**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 [1]. 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 [2]. 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 [3]. In 2014, an international panel of OCT experts agreed on the adequate nomenclature for the retinal layers as visualized on OCT [4]. 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]:


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

**67**

**Figure 2.**

*20/30.*

**Figure 1.**

*external limiting membrane.*

*New Landmarks, Signs, and Findings in Optical Coherence Tomography*

*Spectral domain optical coherence tomography (SD-OCT) scan with external retinal landmarks from a healthy subject. RPE: retina pigment epithelium; IZ: interdigitation zone; EZ: ellipsoid zone; and ELM:* 

*SD-OCT in a patient with retinal detachment macula off (A). Post-surgical aspect through OCT of the same patient in which the integrity of the outer layers is observed (B). The visual acuity was* 

*DOI: http://dx.doi.org/10.5772/intechopen.84242*

*New Landmarks, Signs, and Findings in Optical Coherence Tomography DOI: http://dx.doi.org/10.5772/intechopen.84242*

#### **Figure 1.**

*A Practical Guide to Clinical Application of OCT in Ophthalmology*

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 [1]. 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 [2]. 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 [3]. In 2014, an international panel of OCT experts agreed on the adequate nomenclature for the retinal layers as visualized on OCT [4]. 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]:

1.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

2.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.

3.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

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

4.The retinal pigment epithelial band is formed by the RPE and Bruch's

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

the hyperreflectivity of the RPE band at this location.

**2. New landmarks in OCT**

the photoreceptors.

healthy subjects.

**66**

*Spectral domain optical coherence tomography (SD-OCT) scan with external retinal landmarks from a healthy subject. RPE: retina pigment epithelium; IZ: interdigitation zone; EZ: ellipsoid zone; and ELM: external limiting membrane.*

#### **Figure 2.**

*SD-OCT in a patient with retinal detachment macula off (A). Post-surgical aspect through OCT of the same patient in which the integrity of the outer layers is observed (B). The visual acuity was 20/30.*

IZ, followed by the EZ, and finally the ELM band [7–9]. 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 [10]. 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 [9], and AMD [14]. After macular hole closure, the presence of injured ELM was associated with reduced visual acuity [12]. 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 [9]. Disruption or absence of the EZ line has been shown to correlate with visual acuity and severity in several retinal diseases [5]. In nonneovascular AMD, disruption of the EZ has been associated with visual impairment [15–17]. Furthermore, retinal sensitivity in patients with geographic atrophy was significantly higher in areas with an uninjured EZ [18]. 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 [14]. 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 [21–23]. 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 [11], ERM [21], and RD [24]. 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**) [24]. 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 [14]. 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 [25]. 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 [26]. 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**) [27]. 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 [28]. 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 [26–30]. According to other theory, HRS might be derived from the degenerated photoreceptors or from the macrophages that

**69**

**3.2 Flying saucer sign**

**Figure 3.**

*New Landmarks, Signs, and Findings in Optical Coherence Tomography*

phagocyted them [31]. 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 [32]. 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 [28]. 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 [32].

*Hyperreflective retinal spots (HRS) observed in a patient affected of tuberculosis posterior uveitis.*

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) [33]. 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**) [34]. 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 [3]. All these alterations originate an ovoid appearance in the central fovea [35]. This sign is neither pathognomonic nor necessary for the diagnosis of HCQ

*DOI: http://dx.doi.org/10.5772/intechopen.84242*

*New Landmarks, Signs, and Findings in Optical Coherence Tomography DOI: http://dx.doi.org/10.5772/intechopen.84242*

**Figure 3.** *Hyperreflective retinal spots (HRS) observed in a patient affected of tuberculosis posterior uveitis.*

phagocyted them [31]. 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 [32]. 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 [28]. 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 [32].

#### **3.2 Flying saucer sign**

*A Practical Guide to Clinical Application of OCT in Ophthalmology*

IZ, followed by the EZ, and finally the ELM band [7–9]. 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 [10]. 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 [9], and AMD [14]. After macular hole closure, the presence of injured ELM was associated with reduced visual acuity [12]. 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 [9]. Disruption or absence of the EZ line has been shown to correlate with visual acuity and severity in several retinal diseases [5]. In nonneovascular AMD, disruption of the EZ has been associated with visual impairment [15–17]. Furthermore, retinal sensitivity in patients with geographic atrophy was significantly higher in areas with an uninjured EZ [18]. 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 [14]. 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 [21–23]. 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 [11], ERM [21], and RD [24]. 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**) [24]. 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 [14]. In recent years, new OCT findings and signs have been reported for different retinal diseases. We will describe them with more clinical relevance.

Coscas and cols were the first authors to report the presence of HRS on SD-OCT in exudative AMD [25]. 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 [26]. 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**) [27]. 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 [28]. 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 [26–30]. According to other theory, HRS might be derived from the degenerated photoreceptors or from the macrophages that

**68**

**3. New findings and signs**

**3.1 Hyperreflective retinal spots (HRS)**

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) [33]. 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**) [34]. 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 [3]. All these alterations originate an ovoid appearance in the central fovea [35]. This sign is neither pathognomonic nor necessary for the diagnosis of HCQ

**Figure 4.**

*SD-OCT revealed the "flying saucer" sign in a woman treated with oral chloroquine at a dosage of 3 mg/kg once daily for 8 years.*

retinopathy. Nevertheless, its visualization on SD-OCT images should alert us to possible retinal toxicity due to HCQ toxicity.
