Diabetic Retinopathy Overview: Proliferative and Non-Proliferative Types

Abstract

Diabetic retinopathy is one of the common diabetes-related complications that affect the eyes. The blood vessels in the retina become damaged (swelling or leaking) because of high blood sugar levels. Because of the impossibility to predict the quality of damage and the development of blood vessel growth, diabetic retinopathy is usually classified into proliferative and non-proliferative. Non-proliferative diabetic retinopathy is diagnosed when some blood vessels leak, and the macula swells (macular edema). Blurry vision is the main symptom of this condition. Proliferated diabetic retinopathy is characterized by extensive blood vessel growth (neovascularization). Dark floaters and vision loss are the outcomes of unstable vessels’ bleeding. These conditions have similar etiology and differential diagnoses but various clinical representations and specific treatment approaches. Although diabetic retinopathy is not associated with high mortality and morbidity ratings, this disorder is progressive and results in complete vision loss that seriously challenges diabetic patients. This case report aims at discussing diabetic retinopathy (both forms), including epidemiology, signs, diagnostic tests, and management.

Introduction

Diabetic retinopathy (DR) is one of the well-known diabetes mellitus complications that influence human eyes. This condition is characterized by vision loss and blindness because of retinal microvascular damage of blood vessels.1 Diabetes leads to abnormal changes in glucose levels in the blood, which results in unstable capillaries. Vascular abnormalities include hyperpermeability, hypoperfusion, and neoangiogenesis and lead to changes either functional or anatomical in glial cells and retinal neurons.2 During the last several decades, the diabetic epidemic has already become a global health concern, estimating about 422 million people with diabetes today and predicting about 629 million by 2045.3 In the majority of cases, the populations of low-income and middle-income countries suffer from the diabetes burden. However, the citizens of developed countries should not be ignored. Genome wide association studies (GWAS) were used to identify DR-associated genes to improve an understanding of this disease pathogenesis.4 In addition to diabetes as the main risk factor, such conditions as high blood pressure, cholesterol, tobacco smoking, and pregnancy must be underlined.

From the clinical point of view, DR can be of two types: non-proliferative diabetic retinopathy (NPDR) and proliferative diabetic retinopathy (PDR). NPDR occurs in the early stage of DR when blood vessels leak and cause the retina swell, also known as macular edema. The severity of this condition is classified from mild to severe: mild NPDR includes microaneurysms, moderate NPDR – hemorrhages and hard exudates, and severe NPDR – intraretinal hemorrhage and venous beading.2 In NPDR patients, new blood vessels are not able to grow but dilate in irregular forms. PDR is defined as a more advanced stage due to neovascularization, the experience of serious vision impairments.1 The creation of new abnormal retinal vessels provokes vitreous hemorrhages, tractional retinal detachment, and refractory glaucoma.2 Compared to NPDR when the patient’s vision is blurry, PDR causes a number of new specks or colored spots (red blobs) in vision.

As soon as a patient experiences problematic vision, fluctuation, impaired colors, or sudden vision loss at least in one eye, it is high time to visit a doctor. DR usually affects both eyes within a short period, and instead of relying on the one eye functioning well, a person should take several diagnostic tests. In addition to a physical examination, a comprehensive dilated eye check has to be developed. After allergies and previous medications are defined and analyzed, specific drops are used to dilate the pupils and look into the fundus of the eye. As a rule, abnormal blood vessels, fatty deposits, or optic nerve abnormalities are observed. Patients with PDR or severe NPDR have clinically significant macular edema (CSME) that distorts central vision. The measurement of intraocular pressure (IOP) helps to detect glaucoma. Normal eye pressure is between 12 and 22 mm Hg, and DR patients may not have any changes in this aspect. This case report focuses on the analysis of PDR and NPDR with CSME OD and OS and the discussion of epidemiology, signs, diagnosis, and treatment for DR patients with sudden onsets.

Differential Diagnoses

Diagnosis of DR is based on the evaluation of retinal manifestations that vary from cotton wool spots to neovascularization. However, sometimes, patients may present mimicking DR symptoms, and the development of differential diagnoses turns out to be a critical aspect of doctor-patient cooperation. In the case of a 58-year-old African American male, the following differential diagnoses are recognized:

  • Branch retinal vein occlusion
  • Hypertension
  • Ocular ischemic syndrome
  • Leukemia

Branch retinal vein occlusion (BRVO) occurs because of retinal endothelial vascular damage. This disease presents with such symptoms as peripheral vision loss, blind spots, and decreased vision. In many cases, BRVO can be observed in one eye. The main risk factors of this condition are diabetes and high blood pressure. A thrombus leads to hardening (compression) of the arteries and retinal bleeding. A fluorescein angiogram is used to check the condition of the eye and approve the diagnosis.

Hypertension causes vascular damage that is also known as hypertensive retinopathy. The retina aims at transforming light into nerve signals, and when the blood pressure is high, the walls of blood vessels in that layer thicken and narrow. Limited retinal functions provoke vision problems, and a floater is one of them. Other symptoms of this condition include headache, reduced or double vision, and swelling in the eye. The examination of the retina with the help of an ophthalmoscope is one of the frequent solutions to diagnose a patient.

Ocular ischemic syndrome (OIS) is a rare eye condition that is caused by hypoperfusion of a carotid artery. The main symptoms of this disease are vision loss, visual field changes, and orbital pain. It is frequently observed in the elderly, and males are more affected than women are. An additional risk factor is the presence of cardiovascular disease that decreases blood flow in the vessels and arteries.

Leukemia influences the functions of the eyes in a variety of ways. Some patients may have leukemic retinopathy that presents with retinal hemorrhages in the posterior pole and cotton wool spots in adult patients. Other significant signs are exudates, perivascular sheathing, and retinal lesions of peripheral neovascularization. Chronic myeloid leukemia is the risk factor of this condition. Floaters in one of the eyes can bother patients regularly or suddenly with no recurrence.

Discussion

There is one critical characteristic of non-proliferative and proliferative diabetic retinopathy – the presence of neovascularization. In PDR patients, neovascularization or abnormal blood vessel growth is observed, and in NPDR patients, the early stage of DR without neovascularization occurs.5 In both types, diabetic macular edema causes further complications; therefore, the examination of the eye is necessary to identify a CSME. NPDR is usually asymptomatic, but impaired vision or color discrimination occurs.5 Angiogenic factors are developed and result in neovascularization, which leads to PDR. In the case under analysis, a male African American patient complained of a sudden and severe onset of a floater in vision (a red blob in the right eye). The secondary symptoms included blurred vision at a distance that got worse over the last several weeks. His family history presented a father with glaucoma and cataracts and a mother with cataracts. In addition, the family had a type II diabetes and hypertension history. The current patient took Metformin, Novolog, Atorvastatin, Metoprolol, and Zyrtec. Clinical findings (slit-lamp and dilated fundus examination) proved the diagnosis of DR (PDR with CSME OD and severe NPDR with CSME OS).

Epidemiology

Today, there is clear evidence of the prevalence of diabetes around the globe. At the same time, some researchers admit a decline in the DR incidence among patients of developed countries.6 In addition, visual impairment is frequently caused by diabetic macular edema but not by PDR.6 Still, DR remains one of the leading causes of vision loss among diabetic patients, including 2.6 million working-age adults who had DR in 2015 and 3.2 million in 2020.3 The most common complications in diabetic patients are nephropathy, cardiovascular diseases, and retinopathy. DR threatens vision in about 11% of patients annually, which makes this condition a public health concern.7 Despite the intention to predict diabetes-related complications, the increase remains evident. The number of people having diabetes continues growing in patients aged over 64 years in developed countries, particularly in Asia and Africa.6 In the bloodstream, the connection between high levels of glucose and the work of blood vessels is evident, and one-third of diabetic people develop DR during their lifetime.8 Attention to signs, early detection, and the analysis of clinical features are recommended to predict or delay the progress of DR in adults.

Clinical Features

An eye examination is required to diagnose diabetic retinopathy and identify the stage of the condition at the moment and includes pupil assessment, intraocular pressure, and visual acuity measurement. As soon as the drops were placed in the eye for dilation, a doctor detected all critical clinical features and combined them with personal complaints and other signs. The patient clinical findings were based on the best visual acuity (BVA) results (20/200 OD and 20/60 OS). The visual activity of the left eye was poor, but the condition of the right eye was worse, which was explained by the stage of DR in the patient. NPDR OS was severe because of scattered hemorrhage in all four quadrants of the fundus, several cotton wool spots, and intraretinal microvascular abnormalities (IRMA). In OD, CSME was clinically identified due to the thickening of the retina in the area of 1 disc diameter.9 In addition to the condition of the eyes, attention was paid to several vital signs (blood pressure and pulse). These checkups were used to identify if hypertension or a threat of cardiovascular disease influenced the quality of vision in the patient.

Signs/Symptoms

In the early stage of diabetic retinopathy (NPDR), a patient experiences no evident symptoms, but, with time, the condition gets worse, and signs turn out to be recognizable. The first troubles that patients with NPDR could observe are insignificant changes in the quality of their vision. For example, it could be difficult to read or recognize objects that are far away. However, diabetic patients know that these changes can go and disappear quickly because of the nature of their main disease.1 In later stages of DR, the most critical complaints include floaters or spots in vision. Even when one blood vessel starts bleeding in the retina, a person may see some dark or red spots that decrease visual acuity. Sometimes, floaters may clear up on their own because of the number of vessels being damaged. However, if no examination and treatment are taken in time, new problems could occur, causing additional symptoms and vision changes.2 For example, blurred, fluctuating, and impaired color vision bother the patient. The blindness of both eyes is the sign of PDR at the late stage with fewer or no opportunities to return vision.

Diagnosis

When patients are diagnosed with diabetes, they are informed about the importance of being regularly checked, and eye examination is one of the critical exams. The goal of this diagnostic approach is to observe the eye externally because the changes occur in the fundus. However, this procedure is usually simple and painless, and patients may feel discomfort only when drops reach their eyes to dilate the pupil. Indirect biomicroscopy is a common technique to observe the eye fundus and detect abnormalities. With the help of fluorescein angiography and optical coherence tomography, ophthalmologists assess the condition of blood vessels, including their permeability, thickness, and other changes.10 Compared to retinography, where a camera is used to photograph the fundus, angiography includes the use of the contrast agent injected into the vein to highlight changes in the blood flow. Some people could have fluorescein allergy; therefore, before, patients are asked about their allergies or kidney problems.2, 10 Nowadays, another alternative is available, and doctors use optical coherence tomography angiography by scanning the layers and blood circulation without injections.

Management

Diabetes is a disease that requires regular and immediate treatment to predict health complications, and DR is a condition when treatment may be unnecessary. For example, when a patient has mild or moderate NPDR, the doctor focuses on the examination and control, without any serious treatment options. The goal of treatment strategies is to manage microvascular complications.1 At the early stage, these complications remain insignificant and could disappear with time. However, when PDR or severe NPDR with CSME are detected, it is important to take a number of steps to predict vision loss. In the majority of cases, DR treatment includes the use of intravitreal pharmacological agents, laser photocoagulation, and surgery.1 Anti-angiogenic therapy (pegaptanib, aflibercept, nesvacumab and ranibizumab) was approved by the US Food and Drug Administration.1, 5, 10 Patients with PDR can also be treated with photocoagulation surgery, cryotherapy, and vitrectomy.1, 2, 10 Laser treatment is used to slow down the leakage in the eye or to shrink new blood vessels, and vitrectomy helps to reduce tissue in the eye.

Conclusion

This report explains DR as one of the possible complications that can be observed in diabetic patients. Vision problems may be developed with time or happen suddenly, causing discomfort. In the majority of cases, DR affects both eyes simultaneously, but complaints may differ because of the types of DR. NPDR occurs at an early stage when new blood vessels are not able to proliferate, but the walls of the blood vessels weaken and allow fluid leakage. As a result, irregular problems and vision changes bother patients. PDR is an advanced type of DR that is characterized by severe signs. Retinal neovascularization is a distinctive feature of PDR that is identified during the eye examination. Today, doctors have access to a variety of diagnostic techniques, including tomography, retinography, angiography (either fluorescein or optical), and biomicroscopy. IRMAs may vary in quality and quantity, determining the type of DR and an appropriate treatment method. In addition to pharmacological treatment, surgery and laser therapy can help people predict, delay, or avoid DR.

Footnotes

  1. Wang W, Lo ACY. Diabetic Retinopathy: Pathophysiology and Treatments. Int J Mol Sci. 2018; 19(6):1816.
  2. Kusuhara S, Fukushima Y, Ogura S, Inoue N, Uemura A. Pathophysiology of Diabetic Retinopathy: The Old and the New. Diabetes Metab J. 2018; 42(5):364-376.
  3. Cheloni R, Gandolfi SA, Signorelli C, Odone A. Global Prevalence of Diabetic Retinopathy: Protocol for a Systematic Review and Meta-Analysis. BMJ Open 2019; 9(3):e022188.
  4. Sharma A, Valle ML, Beveridge C, Liu Y, Sharma S. Unraveling the Role of Genetics in the Pathogenesis of Diabetic Retinopathy. Eye. 2019; 33(4):534-541.
  5. Shani M, Eviatar T, Komaneshter D, Vinker S. Diabetic Retinopathy – Incidence and Risk Factors in a Community Setting – A Longitudinal Study. Scand J Prim Health Care. 2018; 36(3):237-241.
  6. Sabanayagam C, Yip W, Ting DS, Tan G, Wong, TY. Ten Emerging Trends in the Epidemiology of Diabetic Retinopathy. Ophthalmic Epidemiol. 2016;23:209–222.
  7. Yang QH, Zhang Y, Zang XM, Li XR. Prevalence of Diabetic Retinopathy, Proliferative Diabetic Retinopathy and Non-Proliferative Diabetic Retinopathy in Asian T2DM Patients: A Systematic Review and Meta-Analysis. Int J Ophthalmol. 2019; 12(2):302-311.
  8. Hill L, Makaroff LE. Early Detection and Timely Treatment Can Prevent or Delay Diabetic Retinopathy. Diabetes Res Clin Pract. 2016; 120:241-243.
  9. Noor-ul-Huda M, Tehsin S, Ahmed S, Niazi FA, Murtaza Z. Retinal Images Benchmark for the Detection of Diabetic Retinopathy and Clinically Significant Macular Edema (CSME). Biomed Tech. 2019; 64(3):297-307.
  10. Whitehead M, Wickremasinghe S, Osborne A, Wijngaarden PV, Martin KR. Diabetic Retinopathy: A Complex Pathophysiology Requiring Novel Therapeutic Strategies. Expert Opin Biol Ther. 2018; 18(12):1257-1270.

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