Diabetic retinopathy

Diabetic retinopathy (DRP, also known as diabetic eye disease (DED), is a medical condition in which damage occurs to the retina due to diabetes mellitus. It is a leading cause of blindness in developed countries.

Diabetic retinopathy
Other namesdiabetic eye disease, DED
Image of fundus showing scatter laser surgery for diabetic retinopathy
Pronunciation
  • ˌrɛtɪnˈɑpəθi[1]
SpecialtyOphthalmology, optometry
SymptomsRanges from asymptomatic to blurry vision, partial vision loss, nyctalopia and blindness
ComplicationsVitreous hemorrhage, Retinal detachment, Glaucoma, Blindness[2]
DurationLifelong
CausesLong-term poor control of diabetes mellitus
Risk factorsDiabetes, poor control of blood sugar, smoking
Diagnostic methodEye examination[3]
TreatmentLaser coagulation, Vitrectomy[3]
MedicationAnti-VEGF Injection[3]
FrequencyNearly all patients with type 1 diabetes and >60% of patients with type 2 diabetes[4]

Diabetic retinopathy affects up to 80 percent of those who have had both type 1 and type 2 diabetes for 20 years or more. In at least 90% of new cases, progression to more aggressive forms of sight threatening retinopathy and maculopathy could be reduced with proper treatment and monitoring of the eyes The longer a person has diabetes, the higher his or her chances of developing diabetic retinopathy. Each year in the United States, diabetic retinopathy accounts for 12% of all new cases of blindness. It is also the leading cause of blindness in people aged 20 to 64.

Signs and symptoms
Proleferative diabetic retinopathy
Emptied retinal venules due to arterial branch occlusion in diabetic retinopathy (fluorescein angiography)

Nearly all people with diabetes develop some degree of retina damage ("retinopathy") over several decades with the disease. For many, that damage can only be detected by a retinal exam, and has no noticeable effect on vision.[5] Over time, progressive retinal damage may appear on a retinal exam, first with microaneurysms; then cotton wool spots, hemorrhages, lipid deposits called "hard exudates", intraretinal microvascular abnormalities, and abnormal-looking retinal veins.[5] Eventually, many progress to a stage where new blood vessels grow throughout the retina. These new blood vessels often break and bleed. Minor bleeding can cause dark floating spots obstructing vision; major bleeding can completely block vision.[6]

Around half of people with diabetic retinopathy develop swelling of the macula, called macular edema, which can begin at any time.[6]

Diabetic retinopathy often has no early warning signs. Even macular edema, which can cause rapid central vision loss, may not have any warning signs for some time. In general, however, a person with macular edema is likely to have blurred vision, making it hard to do things like read or drive. In some cases, the vision will get better or worse during the day.

Macular edema, in which blood vessels leak their contents into the macular region, can occur at any stage of NPDR. Its symptoms are blurred vision and darkened or distorted images that are not the same in both eyes. Ten percent (10%) of diabetic patients will have vision loss related to macular edema. Optical Coherence Tomography can show areas of retinal thickening due to fluid accumulation from macular edema.[7]

Diagnosis

Most early diabetic retinopathy does not impact an affected person's vision, and can only be detected by a retinal exam. The American Academy of Opthalmology divides diabetic retinopathy into five categories of progressive severity. The first category, "no apparent retinopathy", describes those with a healthy retinal exam.[5] The next three categories: mild, moderate, and severe nonproliferative diabetic retinopathy (NPDR) describe increasing levels of damage to the retina. People with mild NDPR have microaneurysms in the retina, but no other damage. Those with severe NDPR have 20+ retinal hemorrhages in each quadrant of the retina, a distinctive pattern of damage on the veins of the retina called "venous beading" in at least two retinal quadrants, and obvious intraretinal microvascular abnormalities anywhere on the retina. Moderate NDPR is defined as more severe than mild NDPR, but not yet meeting the criteria for severe NDPR.[5] The fifth stage, proliferative diabetic retinopathy, is for those with new blood vessels forming throughout the retina ("retinal neovascularization"), or blood leaking into the vitreous humor ("vitreous hemorrhage") or between the vitreous membrane and retina ("preretinal hemorrhage").[5]

The same guidelines separately divide macular edema into two categories: "macular edema apparently absent" and "macular edema apparently present". The latter is further subdivided into "mild" – retinal thickening or lipid deposits far from the macula's center; "moderate" – thickening or deposits near the center; and "severe" – thickening or deposits on the macula center.[5]

The first stage, called non-proliferative diabetic retinopathy (NPDR), has no symptoms. Patients may not notice the signs and have 20/20 vision. The only way to detect NPDR is by fundus examination by direct or indirect ophthalmoscope by a trained ophthalmologist or optometrist, fundus photography can be used for objective documentation of the fundus findings, in which microaneurysms (microscopic blood-filled bulges in the artery walls) can be seen. If there is reduced vision, fluorescein angiography can show narrowing or blocked retinal blood vessels clearly (lack of blood flow or retinal ischemia).

Diabetic retinopathy is detected during an eye examination that includes:

  • Fundus Fluorescein angiography (FFA): This is an imaging technique which relies on the circulation of fluorescein dye to show staining, leakage, or non-perfusion of the retinal and choroidal vasculature.
  • Retinal vessel analysis detects abnormalities of the autoregulation of small retinal arteries and veins in diabetic patients even before the manifestation of diabetic retinopathy.[8]
  • Optical coherence tomography (OCT): This is an optical imaging modality based upon laser beam interference. It produces cross-sectional images of the retina (B-scans) which can be used to measure the thickness of the retina and to resolve its major layers, allowing the observation of swelling.

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.

If macular edema is suspected, OCT and sometimes retinal angiography (FFA) may be performed.

Diabetic retinopathy also affects microcirculation thorough the body. A recent study[9] showed assessment of conjunctival microvascular hemodynamics such as vessel diameter, red blood cell velocity and wall shear stress can be useful for diagnosis and screening of diabetic retinopathy. Furthermore, the pattern of conjunctival microvessels was shown to be useful for rapid monitoring and diagnosis of different stages of diabetic retinopathy.[10]

Screening

Both the American Diabetes Association (ADA) and the International Council of Ophthalmology (ICO) recommend regular eye exams for those with diabetes to screen for diabetic retinopathy (excepting those with gestational diabetes.[11] The ADA recommends a comprehensive eye examination at the time of type 2 diabetes diagnosis, and within five years of the onset of type 1 diabetes. For women with diabetes who become pregnant, the ADA recommends an eye examination before pregnancy, in each trimester, and for a year post partum.[11]

The ICO recommends eye examinations for those with diabetes include a visual acuity examination and a retinal examination via ophthalmoscopy or retinal photography.[11]

In the UK, screening for diabetic retinopathy is part of the standard of care for people with diabetes.[12] After one normal screening in people with diabetes, further screening is recommended every two years.[13] In the UK, this is recommended every year.[14] Teleophthalmology has been employed in these programs.[15]

In The U.S, a current guideline for diabetic retinopathy is recommendation of annual dilated exams for all patients with diabetes. There are barriers to recommended screening that is contributing to the disparity. Such as the patient factor which includes education about diabetic retinopathy and the availability of the treatment. The health care system also contributes to the disparities in diabetic screening, which includes insurance coverage, long waiting time for the appointment and difficulty scheduling appointments which makes the person less likely to screen. Provider factors also influence the barrier to screening which is a lack of awareness of the screening guidelines, skills or having the right tools to perform eye exams which can affect the diagnosis and treatment. A cross-sectional study showed that when physicians treating black patients had more difficulty providing proper subspecialty care and diagnostic imaging for the patients.[16]

There is evidence to support interventions to improve attendance for diabetic retinopathy screening.[17] These might be specifically targeted at diabetic retinopathy screening, or could be general strategies to improve diabetes care. The shortage of ophthalmologists causes delays in regular eye examinations, especially in follow-ups which need to be done after successful treatments to monitor the condition's possible return. According to a study in the UK, support staff who take images of the retina (ophthalmic photographers) could be trained to also assess the eye scans which would reduce waiting times.[18][19]

In addition, significant differences in genetic risk for diabetic retinopathy[20] raises the possibility of risk stratification and screening targeted to individuals with high genetic risk for diabetic retinopathy in the population.

According to a DRSS user manual, poor quality retina images used for screening (which may apply to other methods) may be caused by cataract, poor dilation, ptosis, external ocular condition, or learning difficulties. There may be artefacts caused by dust, dirt, condensation, or smudge.[21]

Causes

Diabetic retinopathy is caused by prolonged high blood glucose damaging the small blood vessels of the retina.[22]

Risk factors

The major risk factors for developing diabetic retinopathy are duration of diabetes, poor blood sugar control, and to a lesser extent high blood pressure.[23] Both chronically high blood sugar (measured by a high HbA1c) and highly variable blood sugar are associated with developing diabetic retinopathy.[24] Several more minor risk factors also exacerbate diabetic retinopathy, namely kidney disease, abnormal blood lipids, high body mass index, and smoking.[24]

Genetic predisposition to diabetic retinopathy in type 2 diabetes consists of many genetic variants across the genome that are collectively associated with diabetic retinopathy (polygenic risk) and overlaps with genetic risk for glucose, low-density lipoprotein cholesterol, and systolic blood pressure.[20] Several variations in the VEGFC gene have also been asociated with an increased risk of developing macular edema.[25]

During pregnancy, diabetic retinopathy may also be a problem for women with diabetes. The US National Institutes of Health recommends that all pregnant women with diabetes have comprehensive eye examination.[26]

People with Down syndrome, who have extra chromosome 21 material, almost never acquire diabetic retinopathy. This protection appears to be due to the elevated levels of endostatin,[27] an anti-angiogenic protein, derived from collagen XVIII. The collagen XVIII gene is located on chromosome 21.

Incidence of Retinitis Pigmentosa is observed to result in fewer and less severe microvascular lesions in both humans and mouse models.[28] Retinitis Pigmentosa results in loss of rod receptors in the mid peripheral field, reducing the oxygen consumption that is linked with release of VEGF and growth of unwanted blood vessels in the retina.

Obstructive sleep apnea (OSA) has been associated with a higher incidence of diabetic eye disease due to blood desaturation caused by intermittent upper airway obstructions. Treatment for OSA can help reduce the risk of diabetic complications.[29]

Pathogenesis
Illustration depicting diabetic retinopathy

Diabetic retinopathy is the result of damage to the small blood vessels and neurons of the retina. The earliest changes leading to diabetic retinopathy include narrowing of the retinal arteries associated with reduced retinal blood flow; dysfunction of the neurons of the inner retina, followed in later stages by changes in the function of the outer retina, associated with subtle changes in visual function; dysfunction of the blood-retinal barrier, which protects the retina from many substances in the blood (including toxins and immune cells), leading to the leaking of blood constituents into the retinal neuropile.[30] Later, the basement membrane of the retinal blood vessels thickens, capillaries degenerate and lose cells, particularly pericytes and vascular smooth muscle cells. This leads to loss of blood flow and progressive ischemia, and microscopic aneurysms which appear as balloon-like structures jutting out from the capillary walls, which recruit inflammatory cells; and advanced dysfunction and degeneration of the neurons and glial cells of the retina.[30][31] The condition typically develops about 10–15 years after receiving the diagnosis of diabetes mellitus.

An experimental study suggests that pericyte death is caused by blood glucose persistently activating protein kinase C and mitogen-activated protein kinase (MAPK), which, through a series of intermediates, inhibits signaling through platelet-derived growth factor receptors — signaling that supports cellular survival, proliferation, and growth. The resulting withdrawal of this signaling leads to the programmed cell death (apoptosis) of the cells in this experimental model.[32]

In addition, excessive sorbitol in diabetics is deposited on retina tissue and it is also proposed to play a role in diabetic retinopathy.[33]

Small blood vessels – such as those in the eye – are especially vulnerable to poor blood sugar (blood glucose) control. An overaccumulation of glucose damages the tiny blood vessels in the retina. During the initial stage, called nonproliferative diabetic retinopathy (NPDR), most people do not notice any change in their vision. Early changes that are reversible and do not threaten central vision are sometimes termed background retinopathy.[34]

A genetic study showed that diabetic retinopathy shares a similar genetic predisposition with levels of glucose, low-density lipoprotein cholesterol, and systolic blood pressure,[20] indicating that glycemic control and cardiometabolic factors may be important in the development of diabetic retinopathy.

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.

Proliferative diabetic retinopathy

As the disease progresses, severe nonproliferative diabetic retinopathy enters an advanced or proliferative (PDR) stage, where blood vessels proliferate/grow. The lack of oxygen in the retina causes formation of new fragile 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 and cause cloudy 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.

Management

There are three major treatments for diabetic retinopathy, which are very effective in reducing vision loss from this disease.[35] In fact, even people with advanced retinopathy have a 95 percent chance of keeping their vision when they get treatment before the retina is severely damaged.[36] These three treatments are laser surgery, injection of corticosteroids or anti-VEGF agents into the eye, and vitrectomy. Although these treatments are very successful (in slowing or stopping further vision loss), they do not cure diabetic retinopathy. Caution should be exercised in treatment with laser surgery since it causes a loss of retinal tissue. It is often more prudent to inject triamcinolone or anti-VEGF drugs. In some patients it results in a marked increase of vision, especially if there is an edema of the macula.[35]

The best way of preventing the onset and delaying the progression of diabetic retinopathy is to monitor it vigilantly and achieve optimal glycemic control.[37]

Since 2008 there have been other therapies (e.g. kinase inhibitors and anti-VEGF) drugs available.[38]

In addition, standard treatment for diabetic retinopathy includes improving control of blood sugar, blood pressure, and blood cholesterol, all of which can reduce diabetic retinopathy progression.[39]

Laser photocoagulation

Laser photocoagulation can be used in two scenarios for the treatment of diabetic retinopathy. Firstly, It can be used to treat macular edema which was common before eye injections were introduced.[40] and secondly, it can be used for treating whole retina (panretinal photocoagulation) for controlling neovascularization. It is widely used for early stages of proliferative retinopathy. There are different types of lasers and there is evidence available on their benefits to treat proliferative diabetic retinopathy.[41]

Modified grid laser

A 'C' shaped area around the macula is treated with low intensity small burns. This helps in clearing the macular edema.

Panretinal laser photocoagulation

For those with proliferative or severe non-proliferative diabetic retinopathy, vision loss can be prevented by treatment with panretinal laser photocoagulation.[39]

The goal is to create 1,600 – 2,000 burns in the retina with the hope of reducing the retina's oxygen demand, and hence the possibility of ischemia. It is done in multiple sittings.

In treating advanced diabetic retinopathy, the burns are used to destroy the abnormal new blood vessels that form in the retina. This has been shown to reduce the risk of severe vision loss for eyes at risk by 50%.[42]

Before using the laser, the ophthalmologist dilates the pupil and applies anaesthetic drops to numb the eye. In some cases, the doctor also may numb the area behind the eye to reduce discomfort. The patient sits facing the laser machine while the doctor holds a special lens on the eye. The physician can use a single spot laser, a pattern scan laser for two dimensional patterns such as squares, rings and arcs, or a navigated laser which works by tracking retinal eye movements in real time.[43][44] During the procedure, the patient will see flashes of light. These flashes often create an uncomfortable stinging sensation for the patient. After the laser treatment, patients should be advised not to drive for a few hours while the pupils are still dilated. Vision will most likely remain blurry for the rest of the day. Though there should not be much pain in the eye itself, an ice-cream headache like pain may last for hours afterwards.

Patients will lose some of their peripheral vision after this surgery although it may be barely noticeable by the patient. The procedure does however save the center of the patient's sight. Laser surgery may also slightly reduce colour and night vision.

A person with proliferative retinopathy will always be at risk for new bleeding, as well as glaucoma, a complication from the new blood vessels. This means that multiple treatments may be required to protect vision.

Intravitreal triamcinolone acetonide

Triamcinolone is a long acting steroid preparation. Treating people with DME with intravitreal injections of triamcinolone may lead to a some degree of improvement in visual acuity when compared to eyes treated with placebo injections.[45] When injected in the vitreous cavity, the steroid decreases the macular edema (thickening of the retina at the macula) caused due to diabetic maculopathy, and that may result in an increase in visual acuity. The effect of triamcinolone is not permnanent and may last up to three months, which necessitates repeated injections for maintaining the beneficial effect. Best results of intravitreal Triamcinolone have been found in eyes that have already undergone cataract surgery. Complications of intravitreal injection of triamcinolone may include cataract, steroid-induced glaucoma, and endophthalmitis.[45]

Intravitreal anti-VEGF

Those with diabetic macular edema benefit from regular injections with anti-VEGF antibodies like ranibizumab, bevacizumab, and aflibercept.[39] There is no widely accepted dosing schedule, though people typically receive more frequent injections during the first year of treatment, with less frequent injections in subsequent years sufficient to maintain remission.[39]

A 2017 systematic review update found moderate evidence that aflibercept may have advantages in improving visual outcomes over bevacizumab and ranibizumab, after one year.[46] In cases with vitreous hemorrhage, however, anti-VEGF injections proved to be less effective in restoring visual acuity than vitrectomy combined with panretinal laser-photocoagulation.[47] Present recommended treatment for diabetic macular edema is multiple injections of anti-VEGF drugs sometimes combined with Modified Grid laser photocoagulation. Sustained delivery systems for anti-VEGF medications can reduce the chances of endophthalmitis development by reducing the number of intravitreal injections necessary for treatment. Hydrogels have shown great promise for this platform.[48]

Topical medications

There is little evidence for the role of topical medications in the treatment of macular edema, for example, topical non‐steroidal anti‐inflammatory agents.[49]

Surgery

Instead of laser surgery, some people require a vitrectomy to restore vision. A vitrectomy is performed when there is a lot of blood in the vitreous. It involves removing the cloudy vitreous and replacing it with a saline solution.

Studies show that people who have a vitrectomy soon after a large hemorrhage are more likely to protect their vision than someone who waits to have the operation. Early vitrectomy is especially effective in people with insulin-dependent diabetes, who may be at greater risk of blindness from a hemorrhage into the eye.

Vitrectomy may be done under general or local anesthesia. The doctor makes a tiny incision in the sclera, or white of the eye. Next, a small instrument is placed into the eye to remove the vitreous and insert the saline solution into the eye.

Patients may be able to return home soon after the vitrectomy, or may be asked to stay in the hospital overnight. After the operation, the eye will be red and sensitive, and patients usually need to wear an eyepatch for a few days or weeks to protect the eye. Medicated eye drops are also prescribed to protect against infection. There is evidence which suggests anti-VEGF drugs given either prior to or during vitrectomy may reduce the risk of posterior vitreous cavity haemorrhage.[50] Vitrectomy is frequently combined with other modalities of treatment.

Epidemiology

Around 34.6% of people with diabetes have some kind of diabetic retinopathy, with around 7% experiencing proliferative diabetic retinopathy, 7% diabetic macular edema, and 10% experiencing loss of vision from diabetic retinopathy.[51] Diabetic retinopathy is the leading cause of vision loss in those 20–74 years old.[51]

The global burden of diabetic retinopathy increased dramatically from 1990 to 2015 – from 1.4 million to 2.6 million people with visual impairment; from 0.2 million to 0.4 million blinded – due in large part to the increasing burden of type 2 diabetes in low- and middle-income countries.[51]

Diabetic retinopathy is more common in those with type 1 diabetes than type 2.[51]

Research

Light treatment

A medical device comprising a mask that delivers green light through the eyelids while a person sleeps was under development in 2016.[52][53] The light from the mask stops rod cells in the retina from dark adapting, which is thought to reduce their oxygen requirement, which in turn diminishes new blood vessel formation and thus prevents diabetic retinopathy.[52] As of 2016 a large clinical trial was underway.[52] As of 2018, the results from the clinical trial showed no long-term therapeutic benefit from using the mask in diabetic retinopathy patients.[54]

C-peptide

C-peptide had shown promising results in treatment of diabetic complications incidental to vascular degeneration.[55] Creative Peptides,[56] Eli Lilly,[57] and Cebix[58] all had drug development programs for a C-peptide product. Cebix had the only ongoing program until it completed a Phase IIb trial in December 2014 that showed no difference between C-peptide and placebo, and it terminated its program and went out of business.[59][60]

Stem cell therapy

Clinical trials are under way or are being populated in preparation for study at medical centers in Brazil, Iran and the United States. Current trials involve using the patients' own stem cells derived from bone marrow and injected into the degenerated areas in an effort to regenerate the vascular system.[61]

Blood pressure control

A Cochrane review examined 15 randomized controlled trials to determine whether interventions that sought to control or reduce blood pressure in diabetics had any effects of diabetic retinopathy.[62] While the results showed that interventions to control or reduce blood pressure prevented diabetic retinopathy for up to 4–5 years in diabetics, there was no evidence of any effect of these interventions on progression of diabetic retinopathy, preservation of visual acuity, adverse events, quality of life, and costs.[62]

Fundoscopic image analyses
Distribution in percentage of pre-processing techniques from 2011 to 2014[63]

Diabetic retinopathy is diagnosed entirely by recognizing abnormalities on retinal images taken by fundoscopy. Color fundus photography is mainly used for staging the disease. Fluorescein angiography is used to assess the extent of retinopathy that aids in treatment plan development. Optical coherence tomography (OCT) is used to determine the severity of edema and treatment response.[64]

Because fundoscopic images are the main sources for diagnosis of diabetic retinopathy, manually analyzing those images can be time-consuming and unreliable, as the ability of detecting abnormalities varies by years of experience.[65] Therefore, scientists have explored developing computer-aided diagnosis approaches to automate the process, which involves extracting information about the blood vessels and any abnormal patterns from the rest of the fundoscopic image and analyzing them.[63]

See also
  • Diabetic diet
  • Diabetic papillopathy
  • Purtscher's retinopathy, a disease with similar abnormalities in the eye, usually caused by trauma.
  • Retinal regeneration[66]

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