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Management of neovascular AMD in secondary care.

This article will provide an overview of the assessment and management of patients with neovascular age-related macular degeneration within the hospital eye service

Optometrists ***

Therapeutic opticians *

Dispensing opticians **

Introduction

Age-related macular degeneration (AMD) is a chronic, degenerative disease affecting the central retina in people over the age of 55 years. (1) It is currently the leading cause of visual impairment in the developed world, and is predicted to affect more than 750,000 people in the UK by the year 2020. (2) In recent years, the use of anti-vascular endothelial growth factor (anti-VEGF) injections in the management of 'wet' or 'neovascular' AMD (nAMD) has improved the visual prognosis in many cases. However, the need for regular follow up appointments has meant that hospital departments are now busier than ever, leading to the expansion of extended roles for optometrists in the management of these patients. This article aims to provide an overview of AMD, followed by an update on the assessment and management of nAMD within secondary care.

Classification of AMD

AMD can be broadly classified as either 'dry' or 'wet.' The dry form of AMD accounts for approximately 85-90% of cases, although varies with patient age, (3,4) and is characterised by the slow accumulation of fatty deposits known as drusen; as these form and coalesce they disrupt the regularity and function of the retinal pigment epithelium (RPE). As RPE function becomes impaired this leads to photoreceptor damage, which manifests as a gradual deterioration of the central vision as the disease progresses. In the late stage of dry AMD large, scalloped regions of depigmentation reflecting regions of RPE atrophy can be seen, known as 'geographic atrophy' (GA). Unfortunately, there are no current treatments for the dry form of AMD. It is crucial that patients are counselled on what to expect from their condition, and given advice on diet, UV protection, lighting and, if necessary, low vision services. Patients must also be educated on the symptoms of wet AMD in case of disease progression, and encouraged to attend annual eye examinations with their optometrist.

Wet or nAMD then accounts for the remaining cases ([approximately equal to]10-15%) and typically arises in patients with pre-existing dry AMD. It is characterised by the growth of new, leaky blood vessels at the macula that originate from the choroid, hence the term 'choroidal neovascularisation' (CNV); these usually grow towards the outer retina, penetrating Bruch's membrane in the process, and accumulate either beneath the RPE or beneath the outer layers of the retina. However, very occasionally neovascularisation can arise from the retinal vessels on the surface, and grow down through the inner retina to meet the choroidal vessels (forming chorioretinal anastomoses). This type of nAMD is referred to as a retinal angiomatous proliferation (RAP) lesion, (5) and is commonly associated with exudates, intraretinal and subretinal haemorrhage, and serous detachments of the RPE.

Unfortunately, the leaking and accumulation of fluid and / or blood from CNV not only causes distortion (metamorphopsia), but also disrupts the architecture of the retinal layers leading to degeneration of the photoreceptors, cell atrophy and eventually scarring (fibrosis); this causes impairment of central vision, which can range from relatively mild to profound depending on the extent and location of the damage. Often patients will present to their optometrist/GP/ accident and emergency department with a recent history of (typically) unilateral, painless, blurred and /or distorted vision, although nAMD may also be discovered incidentally. If nAMD is suspected, patients should be referred urgently to the hospital eye department. Treatments are then aimed at stabilising the condition and maintaining (or improving) visual acuity. Many hospitals operate a dedicated 'fast-track' system for nAMD referrals, which enables faster access to treatment.

Assessing the patient with nAMD

Once referred to secondary care, patients undergo a series of diagnostic tests to confirm whether nAMD is present. This initially includes measuring the visual acuity in each eye using an Early Treatment of Diabetic Retinopathy Study (ETDRS) chart and dilating the pupils. A clinician will perform an indirect examination of the fundus to identify any clinical signs of nAMD, for example haemorrhages, subretinal or sub-RPE neovascularisation (which may appear as a greenish-grey lesion), retinal thickening, pigmentary changes, exudates or fibrosis (see Figure J). It is also important to distinguish nAMD from other types of maculopathy that can mimic the disease, for example, diabetic maculopathy, adult vitelliform macular dystrophy, myopic CNV or central serous retinopathy. Several types of imaging will often be utilised to help with the diagnosis and (later) management of nAMD, including optical coherence tomography (OCT), fluorescein angiography (FA), colour fundus photography and (less frequently) indocyanine green angiography (ICG) and fundus autofluorescence (FAF). An overview of these techniques will now be given below.

OCT

OCT is a high resolution, non-invasive method of imaging cross sections of the retina (see Figure 2). The technology is used extensively within the hospital for diagnosing nAMD and also assessing the patient's progress at each follow up visit. Broadly speaking, it works by directing near-infrared light into the eye and comparing the interference pattern between the light which is reflected back from the retinal tissue, and that of a reference beam. Differences in tissue density within the retina result in different patterns of interference, which can be translated into a greyscale or colour coded image. Regions in which there is no reflected light, for example, the vitreous, appear black, with areas of high reflectance/density, such as the RPE, appearing bright. OCT imaging is quick to perform, and can indicate the presence of intraretinal fluid, subretinal fluid (see Figure 2A, blue arrow, and Figure 3), retinal pigment epithelium detachment (PED) and subretinal hyperreflective material (which may indicate blood, exudate, fibrosis, CNV). In chronic/longstanding disease, outerretinal tabulations may also be seen, which appear as black oval spaces encircled with a ring of hyperreflective material (see Figure 2B red arrow).

Fluorescein angiography

Fluorescein angiography (FA) is still considered the 'gold standard' test for diagnosing CNV, and is used to visualise the chorioretinal circulation. The procedure involves the injection of a non-toxic dye (sodium fluorescein) into the patient's bloodstream through a cannula in the arm. The fluorescein molecules are excited by blue light (=465nm) shone through the pupil, causing them to fluoresce; this allows visualisation of the dye as it enters (and exits) the retinal and choroidal circulation, highlighting any areas of leakage or nonperfusion, that is to say, ischaemia. From the point at which the fluorescein is injected, the photographer starts a timer, and a series of greyscale retinal photographs are taken at specific time points over =10-15 minutes. FA can be used to classify the type of CNV as 'classic' or 'occult' depending on the pattern of leakage. In 'classic' CNV, the new vessels have breached the RPE and invaded the subretinal space, and FA images typically show a 'lacy' pattern of leakage early on in the angiogram (see Figure 4). Comparatively, in 'occult' CNV the new vessels lie underneath the RPE and images show diffuse hyperfluorescence at a later stage of the FA. In reality, a large proportion of CNV is mixed, and shows features of both classic and occult leakage, although one type may dominate. Colour fundus photographs are often used in conjunction with FA images to allow differentiation between haemorrhages, exudates and pigment, which all look dark on FA images.

ICG

ICG can be performed in the same way as FA but using a different dye (indocyanine green); this provides better visualisation of the choroidal vasculature since fluorescein tends to permeate through the blood vessel walls in the choriocapillaris obscuring the vessels beneath. Indocyanine green dye absorbs and emits radiation near the infrared region of the spectrum. Since this wavelength can pass through the RPE and through blood, ICG can be useful in imaging choroidal pathology that may be obscured beneath a macular haemorrhage or pigment. [6] ICG may also be performed to diagnose an atypical form of nAMD known as idiopathic polypoidal choroidal vasculopathy (IPCV), (7-9) in which a branching vascular complex forms within the choroid, terminating in polypoidal dilations (polyps) at the edge of the lesion. These polyps more frequently occur between the macula and the optic disc, and appear as focal 'hot spots' of hyperfluorescence on ICG images.

FAF

Fundus autofluorescence (FAF) is used to study the accumulation of lipofuscin granules within the RPE. Lipofuscin is considered a cellular waste product that is associated with ageing, and accumulations are often seen at the macula in patients with AMD. A useful feature of lipofuscin is that it fluoresces when the molecules are excited by a blue light, revealing areas of hyperfluorescence. FAF is also particularly helpful in exposing areas of RPE atrophy, which appear as clearly delineated dark patches.

Evidence has suggested that repeated anti-VEGF injections might be linked to the development or increase in GA in some patients, (10,11) and, therefore, FAF can be useful in monitoring areas of atrophy at subsequent clinic visits.

Managing the patient with nAMD

Historically, before the introduction of anti-VEGF injections, the main forms of treatment for nAMD were laser photocoagulation and photodynamic therapy (PDT). (12) Unfortunately, laser photocoagulation resulted in a permanent scotoma, and, therefore, was generally reserved for patients with juxtafoveal or extrafoveal lesions. PDT involved intravenously injecting a photosensitising drug called Verteporfin into the patient's circulation, where it became concentrated in areas of neovascularisation within the macula. The lesion was then targeted with a laser which activated the drug, causing occlusion of these new fragile vessels and preventing further growth and/or leakage. This was less damaging to the underlying tissue, but still only tended to reduce the rate of vision loss compared to giving no treatment.

Fortunately, the licensing of intravitreal anti-VEGF drugs (Lucentis and Eylea) for the management of nAMD has revolutionised treatment strategies over the past decade. VEGF is a protein, which stimulates new blood vessel growth, and additionally increases vessel permeability. Anti-VEGF drugs, therefore, aim to prevent this new growth and reduce the leakage of fluid through the vessel walls, essentially 'drying out' the retina (see Figure 3). Compared to PDT, anti-VEGF treatment has been shown, on average, to slightly improve vision, and importantly these results seemed to be maintained longer-term. The results of the ANCHOR study found that compared to baseline, patients receiving Lucentis (ranibizumab) showed an average improvement in vision of [approximately equal to]9 and [approximately equal to]11 letters (0.3mg and 0.5mg doses, respectively) over the course of 12 months, while patients receiving PDT lost [approximately equal to]10 letters in the same time frame. (13) Similarly, the MARINA study compared Lucentis to sham injections (a placebo), and found an average increase of [approximately equal to]7 letters in the Lucentis group yet an average drop of [approximately equal to]10 letters in the sham group after 12 months of treatment. (14) Importantly, the rate of severe complications such as endophthalmitis and retinal detachment following the intravitreal injection was also low. Consequently, the promising results of these (and other) large randomised controlled clinical trials led to NICE approval of Lucentis for the treatment of nAMD in 2008.15 These days, the use of PDT in nAMD tends to be reserved only for patients with IPCV, who can respond poorly to anti-VEGF treatment and may achieve superior visual outcomes with PDT. (16)

In 2013, a second anti-VEGF drug known as Eylea (Aflibercept) also became approved by NICE for the treatment of nAMD. [17] Results from the VIEW study showed that following three initial monthly injections, Eylea only needed to be administered every eight weeks to have the same efficacy and safety as Lucentis. (18,19) This is advantageous for both the patient and the busy hospital department as fewer clinic visits should be necessary each year.

Presently, NICE criteria for the use of anti-VEGF drugs in the treatment of nAMD requires that the patient has signs of active disease, no permanent damage to the fovea, a lesion no larger than 12 times the optic disc area and visual acuity between 6/12 and 6/96. Importantly, this does mean that patients diagnosed with active nAMD who have vision better than 6/12 are not currently eligible for treatment, and consequently must remain under close observation for any sign of visual deterioration.

A registered nurse practitioner or ophthalmologist often administers injections, although optometrists may also be trained in this procedure. The eye is firstly anaesthetised and cleaned before the injection site is marked with calipers. Clips are used to keep the eyelids open. The injection is aimed through the sclera into the centre of the globe, and takes approximately 20 seconds to administer. Immediately after the injection the patient will be asked to confirm that they can count fingers / see hand movements to ensure that the central retinal artery is perfused. While very rare, there are reports of serious ocular and systemic complications following anti-VEGF treatments, including (but not limited to) endophthalmitis, increased intraocular pressure, retinal detachment, heart attack and stroke. (13,14,20) Therefore it is important that informed consent is acquired from the patient prior to initiating any treatment.

Both Eylea and Lucentis are initially given as a course of one injection per month for three consecutive months (known as the 'loading dose' phase), after which the patient is assessed clinically. Following these loading doses, there are three possible treatment strategies that may then be utilised. The choice is often left to the discretion of the treating clinician, as some patients will require more intensive therapy than others. The first option is to follow a pro re nata (PRN) protocol, in which the patient is treated monthly until the maximum level of visual acuity is reached. Following this, patients continue to be seen monthly but are only treated if there is a significant drop in vision or signs of active disease, for example, haemorrhage, exudates, intraretinal fluid, subretinal fluid. Otherwise, if the eye and vision remain stable, the patient is kept under observation.

The second option is the 'treat and extend' (TREX) protocol, in which patients receive an injection at every follow up visit, but if there are no signs of active disease then the interval between visits is extended by two weeks up to a maximum of 12 weeks. Conversely if the vision worsens or there is active disease, the follow up intervals are shortened by two weeks. The aim with this strategy is to extend to the maximum follow up interval, and if the patient can maintain this for three to four consecutive visits with no sign of disease activity, then treatment may be halted. Signs of disease inactivity include no evidence of leakage on FA, no new haemorrhage, no change in the lesion size, stable OCT appearance and no change in vision (attributed to nAMD). Patients would normally be observed for a period of time after cessation of treatment for any reactivation of the disease.

The third option is a fixed dosing (FD) strategy, in which patients are treated at fixed intervals (four weekly for Lucentis and eight weekly for Eylea). After the first year, a decision can be made whether to continue with fixed dosing, move on to TREX / PRN, or trial a period of observation-only.

Unfortunately, a small proportion of patients respond poorly to anti-VEGF treatment, with declining visual acuity or persistent (or increasing) subretinal fluid despite short treatment intervals. (21,22) If an inadequate response is evident, clinicians may choose to switch the type of anti-VEGF therapy, that is to say, change from Lucentis to Eylea or vice versa to see if this has a beneficial effect. Alternatively, if the vision is very poor and unlikely to recover, for example, due to permanent structural damage at the fovea, a decision may be made to discontinue treatment altogether. NICE guidelines indicate that treatment should be halted if a patient's vision is continuing to deteriorate, and there are changes to the eye that show the treatment isn't working. Patients may be kept under observation for a period of time, especially if there is significant risk of nAMD in the fellow eye. Virtual clinics are now being utilised in a number of hospitals for the monitoring of stable patients who do not require treatment.

Conclusion

The use of anti-VEGF treatments has meant that nAMD is no longer associated with the profound loss of central vision that accompanied this diagnosis decades ago. (23) However, this also means that frequent visits to the hospital are necessary for most patients. With an increasingly elderly population, it is vital that with appropriate training, allied healthcare professionals such as optometrists can aid in the management of nAMD in secondary care.

Exam questions and references

Under the enhanced CET rules of the GOC, MCQs for this exam appear online at www.optometry.co.uk. Please complete online by midnight on 27 December 2017. You will be unable to submit exams after this date. Please note that when taking an exam, the MCQs may require practitioners to apply additional knowledge that has not been covered in the related CET article. CET points will be uploaded to the GOC within 10 working days. You will then need to log into your CET portfolio by clicking on 'MyGOC' on the GOC website (www.optical.org) to confirm your points. Visit www. optometry.co.uk, and click on the 'Related CET article' title to view the article and accompanying 'references' in full.

Couse code: C-57694 Deadline: 27 December 2017

Learning objectives

* Be able to explain to patients about the implications of neovascular AMD (Group 1.2.4)

* Understand when it is appropriate to refer patients with neovascular AMD into secondary care (Group 2.6.2)

* Be able to manage patients presenting with neovascular AMD (Group 6.1.9)

* Understand the guidelines relating to management of patients presenting with neovascular AMD (Group 7.1.5)

* Be able to explain to patients about the implications of neovascular AMD (Group 1.2.4)

* Understand the management of patients presenting with neovascular AMD (Group 8.1.3)

Dr Corinne Fulcher PhD

Dr Corinne Fulcher currently works as a specialist optometrist for both the Royal Hallamshire Hospital in Sheffield and Bradford Royal Infirmary (BRI). One of her roles at the BRI includes the management of patients with a variety of macular conditions at the Bradford Macular Centre. Dr Fulcher is also part of the Bradford Ophthalmic Research Network (BORN) team, involved in several national and international clinical trials in the field of medical retina research.

Caption: Figure 1 An example of the clinical appearance of neovascular AMD

Caption: Figure 2 An example of two OCT images for two different patients with nAMD. Blue and red arrows indicate sub-retinal fluid and a retinal tubulation respectively

Caption: Figure 3 OCT images for a patient who has responded well to anti-VEGF therapy. One month after injection there is a significant reduction in subretinal (SR) and intraretinal (IR) fluid

Caption: Figure 4 An example of a fluorescein angiography image for a patient with a classic CNV lesion, in which a 'lacy' pattern of leakage can be seen at the macula
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Author:Fulcher, Corinne
Publication:Optometry Today
Date:Dec 1, 2017
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