**6. Hyperreflective foci**

A concept that came to light with SD-OCTs, that we did not have previously with angiography or retinography, is intraretinal hyperreflective foci (HRF). HRF are well-circumscribed, discrete lesions with an equal or superior reflectivity compared to the RPE band on OCT (**Figure 5**). They are usually associated with hyperpigmentation on color fundus photography. There is an important specific spatial correlation of HRF with the apex of drusen [27] and/or SDD [28]. Additionally, there is an association between HRF overlying drusen and increased risk of atrophy at that location. HRF in eyes with intermediate AMD could be the result of migration of activated RPE cells into the inner retinal layers, as proposed by in vivo OCT study [29].

#### **Figure 5.**

*Hyperreflective foci are observed in the inner (pink arrowhead) and outer retina (orange arrowhead).*

Its development is triggered by a process of gliosis and phagocytosis of the Muller cells, followed by accumulation of decomposed cells in hyperreflective deposits, such as the mechanism observed in MacTel. The debris can be located at the external limiting membrane, external nuclear layer and the plexiform layer. They are biomarkers of poor prognosis, because they reveal that Muller Cells are losing their structure and will collapse [30].

Among patients classified as having intermediate AMD, the choriocapillaris flow deficit is apparently worse in eyes with HRF and is commonly located directly below HRF [31]. The amount of HRF was correlated with EZ normalized reflectivity and drusen volume (DV), that are well-defined markers of photoreceptor damage and AMD progression, respectively. Nassisi et al. [32] evaluated the correlation between HRF quantity and progression to advanced AMD after 1 year. He concluded that the area of HRF measured by en face OCT in eyes with intermediate AMD was highly correlated with development of atrophy [33, 34]*.*

## **7. Acquired Vitelliform lesion**

AVLs are deposits of melanosomes, melanolipofuscin, lipofuscin and outer segment debris located between the RPE and the photoreceptor layer (**Figure 6**). Their pathophysiology may be related to paraneoplastic, toxic, degenerative and vitreoretinal interface disorders of the macula.

AVL were correlated with SDD and cuticular drusen in the past and can occur in conjunction with large drusen. The same dysfunctional processes that lead to drusen formation, or parallel processes, could be related to AVL formation [35].

On fundus exam and SD-OCT, AVLs manifests as yellowish deposits between the EZ or external limiting membrane (ELM) and RPE. On FAF, they appear as areas of hyperautofluorescence that corresponded to the sites where vitelliform material was seen on SD-OCT and fundus exam. In some cases with pseudohypopyon, on FAF it is possible to identify a hypoautofluorescent top portion and a hyperautofluorescent inferior portion. On FA, there is early

#### **Figure 6.**

*Acquired Vitelliform lesion: OCT B-scan detects an accumulation of hyperreflective material between the ellipsoid layer and the RPE. This material (white arrowhead) is located above soft drusen, with discrete thinning of the overlying outer retinal layers.*

hypofluorescence with a halo of hyperfluorescence. A progressive late staining of the lesion was noted during the exam. On red-free imaging studies, AVLs manifest with a slight hyperchromia of the material [36].

The lifecycle of an AVL is characterized by a phase of growth followed resorption and, over time, it can lead to complications as foveal atrophy and choroidal neovascularization (type 1 in 8% of cases). These complications are frequent and can impair central vision. There is a decrease in visual acuity from 0,3 to 0,5 logMAR (2 to 3 lines on log scale) in 7 years. Development of neovascular complexes occurs during the collapse phase of the AVL life cycle, after the AVL peak volume was reached. Type 1 choroidal neovascularization occurs in nearly 10% of cases. The risk of neovascularization and the decline in best corrected visual acuity (BCVA) are both significantly greater among eyes with AMD. Foveal atrophy was the characteristic most significantly associated with final BCVA and with change in BCVA from baseline. The development of neovascularization was not predictive of long-term visual outcomes [37].

### **8. Drusenoid PED**

A drusenoid pigment epithelial detachment (PED) is a large elevation of the RPE that is formed from the coalescence of drusen and colloid material. It is a hallmark feature of AMD and a known precursor of GA. It may be distinguished from hemorrhagic and serous PEDs by its appearance on clinical exam and angiography (**Figure 7**). Drusenoid PEDs have an accelerated growth rate of 0,022 mm3 /month. Additionally, its rate of collapse is 10 times faster: 0,199 mm3 /month, similarly to the observed in AVL. The onset of intraretinal hyperreflective foci and AVL usually precedes its collapse.

Features such as maximal height, volume and diameter of drusenoid PEDs were inversely correlated with visual acuity and directly correlated with the rate of collapse [38].

#### **Figure 7.**

*Drusenoid PED. In this OCT-B scan, it is possible to note a lesion that has an internal homogenous and mild hyperreflectivity. The lesion is delimited by the Bruch's membrane at its base.*
