the photoreceptors overlying this area show extensive degeneration.

The degree of scotoma also depends on the duration of symptoms. Midena et al. detected a dense scotoma in 63.4% of eyes with neovascular AMD, whereas Fujii et al. in 28% of their population [25, 26]. The main difference between these two studies is the duration of symptoms: Midena el al. quantiÞed the sensitivity pattern in neovascular AMD eyes with symptoms lasting > 9 months, whereas 93% of the patients examined by Fujii et al. had symptoms lasting < 3 months. Moreover, classic CNV shows, at least in earlier phases, lower retinal sensitivity when compared to occult CNV. This functional difference disappears with progressing retinal involvement. Visual system is a plastic neuronal net which may be reorganized after the deactivation of some of its circuits. When both eyes are functionally involved by a dense central scotoma, the pattern of Þxation and the perception of the scotoma begin to change.

Doris et al. analyzing the relation between macular morphology and visual function in AMD patients with CNV, observed that larger lesion size, greater area of classic CNV, and greater distance to healthy retina were associated with poorer distance acuity and worse contrast sensitivity [29]. However, when eyes were divided into two groups depending on whether the study eye was the better or worse eye, only the size of the classic component was signiÞcantly correlated with near and distance acuity. When the study eye was the worse eye, functional correlation was documented with overall lesion size, closely followed by the distance to the healthy retina. This means that in the worse eye visual function is more closely correlated with the morphologic macular damage compared to the better eye, where visual function is better than expected from the morphologic point of view. Therefore, in neovascular AMD, lesions of similar morphology may have a different impact on visual function.

Similar Þndings have been documented in other progressing macular diseases [16]. In patients with bilateral involvement, more stable and central Þxation is detected in the functionally better eye, even if the chorioretinal scar is morphologically similar in both eyes: the fellow eye shows eccentric and unstable Þxation. It seems that an eye may never reach its full potential unless forced to by loss of the fellow eye. This also explains the Þlling-in phenomenon observed in late AMD [30]. This phenomenon has been described as

a Þlling-in of the missing information when part of an image falls on a blind area of the visual Þeld. In AMD patients, the Þlling-in phenomenon depends on the presence of a scotoma, it is not seen in eyes whose fellow eye has good vision, and it is only seen in the preferred eye of patients with bilateral macular disease.

11.3.4 Neovascular AMD: Treatment

In the past, detection of retinal Þxation by SLO microperimetry was proposed before laser photocoagulation of well-deÞned juxtafoveal or extrafoveal CNV secondary to AMD. Manual overlapping of SLO static microperimetry to ßuorescein angiography was also performed. After laser treatment, most eyes demonstrated foveal Þxation unless the fovea was involved by laser scar expansion or the scar itself. Some studies were also performed in neovascular AMD eyes treated with photodynamic therapy. A signiÞcant beneÞt of photodynamic therapy in the preservation of the central visual Þeld was reported using SLO microperimetry [31]. In this study, the Þnal scotoma size was signiÞcantly smaller in the photodynamic treated group compared to the placebo one. In eyes with a foveal PRL at baseline, the threshold of retinal sensitivity at the fovea improved after therapy, resulting in visual acuity improvement. On the contrary, in eyes with a parafoveal or unstable PRL before therapy, the dense scotoma persisted despite complete resolution of exudative manifestations following treatment. However, a short-term choroidal ischemic side effect after photodynamic therapy was demonstrated using indocyanine green angiography.

The inßuence of temporary choroidal hypoperfusion on visual function was studied measuring retinal sensitivity threshold over an area located 500 mm from the treated lesion (perilesional area). A signiÞcant reduction of retinal sensitivity in the perilesional area was documented at 1 week, with nearly complete functional recovery at 1 month [32]. These angiographic and functional Þndings highlighted the potential side effects of repeated photodynamic treatments.

A more recent approach to the treatment of exudative AMD involves the use of locally administered (intravitreal) antiangiogenic drugs (bevacizumab, pegaptanib and ranibizumab). Systemic bevacizumab was found to induce a signiÞcant improvement of

retinal sensitivity, as measured by MP1 microperimetry [33]. In eyes with neovascular AMD, mean absolute scotoma size decreased from 33% to 22% (−11%; P = 0.011) at month 3, and to 23% (−10%, P = 0.123) at month 6 after treatment with systemic bevacizumab. Mean differential light threshold increased signiÞcantly throughout the observation period from 3.8 dB at baseline to 5.5 dB (+1.7 dB; P = 0.012) at month 6. SigniÞcant morphologic and functional efÞcacy was observed as early as 1 week following the Þrst intravitreal ranibizumab injection in neovascular AMD [34].

Bolz et al. investigating morphologic and functional effects of the recommended loading regimen with intravitreal ranibizumab, detected that the mean leakage area by ßuorescein angiography signiÞcantly decreased (p < 0.01) and retinal function by visual acuity measurement and microperimetry signiÞcantly increased (both p < 0.01) after 1 week [34]. However, these authors observed signiÞcant changes in morphology and function only between baseline and 1 week, without signiÞcant additional morphologic or functional beneÞt following the second and third injection.

Parravano et al. in a retrospective 24-week study, aimed at evaluating functional changes after intravitreal ranibizumab (loading phase regimen, followed by retreatment if signs of activity were still present) detected that mean retinal sensitivity signiÞcantly improved from 3.89 ± 3.0 dB at baseline to 6.61 ± 3.4 dB at 24 weeks (P = 0.044) [35]. Mean visual acuity signiÞcantly improved from 48.67 ± 8.58 ETDRS letters to 60.72 ± 16.09 (P = 0.026). Improvement of Þxation stability from baseline was also observed in 33.3% of treated eyes. Optical coherence tomography showed that the central mac-

These results showed that mean central macular thickness at 24 weeks was signiÞcantly related to macular thickness at baseline. However, the changes of functional status were unrelated either to the baseline status or to the observed morphologic changes. These Þndings underline that, after intravitreal ranibizumab injection, functional changes are likely to be inßuenced not only by the extent of intraretinal edema, but also by the preexisting and persisting damage to the photoreceptors induced by prolonged subretinal and intraretinal exudation.

These functional Þndings have been recently conÞrmed even after 24 months by the same group [36] (Fig. 11.8). Moreover, although visual acuity and retinal thickness changes had their peak 4 weeks after treatment, these authors documented that retinal sensitivity showed progressive improvement. After 24 months of follow-up, intravitreal injections of 0.5 mg ranibizumab determined progressive improvement of retinal sensitivity until the last examination, whereas visual acuity changes stopped at 6 months, suggesting that microperimetry provides additional prognostic information about macular function on a long time basis [36, 37]. The functional discrepancy reported by these two groups may be explained by the different types of CNV included in each study. In the Bolz et al. series, 31% of the CNV were predominantly classic, 38% minimally classic, and 31% purely occult. Conversely, in Parravano et al. series, 22.2% of CNV were predominantly classic, 16.6% minimally classic, and 61.1% occult. The higher rate of predominantly or minimally classic CNV treated by Bolz et al. may have negatively inßuenced Þnal functional improvement.

Surgical treatment of neovascular AMD has also been investigated by microperimetry showing poor Þxation after submacular surgery [38]. However, preoperative irreversible damage to the neurosensory retina and intraoperative damage resulting from the separation of CNV from the neurosensory retina cannot be distinguished, since after surgery the fovea was relocated over an area surgically devoid of any pigmentation.

Fuji et al. investigated the use of SLO microperimetry to select patients for limited macular translocation [8]. They found that predominantly central Þxation, stable Þxation, absence of central scotoma, and good preoperative visual acuity were positive predictive values (84%, 91%, 81%, and 87%, respectively) for potential visual improvement after surgery. Among these parameters, central Þxation had the highest sensitivity (87%). Visual recovery after macular translocation surgery or RPE transplantation surgery is thought to be due to recovered function of the neurosensory retina placed onto a healthier RPE. With macular translocation, the retina is moved to the healthier RPE site, while with RPE transplantation surgery healthier RPE/ choriocapillaris is moved beneath the fovea.

To investigate this hypothesis Chieh et al. recently measured mean retinal sensitivity in three different

Fig. 11.8 Microperimetry Þxation site and sensitivity map before (a, b) and after (c, d) three intravitreal injections of anti VEGF (ranibizumab) for choroidal neovascularization secondary to age-

related macular degeneration. Retinal Þxation is central and stable both preand postoperatively, whereas macular sensitivity increases (compare retinal sensitivity in dB, in b vs. d pictures)

areas at the posterior pole after macular translocation, using MP1 microperimetry [39]. The fovea translocated over healthier RPE (Area 1), retina translocated over the site of removed CNV (Area 2) and retina translocated over undisturbed RPE (Area 3) were functionally tested. The sensitivity of the translocated macula (Area 1) was signiÞcantly greater than Area 2, site of the removed CNV, however, was lower than

that of the unaffected retina (Area 3), underlining that persisting retinal dysfunction can limit vision recovery. These Þndings also explain poor visual outcomes after submacular surgery. An accurate microperimetric preoperative investigation should be mandatory to distinguish preexisting irreversible functional damage of the neurosensory retina and to detect the morphologic and functional health of the new RPE/choriocapillaris bed.