Age-related macular degeneration (AMD) is a multifactorial disease involving the central region of the retina (the macula). The disease is remarkably common, affecting some 30 per cent of the over-70s in the developed world. It is important to appreciate that the macular region extends to an area of approximately 18°-20° (~5.0mm) in diameter as illustrated by the outer dotted circle in Figure 1. The macula is classically subdivided into the fovea (region a), the parafovea (region b) and the perifovea (region c). Note that only the very central 300µm (1.25°) is cone dominated. Overall, macular rods outnumber cones by around 9:1.1,2
Overview of AMD
AMD is now recognised as a chronic inflammatory condition of the outer retinal tissues.3 The retinal pigment epithelium (RPE), Bruch’s membrane and the choriocapillaris are affected and, in the later stages, there is extensive loss of central retinal photoreceptors. The disease is classified either in terms of an atrophic process (dry AMD) or by neovascularisation (wet AMD). The hallmark of dry AMD is the presence of certain types of drusen and pigmentary changes. Wet AMD is less common but leads to catastrophic loss of vision because of fluid leakage and the subsequent production of fibrous scars. Although we can identify risk factors such as smoking, poor diet or genetic predisposition, currently the pathogenesis of the disease is poorly understood. The details of exactly how environmental factors impact on a predisposing genetic background are largely unknown.4 A crucial sign is the appearance of drusen which vary in molecular composition and clinical significance.
In ageing, a characteristic thickening of Bruch’s membrane occurs and in AMD this is accompanied by the build-up of drusen between the retinal pigment epithelium and Bruch’s membrane. Typical macular drusen are composed of cellular debris, lipids, zinc, carbohydrates and many proteins, including some that are biomarkers for inflammation. They are formed as a result of the failure of the renewal-disposal cycle of photoreceptor outer segments.
A diagnosis of early AMD may be based on the number, severity and distribution of drusen.5,6 Many ophthalmic clinics use OCT images and autofluorescence (AF) to aid the diagnosis and prognosis. In most cases of early AMD, visual acuity is normal and it is important to be able to advise patients about the significance of the drusen. This is often a difficult judgement. In the AREDS study, eyes with multiple small drusen had a 1.3 per cent chance of progressing to severe AMD, whereas those with intermediate drusen and non-central geographic atrophy had an 18 per cent chance. In the highest risk category of large soft confluent drusen there was a 50 per cent chance of progression over five years.7,8 This highlights the inadequacy of relying on fundus images alone to predict progression from early to late AMD. Clearly we need an alternative method of staging AMD. Though valuable, OCT and AF do not inform the practitioner about the functional consequences of drusen. Until relatively recently it was assumed that drusen do not affect vision, but as outlined below the visual consequences of drusen are quite subtle involving mainly rods in the very early stages of the disease.
Dark adaptation
Under normal circumstances our vision switches seamlessly between two different pathways dominated either by rods or cones. Considerable overlap between the two systems means we are totally unaware of whether rods, cones or both are operating at any one time. The transition between the two is rapid, so that we can light adapt in less than a second and dark adapt to moderately low lighting in around 10 to 20 seconds. However, this adaptational ability breaks down under one situation; when we are plunged into darkness after being exposed to a light sufficiently intense to ‘bleach’ a substantial proportion of the visual pigment to its colourless form. Then it takes around 20 to 30 minutes to recover full sensitivity.
This slow recovery is referred to as dark adaptation (DA). Classically the threshold for detection of a light is plotted on a logarithmic scale against time after the bleach.9 As seen in Figure 2, sensitivity recovery proceeds in three phases. The first is relatively rapid and dominated by cones and, as the rods become more sensitive than cones, a steady further bi-phasic improvement in sensitivity occurs which is mediated by rods. The transition between the cone and rod sections is called the a point. The time course of sensitivity recovery in the rod section can be attributed directly to the ability of the eye to regenerate activated rhodopsin, the rod visual pigment.10
Rhodopsin is composed of opsin and a chromophore molecule called retinal. When a photon of light is absorbed by a rhodopsin molecule it induces a change in the shape of retinal and starts a long series of reactions called the retinoid cycle. This is composed of intermediaries between sensitised and de-sensitised rhodopsin. Desensitised retinal molecules (more detail below) are conveyed to the retinal pigment epithelium to be transformed to a sensitised state before being transferred back to the rod outer segments to reactivate the rhodopsin molecules. This activity means that, weight for weight, the retina is one of the highest oxygen consuming tissues in the body.
In 1993 Curcio11 used histological techniques in donor eyes to show that rods are selectively vulnerable to ageing. This observation was followed by a psychophysical study by Jackson et al.12 reporting that dark adaptation gradually becomes slowed with age. They ruled out senile miosis and media changes and confirmed the selectivity of the effect, showing that cone recovery rates remained unchanged throughout the life span. This observation was repeated in Dimitrov et al13 and more recently by Patryas et al.14
Rod vulnerability in the older normal eye was further proven in another study in Manchester using a new digital PC-based method developed by the authors. In this technique, observers view an arc shaped peripheral (~10°) stimulus presented on a PC monitor after being exposed to a bleach. In a totally darkened room they respond by pressing a button when the stimulus becomes visible. This threshold measurement is repeated every few minutes and, as the retina increases in sensitivity, the observer can detect the light at increasingly low intensity. The second rod-mediated section of the recovery function is called S2 and is characterised by its slope, which is about 0.24 log units min-1 in young normal observers. This parameter is considered to be a sensitive marker for the health of the outer retina.15 Figure 2a shows a typical old and young DA curve and Figure 2b illustrates the slope of the rod-mediated section of the DA curve plotted against age, for a group of 20 healthy eyes. These data are re-plotted from Rodrigo-Diaz et al16 and Tahir et al.17
The most likely cause of slowed DA in older people is restricted availability of the activated retinal, called 11-cisretinal, a metabolite of vitamin A. The normal recycling of rhodopsin is critically dependent on sufficient quantities of 11-cisretinal. If rhodopsin regeneration is slowed then poor DA ensues. This effect can be dramatically seen in vitamin A deficient patients in whom vitamin A supplementation improves the rate of DA. Bruch’s membrane is thickened with age, leading to reduced transport of 11-cisretinal from the retinal pigment epithelium and restricting the availability of vitamin A.18,19
Thus normal ageing of the Bruch’s membrane/RPE complex may act as a barrier for the exchange of nutrients that are vital for normal sensitivity recovery, explaining the now well established fact that compared with young adults, older people need significantly more time to recover sensitivity in the dark. In everyday life this might explain why older people encounter difficulty when moving from bright conditions into a darkened room or when driving at night. Of course many patients complain of poor night vision for a wide variety of reasons, but these are compounded by the fact that the recovery from exposure to bright light takes longer as the eye ages.
Dark adaptation in early AMD
There are now extensive reports in the literature that, despite AMD being a disease of central vision, show it is the rods rather than cones that are affected in the very early stages of the disease. Rod loss is thought to be most common in the parafovea20 where there are many millions of rods (Figure 1).
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According to most reports, the cone-mediated part of the curve is quite normal, particularly in the early stages of the disease. This is consistent with the earlier histological work by Curcio et al21 showing that, in donor eyes, many more rods than cones are damaged and rod loss always precedes cone loss. Even in the wet form there is greater retention of cones compared with rods. This means that by the time AMD patients are experiencing VA loss or visual distortion, they are likely to have lost many millions of rods. Note that there is a distinct possibility that the survival of cones is dependent on the health of rods.22 Mohand-Said et al23 reported that rod-cone interactions occur which play a role in cone survival in older eyes.
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In all investigations involving early stage AMD, the vast majority of patients exhibit abnormal dark adaptation curves. For example, in the study by Owsley et al,24 85 per cent of patients were outside the normal range and in a further study25 rod impairment was highly significantly greater (p<0.0001) than cone damage. Dimitrov et al26 investigated 293 AMD patients in order to link retinal dysfunction with AMD grade. Compared with age-matched normals, the patients with early stage disease had significantly impaired rod recovery. Surprisingly, some patients with hard drusen, which are usually regarded as clinically insignificant, had abnormal rod vision. Rodrigo-Diaz et al16 and Tahir et al17 also reported dramatically impaired dark adaptation in a group of 48 early AMD patients. Examples from this investigation are illustrated in Figure 3.
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There are marked differences between age-matched normals and early AMD patients as seen in Figure 3. This shows progressively slowed DA in patients at different stages of early AMD according to the AREDS classification.7 Firstly, in the patients’ data, the a point is delayed. But also the slope of S2 (pink/red/dark red/brown lines) is relatively shallow and overall sensitivity is reduced. It is easy to see from these graphs why early stage AMD patients might complain about their night vision. As stated above, patients complain about poor vision under low lighting for many reasons, but if they require an extra 20 minutes in order to recover in absolute darkness it is likely they will not be able to quickly adapt under regularly encountered mesopic conditions. A primary example is when moving from a well-lit to a dimly lit area. Elderly patients often have falls in these conditions without realising that their night vision is impeded.
Corresponding fundus photographs for the patients’ dark adaptation data in Figure 3 are shown in Figure 4. The fundus in the top left panel (A) is normal while the other panels show increasingly severe early AMD according to the AREDS classification. All of these patients have obvious abnormalities on their OCT images. What is important here is to identify the link between structural and functional changes. Many individuals over 50 have small, so-called hard drusen and these are regarded as fairly innocuous. The OCT image will show these as small bumps between Bruch’s membrane and the retinal pigment epithelium. In order to establish whether they are genuinely pathological, one useful functional approach would be to assess dark adaptation. There are now techniques for doing this in much shorter time than the 20-40 minutes seen in Figure 2. A desktop fast dark adaptometer, ideal for clinical application, is now under development at Manchester University.
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In Figure 5 it may be the slope of the rod phase, called S2, of the dark adaptation curve varies in a group of early AMD patients and age-matched normals.16,17 Different values of S2 are plotted in bins horizontally and the numbers of individuals for each value are indicated vertically. As sensitivity recovery is slowed, the slope becomes increasingly shallow. As described above there is a wide variation in slope across the age span with older eyes tending to have slower dark adaption.
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Note, however, that in Figure 5 there are two individuals who have particularly healthy dark adaptation with slopes of 0.3 and 0.25 despite being over 50 years old. There are some patients and normals who have the same slope of 0.2 and 0.15 and in these cases the patients had much longer a points as illustrated in Figure 3. The majority of the patients had extremely slow dark adaptation with slopes of 0.15 or less which corresponds to other reports in the literature.
Conclusions
So we can conclude the following from our observations:
- There is compelling evidence that rods are affected first in early AMD
- It is possible that preserving rods may aid cone survival
- Early diagnosis is therefore essential
- Dark adaptation abnormalities are highly specific to early AMD.
Model answers
Correct answer is in bold italic
1 What is the ratio of rods to cones in the macular region?
A 1 to 9
B 1 to 1
C 3 to 1
D 9 to 1
2 Dark adaptation occurs through how many phases?
A 1
B 2
C 3
D 4
3 Which of the following statements about receptor recovery is true?
A Cone recovery reduces with age
B The first phase of dark adaptation is dominated by rods
C Dark adaptation reduces with age
D Lens brunescence is the main cause of slowed dark adaptation
4 What is the most likely cause of slowed dark adaptation with age?
A A reduction in receptor density
B Restricted availability of 11-cis retinal
C Reduced RPE activity
D Lipofuscin build-up
5 What is the alpha point?
A The part of the dark adaptation curve representing transition from cone to rod influence
B The point where a patient first reports recovery from glare
C The point where a dark adaptation curve meets the y-axis
D The age at which dark adaptation becomes clinically significant
6 How many patients exhibit abnormal dark adaptation in early stage AMD?
A All
B The vast majority (over 80%)
C Half
D None
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Elena Rodrigo-Diaz, Dr Humza Tahir and Dr Ian Murray are based at the Visual Sciences Lab, Faculty of Life Sciences, University of Manchester, and Dr Neil Parry at the Vision Science Centre, Manchester Royal Eye Hospital