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Current interpretation of optical coherence tomography in the posterior pole
a r c h s o c e s p o f t a l m o l . 2 0 1 6;9 1(1):3–9
ARCHIVOS DE LA SOCIEDAD ESPAÑOLA DE OFTALMOLOGÍA www.elsevier.es/oftalmologia
Review
Current interpretation of optical coherence tomography in the posterior pole夽 A.F. Lasave Departamento de Retina y Vítreo, Clínica Privada de Ojos, Mar del Plata, Buenos Aires, Argentina
a r t i c l e
i n f o
a b s t r a c t
Article history:
Objective: To review the literature in order to describe the current nomenclature for the
Received 2 April 2015
interpretation of retinal images of optical coherence tomography (OCT) in the macular area.
Accepted 15 September 2015
Methods: A comprehensive literature search was conducted in the major biomedical
Available online 21 January 2016
databases since the introduction of OCT in ophthalmological field.
Keywords:
throughout the years are directly related to the technology and equipment used.
Retinal layers
Conclusions: The current nomenclature of normal macular architecture represented in vivo
Central macular thickness
on spectral domain OCT technology provides a clear and valid anatomical interpretation
Optical coherence tomography
that can be applied, not only in research, but also in everyday practice.
Results: Quantitative variations of central macular thickness and proper terminology used
Posterior pole
˜ © 2015 Sociedad Espanola de Oftalmología. Published by Elsevier España, S.L.U. All rights reserved.
Interpretación actual de la tomografía de coherencia óptica en el polo posterior r e s u m e n Palabras clave:
Objetivo: Realizar una revisión bibliográfica para describir la nomenclatura actual en la inter-
Capas retinales
pretación de las imágenes retinales de la tomografía de coherencia óptica (OCT) en el área
Espesor macular central
macular.
Tomografía de coherencia óptica
Métodos: Búsqueda exhaustiva de la bibliografía en las principales bases de datos biomédicas
Polo posterior
desde la introducción de la OCT en el campo oftalmológico. Resultados: Las variantes cuantitativas del espesor macular central y la terminología uti˜ lizada a lo largo de los anos está en relación directa con la tecnología y el equipamiento utilizado.
夽
Please cite this article as: Lasave AF. Interpretación actual de la tomografía de coherencia óptica en el polo posterior. Arch Soc Esp Oftalmol. 2016;91:3–9. E-mail address: [email protected] ˜ 2173-5794/© 2015 Sociedad Espanola de Oftalmología. Published by Elsevier España, S.L.U. All rights reserved.
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Conclusiones: La nomenclatura actual de la arquitectura macular normal representada en imágenes en vivo por la tecnología de OCT de dominio espectral nos proporciona una clara y válida interpretación anatómica para aplicarla no solo en proyectos de investigación, sino en la práctica diaria. ˜ de Oftalmología. Publicado por Elsevier España, S.L.U. Todos © 2015 Sociedad Espanola los derechos reservados.
BV
Introduction and history Optic coherence tomography (OCT) is the biggest technological development of recent years in modern ophthalmology. It has become the diagnostic method of choice for analyzing and following up diseases involving the retina and optic nerve. OCT is a noninvasive, contactless device that captures in vivo images of the retina. In addition it is characterized by an encouraging evolutionary capacity based on continuously evolving technologies. It is likely that in the not too distant future it may produce perfect histological digital sections with sufficient resolution to exceed in detail and durability histological retina sections obtained from cadavers. Before OCT, ocular image technologies did not provide sufficient depth resolution for the posterior segment and there was no equipment capable of producing anatomical crosssections of the retina.1–3 In 1991, a group of researchers of the Massachusetts Institute of technology (Boston, MA, USA) under the leadership of Dr. J. Fujimoto developed the initial prototype of OCT, giving rise to the necessity of developing applications as well as an adequate exploration field for developing this novel technology. In said year, the same group of researchers1 demonstrated that this new technology was able to provide images of human biological microstructural tissue with the certain possibility of application in some branches of medicine, as shown very shortly thereafter in cardiology and particularly ophthalmology.1 Said authors described a system based on low coherence interferometry with time and domain technology (TD-OCT) that was able to obtain sequences of images with a resolution of 17 m, requiring 1.25 s to complete an A scan.1 However, this system required 150 A scans to render a single image, involving 190 s. In the first trials with OCT, axial section retinal images were obtained in vitro, i.e., cadaver eyes were used as experimental models (in vitro specimens) (Fig. 1). The first paper on OCT was published on the basis of these findings. Said paper described the visualization of internal tissue microstructures through bidimensional images in vitro, both of the coronary artery and the peripapillary region of the retina. This was clinically and scientifically very relevant for the time and marked the beginning of a transcendental change in the development of modern day ophthalmology.1 The first in vivo image of the retina was obtained simultaneously by 2 independent research groups that presented a system for acquiring these images at higher scan rates and lower tissue exposure time. This development took place in 1993, with demonstrations being published by Fercher et al.3 and Swanson et al.,4 respectively. Since then, with the encouragement of positive results, research continued in an endeavor to extrapolate these findings to the general population. Accordingly, the first device for visualizing the posterior segment
Retina
Vitreous
BV SRF
RPE
Sclera 300 µm Log reflection
Fig. 1 – In vitro optic coherence tomography (OCT) of a human retina. Tomographic prototype image presented in 1991. The image corresponds to a section of the retina and the optic nerve over the papillomacular bundle of a cadaver eye. Reprinted with the authorization of Huang et al.1
in vivo was marketed in 1995 (Humphrey Instruments, Dublin, USA). In a very short time, the technology was transferred to the industry and introduced into the market for ophthalmological use in 1996 (Carl Zeiss Meditec, Dublin, USA). Also in 1996, Hee et al.5 described the clinical application of OCT as a diagnostic tool and introduced a faster scanner capable of performing 100 A scans in only 2.3 s. However, the definitive worldwide expansion began 5 years later with the arrival in the market of a 3rd generation of devices achieving a revolutionary image resolution of 15 m and a rapid scanning acceleration of 400 A scans per second. The market name of the product was Stratus, by Carl Zeiss (Stratus OCT; Carl Zeiss Meditec, Dublin, USA). Widespread acceptance by ophthalmologists was immediate and since then everything related to this tool has evolved very positively. In 2006, high definition systems were developed with the appearance of spectral domain technology (SD-OCT) with devices such as Cirrus HD Spectral Domain (Carl Zeiss-Meditec, Dublin, USA) or equivalent devices like Spectralis OCT (Heidelberg Engineering, Vista, USA), Topcon 2000 3D (Topcon Corporation, Tokyo, Japan), Optovue (Optovue Inc., Fremont, USA) as well as new emerging industries. Since this breakthrough in the ophthalmological field, devices equipped with the latest SD-OCT technology have become the natural successors of TD-OCT devices. The difference in the anatomical details observed in the scans is so remarkable that the formally revolutionary resolution provided by TD-OCT is now virtually obsolete. Even so, at present these devices continue to be sufficient as diagnostic tools for general ophthalmologists. SD-OCT, with an axial resolution between 3 and 10 m
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A ENL
EPL
ILM/NFL
INL IPL
RPE/choriocapillary
IS-ES
EPL
INL
RPE/choriocapillary
depending on the equipment being used, provides actual, detailed and deep images of macular architecture with a quality unsurpassed by any other available technology.1,5,6 The amazing scan speed, which went from 400 A scans per second to 50,000 A scans per second, as well as unprecedented axial resolution (from 15–10 m to between 3 and 10 m) have enabled complete ultramicroscopic assessment of the posterior pole at an extremely fine scale (Fig. 2). At present, in ordinary circumstances such as for clarifying or supplementing the clinical diagnostic of a disease, justifying new therapies, delaying or halting invasion of procedures, or deciding on a surgical approach, retinologists are exhibiting a high degree of dependency on the results of OCT images.7–12 The quest for the best interpretation of said images has produced a number of changes in the past few years. One of the objectives of the present review is to describe and analyze existing nomenclature for interpreting OCT images in the macular area as well as reviewing the central macular thickness (CMT) equivalences between the most widely used devices.
Interpretation and quantitative analysis of central macular thickness images Interpretation of OCT images The only requirement to interpret OCT images is to understand the normal anatomy of the eye fundus. Axial sections provide a sort of optical biopsy of the surface being studied, outlining in great detail the numerous retina layers (Fig. 3). Despite their innovative and revolutionary breakthrough, the first OCT images rendered low-quality axial sections with diffuse hypo- and hyper-reflective lines and strips. Even so, identifiable anatomical structures were described and named
Choroids ILM/NFL
B
Fig. 2 – Optic coherence tomography (OCT) macular axial section with time domain and spectral domain in normalize. (A) Normal macular axial section with Stratus OCT (time domain). (B) Normal macular axial section with Cirrus SD-OCT. Note the definition and resolution of the external photoreceptor strips rendered by the OCT axial section, comparing examples of healthy eyes with both technologies.
GCL
ENL
IPL
GCL
IS-ES Choroids
Fig. 3 – Evaluation of anatomical equivalences between the postmortem histological section of the macular area and an axial section of the macular area with SD-OCT in eyes exhibiting normal characteristics. (A) Pathological anatomy of the macular area in a normal eye. (B) Normal macular axial section with SD-OCT. GCL, ganglion cell layer; ENL, external nuclear layer; INL, internal nuclear layer; EPL, external plexiform layer; IPL, internal plexiform layer; RPE, retina pigment epithelium; ILM/NFL, internal limiting membrane/nervous fiber layer; IS-ES, internal/external photoreceptor segments (myoid layer, ellipsoid layer and external segments). Reprinted with the authorization of Arevalo et al.11
in different terms by different authors.1,13–17 Mismatches and discord prevailed not only between different groups of researchers but also between publications of the same group.18–20 When the first commercial devices began to be analyzed, anatomical correlations acquired greater consensus together with the evolution of OCT technology. In 1995, Hee et al.5 described 2 main hyper-reflective strips in the macular axial section: the first was an internal layer separated from the vitreous and interpreted as a nerve fiber layer, and the second strip limited the outermost edge of the macular thickness and was defined as the retina pigment epithelium (RPE)/choriocapillary complex. Since 2001, with the introduction of Stratus OCT and equivalent devices, said anatomical correlations were certified and it became possible to interpret nearly the entire thickness of the macular area. Even though only a few strips could not be identified with TD-OCT technology, it has been demonstrated that precisely those thin structures could predict the functional prognostic of some posterior pole pathologies both in their natural evolution as well as during pre- or postsurgery evaluation involving the macular area. Accordingly, since 2006, the SD-OCT technology contributed very valuable information. It is now possible to observe over the foveolar area the exact topographic location of the external strips (hypo- and hyper-reflective) which describes the anatomical and functional condition of the photoreceptor, the most relevant component of the retinal structural mesh.
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Axon
Nucleus
External limiting membrane
Myoid layer Internal segments
Ellipsoid layer
External segments
Fig. 4 – anatomical structure of a photoreceptor (cone) obtained with immunocytochemical eats techniques and confocal microscopy. Courtesy of Dr. Nicolás Cuenca. University of Alicante, Spain. Reprinted with the authorization of Cuenca et al. Cellular responses following retinal injuries and therapeutic approaches for neurodegenerative diseases. Prog Retin Eye Res. 2014;43:17–75.
Each photoreceptor comprises a synaptic terminal, a cellular body and the internal and external segments (IS and ES, respectively) (Fig. 4). The IS of photoreceptors is made up of a myoid layer and an ellipsoid layer. The myoid layer, which is the hypo-reflective strip immediately next to the thin hyperreflective line constituted by the external limiting membrane (ELM),21 is the site where the protein synthesis of the cell is activated and contains ribosomes, the endoplasmic reticulum and the Golgi apparatus. However, there are very few mitochondriae. In contrast, the ellipsoid layer is the energy motor of the microstructure and for this reason it is densely populated by mitochondriae. Unlike any other cell, photoreceptor mitochondriae exhibit an anatomical modification which is the result of bringing together the huge amount of cells in such a small surface, according to which the mitochondriae are placed in parallel to each other, producing a stretching and thinning effect on them. It is believed that this abundant population of mitochondriae, with its peculiar and extremely thin arrangement, accounts for the hyper-reflectiveness of this trip shown in the axial OCT image sections. In turn, normal foveal contours do not have the innermost layers of the retina. On the basis of the evidence provided by TD-OCT technology, the external nuclear layer had been proposed as responsible for the hypo-reflective area between the external plexiform layer and the external limiting membrane. However, at present, ST-OCT image analysis allowed researchers to reach the conclusion that the relative thickness of this hypo-reflective area is significantly larger when compared to that of histologic preparations. One of the findings that contributed to a reassessment of this topic was the hypotheses that indicated that the inclination of the OCT light beam angle could modify the relative thickness of this hyporeflective area and that, in addition to the external nuclear layer, made it possible to visualize an additional layer that could represent the Henle fiber layer,22,23 which would also
contribute to the modification of the size of that area. The Henle fiber layer is one of the exclusive characteristics of the macula because this very close microstructural relationship is not present in the peripheral retina. In the axial sections after this broad hyper-reflective structure it is possible to see the first of the external retina strips. A schematic description and current anatomical correlation of the strips is shown in detail in Fig. 5. The external macular layers are described below on the basis of their reflectiveness.
External limiting membrane (hyper-reflective) The first hyper-reflective strip was attributed to the ELM, which would not be a firm structure but would be made up by the linear conference of multiple joining complexes between
ELM
ELM External PX
Int. S.
External nuclear Myoid
Int. S. Ext. S.
Ext. S.
Ellipsoid L.
External segments Fig. 5 – Magnification of the foveal macular area and scaled schematic characterization of the structural strips and lines.
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the Müller cells and photoreceptors.19 The axial section shows a thin line with a generally weaker hyper-reflectiveness signal.
Myoid layer (hypo-reflective) Immediately next to the ELM a hypo-reflective strip can be seen which, in the beginning, had been attributed to the limits of the anatomical correlation between the photoreceptor IS and ES.20,24 However, both for foveal cones and rods, the length of IS is approximately the same as that of the ES.25,26 This is the reason why said correlation has been discarded, because the limit or mean points between the IS and the ES should be at the same distance between the ELM and RPE. In contrast, this hypo-reflective strip is much closer to the ELM than the RPE. At present, it has been demonstrated that this second strip could correspond to the myoid area of the photoreceptor IS.27,28 It has been proposed that the diminished reflectiveness in this area is due to the lower density of mitochondria occupying this territory.
Ellipsoid layer (hyper-reflective) The third strip was initially attributed to the terminals or pedicles of the ES29 and was also related to the Verhoeff membrane.30,31 However, in-depth inspections, highly detailed image resolutions provided by SD-OCT and the scale schematics developed by research groups21,28 have sufficed to give rise to doubts about the validity of those assumptions. The Verhoeff membrane is an anatomical structure that surrounds the RPE cells,32,33 which is also known as the joining complex between the RPE cells34,35 although the suggested hyper-reflective strip is located at a considerable anatomical distance from the RPE and therefore, if this reflective strip is physically separated from the RPE, it could not be considered as the Verhoeff membrane.36 Another proposal was that it could be the interface between the photoreceptor IS and ES. However, the present day images have allowed us to see that the thickness of the area in SD-OCT is incompatible with the reflection generated upon this area. Another different proposal would have been that the reflection could originate in the connection cilium. However, this seems even less likely as the connecting cilia (between the IS and ES) are dispersed microtubules which, due to their small size, cannot represent the adequate thickness of this strip.25 The most recent data on the basis of SD-OCT histological anatomic and image reconstructions have demonstrated a certain correlation with the ellipsoid photoreceptor component21,28 as this region, being full of mitochondria, could generate intense tissue absorption due to the light beam reflection, which could account for the high reflectiveness of this strip.28
External segments (hypo-reflective) The SD-OCT image allows us to see a hypo-reflective space or line immediately below the ellipsoid of hyper-reflective layer that could correspond to the topographic location of photoreceptor ES.
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Retina pigment epithelium and Bruch’s membrane (hyper-reflective) The outermost layer is a thin hyper-reflective strip that extends below (anatomically outside) the ES. It has been indicated as the graphical representation of interdigitation of apical RPE processes with photoreceptor ES.21 This external hyper-reflective strip was initially attributed merely to the anatomic presence of the RPE. However, high definition devices allow us to see that in some situations this strip is not only a strip because, when the anatomical arrangement allows it, for instance in macular pathology when the thickness of the retina increases and allows us to see 2 strips separated by a hypo-reflective line. These 2 hyper-reflective strips correspond to the RPE and Bruch’s membrane which, under normal conditions, are not visible with OCT. Accordingly, it has been indicated that this strip should be defined as the RPE/Bruch’s membrane complex.
Posterior choroids and sclera The posterior choroids and the sclera are the most difficult structures to obtain with existing OCT devices. These devices utilize a light source of approximately 800 nm, which produces a signal dispersion in the photoreceptor and the RPE with a weak signal from the choroids. In recent years, en face OCT images have appeared, a combination of confocal ophthalmoscopy and OCT, which have contributed to retina observation from another surface plane. More recently, unstained OCT angiography has again opened up new possibilities for studying the macula and posterior pole pathologies.
Quantitative analysis of the central macular thickness The technological developments have also produced quantitative variants for measuring the CMT. The average CMT of a normal eye measured with the Stratus TD-OCT device has been calculated at 147 ± 17 m.37 However, Han and Jaffe38 compared the CMT measurements between the values obtained by Stratus TD-OCT and SD-OCT both in normal eyes and those exhibiting macular pathology. Said authors reported an average foveal thickness of 206 ± 25 m with the Stratus TD-OCT and 259 ± 19 m and 279 ± 21 m in normal eyes with Cirrus SD-OCT and Spectralis SD-OCT, respectively. This marked discrepancy between normal CMT values has produced some degree of confusion in the early stages when SD-OCT devices began to appear in the market. Said quantitatively different reading of CMT by different devices exemplified the difference between the retinal segmentation algorithms developed for different devices. Stratus TD-OCT measures macular thickness from the internal limiting membrane (ILM) up to the junction between the photoreceptor IS and ES. In turn, Cirrus SD-OCT also begins measuring from the ILM but it extends up to the anterior RPE edge, which increases the macular thickness height,39 whereas Spectralis SD-OCT takes into account the distance between the ILM anteroposterior RPE edge. In this way, a normal macular thickness measurement will yield a higher value with Spectralis
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SD-OCT when compared with Cirrus SD-OCT and Stratus TD-OCT. The average difference between these values, which could be interpreted as the equivalence between Stratus TMOCT and Cirrus SD-OCT, was of nearly 50 m, approximately equivalent to the length of the photoreceptor ES.39,40 While the technology firmly continues the development of new instruments it is very important (to say the least) to adequately interpret what we have nowadays within our reach. Understanding the anatomical correlation between OCT images and the macular area under study is an invaluable aid in the search for an adequate diagnostic, a better controlled follow-up as it enables observing the development of the disease with the passage of time, as well as for taking clinical or therapeutic decisions that could improve the anatomical and functional prognosis of retinal diseases.
13.
14.
15.
16.
17.
Conflict of interests No conflict of interests has been declared by the authors.
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references
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ARCHIVOS DE LA SOCIEDAD ESPAÑOLA DE OFTALMOLOGÍA www.elsevier.es/oftalmologia
Review
Current interpretation of optical coherence tomography in the posterior pole夽 A.F. Lasave Departamento de Retina y Vítreo, Clínica Privada de Ojos, Mar del Plata, Buenos Aires, Argentina
a r t i c l e
i n f o
a b s t r a c t
Article history:
Objective: To review the literature in order to describe the current nomenclature for the
Received 2 April 2015
interpretation of retinal images of optical coherence tomography (OCT) in the macular area.
Accepted 15 September 2015
Methods: A comprehensive literature search was conducted in the major biomedical
Available online 21 January 2016
databases since the introduction of OCT in ophthalmological field.
Keywords:
throughout the years are directly related to the technology and equipment used.
Retinal layers
Conclusions: The current nomenclature of normal macular architecture represented in vivo
Central macular thickness
on spectral domain OCT technology provides a clear and valid anatomical interpretation
Optical coherence tomography
that can be applied, not only in research, but also in everyday practice.
Results: Quantitative variations of central macular thickness and proper terminology used
Posterior pole
˜ © 2015 Sociedad Espanola de Oftalmología. Published by Elsevier España, S.L.U. All rights reserved.
Interpretación actual de la tomografía de coherencia óptica en el polo posterior r e s u m e n Palabras clave:
Objetivo: Realizar una revisión bibliográfica para describir la nomenclatura actual en la inter-
Capas retinales
pretación de las imágenes retinales de la tomografía de coherencia óptica (OCT) en el área
Espesor macular central
macular.
Tomografía de coherencia óptica
Métodos: Búsqueda exhaustiva de la bibliografía en las principales bases de datos biomédicas
Polo posterior
desde la introducción de la OCT en el campo oftalmológico. Resultados: Las variantes cuantitativas del espesor macular central y la terminología uti˜ lizada a lo largo de los anos está en relación directa con la tecnología y el equipamiento utilizado.
夽
Please cite this article as: Lasave AF. Interpretación actual de la tomografía de coherencia óptica en el polo posterior. Arch Soc Esp Oftalmol. 2016;91:3–9. E-mail address: [email protected] ˜ 2173-5794/© 2015 Sociedad Espanola de Oftalmología. Published by Elsevier España, S.L.U. All rights reserved.
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Conclusiones: La nomenclatura actual de la arquitectura macular normal representada en imágenes en vivo por la tecnología de OCT de dominio espectral nos proporciona una clara y válida interpretación anatómica para aplicarla no solo en proyectos de investigación, sino en la práctica diaria. ˜ de Oftalmología. Publicado por Elsevier España, S.L.U. Todos © 2015 Sociedad Espanola los derechos reservados.
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Introduction and history Optic coherence tomography (OCT) is the biggest technological development of recent years in modern ophthalmology. It has become the diagnostic method of choice for analyzing and following up diseases involving the retina and optic nerve. OCT is a noninvasive, contactless device that captures in vivo images of the retina. In addition it is characterized by an encouraging evolutionary capacity based on continuously evolving technologies. It is likely that in the not too distant future it may produce perfect histological digital sections with sufficient resolution to exceed in detail and durability histological retina sections obtained from cadavers. Before OCT, ocular image technologies did not provide sufficient depth resolution for the posterior segment and there was no equipment capable of producing anatomical crosssections of the retina.1–3 In 1991, a group of researchers of the Massachusetts Institute of technology (Boston, MA, USA) under the leadership of Dr. J. Fujimoto developed the initial prototype of OCT, giving rise to the necessity of developing applications as well as an adequate exploration field for developing this novel technology. In said year, the same group of researchers1 demonstrated that this new technology was able to provide images of human biological microstructural tissue with the certain possibility of application in some branches of medicine, as shown very shortly thereafter in cardiology and particularly ophthalmology.1 Said authors described a system based on low coherence interferometry with time and domain technology (TD-OCT) that was able to obtain sequences of images with a resolution of 17 m, requiring 1.25 s to complete an A scan.1 However, this system required 150 A scans to render a single image, involving 190 s. In the first trials with OCT, axial section retinal images were obtained in vitro, i.e., cadaver eyes were used as experimental models (in vitro specimens) (Fig. 1). The first paper on OCT was published on the basis of these findings. Said paper described the visualization of internal tissue microstructures through bidimensional images in vitro, both of the coronary artery and the peripapillary region of the retina. This was clinically and scientifically very relevant for the time and marked the beginning of a transcendental change in the development of modern day ophthalmology.1 The first in vivo image of the retina was obtained simultaneously by 2 independent research groups that presented a system for acquiring these images at higher scan rates and lower tissue exposure time. This development took place in 1993, with demonstrations being published by Fercher et al.3 and Swanson et al.,4 respectively. Since then, with the encouragement of positive results, research continued in an endeavor to extrapolate these findings to the general population. Accordingly, the first device for visualizing the posterior segment
Retina
Vitreous
BV SRF
RPE
Sclera 300 µm Log reflection
Fig. 1 – In vitro optic coherence tomography (OCT) of a human retina. Tomographic prototype image presented in 1991. The image corresponds to a section of the retina and the optic nerve over the papillomacular bundle of a cadaver eye. Reprinted with the authorization of Huang et al.1
in vivo was marketed in 1995 (Humphrey Instruments, Dublin, USA). In a very short time, the technology was transferred to the industry and introduced into the market for ophthalmological use in 1996 (Carl Zeiss Meditec, Dublin, USA). Also in 1996, Hee et al.5 described the clinical application of OCT as a diagnostic tool and introduced a faster scanner capable of performing 100 A scans in only 2.3 s. However, the definitive worldwide expansion began 5 years later with the arrival in the market of a 3rd generation of devices achieving a revolutionary image resolution of 15 m and a rapid scanning acceleration of 400 A scans per second. The market name of the product was Stratus, by Carl Zeiss (Stratus OCT; Carl Zeiss Meditec, Dublin, USA). Widespread acceptance by ophthalmologists was immediate and since then everything related to this tool has evolved very positively. In 2006, high definition systems were developed with the appearance of spectral domain technology (SD-OCT) with devices such as Cirrus HD Spectral Domain (Carl Zeiss-Meditec, Dublin, USA) or equivalent devices like Spectralis OCT (Heidelberg Engineering, Vista, USA), Topcon 2000 3D (Topcon Corporation, Tokyo, Japan), Optovue (Optovue Inc., Fremont, USA) as well as new emerging industries. Since this breakthrough in the ophthalmological field, devices equipped with the latest SD-OCT technology have become the natural successors of TD-OCT devices. The difference in the anatomical details observed in the scans is so remarkable that the formally revolutionary resolution provided by TD-OCT is now virtually obsolete. Even so, at present these devices continue to be sufficient as diagnostic tools for general ophthalmologists. SD-OCT, with an axial resolution between 3 and 10 m
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A ENL
EPL
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depending on the equipment being used, provides actual, detailed and deep images of macular architecture with a quality unsurpassed by any other available technology.1,5,6 The amazing scan speed, which went from 400 A scans per second to 50,000 A scans per second, as well as unprecedented axial resolution (from 15–10 m to between 3 and 10 m) have enabled complete ultramicroscopic assessment of the posterior pole at an extremely fine scale (Fig. 2). At present, in ordinary circumstances such as for clarifying or supplementing the clinical diagnostic of a disease, justifying new therapies, delaying or halting invasion of procedures, or deciding on a surgical approach, retinologists are exhibiting a high degree of dependency on the results of OCT images.7–12 The quest for the best interpretation of said images has produced a number of changes in the past few years. One of the objectives of the present review is to describe and analyze existing nomenclature for interpreting OCT images in the macular area as well as reviewing the central macular thickness (CMT) equivalences between the most widely used devices.
Interpretation and quantitative analysis of central macular thickness images Interpretation of OCT images The only requirement to interpret OCT images is to understand the normal anatomy of the eye fundus. Axial sections provide a sort of optical biopsy of the surface being studied, outlining in great detail the numerous retina layers (Fig. 3). Despite their innovative and revolutionary breakthrough, the first OCT images rendered low-quality axial sections with diffuse hypo- and hyper-reflective lines and strips. Even so, identifiable anatomical structures were described and named
Choroids ILM/NFL
B
Fig. 2 – Optic coherence tomography (OCT) macular axial section with time domain and spectral domain in normalize. (A) Normal macular axial section with Stratus OCT (time domain). (B) Normal macular axial section with Cirrus SD-OCT. Note the definition and resolution of the external photoreceptor strips rendered by the OCT axial section, comparing examples of healthy eyes with both technologies.
GCL
ENL
IPL
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IS-ES Choroids
Fig. 3 – Evaluation of anatomical equivalences between the postmortem histological section of the macular area and an axial section of the macular area with SD-OCT in eyes exhibiting normal characteristics. (A) Pathological anatomy of the macular area in a normal eye. (B) Normal macular axial section with SD-OCT. GCL, ganglion cell layer; ENL, external nuclear layer; INL, internal nuclear layer; EPL, external plexiform layer; IPL, internal plexiform layer; RPE, retina pigment epithelium; ILM/NFL, internal limiting membrane/nervous fiber layer; IS-ES, internal/external photoreceptor segments (myoid layer, ellipsoid layer and external segments). Reprinted with the authorization of Arevalo et al.11
in different terms by different authors.1,13–17 Mismatches and discord prevailed not only between different groups of researchers but also between publications of the same group.18–20 When the first commercial devices began to be analyzed, anatomical correlations acquired greater consensus together with the evolution of OCT technology. In 1995, Hee et al.5 described 2 main hyper-reflective strips in the macular axial section: the first was an internal layer separated from the vitreous and interpreted as a nerve fiber layer, and the second strip limited the outermost edge of the macular thickness and was defined as the retina pigment epithelium (RPE)/choriocapillary complex. Since 2001, with the introduction of Stratus OCT and equivalent devices, said anatomical correlations were certified and it became possible to interpret nearly the entire thickness of the macular area. Even though only a few strips could not be identified with TD-OCT technology, it has been demonstrated that precisely those thin structures could predict the functional prognostic of some posterior pole pathologies both in their natural evolution as well as during pre- or postsurgery evaluation involving the macular area. Accordingly, since 2006, the SD-OCT technology contributed very valuable information. It is now possible to observe over the foveolar area the exact topographic location of the external strips (hypo- and hyper-reflective) which describes the anatomical and functional condition of the photoreceptor, the most relevant component of the retinal structural mesh.
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Axon
Nucleus
External limiting membrane
Myoid layer Internal segments
Ellipsoid layer
External segments
Fig. 4 – anatomical structure of a photoreceptor (cone) obtained with immunocytochemical eats techniques and confocal microscopy. Courtesy of Dr. Nicolás Cuenca. University of Alicante, Spain. Reprinted with the authorization of Cuenca et al. Cellular responses following retinal injuries and therapeutic approaches for neurodegenerative diseases. Prog Retin Eye Res. 2014;43:17–75.
Each photoreceptor comprises a synaptic terminal, a cellular body and the internal and external segments (IS and ES, respectively) (Fig. 4). The IS of photoreceptors is made up of a myoid layer and an ellipsoid layer. The myoid layer, which is the hypo-reflective strip immediately next to the thin hyperreflective line constituted by the external limiting membrane (ELM),21 is the site where the protein synthesis of the cell is activated and contains ribosomes, the endoplasmic reticulum and the Golgi apparatus. However, there are very few mitochondriae. In contrast, the ellipsoid layer is the energy motor of the microstructure and for this reason it is densely populated by mitochondriae. Unlike any other cell, photoreceptor mitochondriae exhibit an anatomical modification which is the result of bringing together the huge amount of cells in such a small surface, according to which the mitochondriae are placed in parallel to each other, producing a stretching and thinning effect on them. It is believed that this abundant population of mitochondriae, with its peculiar and extremely thin arrangement, accounts for the hyper-reflectiveness of this trip shown in the axial OCT image sections. In turn, normal foveal contours do not have the innermost layers of the retina. On the basis of the evidence provided by TD-OCT technology, the external nuclear layer had been proposed as responsible for the hypo-reflective area between the external plexiform layer and the external limiting membrane. However, at present, ST-OCT image analysis allowed researchers to reach the conclusion that the relative thickness of this hypo-reflective area is significantly larger when compared to that of histologic preparations. One of the findings that contributed to a reassessment of this topic was the hypotheses that indicated that the inclination of the OCT light beam angle could modify the relative thickness of this hyporeflective area and that, in addition to the external nuclear layer, made it possible to visualize an additional layer that could represent the Henle fiber layer,22,23 which would also
contribute to the modification of the size of that area. The Henle fiber layer is one of the exclusive characteristics of the macula because this very close microstructural relationship is not present in the peripheral retina. In the axial sections after this broad hyper-reflective structure it is possible to see the first of the external retina strips. A schematic description and current anatomical correlation of the strips is shown in detail in Fig. 5. The external macular layers are described below on the basis of their reflectiveness.
External limiting membrane (hyper-reflective) The first hyper-reflective strip was attributed to the ELM, which would not be a firm structure but would be made up by the linear conference of multiple joining complexes between
ELM
ELM External PX
Int. S.
External nuclear Myoid
Int. S. Ext. S.
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External segments Fig. 5 – Magnification of the foveal macular area and scaled schematic characterization of the structural strips and lines.
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the Müller cells and photoreceptors.19 The axial section shows a thin line with a generally weaker hyper-reflectiveness signal.
Myoid layer (hypo-reflective) Immediately next to the ELM a hypo-reflective strip can be seen which, in the beginning, had been attributed to the limits of the anatomical correlation between the photoreceptor IS and ES.20,24 However, both for foveal cones and rods, the length of IS is approximately the same as that of the ES.25,26 This is the reason why said correlation has been discarded, because the limit or mean points between the IS and the ES should be at the same distance between the ELM and RPE. In contrast, this hypo-reflective strip is much closer to the ELM than the RPE. At present, it has been demonstrated that this second strip could correspond to the myoid area of the photoreceptor IS.27,28 It has been proposed that the diminished reflectiveness in this area is due to the lower density of mitochondria occupying this territory.
Ellipsoid layer (hyper-reflective) The third strip was initially attributed to the terminals or pedicles of the ES29 and was also related to the Verhoeff membrane.30,31 However, in-depth inspections, highly detailed image resolutions provided by SD-OCT and the scale schematics developed by research groups21,28 have sufficed to give rise to doubts about the validity of those assumptions. The Verhoeff membrane is an anatomical structure that surrounds the RPE cells,32,33 which is also known as the joining complex between the RPE cells34,35 although the suggested hyper-reflective strip is located at a considerable anatomical distance from the RPE and therefore, if this reflective strip is physically separated from the RPE, it could not be considered as the Verhoeff membrane.36 Another proposal was that it could be the interface between the photoreceptor IS and ES. However, the present day images have allowed us to see that the thickness of the area in SD-OCT is incompatible with the reflection generated upon this area. Another different proposal would have been that the reflection could originate in the connection cilium. However, this seems even less likely as the connecting cilia (between the IS and ES) are dispersed microtubules which, due to their small size, cannot represent the adequate thickness of this strip.25 The most recent data on the basis of SD-OCT histological anatomic and image reconstructions have demonstrated a certain correlation with the ellipsoid photoreceptor component21,28 as this region, being full of mitochondria, could generate intense tissue absorption due to the light beam reflection, which could account for the high reflectiveness of this strip.28
External segments (hypo-reflective) The SD-OCT image allows us to see a hypo-reflective space or line immediately below the ellipsoid of hyper-reflective layer that could correspond to the topographic location of photoreceptor ES.
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Retina pigment epithelium and Bruch’s membrane (hyper-reflective) The outermost layer is a thin hyper-reflective strip that extends below (anatomically outside) the ES. It has been indicated as the graphical representation of interdigitation of apical RPE processes with photoreceptor ES.21 This external hyper-reflective strip was initially attributed merely to the anatomic presence of the RPE. However, high definition devices allow us to see that in some situations this strip is not only a strip because, when the anatomical arrangement allows it, for instance in macular pathology when the thickness of the retina increases and allows us to see 2 strips separated by a hypo-reflective line. These 2 hyper-reflective strips correspond to the RPE and Bruch’s membrane which, under normal conditions, are not visible with OCT. Accordingly, it has been indicated that this strip should be defined as the RPE/Bruch’s membrane complex.
Posterior choroids and sclera The posterior choroids and the sclera are the most difficult structures to obtain with existing OCT devices. These devices utilize a light source of approximately 800 nm, which produces a signal dispersion in the photoreceptor and the RPE with a weak signal from the choroids. In recent years, en face OCT images have appeared, a combination of confocal ophthalmoscopy and OCT, which have contributed to retina observation from another surface plane. More recently, unstained OCT angiography has again opened up new possibilities for studying the macula and posterior pole pathologies.
Quantitative analysis of the central macular thickness The technological developments have also produced quantitative variants for measuring the CMT. The average CMT of a normal eye measured with the Stratus TD-OCT device has been calculated at 147 ± 17 m.37 However, Han and Jaffe38 compared the CMT measurements between the values obtained by Stratus TD-OCT and SD-OCT both in normal eyes and those exhibiting macular pathology. Said authors reported an average foveal thickness of 206 ± 25 m with the Stratus TD-OCT and 259 ± 19 m and 279 ± 21 m in normal eyes with Cirrus SD-OCT and Spectralis SD-OCT, respectively. This marked discrepancy between normal CMT values has produced some degree of confusion in the early stages when SD-OCT devices began to appear in the market. Said quantitatively different reading of CMT by different devices exemplified the difference between the retinal segmentation algorithms developed for different devices. Stratus TD-OCT measures macular thickness from the internal limiting membrane (ILM) up to the junction between the photoreceptor IS and ES. In turn, Cirrus SD-OCT also begins measuring from the ILM but it extends up to the anterior RPE edge, which increases the macular thickness height,39 whereas Spectralis SD-OCT takes into account the distance between the ILM anteroposterior RPE edge. In this way, a normal macular thickness measurement will yield a higher value with Spectralis
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SD-OCT when compared with Cirrus SD-OCT and Stratus TD-OCT. The average difference between these values, which could be interpreted as the equivalence between Stratus TMOCT and Cirrus SD-OCT, was of nearly 50 m, approximately equivalent to the length of the photoreceptor ES.39,40 While the technology firmly continues the development of new instruments it is very important (to say the least) to adequately interpret what we have nowadays within our reach. Understanding the anatomical correlation between OCT images and the macular area under study is an invaluable aid in the search for an adequate diagnostic, a better controlled follow-up as it enables observing the development of the disease with the passage of time, as well as for taking clinical or therapeutic decisions that could improve the anatomical and functional prognosis of retinal diseases.
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Conflict of interests No conflict of interests has been declared by the authors.
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