Retinal vascular disease – part I

Knowledge of retinal vascular disease is critical for an optometrist. These disorders are often caused by relatively common systemic conditions, which may be detected by routine optometric examination, but also indicate conditions which may represent a threat to the patient’s life. They may also be of major impact to our patients’ lifestyles. For example, retinal vascular occlusions account for 2% of severe sight impairment and 1.7% of sight impairment registrations.¹ This article will look at some of the most commonly encountered and important vascular pathologies in primary practice (with the exception of diabetic retinopathy covered here). For each it will cover the prevalence, aetiology, signs, symptoms, assessment and management.

Vasculature of the retina

To best understand the aetiology of retinal vascular disorders it is important to remember the anatomy of the blood supply to the eye. Figure 1 shows the route of blood from the heart to the internal carotid artery, figure 2 the supply to the eye from the ophthalmic artery which branches from the internal carotid, while figures 3a and 3b represent the arterial and vascular routes at the level of the optic nerve and retina respectively.

Figure 1: Arterial route from the heart to the head

The retina has a dual blood supply, both parts of which originate in the internal carotid artery. This branches to the ophthalmic artery which subsequently branches several times. Those branches that are relevant to the retinal vasculature are the central retinal artery (which is the first branch of the ophthalmic artery) and posterior ciliary arteries. The central retinal artery travels beside the optic nerve and penetrates the sclera about 1cm behind the globe, travels centrally in the optic nerve then branches anterior to the lamina cribrosa (LC). It supplies the inner retina to the outer plexiform layer (OPL), but does not supply the foveal area, the ‘foveal avascular zone’ is supplied solely by the choroid.²

Figure 2: Blood supply to the eye

The short posterior ciliary arteries supply the anterior optic nerve, choroid, retinal pigment epithelium (RPE) and outer 130mm of the retina (to the OPL), while the long posterior ciliary arteries supply an area of the choroid temporal to the macula (as well as the iris and ciliary body).³ Occasionally, the short posterior arteries may branch into a cilioretinal artery which assists the supply of the inner retina in the macular region. This may be present in up to 32% of eyes⁴ and may be of benefit in cases of central retinal artery occlusion, however, it itself may become occluded.^5,6

Figure 3a: Arterial supply to the eye

Outflow of blood occurs via the arcade veins and choroidal veins which subsequently drain out though the central retinal vein and vortex veins respectively.

Figure 3b: Venous route from the eye

General signs of retinal vascular disease

There are some features specific to certain diseases and these will be discussed in each section, however, there are some which are present in most (figure 4):

Figure 4: Retinal vascular signs

• Haemorrhages

- Dot and blot haemorrhages are reasonably well defined, circular bleeds located in the inner nuclear layer (INL).⁷

- Flame haemorrhages are unsurprisingly flame-shaped (ie more linear), feathery-edged bleeds which anatomically lie more superficially, specifically in the retinal nerve fibre layer (RNFL).

- Sub-hyaloid and pre-retinal haemorrhages are commonly described as ‘boat-shaped’ as they often have a flat top and rounded bottom. These terms are often interchanged clinically, but in reality are present in slightly different locations. Sub-hyaloid refers to a haemorrhage between the posterior hyaloid face and inner limiting membrane (ILM), while pre-retinal refers to one between the ILM and RNFL.⁷

• Exudates are waxy yellow lesions made up of lipid and proteinaceous material leaking from arterioles. They are mainly present in the OPL.⁸
• Cotton wool spots are sentinels of RNFL pathology, comprising axoplasmic debris.⁹ They appear as clinically fluffy whitish lesions, and because they are superficial obscure the underlying blood vessels.

Figure 4 shows the level within the retina of some of the signs characteristic of retinal vascular disorders.

Retinal vein occlusion

Retinal vein occlusion (RVO) is a term used to describe an obstruction of the retinal venous system, commonly by thrombus but occasionally by compression. It is the second most common retinal vascular disease after diabetic retinopathy with a prevalence of 520 per 100,000 (442 per 100,000 and 80 per 100,000 for BRVO and CRVO respectively), and it is estimated that 16million people worldwide are affected.¹⁰ Thrombosis is the formation of a blood clot within a blood vessel and is contributed to by three factors collectively known as Virchow’s Triad:

• Hypercoagulability – an increased tendency to clot.
• Haemodynamic changes – stasis (slowing down) and turbulence (disruption of flow) causing interruption to the blood flow.
• Endothelial injury – damage to the vascular endothelium, which has a key role in shutting off parts of the coagulation cascade.

Understanding these three factors is key when looking at the risk factors discussed below.

Classification

RVO may be classified by the vessel(s) affected, and whether or not it is ischaemic. The RVO would be classified as central (CRVO) when there is thrombosis posterior to or at the LC, branch (BRVO) when the thrombosis occurs in one particular vein at an arteriovenous crossing or hemiretinal (HRVO) when the thrombosis affects the nasal and temporal branch in one hemisphere.¹¹

The classification of whether it is ischaemic or not is extremely important, as ischaemic RVOs are likely to develop neovascularisation (up to 85%),¹² therefore if the patient has significantly reduced visual acuity, a relevant afferent pupillary defect (RAPD), multiple deep, dark intraretinal haemorrhages, multiple cotton wool spots and/or extensive venous dilation and tortuosity¹³ the practitioner’s index of suspicion should be heightened. This may be confirmed in secondary care by fundus fluorescein angiography (FFA), where ischaemia is defined as an area greater than 10 disc diameters of capillary non-perfusion.¹⁴

The primary cause of visual impairment in RVO is macular oedema (MO), thus it should be determined whether this is a cause of visual impairment so that relevant treatment may be commenced (see below).

Risk factors

• Sex – RVO is more common in men than women, with the recent Gutenberg Health Study putting the risk at 1.7x15.
• Age – Increasing age is the greatest risk factor with the above study finding an almost fivefold increase in risk comparing 35 to 44-year-olds and 65 to 74-year-olds.¹⁵
• Hypertension – This is a well-known systemic risk factor for RVO, with an increased risk of between 1.6x and 3.6x15-17 and is thought to be caused by stiffening of the arteries causing turbulent blood flow.¹⁶
• Obesity – obese patients are almost four times as likely to develop an RVO.¹⁷
• Glaucoma – Patients with chronic open angle glaucoma and raised intraocular pressure (IOP) have an almost threefold increased risk of developing an RVO, with some authors suggesting this being more of a factor in CRVO.¹⁸ This is the single most important ocular factor.¹⁹
• Myeloproliferative disorders – Such as lymphoma increase the risk of thrombosis.
• Hypercoagulable states – Such as protein C deficiency.
• Inflammatory disease – Such as Behçet’s disease can cause occlusive periphlebitis.

Diabetes has traditionally been reported as a risk factor, however current thinking is tending away from defining this as such. Indeed, the current Royal College of Ophthalmologists guidelines state that RVO is no more common in diabetics than in the general population, however, testing glucose levels in patients with RVO is beneficial in detecting undiagnosed cases.²⁰

Likewise, hyperlipidaemia has been conventionally listed as a risk factor (and logically so with it being a risk factor for artherosclerosis), but there is debate within the literature as to its relevance.^16,21 The link between RVO and oral contraceptive use is also debated¹⁹ despite being shown to increase the risk of thromboembolism, as has been reported extensively in the media recently.²²

Symptoms

Some patients are asymptomatic, but often present with acute, painless, unilateral vision loss of varying severity (from mild in BRVO to severe in ischaemic CRVO), metamorphopsia, and visual field loss.

Fundus signs

In primary care this is best visualised by dilated binocular indirect ophthalmoscopy, but may be aided by the use of optical coherence tomography (OCT) and fundus photography (figures 5 and 6). Common signs include:

• Venous dilation and tortuosity.
• Superficial retinal haemorrhaging and cotton wool spots, which are present in one quadrant in BRVO and all four in CRVO (the latter is often referred to as ‘blood and thunder’).
• Disc oedema in CRVO.
• Collateral vessels, hard exudates and ghost vessels in later stages.

Figure 5: Central retinal vein occlusion

Figure 6 Branch retinal vein occlusion

OCT signs

OCT shows retinal thickening, with extensive superficial haemorrhaging. In BRVO, this is understandably more pronounced in one quadrant. MO appears as intraretinal hyporeflective cystoid spaces, specifically in the OPL. Importantly, when considering differential diagnoses (eg wet AMD) the RPE will be intact.²³ (See figure 7.)

Figure 7: OCT scan of retinal vein occlusion

Management in primary care

Optometric management in retinal vein occlusion is urgent referral to HES. If NV is present, the patient requires same day assessment. In the meantime, it is beneficial to refer the patient to their GP for a systemic workup. The latest Royal College of Ophthalmologists guidelines state that patients should have blood pressure (BP) measurement, serum glucose, full blood count (FBC) and erythrocyte sedimentation rate (ESR). They also recommend that ophthalmologists refer the patient to their GP for lipid profile and ambulatory BP (ie ‘24-hour blood pressure monitor’), therefore it may be beneficial for the referring optometrist to request these in the first instance.²⁰

Management in secondary care

Please refer to figure 8 which is based on the latest Royal College of Ophthalmologists guidelines:²⁰

Figure 8: Treatment algorithm for RVO

Ranibizumab (Lucentis) is the most widely used anti-VEGF agent and is recommended by NICE for the treatment of MO secondary to CRVO and BRVO,²⁴ but only in BRVO when laser does not work. Cruise²⁵ (CRVO) and Bravo²⁶ (BRVO) were the key studies investigating its effectivity and both reported a substantial improvement in visual acuity versus sham. Aflibercept (Eylea) is currently only approved by NICE for the treatment of MO secondary to CRVO²⁷ and has the advantage of a longer duration of action (eight weeks versus ranibizumab’s four). Guidelines on its use in BRVO are due to be published in late 2016.²⁸ Galileo²⁹ and Copernicus³⁰ were the landmark studies in assessing its effectivity in CRVO and again showed significant gains versus sham. They also concluded that early treatment proved more effective.

Dexamethasone (Ozurdex) has been shown in studies such as Geneva³¹ to be effective in MO and has a longer duration of action reducing the need for multiple treatments, is useful in patient with a history of recent cardiovascular problems (such as myocardial infarction) and is more effective in those who had previously had vitrectomies.

Retinal artery occlusion

Retinal artery occlusion (RAO) is a term used to describe a blockage in a retinal artery. It is essentially an ocular stroke and is an ophthalmological emergency. Thankfully, RAO is reasonably rare with central retinal artery occlusion (CRAO) having a prevalence of approximately 1/100,000.³² RAO, especially CRAO, often causes a significant burden due to its severe and (potentially) irreversible effect on visual acuity. It is imperative that the optometrist identifies and manages these patients in a timely manner, not only because time is of the essence for potentially restoring vision, but also because of its common links with serious systemic conditions and their associated morbidity and mortality.

Classification

Central retinal artery occlusion (CRAO) is self-explanatory, a blockage of the central retinal artery, while branch (BRAO) refers to a blockage anterior to the LC. While visual function in the latter is determined by the level of ischaemia, the management remains largely the same as CRAO. Cases of combined CRAO and CRVO have been recorded, caused by an occlusion of the central retinal vein at the level of the LC leading to secondary artery occlusion.³³ While the cilioretinal artery may preserve the central vision in those where it is present, as mentioned above the patient may suffer occlusion of this artery itself.^5,6

Risk factors

The commonest cause of CRAO is atherosclerosis (which causes thrombosis), and accounts for 80% of cases.³⁴ The following are linked with atherosclerosis and are risk factors for RAO:

• Men have an increased risk of RAO by a ratio of about 2:1.^35,36
• Increasing age – patients typically present with RAO in their seventh decade.³⁶
• Hypertension is present in up to three-quarters of patients.^35,36
• Carotid artery disease is present in up to half of patients.³⁷
• Diabetes is present in up to a quarter of patients.³⁶
• Stroke (the rates of previous stroke and TIA are higher in those with CRAO and in the months and years following the CRAO the risk is significantly higher).³⁶
• Aortic valve disease.³⁸
• Hypercholesterolaemia.³⁸
• Smoking.³⁸

Other less common risk factors include oral contraceptive use, bacterial endocarditis and cardiac valve mass, polyarteritis nodosa, Wegener’s granulomatosis, retinal vasculitis and sildenafil (Viagra) use among others.³³ Giant cell arteritis (GCA) is also often listed as a risk factor and while this is a common cause of anterior ischaemic optic neuropathy (discussed in part 2), it is rarely a cause of CRAO.³⁴

Symptoms

Patients generally present with a sudden, painless, unilateral loss of vision (counting fingers or worse in CRAO, altitudinal field defect in BRAO), occasionally with reports of previous amaurosis fugax. Patients may also have a known history of cardiovascular disease (myocardial infarction, transient ischaemic attack, stroke etc), and if GCA is the cause, there may be relevant symptoms outlined below.

Fundus signs

CRAO will appear ophthalmoscopically as central retinal pallor with a ‘cherry red spot’ (due to ischaemia and oedema), there will be arteriolar attenuation and venular tortuosity (figure 9), and emboli are visible in a small proportion (11%).³³ Pupillary reactions show a dense RAPD. BRAO will appear as an area of pale, oedematous retina with arteriolar attenuation. Emboli are more common, being visible in just less than half of cases (47%).³³

Figure 9: Retinal artery occlusion

OCT signs

There is increased reflectivity from the RNFL to the OPL, and retinal thickening. Later on (by week 3 or 4) there is thinning of these inner retinal layers and loss of the foveal depression.²³

Management in primary care

The primary objective in treatment is to dislodge the embolus as quickly as possible. A study conducted on rhesus monkeys by Sohan Hayreh and colleagues showed that short duration (<97 minutes) CRAO showed no detectable retinal damage but those lasting for four hours caused ‘massive, irreversible damage’.³⁹ This shows that while the retina may be able to tolerate some level of oedema and ischaemia, if these are present for a reasonable length of time, irreparable damage occurs. Recent work suggests that the key timeframe for treatment is six hours⁴⁰ but recanalisation of the occluded vessel may be possible up to 72 hours after infarction.⁴¹ However, beyond six hours there is little likelihood of recovery, so it is imperative immediate referral is instigated. First aid measures should be carried out by the optometrist:

• Get the patient to breath into a paper bag, which increases the carbon dioxide, levels leading to vasodilation.³³
• Digital massage on closed eyelids (by practitioner or patient), so firm that it is uncomfortable, for periods of 10 minutes releasing intermittently.⁴²
• Placing the patient in the supine position.⁴²

Management in secondary care

There are currently no guidelines from professional bodies on the management of RAO, however, when the patient reaches secondary care, the following may be attempted:

• Retinal perfusion may be enhanced by IOP reduction. This can be achieved by administration of intravenous (IV) acetazolamide (Diamox) 500mg and topical apraclonidine (Iopidine) 1% and timolol 0.5%.³⁴
• Anterior chamber paracentesis may be used to reduce IOP, although a recent study by Feiss and colleagues failed to find a significant improvement in visual outcomes over more conservative measures.³⁷
• Ocular massage is continued (digitally or by fundus contact lens).
• Sublingual isosorbide dinitrate 10mg and breathing of carbogen (95% O2 / 5% CO2 mix) may be used to induce vasodilation.⁴¹
• Antiplatelet and heparin therapy may be used.³³
• The use of systemic thrombolytic agent has been advocated, but as yet show little evidence of improved outcome over traditional measures.⁴⁰
• There have been reports of the use of Nd:YAG embolectomy or embolysis being successful in restoring blood flow and visual function in cases of RAO,^43-45 however, this is yet to gain widespread use.
• Medical tests will include BP, pulse, cardiac auscultation, glucose, lipids, urea and electrolytes and carotid artery assessment (usually by Doppler). Other tests may include echocardiogram (ECG), thrombophilia screen, syphilis serology among others. If GCA is suspected (see symptoms below) the patient has ESR, C-reactive protein (CRP) and FBC measured and a temporal artery biopsy is conducted. In all cases referral to a specialist stroke clinic is advised and systemic treatment is initiated as required.⁴⁶
• The patient should be counselled in dietary risk factors of cardiovascular disease as well as smoking cessation,⁴⁷ maintaining a healthy body mass index (18.5-24.9), exercise⁴⁸ and moderating alcohol consumption (current chief medical officer guidelines are that patients should not regularly exceed 14 units per week, be they male or female).⁴⁹
• Patients are generally followed up within ophthalmology for potential NV (which occurs in approximately 18% of cases of CRVO).⁴⁶

Emboli

As mentioned, emboli are a common cause of RAO.³⁵ In two thirds of cases these come from carotid artery plaques, and the first branch they meet is the ophthalmic artetry.³⁸ They are commonly formed from the following:

• Cholesterol emboli (also known as Hollenhorst plaques) – are small, reflective and yellow. They make up 74% of retinal emboli.
• Fibrin-platelet emboli – are longer and dull white. They account for 16%.
• Calcific emboli – are white in colour and close to the disc. They make up 11%.⁵⁰
• The prevalence of asymptomatic emboli has been reported as high as 1.4% of the population.⁵¹ If an embolus is found on routine eye examination a patient should be referred to the relevant physicians for a full cardiovascular work-up due to the risk of stroke and cardiovascular disease.

Amaurosis fugax

Amaurosis fugax is a term used to describe a painless, usually monocular, fleeting loss of vision (usually like a curtain falling from top to bottom). If an underlying systemic cause is suspected the patient should be referred via their GP to a TIA clinic to investigate the cause. Prior to this care should be taken to rule out any ocular cause. If ocular pathology is suspected, the optometrist should refer accordingly to ophthalmology.

Ocular ischaemic syndrome (OIS)

OIS is uncommon but shares common risk factors with RAO. Blockage of the carotid artery leads to chronic hypoperfusion and subsequent anterior and posterior ocular ischaemia. In the vast majority of patients there is a subacute (weeks or months) reduction in visual acuity, usually in one eye. Clinically, the practitioner may see an atrophic iris, anterior chamber flare, cells and keratic precipitates and rubeosis iridis. Despite the rubeosis, IOP can remain low because of ciliary body hypoperfusion. Posteriorly there may be arteriolar attenuation, venous dilation, retinal haemorrhage, macular oedema and new vessels. Optometrists should treat this as a matter of urgency.^34,46

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Ceri Probert is an optometrist who practises in south Wales