Key points
- Age-related macular degeneration (AMD) can be broadly divided into two sub-groups: dry AMD and wet AMD
- There is currently no treatment for dry AMD, while anti-vascular endothelial growth factor (anti-VEGF) inhibitors are used to treat wet-AMD
- Rapid assessment of concerning visual symptoms, via optical coherence tomography (OCT) +/– angiography, is essential in early detection of wet AMD
Epidemiology
Age-related macular degeneration (AMD) is the leading cause of blindness in over 60 years old in the western world. Prevalence increases with increasing age. Most patients suffer mild visual symptoms. However, 10–15% of patients with AMD suffer from severe central visual loss.
Pathophysiology
Genetic and environmental factors combine to produce an environment of oxidative stress and inflammation at the retinal-choroidal interface. With age adaptive mechanisms begin to fail and the pathological state of AMD ensues. This begins with a build-up of waste material at the retinal-choroidal interface (drusen). Subsequently the following changes occur:
- Dry AMD: The retinal pigment epithelium (RPE) becomes dysfunctional and atrophic, leading to secondary photoreceptor atrophy
- Wet AMD: New vessels grow from the choriocapillaris [choroidal neovascularisation (CNV)], or occasionally from the retina [retinal angiomatous proliferation (RAP)]
Clinical features
Symptoms
Patients may complain of blurred central vision in one or both eyes, often associated with distortion (when straight lines appear crooked or bent). They find it more difficult to read in dim illumination, often requiring good lighting when reading. Sometimes words appear and disappear when reading, as the words move in and out of parafoveal scotomas caused by AMD. Some patients are not aware of visual loss, if the other eye is dominant.
Signs
The AMD can be divided into two categories, dry AMD and wet AMD.
Dry AMD
- Areas of altered RPE pigmentation in the macular region: hyper- and hypopigmentation
- Patches of RPE hypopigmentation, in the shape of islands [geographic atrophy (GA)]
Wet AMD
- Haemorrhage at the macular region (intraretinal, subretinal or sub-RPE)
- Macular oedema and/or submacular fluid
- Intraretinal exudates
- A grey-green lesion in the macular region CNV
- A subretinal fibrotic scar
The AMD normally occurs in the presence of drusen. However drusen alone, in the absence of symptoms or features described above, do not indicate AMD, just the potential to develop it.
Wet AMD usually occurs on a background of preceding dry AMD.
Optical coherence tomography
The OCT scanning is essential in determining if AMD is wet or dry. It is also vital when following up patients treated for wet AMD, as it shows response to treatment.
Key OCT features of dry AMD
- Sub-RPE deposits (drusen – between the RPE layer and Bruch's membrane)
- Subretinal deposits (reticular pseudo-drusen – between the photoreceptor outer segments and the RPE)
- Thinning/loss of the RPE layer (GA) with associated thinning of the overlying photoreceptor layer (outer nuclear and ellipsoid layer) and a bright area of choroid below (due to more OCT light reaching the choroid allowing more to be reflected back)
Key OCT features of wet AMD (Figure 1.1)
- Retinal thickening
- Fluid cysts within the retinal layers (intraretinal fluid – IRF)
- Fluid between the retina and the RPE (subretinal fluid – SRF)
- Fusiform shaped lesion between the retina and the RPE, between the RPE and Bruch's membrane, or both (choroidal neovascularisation – CNV)
- Associated subretinal and intraretinal hyper-reflective material (blood, exudate)
Fundus fluorescein angiography
Fundus fluorescein angiography (FFA) is a useful test in confirming wet AMD, in the presence of suspicious features on OCT scanning. It is also used where there is a diagnostic uncertainty, based on the clinical and OCT findings. If there are no concerning features on OCT scanning, FFA should not be performed.
Figure 1.1: Macular OCT scan showing typical features of wet AMD. Intraretinal (A) and subretinal fluid (B). A pigment epithelial detachment (PED) (C) containing a fusiform lesion [D – choroidal neovascular membrane (CNV)]. Blood is seen as subretinal hyper-reflective material (E).
Key FFA features of wet AMD
- Area of hyperfluorescence, seen early (typically a lacy network at 30 seconds) that gets brighter and bigger later in the FFA. This is a CNV between the retina and the RPE (classic CNV, type-2 CNV) (Figure 1.2)
- Area of hyperfluorescence, seen later in the FFA (1–2 minutes), that gets brighter and bigger later on, associated with a fibrovascular pigment epithelial detachment (PED) or late leakage of unknown origin. This is a CNV hidden underneath the RPE (occult CNV, type-1 CNV) (Figure 1.3)
OCT angiography
The OCT angiography enables the visualisation of choroidal neovascularisation (CNV) without the injection of dye. It is often used instead of traditional FFA imaging and has the following advantages:
- Non-invasive (no dye required)
- Able to detect CNV complexes in patients where traditional FFA is often inconclusive (e.g. elderly patients with only SRF [wet AMD vs. central serous chorioretinopathy (CSCR)]
Fundus autofluorescence
Fundus autofluorescence (FAF) is a non-invasive technique for imaging natural retinal fluorophores (predominantly lipofuscin in the RPE). Healthy RPE fluoresces. Sick/absent RPE has altered/absent autofluorescence. FAF is particularly useful in monitoring progression of GA.3
Figure 1.2: Fundus fluorescein angiogram (FFA) of a type-2 (classic) choroidal neovascular membrane (CNV). (a) Bright lesion seen at 15 seconds. Note: the lacy network and central feeder vessels. (b) At 3 minutes the lesion is brighter and bigger due to leak. (c) Corresponding OCT showing a choroidal neovascular membrane (CNV) between the retina and the RPE (*).
Key FAF features of dry AMD
- Areas of hypofluorescence, due to loss of lipofuscin laden RPE cells in GA
- Drusen have variable fluorescence
Indocyanine green angiography
Indocyanine green angiography (ICG) is used to visualise lesions under the RPE. Unlike fluorescein the excitation and emission wavelengths of ICG can penetrate the RPE. It is particularly useful in the detection of idiopathic polypoidal choroidal vasculopathy (IPCV) and retinal angiomatous proliferation (RAP) lesions.
Multimodal imaging
Multimodal imaging means imaging lesions in two or more different ways (e.g. OCT and FFA) and then reviewing the results together. It leads to both a better understanding of the pathology and also enables more accurate diagnosis.
Diagnosis
Dry AMD
Diagnosing dry AMD is based on the identification of typical RPE abnormalities in a patient over 50 years old. Drusen are invariably present to some degree. An OCT scan has ruled out wet AMD.
Wet AMD
Diagnosing wet AMD is based on typical OCT findings in the presence of macular drusen +/– blood/exudate. The diagnosis is confirmed with FFA or OCT angiography.
Treatment
Dry AMD
Currently there is no treatment for dry AMD. RPE atrophy, with associated photoreceptor atrophy, tends to slowly progress, leading to central and para-central visual loss.4
Figure 1.3: Fundus fluorescein angiogram (FFA) of a type-1 (occult) choroidal neovascular membrane (CNV). (A) Some hyperfluorescence seen at 1 minute. This is later and dimmer than in a type-2 (classic) CNV, due to the overlying retinal pigment epithelium (RPE) obscuring much of the underlying fluorescence. (B) At 4 minutes the lesion is brighter and bigger due to leak. (C) Corresponding OCT showing a fibrovascular pigment epithelial detachment (PED) (*).
Current advice includes smoking cessation, a healthy diet rich in colourful fruit and vegetables and consideration of vitamin supplementation (antioxidant vitamin formulation reduces progression by 25% – AREDS 1 and 2 trials) (Table 1.1).
Wet AMD
Wet AMD is treated with intravitreal injections. Three are in current use:
- Ranibizumab (Lucentis) is a monoclonal antibody fragment (FAb) against vascular endothelial growth factor (VEGF)
- Aflibercept (Eylea) is a recombinant human fusion protein against VEGF. It also binds to placental growth factor (PGF)
- Bevacizumab (Avastin) is a recombinant humanised monoclonal antibody against VEGF. Unlike ranibizumab and aflibercept5 it is not licensed for use in the eye. It is licensed for the treatment of cancer. One vial of bevacizumab can be divided into many separate intravitreal injections. It is widely used worldwide and is considerably less expensive than ranibizumab or aflibercept
Patients are usually treated initially with three intravitreal injections, each 1 month apart. After that, treatment usually follows one of three pathways:
- As required treatment (PRN) – Patients are seen monthly and injected if there are signs of disease activity (OCT macular intra or subretinal fluid, new macular blood, five letter reduction in vision in the presence of macular fluid)
- Fixed dosing (maintenance) – This is traditionally every 4 weeks (ranibizumab) or every 8 weeks (aflibercept). Injections are given regardless of the clinical findings. This dosing regimen most closely mimics the clinical trials
- Treatment and extend (Rx & Extend) – Patients receive a clinical assessment and injection at every visit. However, the interval between visits increases if the condition is stable (vision stable/improving, no new macular blood, OCT dry). If there are signs of activity [new macular blood, OCT new macular fluid, increasing pigment epithelial detachment (PED)] then the interval between injections is reduced. Intervals tend to range between 8 and 16 weeks, occasionally being as short as every 4 weeks
Complications
Complications of the disease
- Central visual loss due to subfoveal GA (dry AMD) or subfoveal scar (wet AMD)
- Central visual loss due to large submacular haemorrhage (bleeding of neovascular tissue). A large macular haemorrhage can sometimes be moved away from the macular with recombinant tissue plasminogen activator (rTPA), intravitreal gas, and posturing
Complications of the treatment
Injection related complications
- Sore eye for 24 hours (corneal exposure, irritation from local anaesthetic and/or antiseptic)
- Subconjunctival haemorrhage
- Intravitreal haemorrhage (1:1000)
- Intravitreal infection (endophthalmitis – 1:1000)
- Mild increase in risk of myocardial infarction or cerebrovascular accidents as compared to controls
Further reading
- National Institute for Health and Care Excellence (NICE) guidance for AMD – updated January 2018; https://www.nice.org.uk/guidance/ng82
Related topics of interest
- Retinal imaging (p. 277)
- Intravitreal injection therapies (p. 193)