The Eye in Systemic Disease: Diabetes Mellitus, Hypertension

Diabetes Mellitus (DM) is a group of metabolic diseases characterized by chronically elevated blood glucose levels. There are different types of diabetes:

• Type 1: Results from pancreatic beta cell failure, leading to insufficient insulin production for effective blood glucose control.
• Type 2: A state of insulin resistance in which target cells do not respond effectively to insulin.
• Gestational Diabetes Mellitus (GDM): Occurs in pregnant women who develop insulin resistance during pregnancy.

In 2013, an estimated 382 million people were diagnosed with diabetes, a number projected to increase to 592 million by 2035. Type 2 diabetes accounts for 90% of these cases.

Diabetic retinopathy (DR) is a common microvascular complication of diabetes mellitus.

• DR accounts for 5% of all blindness globally, affecting 2.5 out of 50 million blind people worldwide.
• It is the leading cause of blindness in people aged 20 – 64 years in industrialized countries.
• It is estimated that about 10% of people with diabetes aged ≥40 years in Nigeria may have sight-threatening diabetic retinopathy.

Diabetic retinopathy can be categorized into two classes:

1. Non-Proliferative Diabetic Retinopathy (NPDR)
2. Proliferative Diabetic Retinopathy (PDR)

Aldose Reductase and Vasoproliferative Factors

• Aldose Reductase Pathway: A persistent increase in blood glucose levels shunts excess glucose into the aldose reductase pathway in certain tissues.
• Sugar Conversion: This pathway converts sugars into alcohol, for example, glucose into sorbitol and galactose into dulcitol.
• Effect on Retinal Capillaries: Increased levels of sorbitol impact intramural pericytes of retinal capillaries.
• Loss of Function: The increased sorbitol levels lead to the loss of pericytes' primary function, which is to autoregulate retinal capillaries.
• Microaneurysms: Pericyte weakness results in saccular outpouching of capillary walls, leading to microaneurysms.
• Retinal Hemorrhages: Ruptured microaneurysms cause retinal hemorrhages, which can manifest as:
  • Flame-Shaped Hemorrhages: Superficial retinal hemorrhages.
  • Blot and Dot Hemorrhages: Hemorrhages in deeper layers of the retina.
• Increased Vessel Permeability: There's an increase in the permeability of these vessels, resulting in:
  • Retinal Thickening: Swelling and thickening of the retinal layers.
  • Exudates: Leakage of fluid and proteinaceous material.
• Macular Involvement: If the swelling and exudation involve the macula (central part of the retina), it can lead to a diminution in central vision.

Hypoxia

• Progression of DM: As diabetes mellitus (DM) progresses, eventual closure of the retinal capillaries occurs, leading to hypoxia.
• Nerve Fiber Infarction: Hypoxia causes infarction of the nerve fiber layer, resulting in the formation of cotton-wool spots. This is associated with stasis in axoplasmic flow.
• Compensatory Mechanisms: More extensive retinal hypoxia triggers compensatory mechanisms in the eye to provide sufficient oxygen to the tissues. This is seen as venous caliber abnormalities, including venous beading, loops, and dilation.

Neovascularization

• Retinal Ischemia: Further increases in retinal ischemia lead to the production of vasoproliferative factors, such as vascular endothelial growth factor (VEGF), which stimulate the formation of new blood vessels.
• Initial Stages: Initially, the new blood vessels are associated with the formation of fibrous tissue.
• Later Stages: In later stages, the new vessels may regress, leaving networks of avascular fibrous tissue adherent to both the retina and the vitreous.
• Tractional Forces: The fibrous tissue may exert tractional forces on the retina through these fibroglial connections.
• Clinical Implications: Traction can cause both tractional retinal detachments and the formation of retinal tears.

NPDR (Non-Proliferative Diabetic Retinopathy)

• Exudate (c): This refers to the presence of exudates in the retina.
• Microaneurysm (d): Microaneurysms are small, localized areas where the walls of tiny blood vessels (capillaries) have ballooned and can leak into the retina.
• Cotton Wool Spot (b): Cotton wool spots are soft, fluffy white spots on the retina.
• Intra Retinal Hemorrhage (dot & blot): This refers to hemorrhages within the retina, which can manifest as either dot or blot-shaped lesions.
• Splinter Hemorrhage (a): Splinter hemorrhages are tiny lines or streaks of blood that may appear in the retina.

• Intraretinal Microvascular Abnormalities (IRMA)
• Venous Beading: Venous beading refers to irregularities or constrictions in retinal veins, which may be a sign of retinal vascular changes.

Proliferative Diabetic Retinopathy (PDR)

• Retinal Neovascularization: The growth of new blood vessels in the retina.
• Preretinal Hemorrhage: Hemorrhage that occurs in front of the retina.
• Vitreous Hemorrhage: Hemorrhage into the vitreous humor, the gel-like substance filling the eye.
• Tractional Retinal Detachment: A condition where the retina is pulled away from its normal position due to traction forces.

New vessels are problematic because they can rupture, leading to vitreous hemorrhage and impaired vision. They can also grow into the vitreous and result in retinal detachment. The blood-retinal barrier helps prevent the entry of plasma, growth factors, and inflammatory factors into the immunologically quiescent eye. Vitreous hemorrhage can trigger additional neovascularization and inflammation that perpetuates PDR.

Diabetic Macular Edema (DME)

Diabetic macular edema is characterized by fragile retinal vessels that leak lipid-rich fluid. This fluid accumulates, leading to a thickening of the macula, which can result in distorted or blurry vision. DME is more common among individuals with type 2 diabetes compared to those with type 1 diabetes. Key features of DME include macular thickening or edema and the presence of macular exudates.

• Long duration of diabetes: After 10-15 years, 58% of Type 2 Diabetes (T2DM) and 95% of Type 1 Diabetes (T1DM) patients show some signs of retinopathy.
• Poor diabetes control: Tight glycemic control (HbA1c value of 7% or less) could reduce the risk of DR development and progression. The Diabetes Control and Complications Trial (DCCT) has shown that in T1DM, good control of metabolic status will reduce the risk of progression of diabetic retinopathy and delays the onset of retinopathy in patients who do not have retinal changes at the time of presentation.
• Hypertension and hyperlipidemia: Every 10 mmHg increase in systolic blood pressure was associated with a 10% increased risk of early DR and a 15% risk of PDR or DME.
• Increased BMI and waist-to-hip ratio (WHR) increase the risk of DR.
• Pregnancy.
• Nephropathy.

Laboratory Studies:

• HbA1c
• Serum lipid profile
• Electrolytes
• Urea and creatinine

Imaging Studies:

• Fundus Fluorescein Angiography (FFA): Microaneurysms appear as pinpoint, hyperfluorescent lesions in the early phases of the angiogram and typically leak in the later phases of the test.
• Optical Coherence Tomography Scanning (OCT): Administered to determine the thickness of the retina and the presence of swelling within the retina, as well as vitreomacular traction.
• B-scan Ultrasonography

Lifestyle Modification: It includes weight loss, smoking cessation, alcohol control, and dietary modifications.

Counseling: Emphasize the importance of good control of blood sugar, lipids, and blood pressure.

Non-Proliferative Diabetic Retinopathy (NPDR): Generally, no treatment is indicated.

Proliferative Diabetic Retinopathy (PDR):

• Retinal Laser Photocoagulation: Considered the definitive treatment.
• Anti-VEGF Intravitreal Injections: These include Eylea (aflibercept), Lucentis (ranibizumab), and Avastin (bevacizumab) for diabetic macular edema.
• Surgery (Pars Plana Vitrectomy): Indicated for tractional retinal detachment, non-clearing vitreous hemorrhage, and severe cases.

Diabetic Macular Edema (DME): Treatment options may include laser photocoagulation, anti-VEGF injections, and steroid (triamcinolone) injections.

1. Optimize Glycemic, Blood Pressure, and Serum Lipid Control: This helps reduce the risk or slow the progression of diabetic retinopathy.

2. Type 1 Diabetes: Adults with type 1 diabetes should have an initial dilated and comprehensive eye examination by an ophthalmologist or optometrist within 5 years after the onset of diabetes.

3. Type 2 Diabetes: Patients with type 2 diabetes should have an initial dilated and comprehensive eye examination by an ophthalmologist or optometrist at the time of the diabetes diagnosis.

4. Regular Examinations: If there is no evidence of retinopathy and glycemia is well controlled, then exams every 1-2 years may be considered.

5. Presence of Retinopathy: If any level of diabetic retinopathy is present, then dilated examinations will be required more frequently.

• Cataract: Cataract is one of the main causes of vision impairment in diabetics. Up to 59–98% of people with T2DM aged 30 to 75 will develop cataract.
• Corneal Nerve Dysfunction: Reduced corneal sensitivity due to diabetes-related microvascular complications (peripheral neuropathy).
• Persistent Cornea Erosion: Corneal problems that may arise due to diabetes.
• Cornea Edema: Swelling of the cornea, which can occur in diabetic individuals.
• Neovascular Glaucoma: A type of glaucoma associated with the growth of new blood vessels in the eye.
• Oculomotor Nerve Palsy: Characterized by ptosis (drooping of the eyelid) and exotropia (outward deviation of the eye).

Hypertension is diagnosed if, when it is measured on two different days, the systolic blood pressure readings on both days are ≥140 mmHg and/or the diastolic blood pressure readings on both days are ≥90 mmHg.

An estimated 1.28 billion adults aged 30-79 years worldwide have hypertension, most (two-thirds) living in low- and middle-income countries.

An estimated 46% of adults with hypertension are unaware that they have the condition.

Less than half of adults (42%) with hypertension are diagnosed and treated.

Approximately 1 in 5 adults (21%) with hypertension have it under control.

Hypertension is a major cause of premature death worldwide.

Acute (malignant HTN, Eclampsia) and chronic (long-standing systemic) hypertensive changes may manifest in the eyes.

Ocular changes can be the initial finding in an asymptomatic patient with hypertension, necessitating a primary care referral.

Hypertensive retinopathy is a spectrum of retinal microvascular changes that are associated with high BP.

Retinal circulation possesses autoregulation and endothelial tight junctions (maintain the blood-ocular barrier).

The terminal arterioles can constrict in response to elevated BP to maintain perfusion pressure.

Choroidal arterioles and capillaries have fenestrations (no blood-ocular barrier) and do not exhibit autoregulation.

In chronic HTN, the initial response is vasospasm and an increase in vasomotor tone, resulting in generalized arteriolar narrowing. Clinically, this appears as focal and diffuse narrowing of the retinal arterioles.

Chronic arteriosclerotic changes then develop, including intimal thickening, media-wall hyperplasia, and hyaline degeneration. These changes are seen as silver or copper wiring.

Subsequently, venules may be compressed by arterioles at their common adventitial sheath, leading to hourglass constrictions on both sides of the crossing, known as Arterio-venous nipping (Gunn sign).

Sclerosis may cause retinal arterioles to shorten or elongate, with branches originating at right angles. This change in length can deflect veins at the common sheath and alter the course of the vein, known as Salus sign.

Acute Hypertensive Retinopathy

In acute HTN with significantly elevated blood pressure, the blood-retinal barrier breaks down, leading to various retinal changes:

• Lipid exudation (hard exudates)
• Hemorrhages
• Nerve fiber layer infarction (cotton-wool spots)

In cases of severely elevated blood pressure, disc swelling develops, which is known as papilledema.

Hypertensive choroidopathy typically occurs in younger individuals with acute systemic hypertension, such as eclampsia or malignant hypertension. This condition is associated with abnormalities in the choroidal circulation.

The chorio-capillaries are fenestrated, allowing the free passage of macromolecules and fluid. Features of hypertensive choroidopathy include:

• Focal, white spots at the level of the retinal pigment epithelium (Elschnig spots)
• Siegrist streaks (sclerosed choroidal vessels with overlying necrosis of the choriocapillaris)
• Serous retinal detachments

The treatment of hypertensive retinopathy involves both medical management of hypertension, which includes lifestyle changes and pharmacotherapy. It's important to control high blood pressure effectively to prevent further retinal damage.

It's worth noting that retinal hypertensive changes correlate with an increased risk for cardiovascular morbidity and mortality in general. Therefore, managing hypertension is not only important for preserving eye health but also for overall well-being.

1. Retinal Vein Occlusion: Retinal vein occlusion is the most common retinal vascular disorder, second only to diabetic retinopathy. It can manifest as central or branch retinal vein occlusion.
2. Retinal Artery Occlusion: This is a sight-threatening condition characterized by a sudden, painless loss of vision with a whitened retina.
3. Optic Nerve Atrophy (Non-Arteritic Anterior Ischemic Optic Neuropathy - NAION): NAION is another potential complication of hypertension that can affect the optic nerve, leading to vision problems.