10.1 Introduction
Discrete, well-defined lines of increased fundus autofluorescence (FAF) may occur in various forms of retinal dystrophies [1–12]. These lines usually have no visible corre- late on fundus biomicroscopy or fluorescein angiography and are thought to originate from excessive fluorophore (e.g. in lipofuscin granules) accumulation at the level of the retinal pigment epithelium (RPE) cell monolayer. There is evidence from com- bined functional investigations that these lines reflect the border of impaired retinal sensitivity [2–4, 8–10]. Despite the variable orientation of this line in different enti- ties—such as orientation along the retinal veins in pigmented paravenous chorio- retinal atrophy (PPCRA) or a ring structure in retinitis pigmentosa (RP) or cone-rod dystrophy (CRD)—the similar appearance on FAF images and the concordance of functional findings indicate that these lines in heterogeneous diseases entities share a common underlying pathophysiologic mechanism.
10.2
Different Orientation of Lines of Increased FAF 10.2.1
Orientation Along Retinal Veins
Orientation of such a line along retinal veins can be observed in patients diagnosed with PPCRA (Figs. 10.1a). The phenomenon of orientation of the progressive atrophy of deep retinal layers including the RPE and the choriocapillaris along anteriorly lo- cated larger retinal venous vessels is obscure. It may be speculated that the topographic distribution of the deep changes results from a release of cytokines from vascular cel- lular elements, and thus “communication” with anatomic levels beneath the inner retina may play a role. It is remarkable that the orientation of the line of increased
Discrete Lines of Increased Fundus Autofluorescence in Various
Forms of Retinal Dystrophies
Monika Fleckenstein, Hendrik P.N. Scholl, Frank G. Holz
10
FAF along the retinal veins of eyes at more advanced stages of PPCRA (Fig. 10.1a, left eye) finally appears to result in the formation of a ring-like structure in the parafoveal region. This finding may also indicate a related pathomechanism leading to formation and constriction of the parafoveal ring in RP.
10.2.2 Ring Shape
A line of increased FAF in the form of a parafoveal ring of variable eccentricity has been described in patients with RP [1–4, 8–11] (Fig. 10.2a), Leber’s congenital amau- rosis (LCA) [5], CRD [6, 7, 9, 11], and X-linked retinoschisis (XLRS) [12].
A ring of increased FAF can be detected in some patients with RP and normal visual acuity and has been demonstrated to surround areas of normal FAF. In some patients, the ring has been shown to constrict progressively over time [10]. It is still unknown why such a ring is not found in all patients with RP who demonstrate clini- cal evidence of macular sparing. Two LCA patients exhibiting a ring of increased FAF have recently been described [5]. Despite severe visual impairment, the ring is surrounded by almost normal FAF. By contrast, in the reports on a ring of increased FAF in CRD [6, 7, 9, 11], and XLRS [12], respectively, the ring has been reported to encircle areas of reduced or absent FAF, corresponding to macular atrophy.
10.3
Functional Correlate of Lines/Rings of Increased FAF
Functional analyses of the line/ring of increased FAF have been performed in RP [3, 4, 8–10] and CRD [9].
In RP it has been demonstrated that patients with larger FAF rings also had larger central visual fields [3, 4, 8, 10]. Furthermore, Robson and colleagues first showed a high correlation between the pattern electroretinogram (ERG) P50 amplitude—
a valuable indicator of macular function—and the size of the abnormal ring [3]. Us- ing fine matrix mapping, they could further demonstrate that photopic sensitivity was preserved over central macular areas, but there was a gradient of sensitivity loss over high-density segments of the ring and severe threshold elevation outside the arc of the ring. Scotopic sensitivity losses were more severe, and they encroached on areas within the ring [4].
Popovic and co-workers confirmed by fundus perimetry that retinal sensitivity was preserved within the ring and was lost outside the ring regardless of whether the FAF pattern was normal or whether atrophic lesions of the RPE were already present or not [8]. (Fig. 10.2c shows the fundus perimetry in a patient with autosomal-dominant RP.)
It has been concluded that the ring of increased FAF in RP demarcates areas of preserved central photopic function and that constriction of the ring may mirror pro- gressive visual field loss by advancing dysfunction that encroaches over areas of cen- tral macula [3, 4, 10].
There are few reports about rings of increased FAF in CRD [6, 7, 9]. In the major- ity of these patients, the ring encircles areas of central atrophy (Fig. 10.3a). Functional assessment has been performed in only a few patients with CRD [9]: Robson et al.
could demonstrate that the pattern ERG P50 amplitude was inversely related to the size of the FAF ring; by fine-matrix mapping they revealed a gradient of sensitivity loss across the arc of increased FAF.
In a patient with macular dystrophy (Fig. 10.3), who displayed a ring of increased FAF that surrounded areas of decreased/absent FAF, fundus perimetry revealed (Figs.
10.3c) that within the ring, independent of a normal or abnormal FAF signal, there was light sensitivity loss. Outside the ring, the FAF signal and light sensitivity were almost normal. These findings were exactly opposite to the findings in RP where the central sensitivity was preserved (Fig. 10.2c).
Despite a different orientation of the line in PPCRA, fundus perimetry has re- vealed that the area with impaired sensitivity exceeded the area of RPE cell loss and was precisely delineated (Figs. 10.1c). In the central retina and in the periphery that was not framed by the line, the FAF signal was normal, and light sensitivity was pre- served. Within the area outlined by increased FAF, independently of a normal or ab- normal FAF signal, there was impaired light sensitivity. These observations are in accordance with the findings in RP whereby the ring or line of increased FAF repre- sented the border between functional and dysfunctional light sensitivity.
At this interface, there may be a higher phagocytic and, thus, metabolic load of the corresponding RPE cells, with subsequent excessive accumulation of fluorophores in the lysosomal compartment resulting in a line of increased signal that can be visual- ized by FAF imaging. It is remarkable that the FAF signal on both sides of this de- marcation line in most of these cases was normal or near normal (Figs. 10.1a, 10.2a, 10.3a), although on one side, there was impaired sensitivity.
Robson and colleagues suggested that restoration of normal FAF intensity over concentric areas outside the ring in RP may indicate continued but possibly impaired phagocytosis and removal of abnormal material, or that it could be explained by loss of photoreceptor cells [3, 4, 10]. Scholl et al. concluded that normal or near-normal FAF may be present in areas of photoreceptor dysfunction and that a normal FAF re- flects the presence of structurally intact photoreceptors and the integrity of the photo- receptor/RPE complex rather than normal photoreceptor function [5].
In the few histopathological reports from eyes with RP, it has been noted that des- pite obvious photoreceptor degeneration, the RPE may display only minor morpho- logical abnormalities. It was hypothesised that there is a high capacity of the “young”
RPE to compensate for excessive photoreceptor cell degeneration before the RPE cell layer eventually suffers collateral damage and, finally, cell death [13].
It remains unknown whether such areas could be prevented from progressive cell death; they therefore represent potential targets for future therapies designed to re- store vision at the photoreceptor level.
In summary, a line of increased FAF in various retinal dystrophies appears to rep- resent the demarcation of impaired retinal sensitivity, independent of its orientation and the localisation of phatologic alterations. This phenomenon may therefore rep- resent a non-specific finding in different disease entities and points to a common downstream pathogenetic pathway.
References
von Rückmann A, Fitzke FW, Bird AC, Autofluorescence imaging of the human fundus. In:
Marmor MF, Wolfensberger TJ (eds) (1998) The retinal pigment epithelium. Oxford Univer- sity Press, Oxford
Holder GE, Robson AG, Hogg CR, et al. (2003) Pattern ERG: clinical overview, and some observations on associated fundus autofluorescence imaging in inherited maculopathy. Doc Ophthalmol 106:17–23
Robson AG, El-Amir A, Bailey C, et al. (2003) Pattern ERG correlates of abnormal fundus autofluorescence in patients with retinitis pigmentosa and normal visual acuity. Invest Oph- thalmol Vis Sci 44:3544–3550
Robson AG, Egan CA, Luong VA, et al. (2004) Comparison of fundus autofluorescence with photopic and scotopic fine-matrix mapping in patients with retinitis pigmentosa and normal visual acuity. Invest Ophthalmol Vis Sci 45:4119–4125
Scholl HP, Chong NH, Robson AG, et al. (2004) Fundus autofluorescence in patients with leber congenital amaurosis. Invest Ophthalmol Vis Sci 45:2747–2752
Ebenezer ND, Michaelides M, Jenkins SA, et al. (2005) Identification of novel RPGR ORF15 mutations in X-linked progressive cone–rod dystrophy (XLCORD) families. Invest Ophthal- mol Vis Sci 46:1891–1898
Michaelides M, Holder GE, Hunt DM, et al. (2005) A detailed study of the phenotype of an autosomal dominant cone–rod dystrophy (CORD7) associated with mutation in the gene for RIM1. Br J Ophthalmol 89:198–206
Popovic P, Jarc-Vidmar M, Hawlina M (2005) Abnormal fundus autofluorescence in relation to retinal function in patients with retinitis pigmentosa. Graefes Arch Clin Exp Ophthalmol 243:1018–1027
Robson A, Michaelides M, Webster A, et al. (2005) Comparison of pattern ERG, multifo- cal ERG and psychophysical correlates of fundus autofluorescence abnormalities in patients with cone–rod (RPGR, RIM1) or rod–cone dystrophy [ARVO abstract]. Invest Ophthalmol Vis Sci 43:552
Robson AG, Saihan Z, Jenkins SAm et al. (2006) Functional characterisation and serial im- aging of abnormal fundus autofluorescence in patients with retinitis pigmentosa and normal visual acuity. Br J Ophthalmol 90:472–479
1.
2.
3.
4.
5.
6.
7.
8.
9.
10.
Wabbels B, Demmler A, Paunescu K, et al. (2006) Fundus autofluorescence in children and teenagers with hereditary retinal diseases. Graefes Arch Clin Exp Ophthalmol 244:36–45 Tsang SH, Vaclavik V, Bird AC, et al. (2007) Novel phenotypic and genotypic findings in X- linked retinoschisis. Arch Ophthalmol 125:259–267
Farber DB, Flannery JG, Bird AC, et al. (1987) Histopathological and biochemical studies on donor eyes affected with retinitis pigmentosa. Prog Clin Biol Res 247:53–67
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12.
13.
Fig. 10.1 FAF image (a), fundus photograph (b), and fundus perimetry (shown with colour-coded scale) superimposed on the FAF image (c) in a patient with bilateral PPCRA. A line of increased FAF that is oriented along the retinal veins can be detected (a) that shows no prominent correlate in fundus photography (b). In the left eye, this line almost merges to a ring-like structure in the para- foveal region (a, right side). Fundus perimetry reveals that this line almost pre- cisely reflects the border of preserved light sensitivity; on both sides of this line, the FAF signal is normal/near normal; however, on one side there is severely impaired light sensitivity (c)
Fig. 10.2 FAF image (a), fundus photograph (b), and fundus perimetry (shown with colour-coded scale) superimposed on FAF image (c) in a patient with bilat- eral autosomal-dominant retinitis pigmentosa. The ring of increased FAF sur- rounds an area displaying a normal FAF signal (a). Fundus perimetry reveals normal light sensitivity within the ring. Despite a normal FAF signal outside this ring, there is severely impaired light sensitivity (c)
Fig. 10.3 FAF image (a), fundus photograph (b), and fundus perimetry (shown with colour-coded scale) superimposed on FAF image (c) in a patient diagnosed with bilateral macular dystrophy. The ring of increased FAF encircles an area that clearly shows reduced FAF centrally and a normal FAF signal between the centre and the ring of increased FAF (a). Within the ring, there is severely im- paired light sensitivity independent of the normal or reduced FAF signal; out- side the ring, sensitivity is almost normal (c)
