projection depends just on stable anatomic landmarks. Moreover, a differential map displays the differential light threshold for static and kinetic tests allowing to monitor disease progression. Mean differential light threshold value and standard deviation in dB are also reported.

The increasing role of microperimetry examination in most macular disorders, and the increasing use of old or new morphologic diagnostic tests of the same retinal areas (ßuorescein and indocyanine green angiography, fundus autoßuorescence, and OCT) makes it possible to integrate all available information. Therefore, it is possible to import in the MP1 microperimeter all retinal images of the same eye taken with any of the above mentioned methods and to obtain an exact and fully reliable overlap of the threshold sensitivity map and Þxation parameters with the original image.

11.2.5 Other Microperimeter

Recently, two new microperimeters became available. The Þrst one is a LCD microperimeter, with the same background and stimulation characteristics as the MP1 microperimeter, combined with a SLO/OCT (SLO/OCT, Opko, USA). With this system it is possible to overlap the mean retinal sensitivity map (interpolated map) with an IR image or the SLO/OCT map. Unfortunately, it lacks the color fundus photograph, thus the overlap of retinal sensitivity and anatomic details or an OCT thickness map is mainly an integration of mean values. The second instrument is a SLO microperimeter (MAIA, Centervue, Italy), with improved imaging compared to an old SLO microperimeter, wider sensitivity range (0Ð34 dB; previously unavailable) and a very efÞcient software, however, without the possibility of overlapping onto a color fundus photograph (except if taken with a different instrument). Normative agerelated data are available, and have been proposed as a screening test for early AMD eyes.

11.3Microperimetry in AMD

In the earlier phases of AMD, patients report difÞculties with the visual activities of daily life compared to age-matched individuals with a healthy retina, even if their far and near visual acuity is normal. If AMD advances, foveal function is progressively

lost (followed by decreased visual acuity) due to the development of geographic atrophy or choroidal neovascularization (CNV). Long-sighted visual acuity is the standard way to measure visual performance in clinical practice, but it poorly describes the functional impact on visual performance in patients with a compromised central visual Þeld due to AMD [10]. A more comprehensive approach to quantify macular function in AMD should be encouraged.

Microperimetry is a non-invasive method to analyze Þxation and central visual Þeld defects. The introduction of microperimetry into clinical research and practice of macular disorders allows us: to better investigate macular function as it strictly relates to macular morphology, to monitor the natural history, and to quantify the beneÞcial or detrimental effects of therapy. The use of microperimetry in clinical studies has provided interesting diagnostic and prognostic information on functional macular changes in AMD patients.

11.3.1 Early AMD

Early manifestations of AMD are characterized by soft intermediate drusen (>63 mm) and areas of changes of the retinal pigment epithelium (RPE), mostly hyperpigmentation. Aging RPE cells show an age-related accumulation of lipofuscin granula as a byproduct of the permanent phagocytosis of lipid-rich distal photoreceptors outer segments. Lipofuscin, responsible for the in vivo fundus autoßuorescence phenomenon (FAF), is considered a biomarker for cellular ageing and a cumulative index for oxidative damage. It is believed that lipofuscin accumulation precedes and induces photoreceptor degeneration, whose functional impact is represented by changes in retinal sensitivity in the central visual Þeld, slower rate of dark adaptation, reduced static and dynamic contrast sensitivity, and Þnally visual acuity changes.

Histopathologic studies examining the retina of eyes affected by AMD have identiÞed cell death, structural, compositional, transcriptional modiÞcations, and morphologic changes in photoreceptors cells directly overlying drusen [11]. Deßection and shortening of rod and cone inner and outer segments with consequent retinal thickness changes have also been documented. This structural retinal change, determined by the degeneration of photoreceptor, may be preceded

Fig. 11.3 Color fundus and fundus autoßuorescence images (a, b) of an eye with large soft drusen and pigment abnormalities with the overlapped sensitivity map. The functional map shows the decrease in sensitivity (relative scotoma is in yellow dots, green is

normal, and red means dense scotoma) over areas with increased fundus autoßuorescence, corresponding to drusen and increased pigmentation

(or followed) by decreased retinal function, rarely or never associated with visual acuity reduction.

In the past, the functional implication of macular drusen was investigated by standard and SLO microperimetry with conßicting results. Recently, the effect of drusen and RPE changes was investigated in detail by Midena et al. [12]. Using MP1 microperimetry, the authors found that macular sensitivity signiÞcantly decreases over large drusen and retinal pigment abnormalities, despite normal visual acuity. When both characteristics are present, the retinal sensitivity reduction is even higher compared to individual lesions. The same authors overlapped microperimetry maps with (blue) fundus autoßuorescence images and were able to show a statistically signiÞcant retinal sensitivity reduction in areas with increased fundus autoßuorescence (Fig. 11.3).

In eyes with early AMD and normal visual acuity time domain OCT also detects a signiÞcant retinal thinning over RPE abnormalities versus areas without pigment abnormalities, as well as over large drusen compared to areas without drusen. The statistical correlation with microperimetry changes is only moderate. This is due to the intrinsic limitation of time domain OCT resolution compared to the high sensitivity of microperimetry in detecting even subtle functional

changes. Recently, using spectral domain OCT, Schuman et al. conÞrmed that retinal thinning over drusen depends on a decrease in the photoreceptor layer; unfortunately, they did not measure retinal sensitivity [13] (Fig. 11.4).

As in early diabetic retinopathy, microperimetry is also in early AMD a precocious biomarker of retinal function alteration. Retinal sensitivity changes develop much earlier than visual acuity changes, and may be even more precocious compared to other metabolic (fundus autoßuorescence) or solely imaging (OCT) techniques. The growing role of retinal sensitivity changes quantiÞed by microperimetry as an end point measurement in the treatment of early AMD conÞrms the importance of retinal function measurement in the integrated therapeutic approach to macular degenerations.

11.3.2 Geographic Atrophy

Geographic atrophy (GA) represents the atrophic latestage manifestation of age-related macular degeneration. GA, which is commonly bilateral, is characterized by the development of areas of retinal pigment epithelium and neural retina atrophy, which slowly progress over time at a median rate of 1.5Ð2.1 mm2 per year [14].

Fig. 11.4 Blue fundus autoßuorescence image (a) and spectral domain OCT linear scan (b) of an eye with large soft drusen. The green line represents the OCT scanned line where corresponding retinal sensitivity is shown by colored squares (green: normal; yellow: relative scotoma). A reduction of retinal sensitivity

is shown (yellow dots) over an area with increased fundus autoßuorescence (a, white arrow), corresponding to soft drusen and abnormalities of photoreceptor inner segment/outer segment retinal layer on OCT (b, white arrow)

The areas of GA are characterized by a dense scotoma whose extension corresponds to the atrophic area. Therefore, the progression of GA is always associated with progressive loss of visual function [14]. Atrophic areas initially occur in the parafoveal retina, and patients are unaware of their functional condition. Over time, several atrophic areas may coalescence and new atrophic areas may occur.

In more advanced stages, atrophic areas form an atrophic ring around the fovea, which can remain stable for a long time, a phenomenon known as Òfoveal sparingÓ [15]. As long as the foveola remains unaffected, retinal Þxation maintains central and stable (Fig. 11.5). This means that even a small residual area of retinal sensitivity is useful for Þxation in patients with progressive atrophic lesions due to AMD, as well as in other slowly progressive atrophic disorders involving the macula [16].

Fixation patterns in eyes with GA and central scotoma were studied in detail by Sunness et al. [17]. Using SLO microperimetry, Sunness et al. looked at the location of the preferred retinal locus (PRL) in patients with GA who had lost foveal function and had a visual acuity in the 20/80Ð20/200 range. The PRL is located at the edge of the main area of atrophy, presumably because this location is closer to the foveal region, thus providing

Fig. 11.5 Fixation site of a patient with geographic atrophy secondary to AMD. The site of Þxation is located in a small residual foveal area which is still spared by atrophy

the best functional result. However, the position of the central scotoma relative to the PRL is a determing factor in the choice of the PRL location. For patients with GA, the preferred Þxation pattern is to place Þxation in such a position that the scotoma is on the right side of

Fig. 11.6 Fundus autoßuorescence image with overlapped sensitivity map in a patient with geographic atrophy secondary to AMD. A dense scotoma (empty red little squares), corresponding to the hypoautoßuorescent area due to atrophy, is visible

the visual Þeld. The second adaptation choice, which is always visual cortex controlled, is to have the scotoma above the Þxation. This phenomenon is partly readingdriven, to prevent that the left-to-right reader has the scotoma projected over the beginning of the text.

The long-term follow-up of these patients showed that most of them retained the Þxation pattern developed at the baseline visit [17]. The progressive enlargement of GA is usually assessed by color fundus photographs. Recently, FAF imaging has been shown to accurately monitor GA progression [18, 19]. Dense scotoma corresponds to hypoßuorescent areas, as documented by FAF imaging. (Fig. 11.6) Moreover, an abnormal autoßuorescence pattern in the junctional zone of GA (the area between atrophy and normal retina, on FAF) has been demonstrated using confocal SLO [18]. Areas of increased FAF in the junctional zone precede the enlargement of preexisting atrophy and the development of new atrophic patches over time [18].

Fine matrix visual Þeld mapping of junctional regions showing increased FAF documented a severe reduction in scotopic sensitivity, with moderate reduction in photopic sensitivity [20]. Schmitz-Valckenberg et al. using SLO microperimetry, found reduced retinal sensitivity in the areas of increased FAF bordering GA compared to areas with normal FAF [21]. This Þnding suggests that pathologic lipofuscin accumula-

tion in the RPE surrounding areas of GA has reduced retinal sensitivity as a functional correlate. However, reduced retinal sensitivity may directly depend on alterations in photoreceptor function along the border of GA, as recently hypothesized by Bearelly et al. [22]. Preliminary data also suggest that near-infrared fundus autoßuorescence better correlates to retinal sensitivity changes compared to blue FAF [23]. Therefore, the GA model shows that retinal sensitivity, whose reliable detection in the macular area is only possible using microperimetry, is one of the best biomarker (with FAF) to detect the progression of this disease and evaluate the efÞcacy of any therapeutic approach. The role of spectral domain OCT as imaging biomarker of GA is still under investigation.

11.3.3 Neovascular AMD

Visual impairment in eyes with neovascular AMD is related to the progressive deterioration of retinal Þxation and macular sensitivity, followed by visual acuity changes (Fig. 11.7). The functional deterioration is documented by decreased Þxation stability, loss of central Þxation, and impaired retinal sensitivity with the development of a dense central scotoma, accurately quantiÞed by microperimetry. When barely detectable (with any imaging technique) neovascular AMD develops, the macula functionally shows the inability to maintain a preferential Þxation within the fovea, until PRL becomes totally eccentric. Eccentric Þxation develops very early in neovascular AMD, showing a fully different functional behaviour compared to GA, and diabetic macular edema [24]. In neovascular AMD, the Þxation pattern also deteriorates with increasing duration of symptoms. From a functional point of view, time is a crucial factor in neovascular AMD, and this parameter should be adequately considered when planning treatment timing.

In eyes with subfoveal CNV due to AMD, Fujii et al. observed that Þxation was central in 75% of eyes, poorly central in 15%, and eccentric only in 9% of the cases, as measured by SLO microperimetry [25]. It was stable in 42%, relatively unstable in 39%, and unstable in 18% of the cases. A more detailed analysis showed that if duration of symptoms was <3 months, the Þxation pattern was better (central and stable in 89% and in 58%, respectively). Using MP1 microperimeter, Midena et al. reported a higher rate of eyes with unstable and eccentric Þxation in patients affected by AMD

Fig. 11.7 Linear scan spectral domain-OCT (a), fundus autoßuorescence image (b) and spectral domain-OCT map (c) with overlapped sensitivity map (d) in an eye with occult chor-

oidal neovascularization secondary to AMD. A reduction of retinal sensitivity (yellow dots) is detected over the neuroretinal detachment

with subfoveal CNV, with symptoms lasting more than 9 months [26]. A relatively unstable or unstable Þxation was present in 35.6% and 38.4% of eyes, respectively. Fixation was poorly central and predominantly eccentric in 15.1% and 63% of eyes, respectively. No statistically signiÞcant difference in location and stability was observed between classic and occult CNV. Moreover, PRL even if eccentric may be stable.

Midena et al. observed that the eyes with eccentric, but more stable Þxation were those with a longer duration of symptoms [26]. This means that the visual system needs time to develop an extrafoveal but stable PRL, and visual (cortex-driven) adaptation is a longlasting process. As in eyes with GA, also in neovascular AMD PRL shows preferred locations. Midena et al. analyzing Þxation patterns in eyes with advanced neovascular AMD, observed that the PRL was located above the neovascular net in most of the cases, thus allowing the projection of the scotoma in the superior visual Þeld and maintaining a functionally efÞcient

inferior visual Þeld [26]. Guez et al. also reported a preferential location of the PRL: superior-temporally to the fovea in the right eye and superior-nasally to the fovea in the left eye [27]. This observation, which is now widely accepted, conÞrms the importance of PRL location for reading (as previously mentioned) and everyday visual tasks.

In patients with neovascular AMD, the presence of several anatomic abnormalities, including neurosensory retinal detachment, subretinal hemorrhage, RPE hyperplasia, RPE atrophy or detachment, and CNV net determines the reduction of retinal sensitivity (from a relative to a dense scotoma). The size of the dense (also called absolute) scotoma correlates with reading ability and reading speed [28]. Chorioretinal scar, retinal pigment epithelium atrophy, and CNV are the major anatomic lesions correlated with dense scotoma in eyes with advanced neovascular AMD. The presence of an absolute scotoma over the CNV conÞrms the histopathologic observation that most of