Fig. 4.1
Parafoveal hyperpigmentation in a patient with retinitis pigmentosa
Fig. 4.2
Wide ring of hyperautofluorescence surrounding area of hypoautofluorescence in same patient as in Fig. 4.1
4.2.3 Bull’s-Eye Maculopathy
Fundoscopic Bull’s-Eye Maculopathy
Bull’s-eye maculopathy (BEM) is a distinctive yet nonspecific macular phenotype characterized by annular atrophy or hypopigmentation of the retinal pigment epithelium (RPE) surrounding the fovea that occurs in various diseases affecting the bipolar cell layer, photoreceptor cell layer, or RPE [12]. BEM was initially described in association with chloroquine retinopathy [13], but now, BEM has also been associated with a heterogeneous group of inherited retinal disorders, including CRD and RP.
In CRD, BEM is often observed, although it often develops into profound macular atrophy over time [6]. In RP, BEM is far less common and has been described in specific forms, including (1) in syndromic RP such as Bardet-Biedl syndrome [14], (2) in nonsyndromic RP (e.g., RPGR-related and IMPG2-related RP) [15–17], and (3) in RP with Stargardt-like maculopathy (Fig. 4.3) [18]. A study in 41 patients with the p.R373C mutation in the PROM1 gene revealed a BEM with large electrophysiological variance: 60 % had macular dystrophy, 36 % had CRD or RP, and 4 % had isolated cone dystrophy [17].
Fig. 4.3
Bull’s-eye maculopathy in a patient with IMPG2-associated retinitis pigmentosa
“Bull’s-Eye” Ring on Fundus Autofluorescence
The hyperautofluorescent ring found in RP patients is thought to represent the transitional zone between abnormal paracentral and normal central photoreceptor outer segment structure, which correlates and delineates the retinal region with visual field preservation (Fig. 4.4) [19–21]. The abnormal autofluorescence may suggest an anomalous high rate of photoreceptor phagocytosis and the changes in the RPE function may be a secondary phenomenon from increased metabolic load on the RPE because of photoreceptor apoptosis. The high load of lipofuscin that causes a maximum intensity of hyperautofluorescence would lead to the RPE atrophy with a subsequent loss of lipofuscin granules [19, 22]. Photoreceptor loss along with RPE atrophy is seen outside the ring and is represented by hypoautofluorescence.
Fig 4.4
Ring of hyperautofluorescence in retinitis pigmentosa
4.2.4 Cystoid Macular Edema
Today, cystic macular edema (CME) represents a known pathologic complication in patients with hereditary retinal degenerations such as RP, X-linked retinoschisis, NR2E3-associated disease (including enhanced S-cone syndrome and Goldmann-Favre syndrome), choroideremia, and gyrate atrophy [23]. CME is characterized by a localized expansion of the macular intracellular and/or extracellular space. The reported prevalence of CME in RP patients varies historically between 8 % and 38 % [5, 7, 24–28]. OCT is highly sensitive for CME and useful for evaluating response to therapy and is more useful than fluorescein angiography (FA) because of a lack of intense fluorescein leakage [29, 30]. On OCT images, CME is represented by increased retinal thickness and the presence of intraretinal low reflectivity characterized as two distinct features: (1) outer retinal swelling represented by an ill-defined, widespread hyporeflective area of thickening and (2) cystic hyporeflective spaces, with high signal elements bridging the retinal layers (Fig. 4.5) [25, 31]. Vitreous traction, as well as epiretinal membranes, probably plays a contributing casual role in the development of CME in RP and other inherited retinal dystrophies [32]. Vitreous abnormalities are well documented in all stages of RP [33–35]. Tangential vitreous traction would potentially lead to a breakdown of the blood-retina barrier and promote the development of CME in retinal dystrophies [36]. In this event, a surgical approach might result in a reduction in CME [32].
Fig. 4.5
Cystoid macular edema in a patient with retinitis pigmentosa type 17
Successful treatment of nontractional CME has been reported with carbonic anhydrase inhibitors (CAIs), which are thought to be effective through their action on the membrane-bound carbonic anhydrase (CA) IV receptors present on the RPE cells (Fig. 4.6) [31, 37, 38]. Moreover, other CAs in different retinal neurons also may play a role. CAIs act both on retinal and RPE cell function by acidifying the subretinal space, decreasing the standing potential, as well as increasing retinal adhesiveness. Retinal adhesiveness probably is enhanced by increasing RPE fluid transport. [39] CAIs therefore decrease the volume of the subretinal space. A significant effect on macular blood flow however has not been demonstrated [40].
Fig. 4.6
Same patient as in Fig. 4.5 after oral treatment with acetazolamide 250 mg three times daily
4.2.5 Epiretinal Membrane
Abnormalities of the vitreous-retinal interface frequently occur in retinal dystrophies [41]. Testa et al. reported 16 % epiretinal membranes in a large Italian cohort of RP patients [7]. ERM was defined as a membrane adherent to the inner retina, which presented as being globally or focally adherent. The diagnosis of ERM by OCT is based on the presence of a green line, with reddish tinges, that runs over the retinal surface, often together with underlying waves in the retinal surface layer due to tractional forces. Depending on the traction and anatomical disturbance of the underlying retinal layers, as well as the burden of symptoms caused by the ERM, there might be an indication for surgery [32].
4.2.6 Macular Atrophy
Macular geographic atrophy is the end-stage observation in CRD and in some forms of RP. In general, earlier and more subtle changes, as described above, precede the geographic atrophy (Fig. 4.7).
Fig. 4.7
Macular atrophy in a patient with retinitis pigmentosa due to IMPG2 mutations
4.3 Macular Changes in Cone Dystrophy
4.3.1 No (Obvious) Macular Abnormalities
In cone dystrophy (CD), 10–20 % of the cases present with no obvious fundus abnormalities at first presentation. Often, the only abnormalities in clinical examination, apart from a decrease in visual acuity, are a reduction of cone potentials on the ERG or abnormal values in multifocal ERG.
However, fundus autofluorescence imaging may reveal subtle central hyperautofluorescence. In case of achromatopsia (although it is stationary, it is often referred to as cone dysfunction), a small central “gap” in the photoreceptor outer segment layer may be apparent on the OCT. [8] New, high-resolution imaging such as adaptive optics may show abnormalities in patients without obvious fundoscopic changes [42].
4.3.2 Pigmentary Changes
Pigmentary changes can be seen in all kind of CD and vary from subtle alterations of the RPE to profound intraretinal pigment deposits due to RPE migration. In our cohort of 139 patients, about 50 % showed pigmentary changes. Most of the CD caused by mutations in the ABCA4 gene show pigmentary changes and may additionally reveal a dark choroid on fluorescence angiography and even small hyperautofluorescent flecks on autofluorescence [11]. It is a matter of dispute whether this phenotype should not be called Stargardt disease. Most of these cases progress into a CRD.
4.3.3 Bull’s-Eye Retinopathy and Macular Atrophy
Bull’s-eye maculopathy represents a heterogeneous group of disorders. The clinical appearance is not helpful in assessing the degree of retinal dysfunction, and the ring of atrophy or hypopigmentation may vary in degrees of eccentricity from the fovea (Figs. 4.8 and 4.9). It is considered distinct from Stargardt maculopathy in which the atrophy is physically discontinuous, as best demonstrated by fundus autofluorescence imaging. The mechanisms by which the degeneration occurs in this striking distribution are not well understood [43]. The appearance may correspond to the pattern of lipofuscin accumulation in RPE cells, which in healthy subjects is highest at the posterior pole and shows a depression at the fovea, thus explaining the annular pattern and central sparing. Furthermore, the small area of central sparing was postulated as being due to a photoprotective effect of the high foveal concentration of luteal pigment. The initially spared center usually becomes involved during the disease, at which point the diagnosis of bull’s-eye maculopathy can no longer be made, and the atrophy is named geographic macular atrophy (Figs. 4.10 and 4.11).
Fig. 4.8
Bull’s-eye maculopathy in a patient with cone dystrophy
