract, cloudy cornea). It is used to look for mass, retinal detachment, and vitreous debris.
The diabetic foot
A complete blood count (CBC) may show leukocytosis with a neutrophilic predominance with infection. Markers of inflammation such as ESR and CRP can also be elevated when bony involvement is present. However, these tests are non-specific.
Blood cultures should be drawn but may not be positive, especially in chronic osteomyelitis. Deep tissue cultures are preferred over wound cultures. Bone biopsy in the operating room is useful for chronic osteomyelitis.
A biothesiometer (electric tuning device) can evaluate the threshold for vibration sensation.
Ankle brachial pressure index (ABI) can detect poor vascular status in peripheral arterial disease.
Plain radiographs can assess for structural foot deformities, foreign bodies, and soft tissue gas. Plain radiographs have low sensitivity for early osteomyelitis; later in the course, plain radiographs may show soft-tissue swelling and periosteal elevation.
Magnetic resonance imaging (MRI) is more sensitive for detecting osteomyelitis. Other imaging modalities for osteomyelitis include the Technetium-99m methylene diphosphonate bone scan, Gallium-67 citrate scan, and Technetium-99m hexamethyl-propyleneamine oxime-labeled white blood cell scan.
Peak plantar pressure assessment
Use a force platform and special software to measure peak and average pressure, force, and area of the foot.
Laboratory Testing: The ADA recommends annual creatinine (Cr) measurement to screen for rises in the creatinine and to estimate the glomerular filtration rate (GFR).
Urine testing should be done annually to screen for proteinuria.
Spot urine albumin to creatinine (Cr) ratio.
24 hour urine collection for albumin.
Ultrasound: Kidney size appears normal or increased in early diabetic kidney disease, but later in disease, size is decreased. Renal ultrasound can also rule out obstruction or possibly stones.
Urinalysis should be done to rule out infection.
Testing for HIV, hepatitis B, hepatitis C, or rheumatologic disease may be indicated based on the patient’s history.
C. Criteria for Diagnosing Each Diagnosis in the Method Above.
Diabetic macular edema
Diabetic macular edema (DME) is retinal thickening and edema involving the macula, and it can occur at any stage of diabetic retinopathy. Macular edema can be visualized most directly by optical coherence tomography (OCT; a non-invasive low energy laser imaging technology), but it can also be appreciated on a fundoscopic exam with stereoscopic viewing and fluorescein angiography.
Clinically Significant Macular Edema (CSME) is an indication for treatment either by vascular endothelial growth factor (VEGF) inhibitor injection or laser.
CSME is defined as one of the following:
Retinal thickening within 500 microns of the center of the macula,
Hard exudates within 500 microns of the center of the macula with adjacent retinal thickening.
Retinal thickening greater than one disc diameter in size, within one disc diameter from the center of the macula.
Non-proliferative diabetic retinopathy
Non-proliferative diabetic retinopathy (NPDR) involves infarcts that appear as cotton-wool spots, intraretinal hemorrhages, hard exudates, and microvascular abnormalities (occluded vessels, dilated vessels, tortuous vessels, microaneurysms). Most of these abnormalities can be seen in the macula and posterior retina.
NPDR is further classified as follows:
Mild NPDR: microaneurysms only.
Moderate NPDR: More than microaneurysms, but not enough to qualify for severe NPDR.
Severe NPDR: at least one of the following:
Severe hemorrhages and microaneurysms in all four quadrants of the fundus.
Venous beading in at least two quadrants.
Severe intraretinal microvascular abnormalities.
The above is also known as the “4-2-1 rule”.
Very Severe NPDR: two or more of the criteria for severe NPDR but without proliferative diabetic retinopathy.
Severe NPDR has a 15% progression to proliferative diabetic retinopathy (PDR) in 1 year. Very severe NPDR has a 50% progression to PDR in 1 year.
Proliferative diabetic retinopathy
Proliferative Diabetic Retinopathy (PDR) is more advanced and is diagnosed when there is neovascularization from the disc, iris, and/or retinal vessels. Neovascularization can lead to preretinal and vitreous hemorrhages, subsequent fibrosis, and traction retinal detachment.
PDR is further classified as follows:
Early PDR: neovascularization present.
High-Risk PDR: one of the following:
Neovascularization of the disk more than 1/3 to 1/2 disk area.
Neovascularization of the disk and vitreous or preretinal hemorrhage.
Neovascularization elsewhere in >1/2 disk area with vitreous or preretinal hemorrhage.
High risk PDR is typically when pan retinal photocoagulation (PRP) is done. Asymmetric diabetic retinopathy (DR) may be a sign of carotid disease and warrants further investigation.
The diabetic foot
The Wagner Classification for diabetic foot wounds is based on clinical evaluation of the foot, but it does not take into account perfusion, extent, depth, infection, and sensation, which are the basis for the PEDIS scoring system:
Grade 0 – No ulcer in a high-risk foot.
Grade 1 – Superficial ulcer involving the full skin thickness but not underlying tissues.
Grade 2 – Deep ulcer, penetrating down to ligaments and muscle, but no bone involvement or abscess formation.
Grade 3 – Deep ulcer with cellulitis or abscess formation, often with osteomyelitis.
Grade 4 – Localized gangrene.
Grade 5 – Extensive gangrene involving the whole foot.
Chronic Renal Insufficiency (CRI) is commonly defined as plasma creatinine concentration >2mg/dl or the need for renal replacement therapy.
Albuminuria is typically classified as follows:
Spot urine albumin to creatinine(Cr) ratio:
<30 mcg/mg Cr = normal.
30-300 mcg/mg Cr = microalbuminuria.
>300 mcg/mg Cr = overt proteinuria.
24 hour urine collection for albumin:
<30 mg/day = normal.
30-300 mg/day = persistent albuminuria or microalbuminuria.
>300 mg/day = overt proteinuria, most commonly diabetic nephropathy.
Classification of Diabetic Nephropathy:
Stage I: Glomerular filtration rate (GFR) and Urinary albumin excretion may be increased, glomerular hyperfiltration may be present. Stage I disease is present at the time of diagnosis.
Stage II: GFR is typically normal. Type 1 diabetics may have normal albumin excretion, whereas type II diabetics often have microalbuminuria at this stage. Within the kidney, the basement membrane may be thickened, and the mesangium may be expanded. Stage II disease is typically present by 5 years after onset of disease.
Stage III: GFR begins to fall. Microalbuminuria is typically present. Stage III disease is usually present 6-15 years after onset of disease.
Stage IV: GFR is below normal for age. Macroalbuminuria is typically present. Most patients have hypertension at this stage. Stage IV disease is typically present 15-25 years after onset of disease.
Stage V: GFR is minimal. This is characterized as end stage renal disease (ESRD). Albumin excretion may be decreasing at this stage and patients often become uremic. Stage V disease is typically present 25-30 years after onset of disease.
D. Over-utilized or “wasted” diagnostic tests associated with the evaluation of this problem.
Annual screening for diabetic retinopathy is cost effective in all patients with type 1 diabetes, insulin dependent type 2 diabetes, and patients with known retinopathy. Routine annual screening for all patients with type 2 diabetes is less cost effective. While retinal photography may serve as a screening tool for retinopathy, it is not a substitute for a comprehensive eye examination.
The diabetic foot
Cultures of wound swabs or material from sinus tracts are unreliable (deep tissue biopsy is preferred).
Computed tomography (CT) should not be used in evaluation for osteomyelitis.
Urine dipstick: Proteins are typically not detected unless protein excretion exceeds 300-500mg per day. This is an insensitive test.
Renal biopsy is usually not indicated unless another cause for renal disease is in question.
III. Management while the Diagnostic Process is Proceeding
A. Management of Clinical Problem.
Presence of retinopathy is not a contraindication to aspirin therapy for cardioprotection, as aspirin does not increase the risk of retinal hemorrhage.
Renin–angiotensin system inhibitors reduce the incidence and risk of progression of diabetic retinopathy in persons with type 1 diabetes and are now standard therapy.
PPAR-agoni, agonist, fenofibrate, reduces the risk of progression by up to 40% among patients with nonproliferative retinopathy, as shown in the Fenofibrate Intervention and Event Lowering in Diabetes (FIELD; Current Controlled Trials number, ISRCTN64783481) and the Action to Control Cardiovascular Risk in Diabetes (ACCORD; NCT00000620) studies.
Medications specific to the eye
Anti-inflammatory corticosteroids are used for treatment of diabetic macular edema and proliferative retinopathy. The anti-inflammatory action inhibits vascular endothelial growth factor (VEGF) in a dose dependent manner, leading to decreased edema, fibrin deposition, collagen deposition, leukocyte migration, capillary dilation, capillary proliferation, and fibroblast proliferation. It can reduce mean foveal thickness and improve visual acuity, but intravitreal triamcinolone can also increase intraocular pressure and cataract progression. Steroid implants are also used for long acting slow release action (i.e. with Ozurdex).
Ranibizumab (Lucentis), bevacizumab (Avastin), and aflibercept (eylea/VEGF trap). These monoclonal antibodies can block the action of VEGF to decreased endothelial cell proliferation, neovascularization of the disc or retina, and vascular leakage. Monoclonal antibodies can also be used to treat vitreous hemorrhage and optic nerve or retinal neovascularization. These are also used in wet (neovascular) age related macular degeneration (AMD) and macular edema after retinal vein occlusion.
Treatment for diabetic macular edema
Traditionally, focal laser photocoagulation was the primary treatment for macular edema. Laser photocoagulation targets microaneurysms and microvascular lesions. However, multiple new studies have shown that VEGF inhibitors alone or in combination with laser photocoagulation are better than laser photocoagulation alone.
Treatment of non-proliferative retinopathy
Laser photocoagulation: non-invasive treatment using a high focused beam of light to create coagulation at the target tissue. It is indicated for clinically significant macular edema in NPDR. However, it can also be used to treat severe and very severe NPDR in patients who may not follow up. Laser photocoagulation has a relatively low complication rate.
Treatment of proliferative retinopathy
Diabetic Retinopathy. American Academy of Ophthalmology Preferred Practice Pattern Guidelines, 4th edition (October 2012).
Pan retinal photocoagulation (PRP)
The Diabetic Retinopathy Study demonstrated that scatter laser PRP can reduce the risk of severe visual loss by more than 50%.
PRP is the mainstay of treatment for proliferative diabetic retinopathy and severe non proliferative diabetic retinopathy. Laser burns are applied over the entire retina via slit lamp, indirect ophthalmoscope, or the Endo Probe. Usually, multiple sessions are required. The central macular area is spared from laser burns. This can reduce the rate of neovascularization and supplement the retinal circulation, but the exact mechanism by which it works is not completely understood.
If macular edema is also present, laser treatment for the macular edema is done first, and then PRP is done over more sessions for the proliferative diabetic retinopathy.
Surgical vitrectomy is indicated in severe proliferative diabetic retinopathy with vitreous hemorrhage or traction. It is a more invasive procedure that removes blood to permit evaluation and treatment of the posterior pole, repairs retinal detachment, removes the scaffolding where neovascular complexes may grow, and releases traction forces on the retina.
Vitrectomy is indicated when vitreous hemorrhage fails to resolve spontaneously after 1-3 months depending on etiology. It is also used for retinal detachment, combined tractional and rhegmatogenous retinal detachment, epiretinal membrane formation, and macular dragging.
Early treatment may be more effective in patients with type 1 diabetes. Delayed treatment increases the risk of macular detachment, and ultrasound is required to monitor the status of the posterior segment.
Cryotherapy can ablate retinal tissue to decrease oxygen demand and induce chorioretinal adhesion, which in turn down-regulates vasoproliferation. It is used when cataracts or vitreous hemorrhage obstruct the view for laser photocoagulation.
The diabetic foot
Diabetic foot infections require wound care, appropriate antibiotic therapy, correction of metabolic abnormalities, and surgical drainage, debridement, or resection.
As recommended by the Infectious Diseases Society of America (IDSA). Empiric antibiotics should include coverage against aerobic gram positive cocci, including Staphylococcus aureus (including methicillin-resistant strains) and Streptococci.
If there is severe infection, chronic infection, or persistent infection despite antibiotics, coverage for aerobic gram negative bacteria should be added.
Anaerobic coverage should be added for necrotic, gangrenous, or foul smelling wounds.
Consider providing empiric therapy directed against methicillin-resistant Staphylococcus aureus (MRSA) in a patient with a prior history of MRSA infection; when local prevalence of MRSA colonization or infection is high; or if infection is clinically severe, antibiotic therapy should be narrowed once there are culture and susceptibility results and clinical improvement.
Oral antibiotics are reasonable for mild to moderate infection, but oral bioavailability and patient compliance must be considered. Severe infections and sepsis warrant parenteral antibiotics. There is no role in topical antibiotics.
Antibiotics may be discontinued when signs and symptoms of infection have resolved, even if the wound is not completely healed. Typical treatment is 1-2 weeks for mild infections, 2-3 weeks for moderate to severe infections. Treatment for osteomyelitis can be much longer and generally warrants an infectious disease consultation.
Elimination of the source often requires consultation of surgery, podiatry, or interventional radiology for drainage, debridement, or amputation. Any wound that has necrotic tissue or surrounding callus should be debrided.
If there is clinical or imaging evidence of significant ischemia in an infected limb, consultation with vascular surgeon for consideration of re-vascularization is strongly recommended.
According to the American College of Foot and Ankle Surgeons, advanced therapy to promote ulcer healing includes negative pressure wound therapy (with vacuum assisted closure), skin substitutes (cultured skin equivalent or bioengineered skin substitutes), growth factors (to promote cellular proliferation and angiogenesis to help wound healing), hyperbaric oxygen.
Close monitoring and treatment of glucose.
Avoiding the following: walking barefoot, heating pads on feet, stepping into a bath without checking temperature, tight fitting shoes, shoes with worn soles.
Foot hygiene: feet should be washed in lukewarm water (not hot water) with mild soap, followed by gentle drying and moisturizing cream or lotion.
Routine nail care by trimming toenails to the shape of the toe and removing sharp edges.
Daily inspection of feet for blisters, redness, swelling, skin breakdown; a mirror may be helpful for this.
Proper fitting shoe, clean cotton socks, insoles that may decrease plantar pressure
Hemoglobin A1c goals and blood glucose targets should be individualized with the goal of minimizing hypoglycemia while maintaining adequate glycemic control.
Type 1 DM: The DCCT and EDIC trials established the benefit of strict glycemic control in patients with type 1 diabetes.
Type 2 DM: Tight glycemic control also slows progression of diabetic renal disease in type 2 diabetes. The Veterans Affairs Diabetes Trial (VADT), Action in Diabetes and Vascular Disease: Preterax and Diamicron MR Controlled Evaluation (ADVANCE), and Action to Control Cardiovascular Risk in Diabetes (ACCORD) trials also showed reduction in albuminuria with more intensive glycemic control.
Blood pressure control
The ADA recommends goal systolic blood pressure of <130mmHg if it can be done safely; otherwise, a goal of systolic blood pressure <140mmHg is acceptable. The diastolic blood pressure goal is under 80mmHg.
Initial treatment of elevated blood pressure (systolic or diastolic) should include dietary intervention, physical activity, and weight control (if appropriate).
Type 1 DM: Anti-hypertensive therapy slows the rate of progression of renal disease. Aggressive blood pressure control is associated with remission and regression of albuminuria.
Type 2 DM: The United Kingdom Prospective Diabetes Study (UKPDS) established that reducing systolic blood pressure reduces diabetic complications. Systolic blood pressure <130 mmHg is associated with decreased onset and progression of albuminuria.
Angiotensin receptor blockers (ARB) and angiotensin converting enzyme inhibitors (ACEI)
These agents decrease systemic blood pressure and reduce intraglomerular pressure.
Type 1 DM: Renin-angiotensin system blockade has shown to slow the progression of diabetic nephropathy. Independent of blood pressure control, ACEI can slow progression of kidney disease in both patients with microalbuminuria and overt nephropathy.
Type 2 DM: Renal protection has been shown with ARBs for patients with nephropathy.
Blood pressure control and proteinuria improve with combination ACEI and ARB therapy, but combination therapy is associated with more adverse events, such as hypotension, hyperkalemia, and renal dysfunction.
Peroxisome proliferator-activated receptor agonists (PPAR-gamma agonists)
These are thiazolidinediones (pioglitazone, rosiglitazone), and they can reduce urinary albumin excretion and reduce blood pressure. Currently, it is not recommended to use these agents in patients with a history of heart failure or those predisposed to edema.
Dietary protein and phosphate restriction may slow down progression of nephropathy.
Sodium restriction and/or diuretics can enhance the effect of renin angiotensin blockade.
This should be done through a combination of diet modification and physical activity. Though more intense physical activity can acutely increase urinary protein excretion, there is no evidence of long term renal damage from physical activity.
Treatment of hyperlipidemia
Hyperlipidemia is associated with glomerulosclerosis, but there is no proven benefit to statin therapy for diabetic nephropathy.
Intensive lifestyle changes, including smoking cessation, in combination with pharmacologic therapy, have been shown to improve albumin excretion.
B. Common Pitfalls and Side-Effects of Management of this Clinical Problem
Diabetic eye disease is often not diagnosed until one has proliferative retinopathy, and treatment options are more limited and less effective at that time.
Favorable prognostic factors:
Circinate exudates of recent onset.
Good perifoveal perfusion.
Unfavorable prognostic factors:
Diffuse edema/multiple leaks.
Lipid deposition in the fovea.
Cystoid macular edema.
Preoperative vision of less than 20/200.
Complications of treatment
Complications of photocoagulation include: pain during treatment; transient increases in intraocular pressure; corneal abrasions; mydriasis due to damage of nerves in the uveal tract; macular edema and visual acuity loss; visual field loss; loss of dark adaptation; choroidal detachment or hemorrhage; exudative retinal detachment; subretinal neovascularization; vitreous hemorrhage from regression of neovascular tissue; lens opacities and vascular occlusions.
Pain during laser treatment is quite variable and depends on the duration of the laser burns, pigmentation of the fundus, previous laser treatment, and patient anxiety level. Similarly, the degree of visual field loss correlates with the percentage of retina ablated, the number of laser burns, the location and intensity of laser burns, and the patient’s visual fields prior to laser treatment. In approximately 75% of patients some impairment in dark adaptation is seen.
Due to neovascularization of the iris and anterior chamber angle, which is a common and serious problem. Significantly elevated intraocular pressures lead to pain, decreased vision, corneal edema, and optic nerve damage.
When sorbitol accumulates in the lens, aldose reductase reduces it to sugar alcohols, which accumulate under the lens capsule and cause osmotic damage.
Fluctuations in refractive error can be seen due to osmotic effects and fluid shifts in the crystalline lens with unstable blood sugar levels. This is the cause for blurred vision when patients present with hyperglycemia.
Cranial nerve palsies
With cranial nerves III, IV, VI, including pupil-sparing CN III complete palsy.
Acute disc swelling causing transient blurry vision.
The diabetic foot
Diabetic foot infections often remain untreated for days to weeks before patients seek care. Many patients who present to the hospital have also failed outpatient oral antibiotic therapy. Reasons for failure of outpatient management include poor compliance, inability for oral intake, poor bioavailability of antibiotics, inappropriate antibiotic selection, inappropriate treatment duration, and failing to debride, drain, or resect areas of infection.
Intensive glycemic control often comes at the risk of hypoglycemia, which could be potentially catastrophic in elderly patients, those with known macrovascular disease, and other high risk patients.
Tight blood pressure control can lead to hypotension, which could lead to falls, cardiovascular events, and other complications, especially in the elderly.
Unmonitored use of ACEIs and ARBs can be associated with rises in creatinine and/or hyperkalemia.
When patients progress to end stage renal disease, hemodialysis and peritoneal dialysis confer many risks and complications.
What Is The Evidence?
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Ciulla, T.A, Amador, A.G, Zinman, B. “Diabetic retinopathy and diabetic macular edema: pathophysiology, screening, and novel therapies”. Diabetes Care. vol. 26. pp. 2653-64.
Costacou, T, Ellis, D, Fried, L, Orchard, T. “Sequence of progression of albuminuria and decreased GFR in persons with type 1 diabetes: a cohort study”. Am J Kidney Diseases. vol. 50. pp. 721
De Graeve, C, Van de Sompel, W, Claes, C. “Ocular ischemic syndrome: two case reports of bilateral involvement”. Bull Soc Belge Ophtalmol. vol. 273. pp. 69-74.
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Duckworth, W, Abraira, C, Moritz, T, Reda, D, Emanuele, N, Reaven, P, Huang, G. “Glucose control and vascular complications in veterans with type 2 diabetes”. N Engl J Med. vol. 360. pp. 129-139.
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Emanuel, N, Klein, R, Moritz, T, Davis, M.D, Glander, K, Anderson, R, Abraira, C. “VADT Study Group. Comparison of dilated fundus examinations with seven-field stereo fundus photographs in the Veterans Affairs Diabetes Trial”. J Diabetes Complications. vol. 23. pp. 323-9.
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Houlihan, C.A., Allen, T.J, Baxter, A.L, Panangiotopoulos, S, Casley, D.J, Cooper, M.E, Jerums, G. “A low-sodium diet potentiates the effects of losartan in type 2 diabetes”. Diabetes Care. vol. 25. pp. 663
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- I. Problem/Condition.
- II. Diagnostic Approach.
- A. What is the differential diagnosis for this problem?
- Diabetic retinopathy
- Hypertensive retinopathy
- Retinal venous occlusion (central retinal vein occlusion or branch retinal vein occlusion)
- Sickle cell retinopathy
- HIV retinopathy
- Radiation retinopathy
- Idiopathic juxtafoveal retinal telangiectasia
- Ocular ischemic syndrome
- Macular edema
- The diabetic foot
- Diabetic nephropathy
- Systemic Lupus Erythematosus (SLE) or cryoglobulinemia
- Hepatitis C
- Hepatitis B
- Polycystic kidney disease
- B. Describe a diagnostic approach/method to the patient with this problem.
- 1. Historical information important in the diagnosis of this problem.
- 2. Physical Examination maneuvers that are likely to be useful in diagnosing the cause of this problem.
- 3. Laboratory, radiographic and other tests that are likely to be useful in diagnosing the cause of this problem.
- C. Criteria for Diagnosing Each Diagnosis in the Method Above.
- D. Over-utilized or “wasted” diagnostic tests associated with the evaluation of this problem.
- III. Management while the Diagnostic Process is Proceeding
- A. Management of Clinical Problem.
- Diabetic retinopathy
- Non-specific therapies
- Medications specific to the eye
- Intravitreal triamcinolone
- Anti-VEGF medications
- Treatment for diabetic macular edema
- Treatment of non-proliferative retinopathy
- Treatment of proliferative retinopathy
- Pan retinal photocoagulation (PRP)
- The diabetic foot
- Antibiotic therapy
- Other therapy
- Diabetic nephropathy
- Glycemic control
- Blood pressure control
- Angiotensin receptor blockers (ARB) and angiotensin converting enzyme inhibitors (ACEI)
- Peroxisome proliferator-activated receptor agonists (PPAR-gamma agonists)
- Protein restriction
- Salt restriction
- Weight reduction
- Treatment of hyperlipidemia
- Smoking cessation
- B. Common Pitfalls and Side-Effects of Management of this Clinical Problem
- What Is The Evidence?