PROYECCIÓN DE LA EXPERIENCIA Y LÍNEAS DE CONTINUIDAD.

Historically, AMD has been evaluated clinically using measures of visual acuity, central visual field testing and fundus photography. However, there are a range of new techniques that may be more sensitive to the changes that occur in early AMD. In particular, psychophysical tests of visual function and advanced imaging techniques may be used to detect subtle changes at the macula before they are visible ophthalmoscopically (Neelam et al., 2009).

1.2.6.1. Fundus photography

Digital retinal photography is the primary method used to image the posterior pole in the clinic and in the absence of more advanced imaging techniques is a useful method for detecting AMD and for monitoring its progression (Jain et al., 2006). It has been suggested that colour fundus photographs should be used in conjunction with optical coherence tomography (OCT) to establish the need for treatment of wet AMD (Hibbs et al., 2011).

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Stereoscopic fundus photography is particularly advantageous as it allows appreciation of the height and depth of retinal features. All of the AMD grading systems described in Section 1.2.3 (Page 14) are based solely on the assessment of morphological changes in the eye using colour stereoscopic photographs and templates to aid assessment of lesion size and location (Bird et al., 1995; AREDS, 2001; Davis et al., 2005; Ferris et al., 2005).

1.2.6.2. Fundus angiography (FA)

Prior to the development of OCT imaging, fundus angiography (FA) was the gold standard for evaluating the integrity of the macula (Yannuzzi, 2011). Fluorescein or Indocyanine Green dye is administered via intravenous injection and sequential fundus photos are taken to assess the choroidal and retinal circulation, using filters to excite the molecules within the dye (Lim et al., 2012). Hyperfluorescence caused by leakage of the dye may is indicative of wet AMD and may be classified by location and type (Lim et al., 2012). A classic neovascular lesion is well defined and causes early leakage of dye, whereas an occult lesion is less well defined and does not leak until later.

1.2.6.3. Fundus autofluorescence (FAF)

As discussed (Section 1.2.5.1, Page 19), the prolonged oxidative stress that is associated both with normal ageing and AMD leads to an accumulation of lipofuscin granules in the lysosomal compartments of RPE cells (Wolf, 2003; Roth et al., 2004; Schmitz- Valckenberg et al., 2009). The autofluorescent phosphores within the granules emit a characteristic yellow fluorescence when stimulated with blue light (Heimes et al., 2008; Schmitz-Valckenberg et al., 2009). The development of the confocal scanning laser ophthalmoscope has facilitated the assessment of the distribution of fundus autofluorescence (FAF) in the eye (Midena et al., 2007; Schmitz-Valckenberg et al., 2009). Changes in autofluorescence have been shown to be associated with drusen (vonRuckmann et al., 1997; Delori et al., 2000; Roth et al., 2004), geographic atrophy (vonRuckmann et al., 1997; Holz et al., 2001; 2007), CNVM (vonRuckmann et al., 1997; Spaide, 2003; Silva et al., 2011) and a reduction in visual sensitivity (Midena et al., 2007).

1.2.6.4. Optical coherence tomography (OCT)

Although retinal photography has previously been used to monitor the progression of AMD over time, in the last decade, optical coherence tomography (OCT) has emerged as a

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valuable clinical tool for the analysis of retinal microstructure (Yasuno et al., 2009; Chung et al., 2011; Wood et al., 2011a). This non-invasive technique constructs high resolution cross-sectional images of the retina (Figure 1.10) by using low coherence light to measure the backscattered light from within the tissue (Wood et al., 2011a). OCT is now acknowledged as the standard clinical method for the assessment of AMD in hospital ophthalmology clinics (Drexler & Fujimoto, 2008) and recently, novel algorithms have been developed to allow automated volumetric analysis of drusen, which can be used to assess disease progression over time (Gregori et al., 2011; Yehoshua et al., 2011).

Figure 1.10. OCT images from our laboratory, obtained using a Spectral Domain OCT

operating at 1050nm, showing soft drusen (top panel), geographic atrophy (middle panel) and CNV (bottom panel).

1.2.6.5. Visual acuity (VA)

Visual acuity is the standard psychophysical test of visual function in the clinic. However, there is considerable variation in the best corrected VA attained by patients with AMD, most likely as a result of the heterogeneity of the lesions associated with the disease (Beirne et al., 2006, Sunness et al., 2008). Although advanced AMD is associated with a significant reduction in VA, during the earlier stages of the disease process, VA remains

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relatively unaffected (Klein et al., 1995). As early AMD is typically characterised by the absence of noticeable vision loss (Bird et al., 1995) and foveal vision often remains intact until relatively late in the disease (Sunness et al., 2008), the measurement of VA in isolation has limited diagnostic potential.

1.2.6.6. Visual field testing

During visual field testing, the sensitivity of the eyes is determined at a range of retinal locations, by presenting stimuli of variable intensity. Generally, lower mean sensitivities in the central field have been reported in patients with AMD compared to healthy controls (Midena et al., 1994; 1997; Owsley et al., 2000) and focal sensitivity losses have been recorded over large soft drusen (Takamine et al., 1998; Midena et al., 1997). However, standard automated perimetry is rarely used in the clinical assessment of AMD.

Conventional visual field testing requires stable foveal fixation and is therefore likely to be inaccurate for the precise evaluation of macular disorders (Rohrschneider et al., 2008). In recent years, microperimetry has been used as an alternative technique to evaluate the central visual field in AMD. Microperimetry is based on integrating fundus images with computerised threshold perimetry, in order to correlate fundus lesions to retinal sensitivity (Rohrschneider et al., 2008). The technique has been used effectively to identify and monitor the progression of geographic atrophy (Rohrschneider et al., 2008; Meleth et al., 2011) and to monitor the accumulation of lipofuscin in the RPE cells (Midena et al., 2007). Furthermore, microperimetry has been shown to be a more sensitive measure of visual outcome after antiVEGF therapy than the assessment of visual acuity (Parravano et al., 2010).

The technique classically used to assess the integrity of the central visual field in macular disease is the Amsler grid (Amsler, 1953). The patient is instructed to fixate the centre of a grid pattern presented monoculary and to report any defects or disturbances to the pattern. The chart may also be used by patients to self-monitor their vision at home. A sudden onset of distortion is considered to indicate incipient wet AMD, requiring urgent ophthalmological assessment.

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1.2.6.7. Contrast sensitivity

As discussed (Section 1.2.6.5, Page 25), visual acuity, that is, the highest spatial frequency that may be resolved by the visual system at 100% contrast (Owsley, 2003), is relatively unaffected by early macular disease (Bird et al., 1995; Klein et al., 1995) and there is considerable variation in the best corrected visual acuity attained by patients with advanced AMD (Beirne et al., 2006; Sunness et al., 2008). Consequently the assessment of contrast sensitivity across a range of spatial frequencies has been investigated as a more comprehensive assessment of visual function in AMD.

A range of studies have demonstrated a loss of contrast sensitivity across all spatial frequencies in early AMD, with the most marked reduction at medium and high spatial frequencies (Kleiner et al., 1988; Stangos et al., 1995; Midena et al., 1997; Feigl et al., 2005a; Mei & Leat, 2007; Hahn et al., 2009). This is accompanied by a shift in the peak of the contrast sensitivity function towards lower spatial frequencies (Mei & Leat, 2007). These changes in contrast sensitivity have been shown to correlate with disease severity (Kleiner et al., 1988; Midena et al., 1997).

1.2.6.8. Temporal sensitivity

Temporal vision describes the eye’s ability to detect flickering stimuli (Neelam et al., 2009). A reduction in temporal sensitivity across a range of temporal frequencies has been demonstrated in patients with early AMD compared to control patients (Mayer et al., 1992; 1994; Phipps et al., 2003; Dimitrov et al., 2011), especially at low to mid-temporal frequencies (Mayer et al., 1992; 1994). In addition flickering stimuli may be more sensitive to functional changes in AMD than static stimuli because of the increased metabolic demand placed on the retina by the flicker (Kiryu et al., 1995).

1.2.6.9. Colour vision

The majority of studies that have examined the relationship between colour vision and AMD indicate that colour discrimination deteriorates in early AMD, with tritan defects most commonly recorded (Eisner et al., 1991; 1992; Cheng & Vingrys, 1993; Frennesson et al., 1995; Arden & Wolf, 2004; Feigl et al., 2005a). These defects have been shown to progressively worsen in patients at high risk of developing wet AMD (Eisner et al., 1991; 1992; Arden & Wolf, 2004).

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1.2.6.10. Dark adaptation

Dark adaptation classically refers to the relatively slow recovery of visual threshold that occurs in the dark following exposure to a bright light (Lamb & Pugh, 2004). Patients with early AMD often report visual difficulties when moving from high to low illumination and there is an emerging body of evidence to suggest that dark adaptation is a sensitive biomarker for the disease (Brown & Lovie-Kitchin, 1983; Eisner et al., 1987a; Collins & Brown, 1989; Eisner et al., 1991; Sandberg & Gaudio, 1995; Midena et al., 1997; Owsley et al., 2001; Phipps et al., 2003; Binns & Margrain, 2007; Owsley et al., 2007; Dimitrov et al., 2008; 2011). That is, it is a characteristic that may be objectively measured and evaluated as an indicator of normal and pathogenic biological processes (Puntmann, 2009). In studies that have measured a range of visual functions in patients with AMD, dark adaptation abnormalities appear to be the most sensitive markers for the condition (Eisner et al., 1991; Phipps et al., 2003; Owsley et al., 2001). For example, Eisner et al. (1991), showed that although colour vision and dark adaptation parameters both provided 100% specificity in AMD, the sensitivity of photopic dark adaptation (65%) was superior to that of the colour matching (48%). A comprehensive discussion of the relationship between dark adaptation and AMD is included later in this chapter (Section 1.3.5.3, Page 42).