Hypertensive Retinopathy

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Hypertensive Retinopathy


Introduction

Hypertension is a risk factor for systemic conditions that can lead to target-organ damage. Specifically, hypertension may lead to multiple adverse effects to the eye that can inevitably cause cause retinopathy, optic neuropathy, and choroidopathy. Moreover, hypertension can also cause occlusion of major retinal vessels such as the branch retinal artery, central retinal artery, branch retinal vein and central retinal vein.[1] This article focuses primarily upon hypertensive retinopathy, which is the most common ocular presentation.

Disease Entity

Disease

The arteriosclerotic changes of hypertensive retinopathy are caused by chronically elevated blood pressure. The American College of Cardiology/American Heart Association (ACC/AHA) suggested the following definitions for high blood pressure in 2017.[2]

Category Systolic (SBP) Diastolic (DBP)
Elevated blood pressure
120-129 mmHg
< 80 mmHg
Stage 1 hypertension
130-139 mmHg
80-89 mmHg
Stage 2 hypertension
≥ 140 mmHg
 ≥ 90 mmHg

Hypertensive retinopathy includes two disease processes. The acute effects of systemic arterial hypertension are a result of vasospasm to autoregulate perfusion.[3] The chronic effects of hypertension are caused by arteriosclerosis and predispose patients to visual loss from complications of vascular occlusions or macroaneurysms.[4]

Epidemiology

In the United States, 33% of adults have hypertension and only 52% have controlled blood pressures.[5] Hypertensive retinopathy ranges from 2-17% in non-diabetic patients but the prevalence varies by demographic groups.[6] Hypertensive retinopathy is more common in African Americans and Chinese descent. In addition, the incidence of blood pressure increases with age. Men are more affected than women in age groups less than 45 years old and women are more affected in age groups greater than 65 years old.[5]

Etiology

The arteriosclerotic changes of hypertensive retinopathy are caused by chronically elevated blood pressure, defined as SBP greater than 140 mmHg and DBP greater than 90 mmHg.[4] Primary hypertension is usually essential and not secondary to another disease process. Essential hypertension is a polygenic disease with multiple modifiable environmental factors contributing to the disease. However, secondary hypertension can develop in the setting of pheochromocytoma, primary hyperaldosteronism, Cushing’s syndrome, renal parenchymal disease, renal vascular disease, coarctation of the aorta, obstructive sleep apnea, hyperparathyroidism, and hyperthyroidism.[7] Many young patients with secondary hypertension may actually present to an ophthalmologist with bilateral vision loss due to serous macular detachment, bilateral optic disc edema, and exudative retinal detachment. In addition, genetic factors have been found to be associated with a higher risk of hypertensive retinopathy.[8]

Risk Factors

Risk factors for essential hypertension include high salt diet, obesity, tobacco use, alcohol, family history, stress, and ethnic background. The major risk for arteriosclerotic hypertensive retinopathy is the duration of elevated blood pressure. The major risk factor for malignant hypertension is the degree of blood pressure elevation over normal.

Some studies suggest a genetic influence on retinal vascular caliber. A 2010 population-based study indicated four novel loci (19q13, 6q24, 12q24, and 5q14) as significantly associated with retinal venular caliber.[9] Furthermore, locus 12q24 was connected with hypertension and coronary heart disease.

Pathophysiology

Hypertensive retinopathy goes through vasoconstrictive, sclerotic, and exudative phases based upon the extent of hypertension control.

Vasoconstrictive Phase:

In the vasoconstrictive phase, due to the elevated luminal pressures, local autoregulatory mechanisms cause retinal arteriole narrowing and vasospasm to reduce flow.

Sclerotic Phase:

In the sclerotic phase, the layers of the endothelial wall undergo changes such as intimal thickening, medial hyperplasia, and hyaline degradation in the arteriolar[10] worsening arteriolar narrowing, AV crossing changes, and silver and copper wiring.

Exudative Phase:

In the exudative phase, there is a disruption of the blood-brain barrier and leakage of plasma and blood causing retinal hemorrhages, hard exudates, retinal ischemia, and necrosis of smooth muscle.[10]

Retinal hemorrhages (Figure 1-3) develop when necrotic vessels bleed into either the superficial retina (nerve fiber layer) (flame shaped hemorrhage) or the inner retina (dot blot hemorrhage). Cotton wool spots (Figure 1 & 3) are caused by ischemia to the nerve fiber layer secondary to fibrinous necrosis and luminal narrowing. Ischemia to the nerve fibers leads to decreased axoplasmic flow, nerve swelling, and ultimately fluffy opacification. Exudates (Figure 2) occur later in the course of disease, surrounding areas of hemorrhage, as a result of lipid accumulation. Malignant hypertension can cause papilledema (Figure 3), which is a result of both leakage and ischemia of arterioles supplying the optic disc that undergo fibrinous necrosis. Ischemia causes optic nerve edema, while leakage causes hemorrhage and disc edema.[11]

Of note, the severity and degree of malignant hypertension corresponds to changes of renal function highlighting the multi-organ damage caused by systemic microvascular dysfunction.[12]

Primary prevention

Routine blood pressure monitoring and treatment will prevent hypertensive retinopathy from developing.

Diagnosis

Hypertensive retinopathy is diagnosed based upon its clinical appearance on dilated fundoscopic exam and coexistent hypertension.

History

The history should focus upon the hypertension disease history, symptoms of hypertension, and history of its complications. To gauge hypertension disease severity, patients should be asked about their severity and duration of hypertension, and about the medications taken as well as compliance. Symptoms of hypertension to ask about include headaches, eye pain, reduced visual acuity, focal neurological deficits, chest pain, shortness of breath, dyspnea on exertion, paroxysmal nocturnal dyspnea, orthopnea, and palpitations. Patients should be asked about the complications of hypertension, including history of stroke or transient ischemic attack, history of coronary or peripheral vascular disease, and history of heart failure.[7] Many patients may be asymptomatic.

Physical examination

Figure 1. Copper-wiring, arteriovenous nicking and silver-wiring seen in a patient with hypertensive retinopathy. © 2019 American Academy of Ophthalmology

The physical exam on a patient with hypertension includes vital signs, cardiovascular exam, pulmonary exam, neurological exam, and dilated fundoscopy. Vital signs should obviously focus on blood pressure. Key elements of the cardiovascular exam include heart sounds (gallops or murmurs), carotid or renal bruits, and peripheral pulses. Pulmonary exam can identify signs of heart failure if rales are present. Signs of cerebral ischemia can be detected by a good neurological exam.[7] And finally, dilated fundus exam is necessary for staging of hypertensive retinopathy.

Signs

The signs of hypertensive retinopathy include constricted and tortuous arterioles, retinal hemorrhage (Figure 1-3), hard exudates (Figure 2), cotton wool spots (Figure 1 & 3), retinal edema, and papilledema (Figure 3). The signs of chronic arterial hypertension in the retina include widening of the arteriole reflex, arteriovenous crossing signs, and copper (Figure 1 & 3) or silver wire arterioles (copper or silver colored arteriole light reflex).[3]

Malignant hypertension can also cause choroidopathy. Fibrinoid necrosis of choroidal arterioles leads to segmental infarction of choriocapillaris.[10] Poor perfusion of the choriocapillaris causes Elschnig spots, defined as hyperpigmented patches in the choroid surrounded by a ring of hypopigmentation, or Siegrist streaks, defined as linear hyperpigmented lesions over choroidal arteries. Hypertensive choroidopathy can cause a focal pigment epithelium detachment, leading to exudative retinal detachment.[4] Generally, hypertensive choroidopathy affects younger patients with malignant hypertension.[13]

Hypertension may lead to optic neuropathy (Figure 3). Hypertensive optic neuropathy, specifically, presents as optic disk swelling.[10] The signs include flame shaped hemorrhages at the disc margin, blurred disc margins, congested retinal veins, papilledema, and secondary macular exudates.[4] Hard exudates can deposit in the macula causing a macular star. Optic nerve pallor is also present in patients with chronic hypertension.

Figure 2. Grade 3-4 Hypertensive Retinopathy. A 56-year old patient presented with acute onset vision loss. Fundus examination revealed Grade 3-4 hypertensive retinopathy changes including arterio-venous crossing changes, macular star and cotton wool spots. © 2019 American Academy of Ophthalmology

Symptoms

Malignant Hypertension

Acute malignant hypertension will cause patients to complain of eye pain, headaches, or reduced visual acuity.[3] However, the complications of arteriosclerotic hypertensive changes will cause patients to present with the typical symptoms of vascular occlusions or macroaneurysms.

Chronic Hypertension

Chronic arteriosclerotic changes from chronic hypertension will not cause any symptoms alone but patients often experience decreased vision.

The Scheie Classification below delves into the retinopathic changes seen in both acute, malignant hypertension and chronic, systemic hypertension.

Clinical diagnosis

The signs of malignant hypertension are well summarized by the Modified Scheie Classification of Hypertensive Retinopathy[4]:

  • Grade 0: No changes
  • Grade 1: Barely detectable arterial narrowing
  • Grade 2: Obvious arterial narrowing with focal irregularities (Figure 1)
  • Grade 3: Grade 2 plus retinal hemorrhages, exudates, cotton wool spots, or retinal edema (Figure 3)
  • Grade 4: Grade 3 plus papilledema (Figure 4)

The signs of chronic arteriosclerotic hypertension are also summarized by the Scheie Classification[3]:

  • Stage 1: Widening of the arteriole light reflex
  • Stage 2: Stage 1 + Arteriovenous crossing sign (Figure 3)
  • Stage 3: Copper wiring of arterioles (copper colored arteriole light reflex)
  • Stage 4: Silver wiring of arterioles (silver colored arteriole light reflex).

Another classification schema is the Keith-Wagner-Barker classification proposed in 1939.[14]

  • Grade 1: Mild, generalized constriction of retinal arterioles
  • Grade 2: Definite focal narrowing of retinal arterioles + AV nicking
  • Grade 3: Grade 2 + flame-shaped hemorrhages + cotton-wool spots + hard exudates
  • Grade 4: Severe Grade 3 retinopathy + papilledema or retinal edema

Of specific interest is the classification of hypertensive retinopathy by Wong and Mitchell (2004) in which the worsening grades of retinopathy were more strongly associated with systemic issues.[15] The classification is as follows:

  • None: no detectable signs
  • Mild: one or more of the following: generalized arteriolar narrowing, focal arteriolar narrowing, arteriovenous nicking, opacity (“copper wiring”) of arteriolar wall
  • Moderate: one or more of the following: retinal hemorrhage (blot, dot, or flame-shaped), microaneurysm, cotton-wool spot, hard exudate, or a combination of these signs
  • Severe: moderate retinopathy plus swelling of the optic disc

A new classification has been proposed recently (2014) based on optical coherence tomography (OCT) features such as subretinal fluid (SRF). The study compared the grading system based on OCT findings to the Keith-Wagner-Barker grading system and found that the following classification was significantly correlated to final best-corrected visual acuity.[16]

  • Mild-Moderate Retinopathy
  • Malignant Retinopathy w/o SRF
  • Malignant R w/ SRF
Figure 3. Common hypertensive retinal changes are flame-shaped hemorrhages in the superficial layers of the retina and cotton-wool patches caused by occlusion of the precapillary arterioles with ischemic infarction of the inner retina. Long-standing hypertension can produce arteriolar sclerotic vascular changes, such as copper or silver wiring of the arterioles, as shown by the two arrows on the right, or arteriorvenous nicking. Another sign of chronic hypertension is lipid exudates resulting from abnormal vascular permeability, as shown by the arrow at left. More ominous in this photograph is swelling of the optic disc, seen here by the blurring of the temporal disc margins. This is the hallmark of malignant hypertension, which carries a poor prognosis for the patient’s health if left untreated. BP must be emergently controlled to decrease the risk of developing heart and renal failure and hypertensive encephalopathy as well as stroke and permanent vision loss.

Diagnostic procedures

Fluorescein angiography (FA) during acute malignant hypertension will demonstrate retinal capillary nonperfusion, microaneurysm formation, and a dendritic pattern of choroidal filling in the early phase. In the late phase, diffuse leakage will be seen.[4] Indocyanine green angiography during malignant hypertension will show a moth eaten appearance of the choriocapillaris.[4] Fluorescein angiography can demonstrate hypertensive choroidopathy. FA will show focal choroidal hypoperfusion in the early phases and subretinal leakage in the later phases.[4]

Differential diagnosis

The differential for hypertensive retinopathy with diffuse retinal hemorrhage, cotton wool spots, and hard exudates includes most notably diabetic retinopathy. Diabetic retinopathy can be distinguished from hypertensive retinopathy by evaluation for the individual systemic diseases.[3] Other conditions with diffuse retinal hemorrhage that can resemble hypertensive retinopathy include radiation retinopathy, anemia and other blood dyscrasias, ocular ischemic syndrome, and retinal vein occlusion. Conditions with optic disc edema also include diabetic papillopathy, anterior ischemic optic neuropathy, and neuroretinitis.

Management

The treatment for hypertensive retinopathy is primarily focused upon reducing blood pressure. It is important to work together with the patient’s primary care doctor to ensure timely evaluation and management to reduce ocular and systemic damage. A thorough history is vital for the proper and timely treatment of hypertensive retinopathy to prevent vision-threatening complications.

General treatment

The treatment for moderate to severe hypertensive retinopathy is to reduce the mean arterial pressure by 10-15% in the first hour. Of note, blood pressure should be lowered in a controlled manner and by no more than 25% compared to baseline by the end of the first day of treatment to prevent further ischemic damage to target end organs. Initial treatment often requires parenteral antihypertensive agents and then transitioned to oral agents. Goal-oriented hypertension treatment aims to lower systolic blood pressure to < 130 mmHG and diastolic pressure to < 80 mm Hg over the next 2-3 months.[17]

Medical therapy

Drugs that are commonly used in the outpatient setting to reduce blood pressure include angiotensin converting enzyme inhibitors, calcium channel blockers, and diuretics. Other less commonly used medications include α-adrenergic blockers, direct vasodilators, and central α2-adrenergic agonists. The patient should be followed by his primary physician closely for management of hypertension. If the patient is in hypertensive crisis, he should be referred to an emergency department for acute management of blood pressure.

Studies have explored intravitreal antibody treatment against vascular endothelial growth factor (bevacizumab) for acute hypertensive retinopathy and showed a reduction in macular edema and retinal hemorrhage.[5] Moreover, another study showed prompt recovery of malignant hypertensive retinopathy in patients after administration of bevacizumab.[18] However, the use of these agents have not yet been widespread or accepted.

Medical follow up

Follow up is dependent upon the degree of hypertension and resistance to medications. Close contact is essential between the ophthalmologist and the primary care physician for consistent follow up individually tailored to each patient.

Surgery

There is no surgical treatment for essential hypertension nor its ocular complications. In cases of secondary hypertension surgical treatment may be effective, depending upon the etiology.

Complications

Hypertension predisposes patients to many other retinal vascular diseases including central or branch retinal artery occlusion, central or branch retinal vein occlusion, and retinal arterial macroaneurysms. Ischemia secondary to vascular occlusions can cause neovascularization, vitreous hemorrhage, epiretinal membrane formation, and tractional retinal detachment. Hypertension also leads to more advanced diabetic retinopathy progression.[4] Hypertensive optic neuropathy can cause chronic papilledema, leading to optic nerve atrophy and severe loss of visual acuity.[3]  It may also be a risk factor for glaucoma. Recently a term 'proliferative hypertensive retinopathy' has been coined.[19]

Prognosis

Patients with severe hypertensive retinopathy and arteriosclerotic changes are at increased risk for coronary disease, peripheral vascular disease, and stroke. Mortality of patients with untreated malignant hypertension was 50% in 2 months and 90% in 1 year.[14] Since arteriosclerotic changes in the retina do not regress, these patients remain at increased risk for retinal artery occlusions, retinal vein occlusions, and retinal macroaneurysms. Most retinal changes secondary to malignant hypertension will improve once blood pressure is controlled but AV changes and arteriolar narrowing will remain. Damage to the optic nerve and macula, however, could cause long term reductions in visual acuity.

Additional Resources

Reference

  1. Tsukikawa, M., & Stacey, A. W. (2020). A Review of Hypertensive Retinopathy and Chorioretinopathy. Clinical optometry, 12, 67–73. https://doi.org/10.2147/OPTO.S183492
  2. 2017ACC/AHA/AAPA/ABC/ACPM/AGS/APhA/ASH/ASPC/NMA/PCNA Guideline for the Prevention, Detection, Evaluation, and Management of High Blood Pressure in Adults: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines.
  3. 3.0 3.1 3.2 3.3 3.4 3.5 Lang, G.K. Ophthalmology: A Pocket Textbook Atlas (Thieme, Stuttgart, 2007).
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  9. Konstantinidis, L., & Guex-Crosier, Y. (2016). Hypertension and the eye. Current opinion in ophthalmology, 27(6), 514–521. https://doi.org/10.1097/ICU.0000000000000307
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  11. Garner, A. &amp; Ashton, N. 1979. Pathogenesis of hypertensive retinopathy: a review. J R Soc Med 72: 362-5.
  12. Shantsila, A., & Lip, G. (2017). Malignant Hypertension Revisited-Does This Still Exist?. American journal of hypertension, 30(6), 543–549. https://doi.org/10.1093/ajh/hpx008
  13. Bourke K, Patel MR, Prisant LM. Marcus DM. Hypertensive choroidopathy. J Clin Hypertens 2004 Aug;6(8):471-2.
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  16. Ahn SJ, Woo SJ, Park KH. Retinal and choroidal changes with severe hypertension and their association with visual outcome. Invest Ophthalmol Vis Sci 2014; 55:7775–7785.
  17. Elliott W, Varon J. Moderate to severe hypertensive retinopathy and hypertensive encephalopathy in adults. UpToDate. January 21. 2020
  18. Kim EY, Lew HM, Song JH. Effect of intravitreal bevacizumab (Avastin((R))) therapy in malignant hypertensive retinopathy: a report of two cases. J Ocul Pharmacol Ther 2012; 28:318–322.
  19. Stryjewski TP, Papakostas TD, Vavvas D. Proliferative Hypertensive Retinopathy. JAMA Ophthalmol 2016;:1. doi:10.1001/jamaophthalmol.2015.5583