Review

Hypertensive eye disease: a review

Samantha Fraser-Bell PhD FRANZCO,1,2 Richard Symes1,3 and Anagha Vaze MPhil
DNB1

1. Save Sight Institute, Sydney University, Sydney, New South Wales, Australia.
2. Sydney Adventist Hospital Clinical School, Sydney University, Sydney, New
South Wales, Australia.
3. Sydney Eye Hospital , Sydney , NSW , Australia.

Correspondence: A/Professor Samantha Fraser-Bell, Save Sight Institute, Sydney

University, Sydney, New South Wales, Australia
sfraserbell@gmail.com

Short running title: Hypertensive eye disease: a review

Received 15 March 2016; accepted 14 December 2016
Conflict of interest: None
Funding sources: None

This article has been accepted for publication and undergone full peer review but has not
been through the copyediting, typesetting, pagination and proofreading process which may
lead to differences between this version and the Version of Record. Please cite this article as
doi: 10.1111/ceo.12905

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ABSTRACT

Hypertension is a risk factor for a number of vision-threatening eye conditions

including retinal vascular occlusion, retinal macroaneurysm and non arteritic anterior
ischaemic optic neuropathy. In addition, hypertension may exacerbate the vision-
threatening effects of diabetic retinopathy and has been implicated in the
pathogenesis of age-related macular degeneration. The effects of sustained
hypertension are directly visible in the eye as hypertensive retinopathy and
choroidopathy, reflecting a pathological process occurring throughout the body.
Close collaboration between ophthalmologists and general practitioners/physicians is
needed to ensure that hypertensive patients are identified and treated. Timely
intervention in these patients may reduce the risk of both vision-threatening and
systemic complications.

Keywords: Hypertension, Retinopathy, Retina

INTRODUCTION

Hypertension is a significant risk factor for myocardial infarction, heart failure,

stroke, renal disease and early death (1). The World Health Organisation defines
hypertension as a systolic pressure greater than 140mmHg and/or a diastolic
pressure greater than 90mmHg and estimates that up to 40% of adults aged over
25 may be hypertensive worldwide (2).
Sustained hypertension causes physical changes in blood vessels, including
thickening of the elastic lamina and hyaline changes (3). In the retina, where blood
vessels are directly visible, the changes associated with hypertension can be viewed
and graded as hypertensive retinopathy. Except in its most severe forms,
hypertensive retinopathy alone would not be expected to cause damage to the
patient’s vision. However, other secondary effects of hypertension may cause or
contribute to significant visual loss. These effects include retinal vascular occlusion
(RVO), retinal macroaneurysm (RAMA), and ischaemic optic neuropathy.
Hypertension may also exacerbate the vision-threatening effects of diabetic

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retinopathy and has been implicated as a risk factor in the development of age-
related macular degeneration (4, 5). Hypertension may also contribute to an
increased risk of suprachoroidal haemorrhage in patients undergoing intraocular
surgery. Therefore, in addition to being a public health issue, hypertension is of
great importance to practicing ophthalmologists.

HYPERTENSIVE RETINOPATHY

The vascular changes associated with systemic hypertension are directly visible in
the retina. Initially, generalized narrowing of the retinal arteriolar vessels is
observed. This narrowing may occur secondary to an increase in vasomotor tone as
a homeostatic response to high systemic BP (4). Later, structural changes in the
vessel wall become evident such as intimal hyperplasia and hyaline degeneration.
These changes are visible macroscopically as focal or diffuse areas of vessel
narrowing, compression of veins crossing arteries termed “nipping”, “nicking” or
“Gunn sign” and changes in the appearance of the vessel described as “copper” and
“silver wiring”, along with the appearance of microaneurysms (4, 5). Alterations in
arteriolar length occurring secondary to the above changes can cause visible
deflections in the adjacent veins “Salus sign”.
With higher levels of blood pressure, focal ischaemic areas of the nerve fibre layer
are clinically visible as “cotton wool spots”. Breakdown of the blood-retinal barrier
causes secondary exudation of blood and lipid “hard exudates”, both of which are
visible on clinical examination. At very high BP levels there may be variable degrees
of optic disc swelling (4, 5).
A variety of grading systems have been proposed for hypertensive retinopathy in an
attempt to classify its severity. Probably the best known is the Keith-Wagener-Baker
(KWB) system, published in 1939 (Table 1) (6, 7). More recently a simplified,
modified classification system (Mitchell-Wong), been proposed (table 2) (5). In this
system, the two earlier grades of retinopathy have been combined because these
two grades are difficult to distinguish clinically, otherwise the systems are similar.

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THE SIGNIFICANCE OF HYPERTENSIVE RETINOPATHY

Hypertensive retinopathy is a marker of vascular disease elsewhere in the body. The

clear media of the eye allow the pathology to be observed directly. The
ophthalmologist or optometrist who discovers hypertensive retinopathy in a patient
with undiagnosed hypertension is in a position to potentially reduce the patient’s
future risk of heart disease or stroke (8, 9). In one study of 2907 patients with
diabetes, the presence of moderate or severe retinopathy according to the Mitchell
Wong classification was a significant risk factor for stroke over a mean follow-up
period of 13 years (moderate hypertensive retinopathy versus no retinopathy,
hazard ratio 2.37 [95% confidence interval, 1.39-4.02]). (10). In the Blue Mountains
Eye Study, over a 12-year period, subjects with hypertensive retinopathy had the
same risk of death from cardiovascular disease as patients with diabetes (mortality
rate per person-year of 0.015 in subjects with diabetes only versus 0.016 in subjects
with hypertensive retinopathy only) (11). The presence of hypertensive retinopathy
is also a risk factor for congestive cardiac failure (relative risk, 1.96; 95% CI, 1.51-
2.54) (12) and for renal impairment odds ratio 2.0; 95% CI, 1.4 to 2.8) (13).
Despite these findings, the usefulness of hypertensive retinopathy grading as a
clinical tool to assess the risk of systemic complications (outlined above) is unclear.
Routine fundoscopy of at-risk patients has a limited application because of large
variation between observers (14). It may be that better availability of digital fundus
photography will facilitate the assessment and management of these patients in the
future. Newer imaging modalities such as optical coherence tomography (OCT) of
retinal vessel diameter may also become clinically useful (15). For now, the presence
of hypertensive retinopathy on routine examination should prompt the examining
ophthalmologist or optometrist to liaise with the patient’s primary care physician or
internist, but no recommendation for routine fundus examination of follow-up in
known hypertensive patients can be made.

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MALIGNANT HYPERTENSION

Malignant or accelerated hypertension is very high blood pressure (e.g. diastolic

>130, although there is no agreed definition based on BP values) associated with
KWB retinopathy grade 3 or 4. This level of blood pressure is sufficient to cause
damage to multiple organ systems including the kidney, heart and brain and in the
early literature, untreated malignant hypertension had a mortality rate of 80% at 2
years. Patients presenting with markedly elevated blood pressure in combination
with end organ damage require urgent treatment under specialist supervision to
prevent irreversible complications such as haemorrhagic stroke (16).

PRE-ECLAMPSIA

This has been defined as one or more of the following occurring during pregnancy:
severe hypertension (diastolic pressure >100 mm Hg), proteinuria, oliguria, cerebral
dysfunction, visual disturbance, abdominal pain, abnormal liver function,
thrombocytopenia, pulmonary edema or fetal growth retardation. Untreated, pre-
eclampsia may convert to eclampsia – (maternal seizures) with a significant risk of
mortality for the mother and baby. The definitive therapy for pre-eclampsia is
delivery of the baby. In cases where immediate delivery is not possible, treatment to
reduce BP is indicated. The difficulty in this situation is balancing the need to reduce
BP against the potential risks of doing so because of toxic effects on the fetus,
including hypoperfusion of the placenta (17)

Fundus signs of severely elevated BP, occurring in conditions such as malignant

hypertension or pre-eclampsia, include high grade retinopathy with or without optic
disc oedema and signs of secondary ischaemia such as cotton wool spots (4). A
further sign is the presence of focal intraretinal periarteriolar transudates (FIPTS)
which appear as small white or oval lesions in the deep retina that leak on
fluorescein angiography. These occur secondary to arteriolar dilatation and
consequent blood/retina barrier breakdown. They may be observed early in
malignant hypertensive states, prior to the onset of choroidopathy (18).

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HYPERTENSIVE CHOROIDOPATHY

The central retinal artery and its branches supply blood to the inner retinal layers.
The effects of hypertension on these vessels lead to vascular changes including
hyalinisation of the vessels and breakdown of blood/retina barrier with the
appearance of exudates and haemorrhages, as outlined above (4, 5). The choroidal
circulation, derived from the long and short posterior ciliary arteries, supplies blood
to the outer retina including the photoreceptors. Choroidal hypertensive changes are
more likely to occur in disease states associated with very high blood pressure such
as malignant hypertension or pre-eclampsia (19). The changes seen are correlated
with the anatomy of the choroidal circulation: linear pigmented streaks (Siegrist
streaks) may develop along the course of underlying choroidal arteries. Areas of
focal ischaemia (Elschnig spots) appear as pale, yellow, well-demarcated lesions
which may eventually become pigmented as a secondary consequence of tissue
infarction. When the BP is severely elevated, global choroidal dysfunction affects the
pumping capacity of the retinal pigment epithelium leading to exudative retinal
detachments and visual loss (19) (figure 1). Occasionally, fundus changes, especially
when chronic, may be mistaken for other conditions such as retinal dystrophies
(figure 2).

ROLE OF HYPERTENSION IN DIABETIC RETINOPATHY

Diabetic retinopathy (DR) is the leading cause of visual loss in working-age adults in
developed countries. Worldwide, it has been estimated that 93 million people have
diabetic retinopathy, of which 28 million have sight-threatening disease (20). DR
results from microvascular damage caused by diabetes and has early non-
proliferative and late proliferative stages. Hypertension has been shown to be
independent risk factor in the development and progression of DR. Due to the
absence of sympathetic innervation in the retinal vessels; blood flow in response to
raised blood pressure depends on auto-regulation. This auto-regulation is impaired
in diabetics, thus providing a mechanism for the detrimental effect of hypertension

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on diabetic retinopathy (21). Retinal capillary endothelial damage is the main
pathophysiological insult leading to the proliferative changes of the DR and
hypertension enhances this damage (21). Studies have shown that hypertension can
also cause increased expression of vascular endothelial growth factor (VEGF) (22,
23). These mechanisms might explain the deleterious effects of hypertension on DR
and may partially explain the principal clinical manifestations of hypertensive
retinopathy itself.
Earlier epidemiological studies provided some evidence of the role of hypertension in
development as well as progression of DR (24-26), however this was not seen in all
the studies (27, 28). Eventually, clinical trial data from prospective studies like the
UKPDS provided more valuable information. In the UKPDS “tight” control aiming at
blood pressure of < 150/85 mm of Hg (average BP = 144/82) reduced the need for
laser treatment by a third in patients with type 2 diabetes (29). However, the recent
Action to Control Cardiovascular Risk in Diabetes Eye Study (ACCORD- EYE)
“Intensive” control of Blood Pressure (BP) with a target systolic BP level < 120 mm
of Hg did not confer any additional benefit to reduce the development or progression
of DR as compared to the target level < 140 mm of Hg (30). ACE inhibitors /
Angiotensin II receptor inhibitors may offer protection for diabetic retinopathy which
is over-and-above their BP-lowering effect (EUCLID, DIRECT and RASS studies),
suggesting that these drugs should be an early choice for BP control in diabetics
(31). It is postulated that the additional benefit is due to a favorable retinal
hemodynamic profile, enhancement of nitric oxide production, reduction of
endothelial dysfunction, blockage of vascular endothelial growth factors and
reduction of activity by matrix metalloproteinases. It remains unclear whether they
would be beneficial in normotensive diabetics with vision-threatening retinopathy.
The results of one of these studies showed the beneficial effect of ACE inhibitors in
type 1 diabetics who were normotensive. However, the results were criticized since
the control group had significantly higher levels of glycosylated haemoglobin levels
(32).

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RETINAL VEIN OCCLUSION (RVO)

Hypertension is a major risk factor for the development of retinal vein occlusion, one
of the most common sight-threatening retinal-vascular disorders (33-35). Clinically,
retinal vein occlusion is characterized by dilated and tortuous veins, retinal
haemorrhages, nerve fibre layer infarcts commonly referred to as cotton wool spots,
macular oedema and occasionally optic disc oedema. These features are present in
all four quadrants along with optic disc oedema in central retinal vein occlusion
(CRVO) (Figure 3.) and only in one quadrant in branch retinal vein occlusion (BRVO).
There is usually only one central retinal vein but in 20% individuals there are two
trunks within the optic nerve, which represents a congenital anomaly. Occlusion of
this trunk sometimes gives rise to an entity called “hemi-central retinal vein
occlusion” (36).
Numerous studies have shown the link between hypertension and BRVO (33-35, 37,
38). The Beaver Dam Eye Study showed that the hypertensive patients were five
times more likely to get BRVO as compared to non-hypertensive participants (33). In
this study mild hypertensive retinopathy characterized by generalized and focal
arteriolar narrowing, arteriolar wall opacification and arteriovenous nipping was
strongly correlated with BRVO with an odds ratio of 17 for focal arteriolar narrowing,
and 23 for arteriovenous nipping. The pathogenesis of RVO and its exact relation to
hypertension is not known. However, it has been postulated that hypertension and
atherosclerosis cause retinal arteriosclerotic changes especially at arteriovenous
crossing where they have a common adventitial sheath, resulting in occlusion of the
venule secondary to endothelial cell damage and thrombosis (33, 39). In addition to
hypertension RVO is associated with other cardiovascular risk factors including
diabetes (37, 38), smoking (37, 38) carotid artery disease and various
haematological abnormalities (homocysteinaemia, anticardiolipin antibodies, protein
S and protein C deficiencies, factor V Leiden mutation etc.) (37, 38, 40-43). The data
of published studies suggest that 48% of RVO is connected to hypertension, 20% to
Hyperlipidemia, and 5% to Diabetes Mellitus (44). The role of thrombophilic risk
factors in RVO is still controversial. Given the conflicting findings, the specific roles of
various thrombophilic factors and hypercoagulability in CRVO need further study

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(44). Assessment of the systemic risk factors including blood pressure control,
haematological function and optimization of other cardiovascular risk factors is
extremely important in the management of patients with RVO, in addition to treating
their ophthalmic complications. Treatment of hypertension has not been shown to
reduce the risk of complications associated with RVO; neither has it been shown to
prevent the development of this condition in unaffected eyes (4). Approximately 5–
10% of RVO cases will develop RVO in the fellow eye during follow-up. Physicians
should closely monitor blood pressure and consider initiation or modification of
treatment in patients who develop retinal vein occlusion.

RETINAL ARTERY OCCLUSION (RAO)

Several studies have shown that RAO more commonly occurs in patients with
hypertension.
Atherosclerosis related thrombus accounts for about 80% of central retinal artery
occlusions, with hypertension accounting for 60% of those cases (37, 43, 45).
These acute retinal arterial ischaemic disorders can be classified into central retinal
arterial occlusion (CRAO), branch retinal arteriolar occlusion (BRAO), cotton wool
spots or retinal nerve fibre layer infarcts and amaurosis fugax (46). CRAO results in
a sudden, painless and catastrophic unilateral visual loss. The fundus appearance is
typically that of a cherry red spot caused by acute retinal oedema surrounding the
fovea. BRAO by contrast presents with a visual field defect only (figure 4.).
Combined CRAO and CRVO have also been reported (46). Arteriosclerotic changes of
hypertensive retinopathy and atherosclerosis are thought to be responsible for
increased incidence of RAO in hypertensive patients (37, 43, 45).
As well as its association with hypertension, retinal artery occlusion is associated
with other cardiovascular risk factors (such as smoking, diabetes and
hypercholesterolaemia), haematological abnormalities, and autoimminue vasculitides
including giant cell arteritis, and infective vasculitis, such as occurs in acute retinal
necrosis (37, 43, 47, 48). In CRAO, it is important to rule out GCA by ESR and CRP.
Thorough cardiovascular and cerebrovascular assessments, including carotid doppler
ultrasound and echocardiography are necessary in patients who present with RAO.

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One study showed that almost half of patients with RAO had echocardiographic
abnormalities (49). There is increased risk of cardiovascular disease and mortality
among patients who present with RAO (47). A prospective study of 99 patients with
RAO with a mean follow up period of 4.2 years estimated an absolute risk of death
to be 8% per year, with death from coronary events in 60% and stroke in just 3%
(50). Mortality rates may vary depending on presence of retinal emboli. A study of
86 patients with retinal artery occlusions showed that mortality rates for those
without visible retinal emboli were similar to age–sex controls, whereas patients with
visible emboli had substantially higher mortality than controls (51). In up to 70% of
patients with BRAO, emboli are either visible at the optic disc or in the branch retinal
arterioles; these signs are present in about 20% of cases when the occlusion is
central (43, 45). A cilioretinal artery occlusion may occur in association with a CRVO.
The raised pressure in the vein reduces arterial flow leading to secondary cilioretinal
occlusion (figure 5).
Although CRAO is regarded as an ophthalmic emergency, all current treatment
strategies lack evidence of beneficial effect on visual outcomes.

RETINAL ARTERY MACROANEURYSM (RAMA)

RAMA is a fusiform or saccular acquired dilatation of a major retinal arteriole most

commonly associated with systemic hypertension that develop in patients usually
after 6th decade of life (mean age of 57-71 years) being more common in females
(52).
These acquired dilatations typically develop within the first three bifurcations, at
branch points, or areas of arteriovenous crossing. RAMA is usually an incidental
finding in an asymptomatic patient, but can present acutely with visual loss
secondary to haemorrhage or exudation (Figure 6), especially if close to the fovea.
The key fundoscopic finding of a ruptured macroaneurysm is the presence of blood
at multiple layers including the preretinal intraretinal, subretinal, and sub-ILM spaces
and the vitreous or the presence of an hourglass hemorrhage, which represents
simultaneous preretinal and subretinal hemorrhage. In most cases there is a
spontaneous visual recovery following thrombosis of the RAMA and resolution of

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haemorrhage and exudation. However, there can be chronic exudation and macular
oedema with persistent poor vision.
Hypertension has been reported in 75% of these patients (4). Macroaneurysm with
visual loss can be presenting feature in patients with uncontrolled hypertension. The
underlying pathophysiology is not well understood. One hypothesis is that
arteriosclerosis leads to vessel wall fibrosis. The resulting decrease in wall elasticity,
combined with elevated luminal pressure results in aneurysmal dilation. An
alternative or accessory hypothesis is that emboli (which have been associated with
vessels harboring macroaneurysms) or intra-arterial thrombosis leads to mechanical
damage of the endothelium or adventitial vessel wall, which predisposes the vessel
to aneurysm formation. Chronic venous stasis from hypertension and arteriosclerosis
may also play a role (52). Fichte et al. described vessel wall thickening and the
presence of fibrin and foamy macrophages upon histological inspection in retinal
arterial macroaneurysms, similar to that seen in age-related arteriosclerotic changes
in vessel walls throughout the body typically seen in patients with long standing
hypertension (53).
Most of the patients recover spontaneously and most aneurysms involute without
requiring intervention. However, a third of cases can develop chronic exudation that
might affect visual outcome (52). Hence most patients can be safely observed.
However, hypertension and other systemic factors should be treated adequately
along with the ophthalmic complications.

NON-ARTERITIC ISCHAEMIC OPTIC NEUROPATHY (NAION)

The optic nerve circulation is also susceptible to the effects of hypertension and
other cardiovascular risk factors. NAION is a significant cause of acute visual loss in
elderly population over the age of 50 years (54).
NAION is characterized by sudden painless loss of vision, relative afferent papillary
defect and altitudinal field defect (inferior more common than superior). The
posterior segment examination shows swelling of the optic disc (typically
hyperaemic, segmental, telangiectasia).

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Although the exact mechanism is unclear, there is perfusion insufficiency in the short
posterior ciliary arteries, which leads to infarction of the retrolaminar portion of the
disc. Non-arteritic ischaemic optic neuropathy has been strongly linked with
hypertension and other cardiovascular risk factors like diabetes and
hypercholesterolemia, which also seem to increase the risk in younger individuals
(55-57). A clinical series has shown that up to 50% of patients with NAION might
have hypertension and 25% might have diabetes (58).
There is no proven effective treatment for NAION. Optic nerve sheath
decompression surgery has been tried but can be harmful (58). The natural history
of the disease can be determined form the control group of the Ischaemic Optic
Neuropathy Decompression Trial, which reported that at 6 months 43% experienced
improvement of three or more lines of acuity, compared with 12% who lost three or
more lines (58). However, referral to a physician for vascular assessment and
treatment is necessary.

HYPERTENSION AND AGE-RELATED MACULAR DEGENERATION

AMD is the commonest cause of blindness in developed world, and mainly affects
people over the age of 50 years (59). Some studies have suggested that
hypertension is a relevant risk factor for development of AMD (59-61). Some have
suggested that hypertension could increase the potential risk for AMD, on the basis
of its effect on the choroidal circulation (59, 60). The Beaver Dam Eye study
reported that a raised systolic blood pressure had an increased 10-year risk of
developing AMD (62). The Australian Blue Mountains study, reported that the focal
arteriolar narrowing which is seen in hypertensive retinopathy was associated with
some signs of AMD (63). However, anti-hypertensive medications do not prevent the
development or progression of this disorder. Epidemiological studies have reported
that medications lowering the blood pressure do not alter the risk of AMD (64).

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HYPERTENSION AND COMPLICATIONS OF OPHTHALMIC SURGERY

Hypertension is a risk factor the development of suprachoroidal haemorrhage (SCH),

which may occur following intraocular surgery including cataract, glaucoma and
retinal surgery (65-67). The mechanism of the haemorrhage appears to involve
atherosclerosis of the ciliary arteries which, in combination with hypertension, pre-
disposes the artery to rupture when the intraocular pressure is suddenly lowered
e.g. during or after surgery. In a closed system, such as a phacoemulsification
cataract extraction or vitrectomy, the haemorrhage may be self-limited and the
macula preserved, but in traditional extracapsular cataract surgery or glaucoma
filtration surgery there is an increased likelihood of macular involvement with
potentially devastating consequences for the vision.

CONCLUSION

Although ophthalmologists do not generally treat raised BP, the ophthalmologist has
unique insight into hypertension because of the ability to directly observe changes in
the retinal vasculature. Hypertension can increase the risk of a variety of vision-
threatening eye conditions. Close partnership between ophthalmologists and general
practitioners/ physicians is needed to ensure that patients receive appropriate
treatment for the benefit of their eyes, and their general health.

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FIGURE LEGENDS

Figure 1: Hypertensive choroidopathy causing secondary exudative retinal

detachment

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Figure 2: Fundus autofluorescence of hypertensive choroidopathy. Without
knowledge of the clinical context, it is possible that the changes could be mistaken
for a retinal dystrophy

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Figure 3: Four-quadrant flame haemorrhages in a central retinal vein occlusion

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Figure 4: Inferior branch retinal artery occlusion showing white retinal oedema
secondary to retinal infarction

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Figure 5: Combined central retinal vein occlusion and cilioretinal artery occlusion
(arrow)

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Figure 6: Fluorescein angiogram image of a ruptured retinal artery macroaneursym

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TABLES

Table 1: The KWB classification of hypertensive retinopathy (table adapted from

Aissopou et al, 7)

Grade Features
1 Generalized arteriolar narrowing
2 Focal narrowing and arteriovenous
nicking/nipping
3 Grade 2 plus exudates, haemorrhages
and cotton wool spots
4 Grade 3 plus optic disc swelling

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Table 2: The Mitchell Wong classification of hypertensive retinopathy. Adapted from
Aissopou et al, 7)

Grade Features
Mild Generalised and/or focal arteriolar
narrowing, arteriovenous
nicking/nipping, opacity of arteriolar
wall (copper/silver wiring)
Moderate Retinal haemorrhages (flame, dot,
blot), exudates, cotton wool spots.
Malignant As for moderate, plus optic disc
swelling.

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