Diabetic retinopathy

Image of fundus showing scatter laser surgery for diabetic retinopathy
Classification and external resources
Specialty Ophthalmology
ICD-10 H36 (E10.3 E11.3 E12.3 E13.3 E14.3)
ICD-9-CM 250.5
DiseasesDB 29372
MedlinePlus 000494 001212
eMedicine oph/414 oph/415
MeSH D003930

Diabetic retinopathy ([ˌrɛtnˈɑpəθi]), also known as diabetic eye disease, is when damage occurs to the retina due to diabetes. It can eventually lead to blindness.[1]

It is an ocular manifestation of diabetes, a systemic disease, which affects up to 80 percent of all patients who have had diabetes for 20 years or more.[2] Despite these intimidating statistics, research indicates that at least 90% of these new cases could be reduced if there were proper and vigilant treatment and monitoring of the eyes.[3] The longer a person has diabetes, the higher his or her chances of developing diabetic retinopathy.[4] 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 for people aged 20 to 64 years.[5]

Signs and symptoms

Normal vision
The same view with diabetic retinopathy.

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.

In the first stage which is called non-proliferative diabetic retinopathy (NPDR) there are no symptoms, the signs are not visible to the eye and patients will 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 in which blood vessels leak their contents into the macular region can occur at any stage of NPDR. The symptoms of macular edema 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 the areas of retinal thickening (due to fluid accumulation) of macular edema.[6]

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 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.

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.

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 their risk of developing some ocular problem. Between 40 and 45 percent of Americans diagnosed with diabetes have some stage of diabetic retinopathy.[7] 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.

Prior studies had also assumed a clear glycemic threshold between people at high and low risk of diabetic retinopathy.[8][9]

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.[10] 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.[11]

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 extra chromosome 21 material, almost never acquire diabetic retinopathy. This protection appears to be due to the elevated levels of endostatin,[12] an anti-angiogenic protein, derived from collagen XVIII. The collagen XVIII gene is located on chromosome 21.

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 detected in the retina in diabetes leading to diabetic retinopathy include a narrowing of the retinal arteries associated with reduced retinal blood flow; dysfunction of the neurons of the inner neurons, 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.[13] Later, the basement membrane of the retinal blood vessels thickens, capillaries degenerate and lose cells, particularly pericytes and vascular smooth muscle cells (leading 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.[13][14]

An experimental study suggests that the pericyte death is caused when 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.[15]

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.[16]

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.

Diagnosis

Diabetic retinopathy is detected during an eye examination that includes:

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, FFA and sometimes OCT may be performed.

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.[17]

Management

There are three major treatments for diabetic retinopathy, which are very effective in reducing vision loss from this disease.[18] 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.[19] 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.[18]

Avoiding tobacco use and correction of associated hypertension are important therapeutic measures in the management of diabetic retinopathy.[20]

The best way of preventing the onset and delaying the progression of diabetic retinopathy is to monitor it vigilantly and achieve optimal glycemic control.[21]

Since 2008 there have been other therapies (e.g. kinase inhibitors and anti-VEGF) drugs available.[22]

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%.[2]

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.

Intravitreal anti-VEGF drugs

There are good results from multiple doses of intravitreal injections of anti-VEGF drugs such as bevacizumab.[23] Present recommended treatment for diabetic macular edema is Modified Grid laser photocoagulation combined with multiple injections of anti-VEGF drugs.

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.

Screening

In the UK, screening for diabetic retinopathy is part of the standard of care for people with diabetes.[24] Annual screening for people with diabetes is recommended by the American Ophthalmological Association.[25] Teleophthalmology has been employed in these programs.[26]

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.[27][28] 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.[27] As of 2016 a large clinical trial was underway.[27]

C-peptide

C-peptide had shown promising results in treatment of diabetic complications incidental to vascular degeneration.[29] Creative Peptides,[30] Eli Lilly,[31] and Cebix[32] 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.[33][34]

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.[35]

Blood pressure control

A Cochrane review examined 15 randomized controlled trials do determine whether interventions that sought to control or reduce blood pressure in diabetics had any effects of diabetic retinopathy.[36] 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.[36]

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.[37]

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.[38] 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.[39]

Distribution in percentage of pre-processing techniques from 2011-2014 [39]

See also

References

  1. ↑ "Diabetic retinopathy". Diabetes.co.uk. Retrieved 25 November 2012.
  2. 1 2 Kertes PJ, Johnson TM, eds. (2007). Evidence Based Eye Care. Philadelphia, PA: Lippincott Williams & Wilkins. ISBN 0-7817-6964-7.
  3. ↑ Tapp RJ; Shaw JE; Harper CA; et al. (June 2003). "The prevalence of and factors associated with diabetic retinopathy in the Australian population". Diabetes Care. 26 (6): 1731–7. doi:10.2337/diacare.26.6.1731 (inactive 2015-01-12). PMID 12766102.
  4. ↑ Caroline MacEwen. "diabetic retinopathy". Retrieved August 2, 2011.
  5. ↑ Engelgau, Michael, Linda Geiss, Jinan Saaddine, Jame Boyle, Stephanie Benjamin, Edward Gregg, Edward Tierney, Nilka Rios-Burrows, Ali Mokdad, Earl Ford, Giuseppina Imperatore, K. M. Venkat Narayan. "The Evolving Diabetes Burden in the United States." Annals of Internal Medicine, 1 June 2004. Web. 22 Apr. 2014.
  6. ↑ "Nonproliferative Diabetic Retinopathy (Includes Macular Edema)". Retrieved August 17, 2013.
  7. ↑ "Causes and Risk Factors". Diabetic Retinopathy. United States National Library of Medicine. 15 September 2009.
  8. ↑ Expert Committee on the Diagnosis and Classification of Diabetes Mellitus (January 2003). "Report of the expert committee on the diagnosis and classification of diabetes mellitus". Diabetes Care. 26 (Suppl 1): S5–20. doi:10.2337/diacare.26.2007.S5. PMID 12502614.
  9. ↑ The Expert Committee On The Diagnosis And Classification Of Diabetes Mellitus; James R. Gavin III, MD, PhD (Chair), Howard Hughes Medical Center, Bethesda, MD; K.G.M.M. Alberti, MD, University of Newcastle, Newcastle, U.K.; Mayer B. Davidson, MD, University of California, Los Angeles, CA; Ralph A. DeFronzo, MD, University of Texas, San Antonio, TX; Allan Drash, MD, University of Pittsburgh, Pittsburgh, PA; Steven G. Gabbe, MD, University of Washington, Seattle, WA; Saul Genuth, MD, Case West- ern Reserve University, Cleveland, OH; Maureen I. Harris, PhD, MPH, National Institutes of Health, Bethesda, MD; Richard Kahn, PhD, American Diabetes Associa- tion, Alexandria, VA; Harry Keen, MD, FRCP Guys Hospital, London, U.K.; William C. Knowler, MD, DrPH, National Institutes of Health, Phoenix, AZ; Harold Lebovitz, MD, State University of New York, Brooklyn, NY; Noel K. Maclaren, MD, University of Florida, Gainesville, FL; Jerry R Palmer, MD, University of Wash- ington, Seattle, WA; Philip Raskin, MD, University of Texas, Dallas, TX; Robert A. Rizza, MD, Mayo Clinic, Rochester, MN; Michael R Stern, MD, University of Texas, San Antonio, TX. (July 1997). "Report of the Expert Committee on the Diagnosis and Classification of Diabetes Mellitus" (PDF). Diabetes Care. 20 (7): 1183–1197. doi:10.2337/diacare.20.7.1183 (inactive 2015-01-12). PMID 9203460. Retrieved Nov 23, 2013.
  10. ↑ Wong TY; Liew G; Tapp RJ; et al. (March 2008). "Lancet Revision, D-07-06757 The Relationship of Fasting Glucose to Retinopathy: Re-visiting a Key Criterion Used to Diagnose Diabetes". Lancet. 371 (9614): 736–43. doi:10.1016/S0140-6736(08)60343-8. PMC 2350208Freely accessible. PMID 18313502.
  11. ↑ Williams R, Airey M, Baxter H, Forrester J, Kennedy-Martin T, Girach A; Airey; Baxter; Forrester; Kennedy-Martin; Girach (October 2004). "Epidemiology of diabetic retinopathy and macular oedema: a systematic review". Eye. 18 (10): 963–83. doi:10.1038/sj.eye.6701476. PMID 15232600.
  12. ↑ Ryeom, Sandra; Folkman, Judah (2009). "Role of Endogenous Angiogenesis Inhibitors in Down Syndrome". Journal of Craniofacial Surgery. 20 (Suppl 1): 595–6. doi:10.1097/SCS.0b013e3181927f47. PMID 19795527.
  13. 1 2 Xu, Heping; Curtis, Timothy; Stitt, Alan (13 August 2013). "Pathophysiology and Pathogenesis of Diabetic Retinopathy [internet]". Diapedia. 7104343513 (14). doi:10.14496/dia.7104343513.14. Retrieved 26 August 2016.
  14. ↑ Pardianto G; et al. (2005). "Understanding diabetic retinopathy". Mimbar Ilmiah Oftalmologi Indonesia. 2: 65–6.
  15. ↑ Geraldes, Pedro; Hiraoka-Yamamoto, Junko; Matsumoto, Motonobu; Clermont, Allen; Leitges, Michael; Marette, Andre; Aiello, Lloyd P; Kern, Timothy S; King, George L (2009). "Activation of PKC-δ and SHP-1 by hyperglycemia causes vascular cell apoptosis and diabetic retinopathy". Nature Medicine. 15 (11): 1298–306. doi:10.1038/nm.2052. PMC 3290906Freely accessible. PMID 19881493.
  16. ↑ Toke, Bek; Hammes, H-P; Porta, M. (eds) (2010). "Experimental Approaches to Diabetic Retinopathy - Front Diabetes". Clinical Presentations and Pathological Correlates of Retinopathy (PDF). Karger.com. 20. Basel. pp. 1–19.
  17. ↑ Central Mersey Diabetic Retinopathy Screening Programme (NHS England), DRSS User Manual , 2009
  18. 1 2 Mitchell, Paul; Wong, Tien Yin; Diabetic Macular Edema Treatment Guideline Working Group (2014-03-01). "Management paradigms for diabetic macular edema". American Journal of Ophthalmology. 157 (3): 505–513.e1–8. doi:10.1016/j.ajo.2013.11.012. ISSN 1879-1891. PMID 24269850.
  19. ↑ "Facts About Diabetic Eye Disease | National Eye Institute". nei.nih.gov. Retrieved 2016-07-18.
  20. ↑ Masharani, Umesh (2006). "Diabetes Ocular complications". Chronic Complications of Diabetes. Armenian Medical Network.
  21. ↑ Hooper, Philip; Boucher, Marie Carole; Cruess, Alan; Dawson, Keith G.; Delpero, Walter; Greve, Mark; Kozousek, Vladimir; Lam, Wai-Ching; Maberley, David A. L. (2012-04-01). "Canadian Ophthalmological Society evidence-based clinical practice guidelines for the management of diabetic retinopathy". Canadian Journal of Ophthalmology. Journal Canadien D'ophtalmologie. 47 (2 Suppl): S1–30, S31–54. doi:10.1016/j.jcjo.2011.12.025. ISSN 0008-4182. PMID 22632804.
  22. ↑ Fraser-Bell S, Kaines A, Hykin PG; Kaines; Hykin (May 2008). "Update on treatments for diabetic macular edema". Current Opinion in Ophthalmology. 19 (3): 185–9. doi:10.1097/ICU.0b013e3282fb7c45. PMID 18408491.
  23. ↑ O'Malley, PG (Jul 9, 2012). "Comparative effectiveness of anti-growth factor therapies for diabetic macular edema: summary of primary findings and conclusions". Archives of Internal Medicine. 172 (13): 1014–5. doi:10.1001/archinternmed.2012.2335. PMID 22688778.
  24. ↑ "Diabetic eye screening - NHS Choices". NHS Choices. 12 July 2016.
  25. ↑ "Diabetic Retinopathy PPP - Updated 2016". American Academy of Ophthalmology. 24 February 2016.
  26. ↑ Gupta, Aditi; Cavallerano, Jerry; Sun, Jennifer K.; Silva, Paolo S. (17 October 2016). "Evidence for Telemedicine for Diabetic Retinal Disease". Seminars in Ophthalmology: 1–7. doi:10.1080/08820538.2016.1228403. PMID 27748634.
  27. 1 2 3 Sivaprasad, S.; Arden, G. (2016-02-01). "Spare the rods and spoil the retina: revisited". Eye (London, England). 30 (2): 189–192. doi:10.1038/eye.2015.254. ISSN 1476-5454. PMC 4763134Freely accessible. PMID 26656085.
  28. ↑ "Noctura 400 Sleep Mask for diabetic retinopathy ‐ Horizon Scanning Research & Intelligence Centre". www.hsric.nihr.ac.uk. Retrieved 2015-09-24.
  29. ↑ Bhatt, Mahendra Prasad; Lim, Young-Cheol; Ha, Kwon-Soo (2014-11-01). "C-peptide replacement therapy as an emerging strategy for preventing diabetic vasculopathy". Cardiovascular Research. 104 (2): 234–244. doi:10.1093/cvr/cvu211. ISSN 1755-3245. PMID 25239825.
  30. ↑ "C-peptide - Creative Peptides -". AdisInsight. Retrieved 22 October 2016.
  31. ↑ "C-peptide - Eli Lilly". AdisInsight. Retrieved 22 October 2016.
  32. ↑ "C-peptide long-acting - Cebix". adisinsight.springer.com. AdisInsight. Retrieved 22 October 2016.
  33. ↑ Bigelow, Bruce V. (23 February 2015). "Cebix Shuts Down Following Mid-Stage Trial of C-Peptide Drug". Xconomy.
  34. ↑ Garde, Damian (February 24, 2015). "Cebix hangs it up after raising $50M for diabetes drug". FierceBiotech.
  35. ↑ Ljubimov, Alexander. "Stem Cell Therapy for Diabetic Retinopathy" (PDF). Cedars-Sinai Medical Center, Regenerative Medicine Institute, Los Angeles, CA, USA Medicine, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA.
  36. 1 2 Do DV, Wang X, Vedula SS, Marrone M, Sleilati G, Hawkins BS, Frank RN (2015). "Blood pressure control for diabetic retinopathy". Cochrane Database Syst Rev. 1: CD006127. doi:10.1002/14651858.CD006127.pub2. PMID 25637717.
  37. ↑ "Diabetic Retinopathy". Merck Manuals Professional Edition. Retrieved 2016-11-13.
  38. ↑ Kaur, M; Talwar, R (2014). "Review on: Blood Vessel Extraction and Eye Retinopathy Detection". International Journal of Computer Science and Information Technologies. 5 (6): 7513–7516.
  39. 1 2 Ahmad, A.; Mansoor, A. B.; Mumtaz, R.; Khan, M.; Mirza, S. H. (2014-12-01). "Image processing and classification in diabetic retinopathy: A review". 2014 5th European Workshop on Visual Information Processing (EUVIP): 1–6. doi:10.1109/EUVIP.2014.7018362.
  40. ↑ Grossman, Samuel. "A New Treatment for Diabetic Retinopathy". Diabetescare.net. Diabetescare.net. Retrieved 19 March 2015.
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