Journal of Human (2002) 16, 667–675 & 2002 Nature Publishing Group All rights reserved 0950-9240/02 $25.00 www.nature.com/jhh REVIEW ARTICLE Hypertension and the eye: changing perspectives

S Chatterjee1, S Chattopadhya2, M Hope-Ross1 and PL Lip1 1The Birmingham and Midland Eye Centre, City Hospital, Birmingham, UK; 2Department of Academic Cardiology, University of Hull, Kingston-upon-Hull, UK

Systemic hypertension is a common condition stratification of hypertensive individuals. This review associated with significant morbidity and mortality. reevaluates the changing perspectives in the pathophy- Hypertension confers cardiovascular risk by causing siology, classification and prognostic significance of target-organ damage that includes in addi- fundal lesions in hypertensives. tion to heart disease, stroke, renal insufficiency and Journal of Human Hypertension (2002) 16, 667–675. peripheral vascular disease. The recognition of hyper- doi:10.1038/sj.jhh.1001472 tensive retinopathy is important in cardiovascular risk

Keywords: hypertensive retinopathy; target-organ damage; classification

Introduction Sex: The prevalence of hypertensive retinopathy is higher in women than in men.11 Hypertension produces cardiovascular risk by caus- 1 Smoking: Though the true association between ing end-organ damage that includes retinopathy. smoking, hypertension and target-organ damage is Current studies have shown that the effects of difficult to assess due to the confounding effects of systemic hypertension on the retinal, other life-style and socio-economic factors, studies head and choroidal circulation produce three focusing on malignant hypertension have shown a distinct and independent manifestations: (i) hyper- strong association between smoking and grade IV tensive retinopathy, (ii) hypertensive optic neuro- 12–16 2,3 hypertensive retinopathy. pathy, and (iii) hypertensive choroidopathy. The Genetic factors: Certain specific genotypes established classification techniques for grading are linked with an increased risk of hypertensive hypertensive retinopathy have poor correlation 2 retinopathy. The D (deletion) allele of the angio- with the severity of hypertension. Large population- tensin converting enzyme (ACE) gene is an based studies suggest that lesions described independent risk factor for the development of in hypertensive individuals may also occur in non- 4–7 end-organ damage in patients with essential hyper- hypertensives. tension17 and entails a 2.4-fold higher chance of Poorly controlled systemic hypertension causes retinopathy.18 The hypertensive individuals who worsening of microvascular disease of the eye like 8–10 carry the apoepsilon4 allele of apolipoprotein E . Systemic hypertension is gene or are homozygous carriers of a point mutation associated with a number of ocular conditions (cytosine to thymidine substitution) in the gene although the exact causal relationships are yet to encoding 5,10-methylenetetrahydrofolate reductase be fully defined. (IT polymorphism) are at a significantly higher risk of retinopathy.19,20 A Turkish kindred of autosomal dominant monogenic hypertension Aetiology has been described, where the affected individuals Race: Afro-Caribbeans have a higher prevalence of have brachydactyly and are 10 cm shorter hypertension and hypertensive retinopathy than than the unaffected individuals. They had no retino-pathy, despite very early onset of severe Europeans but the relationship between hyperten- 21 sion and the prevalence of retinopathy is poorer hypertension. amongst Afro-Caribbeans.11 The relationship is Renal status: In patients with essential hyper- tension, persistent microalbuminuria is a marker of strongest for European women and weakest for 22,23 Afro-Caribbean women.11 early end-organ damage including retinopathy. Patients with retinal vascular changes were shown to have a significantly lower glomerular filtration Correspondence: Mrs PL Lip, The Birmingham and Midland Eye rate as indicated by creatinine clearance.22 Centre, City Hospital, Dudley Rd, Birmingham B18 7QU, UK. E-mail: [email protected] Cardiac status: Left ventricular hypertrophy and Received 1 May 2000; revised and accepted 25 July 2002 retinal vascular disease appear early in the course of Hypertension and the eye: perspectives S Chatterjee et al

668 elevation and both changes develop resistance to flow.2 Resistance to blood flow in parallel.24 The severity of hypertensive retino- depends upon the state and calibre of the ocular pathy and the renal involvement are more severe in arteries and is influenced by hypertensive arterial patients with concentric rather than eccentric left changes and the efficiency of the autoregulation of ventricular hypertrophy.25 It is postulated that the blood flow.2 predominantly volume overload, resulting in ec- Autoregulation maintains a constant ocular blood centric left ventricular hypertrophy is less likely to flow to tissues during changes in perfusion pressure. cause extracardiac target-organ damage.26 Endothelial-derived molecules, ie; endothelins, Plasma leptin: A critical plasma leptin level for thromboxane A2, prostaglandins and nitric oxide the development of retinopathy has been identified play a role in autoregulation by modulating vascular (10.2 ng/ml).27 Leptin, an angiogenesis factor, was tone.38 Breakdown of autoregulation occurs with significantly higher in patients with grade 1 retino- rise or fall of perfusion pressure beyond a critical pathy even after correction for body mass index.27 range. In hypertensives, where the autoregulation The elevated concentrations possibly relate to the range is set to higher levels, episodic hypotension damage of the vascular endothelium by high blood (spontaneously, as during sleep or due to over- pressure.27 treatment), changes in the tone of the precapillary Salt sensitivity: Hypertensive retinopathy is more arterioles (mediated by angiotensin or antihyperten- common in salt-sensitive hypertension than in salt- sive drugs) and vascular endothelial changes resistant hypertension.28 (leading to reduced nitric oxide synthesis) lead to Secondary hypertension: Renal hypertension sec- breakdown of autoregulation.39–41 ondary to focal segmental sclerosis and membrano- The tight junctions of the retinal endothelium and proliferative glomerulonephritis is associated with the retinal pigment epithelium form the inner and more severe retinopathy than essential hyperten- outer blood–retinal barriers. Acute hypertension sion. The hypertensive retinopathy deteriorates as causes disruption of the blood–retinal barriers.2 the renal disease progresses.29 Atherosclerotic reno- The retinal and optic nerve head vascular beds have vascular disease is associated with high-grade autoregulation but the choroidal vascular bed does retinopathy.30 Severe end-organ damage including not.2 The fenestrated choroidal vessels do not have a grade III or IV retinopathy is common in hyperten- blood–ocular barrier.2 The retinal vessels are devoid sion secondary to pheochromocytoma.31 No differ- of an autonomic nerve supply but the choroidal ence, however, is seen in the prevalence of vessels are richly supplied by both sympathetic and malignant hypertension, between malignant and parasympathetic nerves.2 The different anatomical nonmalignant pheochromocytomas.32 In primary and physiological properties of the retinal, optic hyperaldosteronism hypertensive retinopathy is nerve head and choroidal blood vessels produces usually less severe.26 three distinct and unrelated manifestations, ie Refractory hypertension: Refractory hypertension retinopathy and choroidopathy.2 is associated with a high prevalence of target-organ damage at cardiac, macro- and microvascular level with advanced retinal involvement (grades II and III Hypertensive retinopathy retinopathy).33 Definition Hypertensive retinopathy represents target-organ Pathophysiology damage in patients with high systemic arterial blood pressure and was first described by Liebreich in Retinal microvasculature: A cross-sectional study 1859.42 on retinal microvasculature has demonstrated a lower number of perifoveal arterioles and venules 34 in hypertensives. Decreasing perifoveal capillary Classification flow velocity is seen in patients with essential hypertension despite adequate blood pressure con- The classification of hypertensive retinopathy is trol.35 Measurements of bifurcation angles and shown in Table 1. Current literature challenges the retinal arteriolar diameters in response to acute prognostic significance of the early graded classifi- hyperoxic and hypercapneic stress have demon- cations of hypertensive retinopathy by Keith–Wage- strated diminished vascular reactivity in hyperten- ner-Barker and Scheie.43–45 The poor correlation sive subjects.36 Hypertension may be associated with the severity of hypertension, variation in the with a disadvantageous branching geometry in the onset and progression of the clinical signs, and retinal vasculature, with reduced circulatory effi- recognition of optic neuropathy and choroidopathy ciency and microvascular rarefaction.37 as independent entities have prompted some in- Dynamics of ocular blood flow: The ocular and vestigators to stress the importance of describing optic nerve head blood flow is directly related to fundal appearance rather than assigning a grade.2 perfusion pressure (mean arterial pressure minus A simple two-grade classification of retinopathy intraocular pressure) and inversely related to the into nonmalignant (nonaccelerated) vs malignant

Journal of Human Hypertension Hypertension and the eye: perspectives S Chatterjee et al

669 Table 1 Classifications of hypertensive retinopathy: Keith–Wagener-Barker (grade I–IV) was based on the level of severity of the retinal findings; and Scheie (grade 0–4) attempted to quantify the changes of both hypertension and arteriolosclerosis

Keith–Wagener-Barker Scheie

Grade Features Grade Features

0 No changes I Mild generalised retinal arteriolar narrowing 1 Barely detectable arterial narrowing II Definite focal narrowing and arteriovenous nipping 2 Obvious arterial narrowing with focal irregularities plus light reflex changes III The above and retinal haemorrhages, exudates 3 Grade 2 plus copper wiring and retinal haemorrhages/exudate and cotton-wool spots IV Severe grade III and papilloedema 4 Grade 3 plus silver wiring and papilloedema

(accelerated) has been proposed that provides a , papilloedema secondary to raised useful correlation between clinical features and intracranial pressure or Leber’s stellate maculo- prognosis.43 A similar classification has been pathy.50 Complications of severe untreated hyper- suggested to encourage the utilisation of the eye as tension include haemorrhagic detachment of the a hypertensive target organ for risk stratification and internal limiting membrane of the , subhyaloid therapeutic decision making.46 The significant an- and vitreous haemorrhage50 (Figure 1b). giographic differences in the density of the peri- Secondary arteriolosclerosis of the common vas- foveal capillaries and capillary blood velocity cular adventitial sheath, at the level of the arterio- between mild and severe forms of hypertensive venous crossing, produces compression of the retinopathy correlate with a two-grade rather than venule.49 Arteriovenous crossing changes include four-grade classification system.47 banking of the venule distal to the crossing (Bonnet’s sign), nipping of the blood column (Gunn’s sign) and displacement of the venule at right angles to the 49 Clinical features arteriole (Salus’s sign). The increased arteriolar light reflex correlates with hyalinisation of the The primary response of the retinal arterioles to arteriolar wall. Obscuration of the red blood cell systemic hypertension is vasoconstriction. Sus- column with copper wire or silver wire appearance tained hypertension leads to disruption of the of the light reflex has classically been described in blood–retinal barrier, increased vascular permeabil- grade II or III retinopathy, respectively.49 ity and secondary arteriolosclerosis. Most features of acute hypertensive retinopathy The fundus features commonly described in regress over 6–12 months with timely antihyperten- hypertensive retinopathy45 include focal and gen- sive therapy51 (Figures 1c and d). Despite resolution eralised arteriolar narrowing, microaneurysms, intra- of fundus signs, in one study electroretinogram retinal haemorrhages, cotton-wool spots, hard recordings continued to remain abnormal up to 2–4 exudates and swelling. Changes of years following the acute episode.52 secondary arteriolosclerosis are arteriovenous nip- In the animal model, the early signs of acute ping, changes in the arteriolar light reflex and hypertensive retinopathy were focal intraretinal peri- arteriolar sheathing and occlusion.45 arteriolar transudates, cotton-wool spots, retinal hae- Clinically focal arteriolar narrowing is easier to morrhages and oedema.2 Retinal arteriolar changes, assess than generalised narrowing but with new cystoid macular changes, hard exudates and nerve computer-assisted quantification, generalised ret- fibre loss were late manifestations.2 Retinal arteriolar inal arteriolar narrowing can be ascertained reliably spasm, a typical finding of malignant hypertension in by standardised photographic grading methods.48 humans, was described as an ophthalmoscopic Abnormal vascular permeability produces flame- artefact produced by retinal oedema masking the shaped haemorrhages, retinal oedema and lipid arterioles from the sides (pseudo-narrowing).2 exudates.49 The deeper blot haemorrhages appear In the absence of the characteristic clinical signs with progression of hypertension and indicate fluorescein angiography is useful for delineation of worsening ischaemia.49 Deposition of lipid around the microvascular abnormalities.53 the fovea may lead to the formation of a macular star50 (Figure 1a). Acute hypertension may cause obstruction of the precapillary arterioles and devel- Arteriolosclerosis or hypertensive retinopathy? opment of nerve fibre layer infarcts (cotton-wool spots) or swelling of the optic disc.50 Severe acute Several epidemiological studies have described hypertension may present with a macular star and retinal microvascular abnormalities in nondiabetic disc swelling in the presence of minimal micro- hypertensive and normotensive populations. The vascular change and can be confused with neuro- Blue Mountain Eye Study6 found a prevalence of

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670

Figure 1(a–d) A 35 years old Caucasian woman presented with severe malignant hypertension. Fundoscopy revealed bilateral papilloedema with macular hard exudates (partial macula star), flame shaped retinal haemorrhages and a pre-retinal (boat shaped) haemorrhage. Fundoscopy four months following control of elevated blood pressure showed resolution of almost all the retinopathy. Bilateral disc pallor and residual hard exudates remained.

retinopathy, defined as retinal microaneurysms and Wagener-Barker classification.55 It was considered haemorrhages, of 9.8% in older nondiabetic sub- an essential criterion of malignant hypertension.55 jects. These were significantly related to the pre- Traditionally papilloedema in hypertension has sence and severity of hypertension but only 42% of been considered to be a poor prognostic sign these lesions could be explained by hypertension. for survival.55 Other clinical56 and experimen- The Beaver Dam Eye Study3–5 described arteriolar tal39,57 studies have refuted the prognostic signifi- narrowing, arteriovenous nicking and retinopathy cance of papilloedema. These studies concluded in both nondiabetic hypertensive and normotensive that papilloedema was not a necessary feature of individuals. The predictive value for systemic malignant hypertension. The WHO criterion for hypertension was 47% when any retinopathy was malignant hypertension is severe hypertension with present and 53% when arteriovenous nicking was bilateral retinal haemorrhages and exudates.58 present. Therefore, 47–63% of people in the study Conversely, it has been suggested that in the with arteriolar narrowing, arteriovenous nicking or presence of elevated systemic blood pressure, iso- retinopathy did not have hypertension. The athero- lated papilloedema without retinopathy could sclerosis risk in communities study54 found that in represent a variant of malignant hypertension.59 nondiabetic individuals both arteriovenous nicking Other causes of papilloedema like space-occupying and generalised arteriolar narrowing were strongly lesions and benign intracranial hypertension, how- and monotonically related to current and past blood ever, need to be excluded.59 pressure, irrespective of antihypertensive medica- The pathogenesis of papilloedema secondary to tion. Abnormalities of the retinal vasculature there- systemic hypertension is controversial and the fore may reflect microvascular damage due to several theories include:2 (i) ischaemia, (ii) raised hypertension or arteriolosclerosis or both. intracranial pressure, and (iii) as a part of hyper- tensive retinopathy/encephalopathy. Both clinical studies using visual evoked potentials and electro- 52 Hypertensive optic neuropathy retinogram recordings in accelerated hypertension and experimental animal studies39,57 found ischae- Papilloedema or bilateral disc swelling represents mia to be the possible underlying mechanism. grade IV hypertensive retinopathy in the Keith– Papilloedema secondary to hypertension usually

Journal of Human Hypertension Hypertension and the eye: perspectives S Chatterjee et al

671 resolved following good control of blood pressure retinal vein occlusion) or at an arteriovenous cross- although some developed disc pallor.52 Longstand- ing (branch retinal vein occlusion).66,67 They com- ing chronic hypertension may result in retinal nerve monly present with sudden painless visual loss or fibre loss.60 a field defect. The signs in the acute phase may include engorged tortuous retinal veins, superficial Hypertensive choroidopathy flame retinal haemorrhages, retinal oedema, cotton- wool spots and disc swelling66 (Figure 3). Central Choroidal lesions secondary to elevated blood retinal vein occlusions are clinically divided into pressure are less well recognised than retinopathy nonischaemic and ischaemic.66 In the presence of in the current literature. The underlying mechanism persisting retinal nonperfusion, neovascularisation relates to choroidal ischaemia and its effects on the may develop on the disc, retina or . Treatment 40 retinal pigment epithelium and retina. with laser photocoagulation is indicated in these The more commonly described features of hyper- cases.66,67 If untreated, sight-threatening complica- tensive choroidopathy are choroidal vascular sclero- tions such as vitreous haemorrhage and secondary sis, Elschnig spots representing focal areas of rubeotic may develop.66 Several studies degenerative retinal pigment epithelium (Figure 2) have demonstrated that systemic hypertension is and the diffuse patchy atrophic retinal pigment associated with an increased risk of developing epithelial degeneration of chronic hyperten- central, branch and hemi-central retinal vein occlu- 61,62 sions. Siegrist’s streaks, linear retinal pigment sions.68–70 Systemic hypertension was also found to epithelial changes, are the sequelae of acute hyper- be associated with branch macular vein occlusions tensive choroidopathy and generally indicative of a in younger patients.71 A recent study72 found a 63 poor prognosis. Serous , a significantly higher prevalence of arterial hyperten- prominent feature in the animal model, is less sion in branch retinal vein occlusion compared with 64,65 common in clinical settings. central and hemi-central retinal vein occlusion. Arterial hypertension was also more likely to be Ocular diseases secondary to systemic present in ischaemic rather than nonischaemic hypertension central retinal vein occlusion.72 Systemic hypertension has been associated with a large number of ophthalmic conditions. They are Retinal arterial macroaneurysm described briefly in the context of the current literature. Retinal arterial macroaneurysms are acquired focal aneurysmal dilatations of the retinal arterioles, Retinal vein occlusion usually occurring in the first three orders of the arteriolar tree.73 They are commonly seen in Retinal vein occlusions occur most commonly at the hypertensive retinopathy giving rise to star- level of the lamina cribrosa (central or hemispheric shaped exudation and sometimes complicated by

Figure 2 Retinal pigment epithelial changes of the peripheral fundus following an episode of malignant hypertension showing Elschnig’s spots (arrows).

Journal of Human Hypertension Hypertension and the eye: perspectives S Chatterjee et al

672 clude a classical altitudinal field defect or a central .76 The exact mechanism may be chronic hypoperfusion of the small end-arterial optic nerve head vessels caused by over-treated hypertension or abnormal vascular autoregulation.77 Recent studies have suggested that ocular or optic nerve head ischaemic disorders may be due to a combination of systemic arterial hypertension and hypotension.78–80

Cranial nerve palsies Cranial nerve palsies, including third, fourth, sixth and seventh cranial nerve palsies, are commonly found secondary to systemic hypertension.81–84 They are often isolated events causing acute symp- tomatic .85 They usually resolve sponta- 85 Figure 3 Inferior temporal branch retinal vein occlusion with neously within three months. Neuroimaging may retinal haemorrhages and cottonwool spots (white lesions). not be indicated in the absence of other neurological signs or pupillary abnormalities.85

pre-retinal or intravitreal haemorrhage.73,74 Sponta- Diabetic retinopathy neous resolution with thrombosis within the macro- 73 Diabetic retinopathy is a microvascular disorder in aneurysm may occur (Figure 4). In the presence of which endothelial cell malfunction and impaired active leakage laser photocoagulation may be ap- plied directly to the macroaneurysm.73 regulation of retinal perfusion occur owing to chronic glucotoxicity.86 UKPDS 50 demonstrated that the incidence Non-arteritic anterior ischaemic optic neuropathy of diabetic retinopathy was strongly associated with higher blood pressure.87 UKPDS, EUCLID Essential arterial hypertension is significantly asso- and other studies have shown retardation in the ciated with non-arteritic anterior ischaemic optic progression of diabetic retinopathy with improved neuropathy.75 Clinically, this presents with uni- control of blood pressure.88 The HOPE study lateral painless disc swelling followed by disc pallor results showed that it was both safe and beneficial and irreversible visual loss.76 Symptoms may in- to lower BP already within the ‘normal’ range with

Figure 4 Fundoscopy of the right eye showing a macroaneurysm arising from the inferior temporal retinal arteriole producing star shaped macular exudates and oedema. It has undergone spontaneous thrombosis. (Arrow showing round white lesion.)

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