|Image of fundus showing scatter laser surgery for diabetic retinopathy|
|Symptoms||May have no symptoms; blurry vision, vision loss, blindness|
|Causes||Long-term poor control of diabetes mellitus|
Diabetic retinopathy affects up to 80 percent of those who have had diabetes for 20 years or more. At least 90% of new cases 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
Diabetic retinopathy often has no early warning signs. Even macular edema, which can cause rapid 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.
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 photography, 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).
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.
In the second stage, abnormal new blood vessels (neovascularisation) form at the back of the eye as part of proliferative diabetic retinopathy (PDR); these can burst and bleed (vitreous hemorrhage) and blur the vision, because these new blood vessels are fragile. The first time this bleeding occurs, it may not be very severe. In most cases, it will leave just a few specks of blood, or spots floating in a person's visual field, though the spots often go away after a few hours.
These spots are often followed within a few days or weeks by a much greater leakage of blood, which blurs the vision. In extreme cases, a person may only be able to tell light from dark in that eye. It may take the blood anywhere from a few days to months or even years to clear from the inside of the eye, and in some cases the blood will not clear. These types of large hemorrhages tend to happen more than once, often during sleep.
All people with diabetes are at risk – those with Type I diabetes and those with Type II diabetes. The longer a person has had diabetes, the higher their risk of developing some ocular problem. Between 40 and 45 percent of Americans diagnosed with diabetes have some stage of diabetic retinopathy. After 20 years of diabetes, nearly all patients with Type I diabetes and >60% of patients with Type II diabetes have some degree of retinopathy; however, these statistics were published in 2002 using data from four years earlier, limiting the usefulness of the research. The subjects would have been diagnosed with diabetes in the late 1970s, before modern fast-acting insulin and home glucose testing.
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, an anti-angiogenic protein, derived from collagen XVIII. The collagen XVIII gene is located on chromosome 21.
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. 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.
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.
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 simplex retinopathy or background 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 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.
Diabetic retinopathy is detected during an eye examination that includes:
- Visual acuity 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 dilate 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 or fundus photography: Ophthalmoscopy is an examination of the retina in which the eye care professional: (1) looks through a slit lamp biomicroscope with a special magnifying lens that provides a narrow view of the retina, or (2) wearing a headset (indirect ophthalmoscope) with a bright light, looks through a special magnifying glass and gains a wide view of the retina. Hand-held ophthalmoscopy is insufficient to rule out significant and treatable diabetic retinopathy. Fundus photography generally captures considerably larger areas of the fundus, and has the advantage of photo documentation for future reference, as well as availing the image to be examined by a specialist at another location and/or time.
- 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.
- Optical coherence tomography (OCT): This is an optical imaging modality based upon interference, and analogous to ultrasound. 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:
- leaking blood vessels,
- retinal swelling, such as macular edema,
- pale, fatty deposits on the retina (exudates) – signs of leaking blood vessels,
- damaged nerve tissue (neuropathy), and
- any changes in the blood vessels.
If macular edema is suspected, FFA and sometimes OCT may be performed.
Diabetic retinopathy also affects microcirculation thorough the body. A recent study 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.
In April 2018 the FDA approved a similar device called IDx-DR. IDx-DR is an AI diagnostic system that autonomously analyzes images of the retina for signs of diabetic retinopathy. As an autonomous, AI-based system, IDx-DR is unique in that it makes an assessment without the need for a clinician to also interpret the image or results, making it usable by health care providers who may not normally be involved in eye care.
According to a DRSS user manual, poor quality images (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.
In the UK, screening for diabetic retinopathy is part of the standard of care for people with diabetes. After one normal screening in people with diabetes, further screening is recommended every two years. In the UK, this is recommended every year. Teleophthalmology has been employed in these programs. 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.
There are three major treatments for diabetic retinopathy, which are very effective in reducing vision loss from this disease. 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. 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.
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.
Since 2008 there have been other therapies (e.g. kinase inhibitors and anti-VEGF) drugs available.
Laser photocoagulation can be used in two scenarios for the treatment of diabetic retinopathy. It can be used to treat macular edema by creating a Modified Grid at the posterior pole and it can be used for panretinal coagulation for controlling neovascularization. It is widely used for early stages of proliferative retinopathy.
A 'C' shaped area around the macula is treated with low intensity small burns. This helps in clearing the macular edema.
Panretinal photocoagulation, or PRP (also called scatter laser treatment), is used to treat proliferative diabetic retinopathy (PDR). 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 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%.
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 or a pattern scan laser for two dimensional patterns such as squares, rings and arcs. 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. When injected in the vitreous cavity, it decreases the macular edema (thickening of the retina at the macula) caused due to diabetic maculopathy, and results in an increase in visual acuity. The effect of triamcinolone is transient, lasting 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 include cataract, steroid-induced glaucoma and endophthalmitis. A systematic review found evidence that eyes treated with the intravitreal injection of triamcinolone had better visual acuity outcomes compared to eyes treated with macular laser grid photocoagulation, or sham injections.
There are good results from multiple doses of intravitreal injections of anti-VEGF drugs such as bevacizumab. A 2017 systematic review update found moderate evidence that aflibercept may have advantages in improving visual outcomes over bevacizumab and ranibizumab, after one year. Present recommended treatment for diabetic macular edema is Modified Grid laser photocoagulation combined with multiple injections of anti-VEGF drugs.
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 is often done under 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.
Vitrectomy is frequently combined with other modalities of treatment.
A medical device comprising a mask that delivers green light through the eyelids while a person sleeps was under development in 2016. 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. As of 2016 a large clinical trial was underway.. As of 2018, the results from the clinical trial showed no long-term therapeutic benefit from using the mask in diabetic retinopathy patients.
C-peptide had shown promising results in treatment of diabetic complications incidental to vascular degeneration. Creative Peptides, Eli Lilly, and Cebix 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.
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.
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. 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.
Fundoscopic image analyses
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.
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. 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.
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