DR

Objectives

A. Review of diabetes
B. Eye anatomy and physiology
C. Diabetic retinopathy basics
A. How does it develop?
B. How does it change over time?
D. Detection
E. Treatments
A. Laser Therapy (Focal and scatter)
B. Vitrectomy
C. Anti-angiogenic
D. Anti-inflammatory

Diabetes Mellitus

Diabetes mellitus is characterized by elevated blood glucose levels due to defects in the body's ability to produce and/or utilize insulin effectively.

  • Insulin Functionality:

    • Insulin is a peptide hormone released by the beta cells (b cells) of the pancreas into the bloodstream.

    • It facilitates the uptake of glucose by cells and promotes the conversion of glucose into glycogen for storage.

    • After glucose is taken up, blood glucose levels drop, prompting the pancreas to release glucagon from alpha cells (a cells), another peptide hormone.

    • Glucagon triggers the breakdown of glycogen, allowing glucose to be released back into the bloodstream.

Diabetes mellitus includes a group of diseases that manifest through an inability to manage insulin and high glucose levels.

  • Type 1 Diabetes:

    • Usually diagnosed in childhood or young adulthood.

    • Characterized by the body’s inability to produce insulin, leading to a prevalence of approximately 10% of diabetic patients.

    • Results in Hyperglycemia due to lack of insulin release, preventing glucose uptake.

  • Type 2 Diabetes:

    • More common (approximately 90% of cases).

    • Results from cellular insensitivity to insulin and/or inadequate insulin production.

    • Develops hyperglycemia, often accompanied by hyperinsulinemia due to the body's compensatory release of insulin in response to insulin insensitivity.

Types of Diabetes Mellitus

Prevalence of Diabetic Retinopathy

Diabetic retinopathy (DR) is recognized as the leading cause of blindness among working-age individuals within developed countries.

  • Statistics (CDC, 2010):

    • 30% of diabetic population in the U.S. will demonstrate mild to severe forms of DR.

    • In raw figures: approx. 4.2 million adults affected by DR, including 655,000 experiencing vision-threatening DR.

    • DR is observed to occur twice as frequently in Mexican Americans and three times in African Americans relative to other demographics.

    • Economic burden of diabetes-related blindness is estimated at $500 million annually and continues to increase.

    • Global prevalence is currently at 126 million, with projections of 191 million by 2030 (Zheng et al., 2012).

Diabetic Retinopathy Epidemiology

The duration of diabetes is the most reliable predictor for the development of diabetic retinopathy.

  • Long-term Outcomes:

    • After 20 years of living with diabetes:

    • 99% of patients with Type 1 diabetes will develop diabetic retinopathy.

    • 60% of patients with Type 2 diabetes will develop diabetic retinopathy.

    • Individuals with diabetes hold a 25-fold increased risk of blindness compared to the general population.

  • Other Risk Factors Influencing Severity:

    • Poor blood sugar control

    • High blood pressure

    • Hyperlipidemia

    • Accessibility barriers to care

Symptoms of Diabetic Retinopathy

In the initial stages, diabetic retinopathy is often asymptomatic. However, as the disease progresses, various symptoms may manifest, including:

  • Blurred or distorted vision

  • Floaters (visual disturbances)

  • Fluctuating vision

  • Scotomas (dark areas in the field of vision)

  • Impaired color vision

  • Night vision difficulties

  • Partial or complete vision loss

Basics of Eye Anatomy and Physiology

The eye consists of three primary tunics (layers):

  1. Fibrous or Corneoscleral Tunic

  2. Vascular or Uveal Tunic

  3. Retinal Tunic

  • Vascular or Uveal Tunic Components:

    • Includes choroid, ciliary body, and iris:

    • Choroid: provides nutrition

    • Ciliary Body: responsible for generating aqueous humor. The ciliary muscle controls lens shape for focusing.

    • Iris: functions as a contractile diaphragm.

    • Note: Diabetic retinopathy influences the retinal vasculature.

Anterior Segment vs. Posterior Segment

  1. Anterior Segment Components:

    • Aqueous humor (produced by the ciliary body)

    • Cornea

    • Iris

    • Pupil

    • Lens

  2. Posterior Segment Components:

    • Vitreous humor

    • Retina

Retina and Its Functioning

The retina comprises multiple layers, where photoreceptors transduce light signals into a format interpretable by neurons.

  • Functions:

    • Ganglion cells convey visual information to specialized regions of the brain including the visual cortex, which is key to perception of the visual field.

Retinal Vasculature

The retina has the highest oxygen consumption of any human tissue and is served by two major blood sources:

  1. Choroid

  2. Retinal blood vessels

  • Both supply oxygen and nutrients crucial for tissue survival.

  • Microvessels:

    • Central Retinal Artery and Vein

    • There exists a blood-retina barrier, maintaining inner and outer retinal stability and selective permeation of substances (via tight junctions of endothelial cells).

Neurovascular Unit

The neurovascular unit comprises various retinal cell types allowing communication regarding oxygen and glucose demands, which regulates vascular dilation or constriction.

  • Components of Inner Retinal Barrier: 1) Vascular Elements:

    • Pericytes: help endothelial cells survive and maintain the blood-brain barrier.

    • Endothelial cells: express essential survival factors for pericytes.
      2) Glial Cells:

    • Retinal astrocytes

    • Müller glia

    • Microglia (innate immune cells)
      3) Neuronal Cells

Fundus Photography

Fundus photography constitutes a digital capture of the retina’s back, using a high magnification device attached to an ophthalmoscope.

  • It allows for visualization of superficial vascular plexus abnormalities and damage.

Diabetic Eye Diseases

Diabetic eye diseases encompass various ocular conditions affecting those with diabetes:

  • Diabetic Retinopathy:

    • The primary cause of vision loss among individuals with diabetes, representing a degenerative condition impacting the retinal microvasculature.

    • Chronic hyperglycemia correlates with structural damage to blood vessels, resulting in fluid leakage and potential hemorrhaging, which distorts vision and threatens retinal cell health.

  • Diabetic Macular Edema:

    • Results from vascular leakage leading to macular swelling and vision distortion.

  • Cataracts:

    • Clouding of lenses, where individuals with diabetes are 2-5 times more susceptible, developing at earlier ages.

  • Glaucoma:

    • A suite of disorders damaging the optic nerve; diabetes doubles the risk of glaucoma onset.

Stages of Diabetic Retinopathy

Diabetic retinopathy progresses through four recognized stages:

  1. Nonproliferative:

    • Includes mild, moderate, and severe variations of nonproliferative retinopathy.

  2. Proliferative Diabetic Retinopathy:

    • Characterized by excessive blood vessel proliferation, often leading to severe visual complications.

Mild Nonproliferative Retinopathy

  • Clinical Indicators:

    • Funduscopic examination may reveal microaneurysms (dilations of retinal capillaries) and potentially macular edema.

  • Cellular Changes:

    • Early glycation of proteins and lipids

    • Initial loss of pericyte cells leading to microaneurysm formation

    • Loss of endothelial cell tight junction integrity

    • Basement membrane thickening, leading to blood flow impairment and increased oxidative stress.

Glycation Process

What is Glycation?

  • Glycation refers to glucose-mediated glycosylation, resulting in three general types of glycation products:

    1. Fluorescent structures that cross-link lysine and arginine

    2. Non-fluorescent cross-linking structures affecting amino acids.

    3. Non-cross-linking adducts like carboxymethyl lysine (CML).

  • Mechanism of Formation:

    • An open-chain glucose reacts with free amine groups on proteins to produce Schiff bases and undergoes further modification to produce cross-link products such as CML.

Implications of Glycation

Glycation occurs intracellularly and extracellularly, compromising the protein molecular structure, thus affecting functionality.

  • Consequences of Advanced Glycation End Products (AGEs):

    • Insulin: - Levels of active insulin in the bloodstream can decrease by up to 10%.

    • Albumin: - Elevated glycated albumin levels in the retina can trigger Vascular Endothelial Growth Factor (VEGF) expression, promoting neovascularization.

    • LDL (Low-Density Lipoprotein): - Increased glycation predisposes LDL to prolonged tissue retention and oxidation.

    • Collagen: - Glycation worsens the cross-linking of collagen, disrupting the collagen network and increasing the risk of endothelial cell growth.

    • Growth Factors: - Particularly PDGF-BB, which is vital for pericyte and endothelial cell survival.

Moderate Nonproliferative Retinopathy

  • Clinical Features:

    • Funduscopic examination might show distorted blood vessels and fluid leakage into the retina, contributing to macular edema and visible hemorrhages.

    • Ischemia could manifest as blood vessels blockages.

    • The appearance of cotton wool spots and hard exudates may also be observed.

  • Cellular Activity:

    • Activation of innate immune cells (microglia), inducing gliosis in retinal astrocytes, along with initial signs of neuronal stress indicating impending cell loss.

Severe Nonproliferative Retinopathy

  • Funduscopic Findings:

    • Notable for venous beading and intraretinal microvascular abnormalities (IRMA), coupled with macular edema without proliferative changes.

  • Cellular Activity:

    • Increased inflammation levels, loss of blood flow and essential nutrients, alongside heightened gliosis contributing to significant neuronal loss.

Proliferative Diabetic Retinopathy

  • Funduscopic Characteristics:

    • Emergence of neovascularization (new blood vessels), evident large pre-retinal hemorrhages, and greater prevalence of macular edema.

  • Cellular Impacts:

    • Newly formed blood vessels disrupt retinal organization, contributing to fragility and leakage.

    • The neuronal loss incurred results in vision impairment, exacerbated by scar tissue formation that may lead to retinal detachment and blindness.

End Stage of Diabetic Retinopathy

  • Refers to a condition termed phthisis bulbi, characterized by shrunken and non-functional eyeballs with opaque vascularized corneas.

Other Diabetic Eye Diseases

  • Neovascular Glaucoma:

    • Occurs due to altered aqueous humor dynamics leading to increased intraocular pressure (IOP), which ultimately damages optic nerve axons, resulting in neuronal death and new vascular growth obstructing aqueous outflow.

  • Senile Cataracts:

    • Formed as a consequence of diabetes-induced hyperglycemia causing sorbitol accumulation within lens cells, creating osmotic stress and leading to cell apoptosis.

International Clinical Diabetic Retinopathy Disease Severity Scale

  • Assessment findings under dilated ophthalmoscopy:

    1. No apparent retinopathy: no abnormalities observed

    2. Mild nonproliferative diabetic retinopathy: microaneurysms present

    3. Moderate nonproliferative diabetic retinopathy: presence of additional effects beyond microaneurysms, but not qualifying as severe

    4. Severe nonproliferative diabetic retinopathy: includes significant intraretinal hemorrhages, venous beading, and IRMAs without proliferative changes

    5. Proliferative diabetic retinopathy: neovascularization or preretinal hemorrhage indicative of advanced retinal pathology.

Summary

  • Diabetic retinopathy affects approximately one-third of the diabetic population.

  • The eye has three primary tunics (layers): the corneoscleral, vascular, and retinal.

  • The neurovascular unit connects neuronal needs with their blood supply, critical for maintaining retinal health and function.

  • Diabetic retinopathy is characterized by retinal microvascular disease progression through four stages: mild, moderate, and severe nonproliferative retinopathy and proliferative stages.

  • Funduscopic examination findings include microaneurysms, macular edema, hemorrhages, cotton wool spots, hard exudates, ischemia indicators, IRMAs, and neovascularization indicative of the progression of diabetic retinopathy.

Detection of Diabetic Retinopathy and Diabetic Macular Edema

Detection methods include visual acuity testing, tonometry, ophthalmoscopy and fundus photography, optical coherence tomography (OCT), and fluorescein angiography.

  • Importance of Regular Eye Exams:

    • Early stages can be asymptomatic; hence, consistent monitoring is essential, particularly for diagnosed individuals.

Tonometry

Tonometry measures intraocular eye pressure (IOP). Various methods exist, with applanation tonometry being the most common; it determines pressure needed to flatten a corneal area.

Optical Coherence Tomography

This non-invasive imaging technique allows for cross-sectional visual assessment of retinal tissue layers, enabling determination of changes in thickness or structural organization indicative of diabetic changes.

Fluorescein Angiography

An injection of fluorescein can highlight choroidal and retinal vascular structures through its light-emitting properties upon stimulation, helping detect leakage, ischemic areas, and more.

Treatment modalities encompass laser photocoagulation therapy, anti-angiogenic agents, anti-inflammatory therapies, vitrectomy, and risk factor controls such as managing hypertension, renal diseases, obesity, hyperlipidemia, and smoking.

Treatments for Diabetic Retinopathy

Laser Photocoagulation Therapy

This therapy employs laser heat to seal or destroy abnormal vasculature.

  • Types of Treatment:

    • Focal: Treats small areas primarily for macular edema due to localized leakage.

    • Grid: Addresses more extensive areas compared to focal treatment for diffuse leakage.

    • Scatter (Pan-retinal): Covers a larger section of the retina to slow new vessel growth.

Anti-Angiogenic Treatments

  • VEGF blockers, like Avastin and Lucentis, combat detrimental neovascularization in diabetic retinopathy.

  • Heparin sulfates play a competitive role in mitigating angiogenic factors like VEGF and FGF (fibroblast growth factor).

  • Tyrosine Kinase Inhibitors (such as Tykerb and Sutent) serve to reduce proliferation linked with abnormal vascular growth, while PDGF-BB blockers protect pericyte and endothelial cell survival.

Anti-Inflammatory Therapy

This involves the use of corticosteroids, TNF-alpha inhibitors, and non-steroidal anti-inflammatories (NSAIDs) to mitigate inflammation and associated retinal changes.

  • Corticosteroids:

    • These hormones have significant anti-inflammatory properties but can elevate IOP as a side effect.

Vitrectomy

A surgical intervention that removes vitreous humor from the eye, particularly effective in instances of pre-retinal hemorrhages or vitreous opacity obstructing treatment.

  • Scar tissue that may become contractile can lead to retinal detachment, necessitating this procedure to avert blindness.

Conclusion

Diabetic retinopathy requires vigilant monitoring and multifaceted treatment approaches, including regular exams and targeted therapies to manage the condition and preserve vision.