Diabetic retinopathy

Diabetic retinopathy, ([ˌrɛtnˈɑpəθi]) is retinopathy (damage to the retina) caused by complications of diabetes, which can eventually lead to blindness. It is an ocular manifestation of diabetes, a systemic disease, which affects up to 80 percent of all patients who have had diabetes for 10 years or more. 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. The longer a person has diabetes, the higher his or her chances of developing diabetic retinopathy.

Signs and symptoms
Diabetic retinopathy often has no early warning signs. Even macular edema, which may cause vision loss more rapidly, 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.

In the first stage which is called non-proliferative diabetic retinopathy (NPDR) there are no symptoms, it is not visible to the naked eye and patients will have 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 be done to see the back of the eye. Narrowing or blocked retinal blood vessels can be seen clearly and this is called retinal ischemia (lack of blood flow).

Macular edema may occur in which blood vessels leak contents into the macular region can happen at all stages of NPDR. The macular oedema symptoms are blurring, darkening or distorted images with not the same between two eyes. 10 percent of diabetic patients will get vision loss related with macular oedema. Optical Coherence Tomography can show areas of retinal thickening (fluid accumulation) of macular oedema.

On the second stage, as abnormal new blood vessels (neovascularisation) form at the back of the eye as a part of proliferative diabetic retinopathy (PDR), they can burst and bleed (vitreous hemorrhage) and blur vision, because the new blood vessels are weak. The first time this happens, 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 vision. In extreme cases, a person will 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.

On funduscopic exam, a doctor will see cotton wool spots, flame hemorrhages (similar lesions are also caused by the alpha-toxin of Clostridium novyi), and dot-blot hemorrhages.

Pathogenesis
Diabetic retinopathy is the result of microvascular retinal changes. Hyperglycemia-induced intramural 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 the retinal blood vessels become more permeable.

The pericyte death is caused when "hyperglycemia persistently activates protein kinase C-δ (PKC-δ, encoded by Prkcd) and p38 mitogen-activated protein kinase (MAPK) to increase the expression of a previously unknown target of PKC-δ signaling, Src homology-2 domain–containing phosphatase-1 (SHP-1), a protein tyrosine phosphatase. This signaling cascade leads to PDGF receptor- dephosphorylation and a reduction in downstream signaling from this receptor, resulting in pericyte apoptosis…"

Small blood vessels – such as those in the eye – are especially vulnerable to poor blood sugar (blood glucose) 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 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 when blood vessels proliferate (i.e. 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.

Risk factors
All people with diabetes mellitus are at risk – those with Type I diabetes and those with Type II diabetes. The longer a person has diabetes, the higher the risk of developing some ocular problem. Between 40 to 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 today. The subjects would have been diagnosed with diabetes in the late 1970's, before modern fast acting insulin and home glucose testing.

Prior studies had also assumed a clear glycemic threshold between people at high and low risk of diabetic retinopathy.

However, it has been shown that the widely accepted WHO and American Diabetes Association diagnostic cutoff for diabetes of a fasting plasma glucose ≥ 7.0 mmol/l (126 mg/dl) does not accurately identify diabetic retinopathy among patients. The cohort study included a multi-ethnic, cross-sectional adult population sample in the US, as well as two cross-sectional adult populations in Australia. For the US-based component of the study, the sensitivity was 34.7% and specificity was 86.6%. For patients at similar risk to those in this study (15.8% had diabetic retinopathy), this leads to a positive predictive value of 32.7% and negative predictive value of 87.6%.

Published rates vary between trials, the proposed explanation being differences in study methods and reporting of prevalence rather than incidence values.

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.

People with Down's syndrome, who have three copies of chromosome 21, 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.

Diagnosis
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 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 recreate 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, leaking, 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.
 * 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 and the NHS Diabetic Eye Screening Programme
 * Computer Vision Approach: It is a System developed by Researchers at IIT Kharagpur in collaboration with IBM India. It uses data analytics capabilities to automatically compare and analyse retina images of the patient. It can tell if the patient has DR and also provides risk categorisation ranging from low to medium and high.
 * 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.

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.

Should the doctor suspect macular edema, he or she may perform fluorescein angiography and sometimes OCT.

Management
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 90 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 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. In some patients it results in a marked increase of vision, especially if there is an edema of the macula.

Avoiding tobacco use and correction of associated hypertension are important therapeutic measures in the management of diabetic retinopathy.

The best way of addressing diabetic retinopathy is to monitor it vigilantly and achieve euglycemia.

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

Laser photocoagulation
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.

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

Panretinal photocoagulation
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 anesthetic 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.

Intravitreal Anti-VEGF
There are good results from multiple doses of intravitreal injections of Anti-VEGF drugs such as bevacizumab. Present recommended treatment for diabetic macular edema is Modified Grid laser photocoagulation combined with multiple injections of Anti-VEGF.

Vitrectomy
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.

C-peptide
Though not yet commercially available, c-peptide has shown promising results in treatment of diabetic complications incidental to vascular degeneration. Once thought to be a useless byproduct of insulin production, it helps to ameliorate and reverse many symptoms of diabetes.

Pine bark extract
In a small clinical trial of 24 patients pine bark extract of oligomeric proanthocyanidins improved some measures of eye damage and visual acuity in the early stages of diabetic retinopathy.