Diabetic retinopathy

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Rohan Bir Singh, M.B.B.S.[2] Priyamvada Singh, M.B.B.S. [3]; Cafer Zorkun, M.D., Ph.D. [4]

Diabetic retinopathy is the most severe form of the several kinds of ocular complications causing damage to the retina, as a result of diabetes.It is an ocular manifestation of systemic disease which affects up to 80% of all diabetics who have had diabetes for 15 years or more. It is the leading cause of non traumatic blindness in adults. People with untreated diabetes are 25 times more at risk for blindness than the general population. Despite these intimidating statistics, research indicates that at least 90% of these new cases could be reduced if there was proper and vigilant treatment and monitoring of the eyes.

• 
  Normal vision. Courtesy NIH National Eye Institute
• 
  The same view with diabetic retinopathy.

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Rohan Bir Singh, M.B.B.S.[2]

Although diabetes was a well-known disease as from the 2nd century AD, no clinician attempted to link this endocrine disorder with eye-pathology before the middle of the 19th century. In 1846, the French ophthalmologist and Professor of Hygiene in Paris, Appolinaire Bouchardat (1806-1886), reported the development of visual loss in the absence of cataract in diabetics. This was partly reversible and in most cases improvement was associated with better control of diabetes. A few years later, François Tavignot made similar observations.^[1] However, no histopathological specimens were examined and the implication of macular disease in diabetes remained tentative until the invention of the ophthalmoscope.

Jäger had inexhaustible patience and exemplary precision in ophthalmoscopy and, in illustrating his findings, meticulously incorporated the smallest details into his pictures. He used the newly developed direct ophthalmoscope in order to produce one of the first atlases containing 21 colour plates of fundus paintings, which were drawn after 20-40 clinical sessions per patient. He described ‘roundish’ or oval, yellowish spots and full or partial thickness extravasations through the retina in the macular region of a diabetic patient.^[1] His findings were controversial at the time and Albrecht von Graefe (1828-1870) claimed that there was no proof of a cause-effect relationship between diabetes and retinal complications. Von Graefe’s scepticism was adopted by many of his colleagues, with the exception of Louis Desmarres (1810-1882) in 1858.

No further evidence was presented until 1869, when Henry Noyes (1832-1900) published an article in the USA supporting the link between diabetes mellitus and maculopathy. His observations were confirmed in 1872 by Edward Nettleship (1845-1913) in London, who expanded on this theme in his paper entitled ‘On oedema or cystic disease of the retina’ and presented the first histopathological proof of a cystoid degeneration of the macula in diabetic patients.Five years later, Nettleship published another article with Sir Steven Mackenzie (1791-1868), which described in detail the abnormal retinal changes induced by diabetes. n 1876, Wilhelm Manz (1833-1911) published his seminal paper on ‘Retinitis proliferans’ containing several drawings of fibrovascular degeneration of the optic disc and vitreoretinal adhesions in the retina. Fourteen years later, in 1890, Julius Hirschberg (1843-1925) classified diabetic retinopathy into four types (retinitis centralis punctuate, haemorrhagic form, retinal infarction, and haemorrhagic glaucoma), thus describing the full natural history of diabetic retinopathy. The descriptive term, diabetic retinitis, though erroneous since the disease is not of inflammatory origin, continued to be used for several years.

At the beginning of the 20th century there was still the unresolved debate as to whether macular changes were directly related to diabetes or whether they were caused by atherosclerosis and hypertension. Arthur James Ballantyne (1876-1954) of Glasgow suggested that diabetic retinopathy represents a unique form of vasculopathy and his work showed for the first time the role of capillary wall alterations in the development of diabetic retinopathy, as well as the presence of deep waxy exudates in the outer plexiform layer.

Today the retinal manifestations of diabetes are classified as Early Non-proliferative Diabetic Retinopathy, Advanced Non-proliferative Diabetic Retinopathy, and Proliferative Diabetic Retinopathy.

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Rohan Bir Singh, M.B.B.S.[2] Afsaneh Morteza, MD-MPH [3]

Modified Airlie House Classification

In 1968 experts met in Airlie House, Virginia to develop a standarized classification of DR^[1]. This classification was modified and used in the Diabetic Retinopathy Study (DRS). It consisted of comparing stereophotographs in 7 standard photographic fields with the patient’s findings in those same 7 photographic fields.

This same classification was modified for use in the Early Treatment of Diabetic Retinopathy Study (ETDRS). It became the gold standard for many years. The modified Airlie House Classification of DR is based on grading of stereophotographs of 7 fields and classifies DR into 13 complex levels ranging from level 10 (absence of retinopathy) to level 85 (severe vitreous hemorrhage or retinal detachment involving the macula).^[2] It is an excellent tool in the research setting but its clinical applicability is limited due to its complexity. Most ophthalmologists do not use this classification in their daily clinical work.

International Clinical Disease Severity Scale

This disease severity scale is based upon the findings of the Wisconsin Epidemiologic Study of Diabetic Retinopathy (WESDR) and the ETDRS. There are five stages that are recognized as per the scale. The first is “no apparent retinopathy”. As the name implies there are no diabetic fundus changes. The second stage is “mild non-proliferative retinopathy” (NPDR). This stage is characterized by the presence of a few microaneurysms. The third stage is “moderate NPDR” which is characterized by the presence of microaneurysms, intraretinal hemorrhages or venous beading. “Severe NPDR”, the fourth stage, is the key level to identify.

The disease is classified according to types of lesions detected on fundoscopy into non-proliferative diabetic retinopathy (NPDR) and proliferative diabetic retinopathy (PDR). Diabetic retinopathy affect both eyes in parallel. NPDR is subdivided into mild and moderate-to-severe forms.

1. Microaneurysms
2. Dot and blot hemorrhages
3. Hard (intra-retinal) exudate

Is mild NPDR plus:

1. Cotton-wool spots
2. Venous beading and loops
3. Intraretinal microvascular abnormalities ( IRMA )

1. Neovascularization of the retina, optic disc or iris
2. Fibrous tissue adherent to vitreous face of retina
3. Retinal detachment
4. Vitreous hemorrhage
5. Pre-retinal hemorrhage

Some people develop a condition called macular edema. It occurs when the damaged blood vessels leak fluid and lipids onto the macula. The fluid makes the macula swell, which blurs vision.

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Rohan Bir Singh, M.B.B.S.[2] Priyamvada Singh, M.B.B.S. [3], Afsaneh Morteza, MD-MPH [4]

Diabetic retinopathy is the result of microvascular abnormalities of the retina.

The retina is a multicellular photon sensor, a unique component of the central nervous system, which is structured on the vessels.

Promoted by the observations that there is a selective loss of pericytes early in diabetic retinopathy, many researchers were attracted to these cells as the origin of the disease.^[1]. Pericytes are enigmatic cells, which are regular components of all human tissues and organs. In contrast to arteries and arterioles where the coverage consists of the smooth muscle cells, the capillary system is individually covered by the pericytes. Pericytes are codependent on the endothelial cells. Normal pericytes have a contractile function that helps to regulate capillary blood flow. The loss of pericytes, due to diabetic inflammation, is followed by the loss of capillary endothelial cells. Apoptosis of the pericytes, leads to the disappearance of both types of cells. Since neurons in the retina have high metabolic requirements, the hypoxia that results from extensive retinal capillary cell death is a probable stimulus for the increased expression of molecules that enhance the breakdown of the blood–retinal barrier and lead to vascular proliferation or angiogenesis. ^[2] Angiogenesis is a complex process, characterized by a cascade of events:

1: Initial vasodilatation of existing vessels

2: Increased vascular permeability and degradation of the surrounding matrix,

3: Migration and tube forming of the activated and proliferating endothelial cells

4: Maturation and remodeling of these new vessels takes place to form a vascular network.

These new blood vessels are abnormal and fragile. They grow along the retina and along the surface of the vitreous. By themselves, these blood vessels do not cause symptoms or vision loss. However, they have thin, fragile walls, and they ultimately leak blood. Retinal damage can result from persistent vitreous haemorrhage. On the other hand, contraction of associated fibrous tissue formed by proliferative disease tissue can result in deformation of the retina and tractional retinal detachment. The detachment may tear the retina (rhegmatogenous) or may not (non-rhegmatogenous). The non-rhegmatogenous retinal detachment is worse and is characterized by the

1: Confined retina

2: A taut and shiny appearance

3: Concave retina toward the pupil

4: Disappearance of the sub retinal fluid shifting

The cascade of these events causes vision loss.^[3]

Recent studies which are focused on the neural component of the retina, have shown that diabetic neuropathy of the neuroglial cells may play an important role in the pathophysiology of disease.^[4]

Hyperglycemia-induced pericyte death and thickening of the basement membrane lead to incompetence of the vascular walls. These damages change the formation of the blood-retinal barrier and also make retinal blood vessel become more permeable.^[5]

Small blood vessels – such as those in the eye – are especially vulnerable to poor blood sugar control. An overaccumulation of glucose and/or fructose damages the tiny blood vessels in the retina. During the initial stage, called nonproliferative diabetic retinopathy (NPDR), most people do not notice any changes in their vision.

Some people develop a condition called macular edema. It occurs when the damaged blood vessels leak fluid and lipids onto the macula, the part of the retina that lets us see detail. The fluid makes the macula swell, which blurs vision.

As the disease progresses, severe nonproliferative diabetic retinopathy enters an advanced, or proliferative, stage. The lack of oxygen in the retina causes fragile, new, blood vessels to grow along the retina and in the clear, gel-like vitreous humour that fills the inside of the eye. Without timely treatment, these new blood vessels can bleed, cloud vision, and destroy the retina. Fibrovascular proliferation can also cause tractional retinal detachment. The new blood vessels can also grow into the angle of the anterior chamber of the eye and cause Neovascular Glaucoma. Nonproliferative diabetic retinopathy shows up as cotton wool spots, or microvascular abnormalities or as superficial retinal hemorrhages. Even so, the advanced proliferative diabetic retinopathy (PDR) can remain asymptomatic for a very long time, and so should be monitored closely with regular checkups.

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Rohan Bir Singh, M.B.B.S.[2]

Between 40 to 45 percent of Americans diagnosed with diabetes have some stage of diabetic retinopathy. ^[1]

The prevalence of all types of diabetic retinopathy in the diabetic population increases with the duration of the disease and patient age.

Diabetic retinopathy is rare in children younger than 10 years of age. However , the risk of developing diabetic retinopathy increases after puberty.

The Wisconsin Epidemiologic Study of Diabetic Retinopathy

The Wisconsin Epidemiologic Study of Diabetic Retinopathy (WESDR) is an ongoing epidemiologic study the progression of diabetic retinopathy on basis of monitoring the stereoscopic fundus by taking photographs in 7 standard fields along with measurements of glycosylated hemoglobin levels and visual acuity.^[2]

An important epidemiologic finding of the WESDR was the direct association of an increased prevalence of diabetic retinopathy, in both type 1 and type 2 forms, with the duration of diabetes mellitus.^[2]

After 20 years of diabetes mellitus, nearly 99% of patients with type 1 and 60% with type 2 disease demonstrated some degree of diabetic retinopathy. Proliferative diabetic retinopathy was found in 50% of type 1 patients who had 20 years’ duration of disease and in 25% of type 2 patients who had 25 years’ duration of disease. Furthermore, 3.6% of younger-onset patients (aged <30 years at diagnosis, an operational definition of type 1 diabetes mellitus) and 1.6% of older-onset patients (aged ≥30 years at diagnosis, an operational definition of type 2 diabetes mellitus) were found to have a visual acuity of 20/200 or worse. Such vision loss was attributable to diabetic retinopathy in 86% of the younger-onset patients and in 33% of the older-onset group. WESDR epidemiologic data were based largely on white populations of northern European descent and therefore are not entirely applicable to other racial groups.

According to the National Health and Nutrition Examination Survey (NHANES) III, in 2011, the age-adjusted percentage of adults with diagnosed diabetes mellitus who reported visual impairment was 20.7% for blacks, 17.1% for whites, and 15.6% for Hispanics.^[3]

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Priyamvada Singh, M.B.B.S. [2]; Cafer Zorkun, M.D., Ph.D. [3]

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All patients with diabetes mellitus are at risk of developing diabetic retinopathy. This includes those with Type I diabetes (juvenile onset) and those with Type II diabetes (adult onset). The longer a person has diabetes, the greater the risk of developing an ocular complication. During pregnancy, diabetic retinopathy may also be a problem for women with diabetes. It is recommended that all pregnant women with diabetes have dilated eye examinations each trimester to protect their vision.

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Clinical practice guidelines  (PMID 30559232) by the American Diabetes Association in 2019 stated to avoid diabetic complications: 

• The  ADA recommends “Adults with type 1 diabetes should have an initial dilated and comprehensive eye examination by an ophthalmologist or optometrist within 5 years after the onset of diabetes.” 
• The  ADA recommends “Patients with type 2 diabetes should have an initial dilated and comprehensive eye examination by an ophthalmologist or optometrist at the time of the diabetes diagnosis.”
• The  ADA recommend that “If there is no evidence of retinopathy for one or more annual eye exam and glycemia is well controlled, then exams every 1–2 years may be considered.”  
• The  ADA recommend that “If any level of diabetic retinopathy is present, subsequent dilated retinal examinations should be repeated at least annually by an ophthalmologist or optometrist.

• The  ADA recommend that “If retinopathy is progressing or sight-threatening, then examinations will be required more frequently

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All patients with type 2 diabetes should be visited by an ophthalmologist prior to diabetes diagnosis.

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If left untreated it can lead to permanent blindness.

Prognosis of diabetic retinopathy depends on:

• Whether blood sugar and blood pressure are well controlled.
• Whether retinopathy is treated early.

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-In-Chief: Priyamvada Singh, M.B.B.S. [2]; Cafer Zorkun, M.D., Ph.D. [3]

Diabetic retinopathy is detected during an eye examination that includes:

• Visual acuity test: This test uses an eye chart to measure how well a person sees at various distances (i.e., visual acuity).
• Pupil dilation: The eye care professional places drops into the eye to widen the pupil. This allows him or her to see more of the retina and look for signs of diabetic retinopathy. After the examination, close-up vision may remain blurred for several hours.
• Ophthalmoscopy: This is an examination of the retina in which the eye care professional: (1) looks through a device with a special magnifying lens that provides a narrow view of the retina, or (2) wearing a headset with a bright light, looks through a special magnifying glass and gains a wide view of the retina. Note that hand-held ophthalmoscopy is insufficient to rule out significant and treatable diabetic retinopathy.
• Ocular Coherence Tomography or OCT: This is a scan similar to an ultrasound which is used to measure the thickness of the retina. It produces a cross section of the retina and can determine if there is any swelling or leakage.
• Tonometry: A standard test that determines the fluid pressure (intraocular pressure) inside the eye. Elevated pressure is a possible sign of glaucoma, another common eye problem in people with diabetes.
• Digital Retinal Screening Programs: Systematic programs for the early detection of eye disease including diabetic retinopathy are becoming more common, such as in the UK, where all people with diabetes mellitus are offered retinal screening at least annually. This involves digital image capture and transmission of the images to a digital reading center for evaluation and treatment referral. See Vanderbilt Ophthalmic Imaging Center [4] and the English National Screening Programme for Diabetic Retinopathy [5]
• Slit Lamp Biomicroscopy Retinal Screening Programs: Systematic programs for the early detection of diabetic retinopathy using slit-lamp biomicroscopy. These exist either as a standalone scheme or as part of the Digital program (above) where the digital photograph was considered to lack enough clarity for detection and/or diagnosis of any retinal abnormality.

Of the 18 million to 20 million diabetics in the United States, only about half receive annual eye examinations for retinopathy risk. In an effort to increase diabetic patient’s compliance for regular eye exams, Digital Healthcare, a Wake Forest, NC company specializing in retinal risk assessment, has announced the introduction of Retasure, a new retinal imaging risk assessment solution that connects primary care physicians with ophthalmic specialists to perform retinal imaging.

Retasure allows primary care physicians to capture digital images of diabetic patients’ retinas in a non-invasive procedure that takes just a few minutes. The images are then transmitted over a secure, HIPPA compliant network to a board certified ophthalmologist at an accredited reading center for examination. Results are returned to the primary care physician within 72 hours.

Retasure has been available throughout Europe, and more than one million people have benefited from the system annually.

The eye care professional will look at the retina for early signs of the disease, such as:

1. leaking blood vessels,
2. retinal swelling, such as macular edema,
3. pale, fatty deposits on the retina (exudates) – signs of leaking blood vessels,
4. damaged nerve tissue (neuropathy), and
5. any changes in the blood vessels.

Additionally;

• Should the doctor suspect macular edema, he or she may perform a test called fluorescein angiography.
• In this test, a special dye is injected into the arm.
• Pictures are then taken as the dye passes through the blood vessels in the retina.
• This test allows the doctor to find the leaking blood vessels.

• Diabetic Retinopathy Resource Guide from the National Eye Institute (NEI).
• National Diabetes Information Clearinghouse
• Lions Eye Institute, Perth, Australia

cs:Diabetická retinopatie de:Diabetische Retinopathie nl:Diabetische retinopathie fi:Diabeettinen retinopatia

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