Spectral domain optical coherence tomography (SD-OCT) is a common useful noninvasive imaging instrument which is used for the diagnosis and follow-up of macular disorders. The clinical findings by OCT in these pathologies are well known. Currently, due to the development of this technology and its wide use, new OCT findings have been reported in the literature. The aim of this chapter is to describe new pathological or abnormal signs and findings in SD-OCT, including hyperreflective spots or dots, flyer saucer sign, outer retinal tubulations, dipping sign, focal choroidal excavation, outer retina-choroid complex splitting, foveal pseudocyst, brush border pattern, dome-shaped macula, pearl necklace sign, choroidal macrovessel, cystoid foveal degeneration, and disorganization of the retinal inner layers (DRIL).
- hyperreflective spots
- perifoveal cupping
- flyer saucer sign
- dipping sign
- outer retina-choroid complex splitting
- foveal pseudocyst
- brush border pattern
- dome-shaped macula
- pearl necklace sign
- disorganization of the retinal inner layers
Spectral domain optical coherence tomography (SD-OCT) is a common useful noninvasive imaging instrument which is used for the diagnosis and follow-up of macular diseases, such as age-related macular degeneration (AMD), diabetic macular edema (DME), epiretinal membrane (ERM), or macular hole. The clinical findings by OCT in these pathologies are well known. SD-OCT allows detail assessment of the retinal thickness and morphologic evaluation of the retinal layers. Currently, due to the development of this technology and its extensive use, new OCT findings have been reported in the literature. The higher resolution and speed of SD-OCT have improved the accuracy and reproducibility of macular imaging and have allowed an enhanced assessment of the integrity of the outer retinal bands.
2. New landmarks in OCT
OCT imaging is similar to ultrasonography, except that it uses infrared light reflections instead of acoustic waves. The OCT image is displayed using a false color map that corresponds to detected backscattered light levels from the incident light. White and red colors represent high reflectivity signals, while the low reflectivity signals correspond to black and blue colors . OCT interpretations make necessary knowledge of the normal anatomy of the retina. In a usual SD-OCT scan, a highly scattering layer delineates the posterior boundary of the retina and corresponds to the retinal pigment epithelium (RPE) and choriocapillaris complex. The nerve fiber layer is manifest as a highly backscattering red layer at the vitreoretinal interface. Both layers are the posterior and anterior boundaries of the sensory retina and are essential to quantify the neurosensorial retinal thickness . The rest of the layers of the neurosensorial retina are disposed between the two limits, and they are observed with OCT in a similar way to a histological section. The high reflectivity signal (yellow and red colors) come from the retinal nerve fiber layer (RNFL), inner plexiform layer, outer plexiform layer (OPL), internal limiting membrane (ILM), junction between inner and outer segments of photoreceptors (IS/OS), and RPE and choriocapillaris complex. The low reflectivity signals (black and blue colors) correspond to the nuclear layers . In 2014, an international panel of OCT experts agreed on the adequate nomenclature for the retinal layers as visualized on OCT . The new terminology of the outer retinal bands and their anatomical correspondence are described below, from the innermost to the outermost (Figure 1) [4, 5]:
The external limiting membrane band (ELM) is located at the boundary between the nuclei (cell bodies) and the inner segments of the photoreceptors and comprises clusters of junctional complexes between the Müller cells and the photoreceptors.
The ellipsoid zone (EZ), which was previously referred as the photoreceptor inner segment/outer segment (IS/OS) junction, is considered to be formed mainly by mitochondria within the ellipsoid layer of the outer portion of the inner segments of the photoreceptors. In a normal fovea, the distance from the EZ line to the ELM line is shorter than that from the EZ line to the RPE. The EZ “elevation” in the foveal center is due to elongated foveal cone outer segments.
The interdigitation zone (IZ) is considered to be the contact cylinders formed by the apices of the RPE cells that encase the part of the cone outer segments. This layer is not always recognizable from the underlying RPE layer, even in healthy subjects.
The retinal pigment epithelial band is formed by the RPE and Bruch’s membrane. Both structures are indistinguishable from each other using the currently commercial SD-OCT. In the fovea, this band is thicker compared to other regions, which indicates that choroidal structures may also participate in the hyperreflectivity of the RPE band at this location.
Recent publications have reported that the damage or the alteration of the photoreceptors supposes a loss of integrity of some of these four bands previously described [6, 7]. Series of OCT images in different phases of degenerative diseases of the retina have demonstrated that IZ, EZ, and ELM lengths are highly correlated with each other. The affectation seems to occur in a stepwise sequence: first at the IZ, followed by the EZ, and finally the ELM band [7, 8, 9]. Similarly, photoreceptor restoration seems to occur in the reverse order. After closing a macular hole, it has been documented that the ELM zone is the first structure to recover, and its recovery has been considered a sign of intact Müller cells and photoreceptor cell bodies . Also, OCT findings after ERM and macular hole surgeries showed that recovery of EZ line only occurred in areas with intact ELM, and IZ recovery was only observed in eyes with EZ and ELM uninjured [11, 12]. The recovery of the ELM line following treatment has been correlated with visual acuity outcomes for macular hole [11, 13], retinal detachment , and AMD . After macular hole closure, the presence of injured ELM was associated with reduced visual acuity . In retinal detachment (RD), preservation of the ELM line postoperatively was related with better visual acuity result and also seems to predict the subsequent restoration of the photoreceptor layer . Disruption or absence of the EZ line has been shown to correlate with visual acuity and severity in several retinal diseases . In nonneovascular AMD, disruption of the EZ has been associated with visual impairment [15, 16, 17]. Furthermore, retinal sensitivity in patients with geographic atrophy was significantly higher in areas with an uninjured EZ . In neovascular AMD, intact EZ at baseline was reported as a favorable prognostic factor for visual acuity outcome following intravitreal anti-vascular endothelium growth factor (anti-VEGF) treatment . In diabetic patients with macular edema, the EZ disruption at the fovea was reported as a significant predictor of visual acuity [19, 20]. In eyes with ERM, preoperative disruptions of the EZ line were also associated with poorer visual acuity outcomes [21, 22, 23]. The IZ line is very difficult to identify even in healthy subjects. A correlation between the postoperative status of IZ and visual acuity has been described for macular hole , ERM , and RD . Gharbiya and collaborators reported that the integrity of the IZ line was the strongest predictor of visual acuity outcome after primary RD repair (Figure 2) . Following macular hole surgery, patients with irregular or discrete IZ line had significantly better visual acuity compared with those eyes with a disrupted or absent IZ line at the one-year visit follow-up . In recent years, new OCT findings and signs have been reported for different retinal diseases. We will describe them with more clinical relevance.
3. New findings and signs
3.1 Hyperreflective retinal spots (HRS)
Coscas and cols were the first authors to report the presence of HRS on SD-OCT in exudative AMD . These dots are described as small in size (20–40 μm in diameter), punctiform hyperreflective elements (equal or higher reflectivity than the RPE band), distributed throughout all retinal layers. HRS are mainly located at the border of the ONL and within the OPL . They have also been reported in early stages of DR and also in diabetics without any clinical sign of DR, DME, retinal venous occlusion (RVO), central serous chorioretinopathy (CSCR), macular telangiectasias, and certain types of uveitis (Figure 3) . It has been hypothesized that HRS represent aggregates of microglial activated cells and could indicate a retinal inflammatory response. Therefore, it has been reported reduction of HRS number following intravitreal anti-VEGF or dexamethasone therapies . There are various theories on the pathogenesis of HRS. Some authors hypothesize that HRS are focal pigment accumulations of lipofuscin granules. Others consider that there could be small intraretinal protein or lipid deposits/exudates secondary to the breakdown of the blood-retinal barrier in retinal vascular diseases [26, 27, 28, 29, 30]. According to other theory, HRS might be derived from the degenerated photoreceptors or from the macrophages that phagocyted them . Concerning the clinical implications of the HRS, we have already commented that they represent a certain degree of retinal inflammation. HRS are associated with poorer visual outcome in patients with macular edema due to retinal vascular diseases such as RD or RVO. The therapeutic response to specific treatments might be different according to the number of HRS. Hwang et al. reported an inadequate response to intravitreal bevacizumab for DME and macular edema due to RVO in eyes with a greater number of HRS. Eyes that responded poorly to bevacizumab were treated with dexamethasone implants. About 75% of such eyes showed a good response and corresponded to the eyes with a higher number of HRS . Vujosevic and cols have also suggested that DME with a high number of HRS and a large area of increased foveal autofluorescence showed better morphologic and functional results (better retinal sensitivity) if, at least initially, was treated with intravitreal steroids versus anti-VEGF . These findings suggest that in eyes with several HRS, the inflammatory pathway might contribute to the pathogenesis of the macular edema more than the VEGF pathway. Therefore, in patients with macular edema and many HRS, anti-inflammatory drugs (e.g., dexamethasone intravitreal implant) might be more effective than intravitreal anti-VEGF treatment .
3.2 Flying saucer sign
The use of hydroxychloroquine (HCQ), an antimalarial drug utilized for a range of rheumatologic and dermatologic diseases, is associated with a low incidence of retinopathy (1% after 5 years) when used at recommended doses (<6.5 mg/kg/day) . However, the retinopathy described as a bull’s-eye is untreatable and tends to progress even after cessation of the drug. In recent years, there is an increased interest in screening by using multimodal imaging techniques to detect early signs of retinal toxicity. SD-OCT may detect significant structural alterations before the development of visible HCQ retinopathy. Several OCT findings have been described in the literature such as disruption of the EZ line, loss of the ELM, parafoveal thinning of the ONL, and RPE damage. These studies suggest that there is a foveal resistance to HCQ damage as demonstrated by the preservation of the subfoveal outer retinal layers. This foveal sparing originates the “flying saucer” sign on HCQ retinopathy (Figure 4) . The main characteristics of this sign include the loss of the normal foveal depression, perifoveal thinning of the ONL, an ovoid appearance of the central fovea, conservation of the outer retinal structures and photoreceptor IS/OS junction in the central fovea, an apparent posterior displacement of the inner retinal structures toward RPE, and perifoveal loss of the photoreceptor IS/OS junction . All these alterations originate an ovoid appearance in the central fovea . This sign is neither pathognomonic nor necessary for the diagnosis of HCQ retinopathy. Nevertheless, its visualization on SD-OCT images should alert us to possible retinal toxicity due to HCQ toxicity.
3.3 Outer retinal tubulation (ORT)
ORT is a degenerative process of outer retinal reorganization located primarily in eyes where the macula is disrupted and RPE is absent. ORTs are ovoid or circular hyporeflective lesions surrounded by a hyperreflective ring always located in the ONL in eyes with advanced outer retinal diseases (Figure 5) . It has been described in numerous retinal disorders showing macular atrophy involving RPE, such as AMD , mitochondrial diseases , and retinal dystrophies . They have also been reported in cases of macular neovascularization including AMD, choroidal nevus, pseudoxanthoma elasticum , multifocal choroiditis with uveitis and CNMV, choroideremia , and enhanced S-cone syndrome . Histologic studies showed interconnecting tubes of surviving cone photoreceptors interleaved with and contained by processes of Müller cells . Histologically, the hyperreflective border of ORS seen in SD-OCT images corresponds with the presence of both an EML delimiting the lumen and mitochondria migrating from the inner segments to the cell bodies of degenerating cone photoreceptor. The main histologic characteristics of ORTs are :
location at the level of ONL
presence of an ELM surrounding all or part of the lumen
presence of enclosing radially oriented photoreceptors pointing to the lumen
disruption or absence of the underlying RPE
There are different shapes of ORTs: open, closed, forming, and branching. A branching or pseudodendritic pattern is observed mainly in macular neovascularization, whereas a single tube is more frequent in the border of geographic atrophy . Regarding the etiology of these tubulations, it has been hypothesized to be related to the different shapes of the ELM descent (flat, curved, and reflected). As the RPE begins to atrophy, the ELM descent changes from flat to curved, then reflected to scrolled, and finally, an area of ORT may appear. In this process, Müller cells expand and fill the spaces created by the loss of photoreceptors, as they are the only structure persisting in end-stage of ORT. The presence of a scrolled ELM descent may represent a predictive factor for progression toward ORT. It has been reported that in cases of neovascularization, the progression to ORT experienced a shorter period between the steps of flat and curved ELM than eyes only with atrophic . ORTs have a significant prognostic value since their presence suggests a poor visual acuity. They should be differentiated from intraretinal or subretinal fluid cysts located at the outer retinal layers. Intraretinal fluid cysts in cystoid macular edema (CME) have the arrangement as a petaloid manner, while ORTs are randomly arranged at the macula. Pseudocysts are usually distinguished from ORTs because they are located in the inner nuclear layer. Retinal tubulations are always located at the level of the ONL . ORTs are circular hyporeflective lesions surrounded by a hyperreflective ring. This hyperreflective border is absent in cysts. Likewise, ORTs may contain a few focal hyperreflective spots in contrast to the completely hyporeflective cystoid lesions. The recognition of ORT may avoid unnecessary treatment because it is more refractory to anti-VEGF treatment compared to the cysts. Because outer tubulations tend to change slowly over time, it is unlikely to be associated with an active exudative or inflammatory process. For that reason, they do not require treatment [3, 42]. ORT can also be differentiated from rosettes described in retinoblastoma by their large size, tubular structure, and degenerative instead of developmental nature. In retinitis pigmentosa, there are also rosettes which are distinguished from ORTs by their location outside the macula and absence of degeneration of the underlying RPE .
3.4 Dome-shaped macula
Dome-shaped macula (DSM) is an inward protrusion of the macula as visualized by OCT (Figure 6). Different patterns have been described by OCT: a horizontal or vertical oval-shaped dome and a round dome . DSM was first reported in myopic eyes with posterior staphyloma, but more recently has also been described in patients without staphyloma, emmetropic, or hypermetropic eyes [44, 45]. A variety of hypotheses have been postulated to explain it: an adaptive mechanism to minimize defocus in highly myopic eyes , vitreomacular traction , ocular hypotony , resistance of the sclera to the staphylomatous deformation , or localized choroidal thickening . However, it has been recently indicated that the main problem is the different degrees of scleral thinning in the foveal region [46, 49, 50]. Subretinal fluid (SRF) in the fovea has been associated continuously with DSM in 28.5–66.6% of patients . It may be due to RPE dysfunction  or as a consequence of not uniform scleral thickness that can affect choroidal fluid . Although photodynamic therapy and anti-VEGF agents have been applied, they had no effects in terms of improvement in BCVA and resolution of SRF, because the fluid remained chronic and stable in most of the eyes over time , and it was even spontaneously resolved in 47% of the cases .
3.5 Brush border pattern or elongation of photoreceptor outer segment
Brush border pattern is defined as an accumulation of waste products in the photoreceptor outer segment on the outer surface of the detached neurosensory retina over subretinal fluid (Figure 7). This provides an irregular, serrated, and thicker appearance of the detached neurosensory retina. Other authors denominate it as “elongation of the outer photoreceptor segment”, and it can be found in almost 73–75% of OCT images from patients who suffer CSCR . The loss of the contact between RPE and photoreceptor outer segments that occur in CSCR prevents the waste product of photoreceptors being phagocytosed by RPE . These subretinal proteins or accumulated macrophages with outer photoreceptor segments can be observed as hyperfluorescent white-yellowish precipitates in the retinal examination if they contain precursors of lipofuscin . If this process persists, despite subretinal fluid absorption, subretinal deposits may progress to be permanent with the subsequent poor visual outcome. Complete disappearance of outer segments as observed in very long-standing CSCR correlates with poor visual prognosis .
3.6 Outer retina-choroid complex (ORCC) splitting
Patients at intermediate clinical stages in Best vitelliform macular dystrophy (BVMD) show split in the ORCC by OCT. The ORCC has multiple components, and it is split into subcomponents showing different patterns . Such patterns of ORCC splitting represent the separation between the apical surface of the RPE and photoreceptors causing neurosensory macular retinal detachment (Figure 8) . OCT shows a diffuse, irregular, and thickened ORCC by underlying hyporeflective area .
3.7 Disorganization of retinal inner layers (DRIL)
DRIL is observed on OCT as the difficulty to identify limits between the ganglion cell-inner plexiform layer complex, inner nuclear layer, and OPL (Figure 9). It represents an interrupted transmission pathway between the photoreceptors and ganglion cells due to the disruptions of synaptic connections of amacrine, bipolar, and horizontal cells . Several hypotheses explain the pathogenesis:
3.8 Pearl necklace sign
The pearl necklace sign refers to HRD in a continuous ring around the cystoid spaces in the retina that has been seen in diseases with exudative maculopathy, vascular leakage, and chronic CME such as neovascular AMD, DME, retinal vein occlusion, retinal arterial macroaneurysm, or Coats disease (Figure 10) . The authors speculated that HRD indicated the presence of lipid material from retinal vascular leakage similar to hard exudates. These pearls may represent lipid-filled macrophages along the inner wall of retinal edema . Moreover, it is considered a frequent precursor sign on the location of the hard exudates which appear later. Therefore, this sign can change shape and may resolve under treatment or spontaneously. The presence of pearl necklace sign has not been associated with worse visual acuity in RD .
The pearl necklace sign should be differentiated from ORTs, which are located deeper in the ONL of the retina. In ORT, the ring is continuous and homogeneous, whereas the hyperreflective ring is as small foci in the pearl necklace sign .
3.9 Focal choroidal excavation (FCE)
FCE is a localized depression of the choroid detected only by using OCT, without any evidence of posterior staphyloma or scleral ectasia. It affects Bruch’s membrane-RPE-choriocapillaris line complex line and photoreceptors (Figure 11). Patients are mostly asymptomatic and have good visual acuity. Nevertheless, some lesions may be associated with the development of choroidal neovascular membrane. It has been reported that FCE may appear in certain macular disorders such as CSCR, AMD, ERM, CNVM, polypoidal choroidal vasculopathy, BVMD, Vogt-Koyanagi-Harada disease, punctate inner choroidopathy, focal retinochoroiditis, foveoschisis, torpedo maculopathy, multiple evanescent white dot syndrome, multifocal choroiditis, and combined hamartoma of the retina and RPE . OCT allows to identify retinal and choroidal structures that are affected in the excavation, which usually includes RPE, Bruch’s membrane, EZ line, ELM, and ONL which followed the contour of the FCE. In some cases, it can be appreciated an attenuation or absence of IS/OS junction at the excavation, and ONL was thickened in most conforming eyes . However, the layers from the OPL to the ILM were undisturbed, and also the sclerochoroidal junction appeared reasonably preserved without scleral excavation [72, 73]. FCE may be organized in two patterns, whether or not the photoreceptor layer is detached from the RPE. Thus, conforming FCE describes those types of lesions without separation between the two layers and the photoreceptors adapt to the contour of the RPE layer. On the other hand, in nonconforming FCE, photoreceptors appeared to be detached from the RPE showing a hyporeflective space. Factors contributing to the formation of each pattern are unknown . Other authors have classified the lesions into three morphological patterns based on SD-OCT findings: bowl shaped, cone shaped, and mixed shaped . They observed that all bowl-shaped types showed atrophic changes and RPE irregularities, whereas in cone-shaped FCE, a less atrophic change is detected at the center of the lesion. The pathogenesis of FCE is still unknown. Some authors suggest it could be related to a congenital defect within the choroid, which is supported by the fact that shape and size remained stable during the follow-up in most of the reported cases . Nevertheless, no family history and low prevalence in young people suggest that it may be an acquired condition . Some authors proposed FCE is an entity related to inflammatory diseases like Vogt-Koyanagi-Harada disease, multiple evanescent white dot syndrome, and other types of retinochoroiditis .
3.10 Foveal pseudocyst
Foveal pseudocyst is an OCT pathologic sign that is caused by subretinal retention of perfluorocarbon liquid (PFCL) after vitreoretinal surgery. Subretinal PFCL is a serious complication if it affects fovea. The incidence ranges from 1 to 11% after retinal detachment surgery . Main risk factors for this entity are the presence of a large size retinal tear, large retinotomy (especially in 360°), and retinal traction at retinal breaks . It is rare to find it in conventional surgery, but in these cases, it is usually caused by small bubbles which can be produced by turbulence by the interface between PFCL and saline solution . OCT is a useful tool to identify intraretinal bubbles of PFCL. In many cases, the bubbles remain stable without size changing. The most common signs in OCT are RPE pigment disorganization, disruption of ellipsoid layer, and hyperreflectivity at the base of the PFCL bubble (Figure 12) . It has been reported several cases with retinal hole secondary to long-standing subretinal PFCL . Subretinal PFCL is responsible for retinal damage resulting in loss of visual acuity, scotomas, and retinal thinning. Long-time exposure to PFCL can lead to RPE atrophy, photoreceptor damage because there is a direct toxic defect, or inflammatory response including macrophages phagocyted PFCL . It is recommended to remove PFCL bubbles located beneath the macula or if there is a tendency to move to the macular area .
3.11 Choroidal macrovessel
It is a rare ocular lesion which appears on fundus examination as an abnormal, tortuous vessel deep to the retina. It was first described as a serpiginoid atrophic lesion in the temporal macula, with an orange-red aspect and several unspecific choroidal spots in the posterior pole . Choroidal macrovessel is not associated with acute inflammation and symptoms. Some reports have shown hyperpigmentation of the RPE, debris in the subretinal space, and changes in the outer nuclear layer (ONL) thickness [82, 83]. SD-OCT reveals a tubular structure which shows hyperreflectivity band below RPE representing the superior edge of the lesion, with an elevation of RPE and photoreceptor and posterior shadowing . In recent studies, it has been explored with enhanced-depth imaging spectral domain optical coherence tomography (EDI SD-OCT) showing a vascular structure that traversed the entire choroidal thickness and produces an indentation at the choroidal-scleral junction and the ellipsoid zone (EZ) causing a reduction of the ONL thickness [82, 83]. A differential diagnosis from choroidal macrovessel should be made with subretinal nematode tract, choroidal hemangioma, inflammatory choroidopathy, retinochoroidal anastomosis, vortex varix, and aberrant long posterior ciliary artery [81, 83].
3.12 Dipping sign
It is a pathologic retinal sign that may be appreciated with high-resolution OCT images in some patients with acute CSCR. It is characterized by getting an inverted triangle shape at the outer surface of the detached retina, in those eyes with fibrinous exudate in the subretinal space that protrudes over the RPE . The primary cause of dipping sign seems to be traction due to the fibrinous exudates and the swelling of the ONL. It has been reported that some of the leakage sites (20.3%) show fibrinous exudate as a highly reflective area in the subretinal space, around the leakage site . Additional observations with SD-OCT include thickening of the outer photoreceptor segment layer with invisibility of the inner segment-outer segment junction line and “dipping” of the posterior retinal layer toward the RPE [84, 85]. In later stages, granular deposits may become visible at the posterior surface of the detached retina . It has been documented a decrease in foveal thickness once CSCR is resolved.
3.13 Cystoid foveal degeneration (CDF)
CDF is a rare form of macular pathology that can be precisely diagnosed only with OCT. It is characterized by large cystic spaces, or in some cases, giant single cyst in the fovea. It can occur with or without thinned septa between cystic spaces. Usually, it affects patients with diabetic maculopathy, uveitis, RVO, AMD, associated with Streptococcus constellatus endocarditis, and CSR [3, 86]. The hyperreflective OCT appearance of these lesions, followed by cystic change and permanent visual loss, suggests that they might represent retinal infarctions. Their predilection for the fovea may reflect the high metabolic demand at this area of the retina and the narrow-bore capillaries of the perifoveal vasculature.
This pathology is associated with a distortion of IS/OS layer and loss of outer segment of photoreceptors. In comparison with CME, CDF has a more extensive and multitude cysts. As opposed to CME, although CDF cysts may shrink or disappear, there is a limited improvement in visual acuity . FA and fundus autofluorescence (FAF) are not capable of distinguishing CME from CDF.
Thanks to Antonio Arias Palomero and José Juan Valdés González for the effort of searching some of the images showed in this chapter.
Conflicts of interest
Dr. Ascaso reports nonfinancial support from Topcon and Zeiss. All remaining authors have declared no conflicts of interest. All coauthors have seen and agreed with the contents of the manuscript.
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