Background: Recent studies investigating the use of optical coherence tomography (OCT) in multiple sclerosis (MS) patients have resulted in wide-ranging and often contradictory outcomes. This is mainly due to the complex etiology and heterogeneity of MS, physiological variations in the retinal nerve fiber layer (RNFL) and/or total macular volume (TMV), and limitations in methodology. It remains to be discovered whether any retinal changes in MS develop continuously or in a stepwise fashion, and whether these changes occur in all or a subset of patients. High-resolution spectral domain-OCT devices (SD-OCT) would be required to detect subtle retinal changes and longitudinal studies would have to be carried out to investigate retinal changes over time. In addition, if the hypothesis is correct, then retinal and global brain tissue changes should be detected in a substantial majority of MS patients and detection should be possible with a high degree of disease activity and/or long disease course.
Methodology: In order to address the factors above, 37 MS patients (relapsing–remitting, n = 27; secondary progressive, n = 10) were examined prospectively on two occasions with a median interval of 22.4 ± 0.5 months [range 19–27]. SD-OCT was utilized with the Spectralis 3.5 mm circle scan protocol (with locked reference images and eye-tracking mode). None of the patients had optic neuritis 12 months prior to study entry or during the observation period.
Principal Findings: The initial TMV pattern differed between study participants, but remained relatively unchanged over the 2-year observation period despite high disease activity or long disease course. The TMV correlated well with the RNFL.
Conclusion: The significance of differences in TMV (and RNFL) between study participants remains unclear. Until these differences have been explored further, OCT data in MS patients should be interpreted with caution.
MS; OCT; macula lutea; neurodegenerative diseases; MRI
We present a new instrument that is capable of imaging human photoreceptors in three dimensions. To achieve high lateral resolution, the system incorporates an adaptive optics system. The high axial resolution is achieved through the implementation of optical coherence tomography (OCT). The instrument records simultaneously both, scanning laser ophthalmoscope (SLO) and OCT en-face images, with a pixel to pixel correspondence. The information provided by the SLO is used to correct for transverse eye motion in post-processing. In order to correct for axial eye motion, the instrument is equipped with a high speed axial eye tracker. In vivo images of foveal cones as well as images recorded at an eccentricity from the fovea showing cones and rods are presented.
(170.3890) Medical optics instrumentation; (110.1080) Active or adaptive optics; (170.4470) Ophthalmology; (330.5310) Vision - photoreceptors; (110.4500) Optical coherence tomography
We present a novel polarization sensitive optical coherence tomography (PS-OCT) system with an integrated retinal tracker. The tracking operates at up to 60 Hz, correcting PS-OCT scanning positions during the acquisition to avoid artifacts caused by eye motion. To demonstrate the practical performance of the system, we imaged several healthy volunteers and patients with AMD both with B-scan repetitions for frame averaging and with 3D raster scans. Under large retinal motions with up to 1 mm amplitude at 0.5 ~a few Hz frequency range, motion artifact suppression in the PS-OCT images as well as standard deviation noise reduction in the frame averaged retardation images are presented.
(170.0170) Medical optics and biotechnology; (170.0110) Imaging systems; (170.2655) Functional monitoring and imaging; (170.4470) Ophthalmology; (170.4500) Optical coherence tomography
To image the retinal pigment epithelium (RPE) after macular laser and to monitor healing responses over time in vivo in patients with diabetic maculopathy using polarization-sensitive optical coherence tomography (OCT).
Prospective, nonrandomized clinical trial.
In this single-center trial (Department of Ophthalmology and Optometry, Medical University of Vienna, Vienna, Austria), 13 patients (13 eyes) underwent grid photocoagulation for diabetic maculopathy. Retinal healing processes were continuously followed over the course of 3 months. A polarization-sensitive OCT prototype was used, allowing detection and measurement of the RPE changes based on their specific polarization-scrambling qualities.
After 1 day, the intraretinal photocoagulation lesions were sharply demarcated, whereas RPE changes were rather subtle. At 1 week, all lesions exhibited traction of the inner retinal layers toward the RPE and loss of photoreceptor cells. In tissue-sensitive polarization-sensitive OCT imaging, polarization-scrambling columns were found at the level of the RPE. During follow-up, different healing responses were seen in the polarization-scrambling RPE layer, ranging from hyperproliferation to focal atrophy.
Because of the properties of the polarization state of backscattered light, polarization-sensitive OCT revealed specific morphologic changes in the RPE and outer retinal layers secondary to retinal laser treatment undetectable with intensity-based spectral-domain OCT. The increase in polarization-scrambling tissue over the course of 3 months indicates a more intense healing reaction and proliferation of RPE cells than previously characterized in rodent studies.
We present a novel spectral domain polarization sensitive OCT system (PS-OCT) that operates at an
A-scan rate of 70 kHz and supports scan angles of up to 40° × 40°. The
high-speed imaging allows the acquisition of up to 1024 × 250 A-scans per 3D scan, which,
together with the large field of view, considerably increases the informative value of the images.
To demonstrate the excellent performance of the new PS-OCT system, we imaged several healthy
volunteers and patients with various diseases such as glaucoma, AMD, Stargardt’s disease, and
albinism. The results are compared with clinically established methods such as scanning laser
polarimetry and autofluorescence.
(170.0170) Medical optics and biotechnology; (170.0110) Imaging systems; (170.2655) Functional monitoring and imaging; (170.4470) Ophthalmology; (170.4500) Optical coherence tomography
Polarization sensitive optical coherence tomography (PS-OCT) is a functional extension of OCT. In addition to imaging based on tissue reflectivity, PS-OCT also enables depth-resolved mapping of sample polarization properties such as phase-retardation, birefringent axis orientation, Stokes vectors, and degree of polarization uniformity (DOPU). In this study, PS-OCT was used to investigate the polarization properties of melanin. In-vitro measurements in samples with varying melanin concentrations revealed polarization scrambling, i.e. depolarization of backscattered light. Polarization scrambling in the PS-OCT images was more pronounced for higher melanin concentrations and correlated with the concentration of the melanin granules in the phantoms. Moreover, in-vivo PS-OCT was performed in the retinas of normal subjects and individuals with albinism. Unlike in the normal eye, polarization scrambling in the retinal pigment epithelium (RPE) was less pronounced or even not observable in PS-OCT images of albinos. These results indicate that the depolarizing appearance of pigmented structures like, for instance, the RPE is likely to be caused by the melanin granules contained in these cells.
(170.4500) Optical coherence tomography; (230.5440) Polarization-selective devices; (170.6935) Tissue characterization; (170.4580) Optical diagnostics for medicine; (170.4470) Ophthalmology
Currently, the border of idiopathic epiretinal membranes (iERM) is outlined intraoperatively using vital dyes. Therefore, the authors set out to investigate the role of the preoperative retinal thickness map (RTM) of the optical coherence tomography (OCT) in identifying the shape and the size of the iERMs.
15 eyes of 15 patients with iERM who underwent vitrectomy with indocyanine green-assisted membrane peeling were included in this study. The authors analysed the intraoperative fundus images and preoperative Cirrus HD-OCT to detect the shape and the size of the iERM as well as the shape and the size of each thickness-indicating colour (white, red, orange and yellow) on the RTM, respectively. The correlation of areas and morphologic characteristics between both groups was explored.
Analysis of iERM morphologic characteristics (shape) showed a similarity between the iERM contour and the corresponding RTM in 13 cases (86.6%). Furthermore, retinal folds were found in six iERMs and in their corresponding RTMs. Analysis of iERM size (area) revealed a positive correlation between the iERM area and each studied coloured area in RTM. The most significant correlation was between iERM and the red area (440–480 μm; r=0.87, p<0.0001).
The iERM-related retinal folds are clearly distinguishable on the HD-OCT. The red area in RTM representing the 440–480 μm retinal thickness can be a reliable predictor of the extent and the shape of the iERM.
Optical coherence tomography; epiretinal membrane; indocyanine green; retinal thickness map; retina; vitreous; treatment surgery; imaging; neovascularisation; treatment lasers
To characterise the extension and progression of alteration of neurosensory layers following acute and chronic branch retinal artery occlusion (BRAO) in vivo using spectral-domain optical coherence tomography.
In this observational case series, eight eyes with acute BRAO and nine eyes with chronic BRAO were analysed using a Spectralis Heidelberg Retina Angiograph (HRA)+optical coherence tomography system including eye tracking. Patients with acute BRAO were examined within 36±5 h after primary event and at weekly/monthly intervals thereafter. Segmentation measurements of all individual neurosensory layers were performed on single A-scans at six locations in affected and corresponding non-affected areas. The thickness values of the retinal nerve fibre layer together with the ganglion cell layer (NFL/GCL), inner plexiform layer (IPL), inner nuclear layer together with outer plexiform layer (INL/OPL), outer nuclear layer (ONL), and photoreceptor layers together with the retinal pigment epithelium (PR/RPE) were measured and analysed.
Segmentation evaluation revealed a distinct increase in thickness of inner neurosensory layers including the NFL/GCL (35%), IPL (80%), INL/OPL (48%) and mildly the ONL by 21% in acute ischaemia compared with corresponding layers in non-ischaemic areas. Regression of intraretinal oedema was followed by persistent retinal atrophy with loss of differentiation between IPL and INL/OPL at month 2. In contrast, the ONL and subjacent PR/RPE retained their physiological thickness in patients with chronic BRAO.
In vivo assessment of retinal layer morphology allows a precise identification of the pathophysiology in retinal ischaemia.
Branch retinal artery occlusion; optical coherence tomography; retina; imaging
Optical coherence tomography (OCT) has become a well established imaging tool in ophthalmology. The unprecedented depth resolution that is provided by this technique yields valuable information on different ocular tissues ranging from the anterior to the posterior eye segment. Polarization sensitive OCT (PS-OCT) extends the concept of OCT and utilizes the information that is carried by polarized light to obtain additional information on the tissue. Several structures in the eye (e.g. cornea, retinal nerve fiber layer, retinal pigment epithelium) alter the polarization state of the light and show therefore a tissue specific contrast in PS-OCT images. First this review outlines the basic concepts of polarization changing light–tissue interactions and gives a short introduction in PS-OCT instruments for ophthalmic imaging. In a second part a variety of different applications of this technique are presented in ocular imaging that are ranging from the anterior to the posterior eye segment. Finally the benefits of the method for imaging different diseases as, e.g., age related macula degeneration (AMD) or glaucoma is demonstrated.
Optical coherence tomography; Polarization sensitive imaging; Retina; Age related macula degeneration; Glaucoma; Cornea
“Non-invasive, faster and less expensive than MRI” and “the eye is a window to the brain” are recent slogans promoting optical coherence tomography (OCT) as a new surrogate marker in multiple sclerosis (MS). Indeed, OCT allows for the first time a non-invasive visualization of axons of the central nervous system (CNS). Reduction of retina nerve fibre layer (RNFL) thickness was suggested to correlate with disease activity and duration. However, several issues are unclear: Do a few million axons, which build up both optic nerves, really resemble billions of CNS neurons? Does global CNS damage really result in global RNFL reduction? And if so, does global RNFL reduction really exist in all MS patients, and follow a slowly but steadily ongoing pattern? How can these (hypothesized) subtle global RNFL changes be reliably measured and separated from the rather gross RNFL changes caused by optic neuritis? Before generally being accepted, this interpretation needs further critical and objective validation.
We prospectively studied 37 MS patients with relapsing remitting (n = 27) and secondary progressive (n = 10) course on two occasions with a median interval of 22.4±0.5 months [range 19–27]. We used the high resolution spectral domain (SD-)OCT with the Spectralis 3.5 mm circle scan protocol with locked reference images and eye tracking mode. Patients with an attack of optic neuritis within 12 months prior to the onset of the study were excluded.
Although the disease was highly active over the observation period in more than half of the included relapsing remitting MS patients (19 patients/32 relapses) and the initial RNFL pattern showed a broad range, from normal to markedly reduced thickness, no significant changes between baseline and follow-up examinations could be detected.
These results show that caution is required when using OCT for monitoring disease activity and global axonal injury in MS.
Using a spectral domain OCT system, equipped with a broadband Ti:sapphire laser, we imaged the human retina with 5 µm x 1.3 µm transverse and axial resolution at acquisition rate of 100 kHz. Such imaging speed significantly reduces motion artifacts. Combined with the ultra-high resolution, this allows observing microscopic retinal details with high axial definition without the help of adaptive optics. In this work we apply our system to image the parafoveal capillary network. We demonstrate how already on the intensity level the parafoveal capillaries can be segmented by a simple structural high pass filtering algorithm. This data is then used to quantitatively characterize the capillary network of healthy and diseased eyes. We propose to use the fractal dimension as index for capillary integrity of pathologic disorders.
(170.3880) Medical and biological imaging; (170.4500) Optical coherence tomography; (170.4470) Ophthalmology; (170.0110) Imaging systems; (170.6900) Three-dimensional microscopy; (170.6960) Tomography
We present polarization-sensitive optical coherence tomography (PS-OCT) for quantitative assessment of retinal pathologies in age-related macular degeneration (AMD). On the basis of the polarization scrambling characteristics of the retinal pigment epithelium, novel segmentation algorithms were developed that allow one to segment pathologic features such as drusen and atrophic zones in dry AMD as well as to determine their dimensions. Results from measurements in the eyes of AMD patients prove the ability of PS-OCT for quantitative imaging based on the retinal features polarizing properties. Repeatability measurements were performed in retinas diagnosed with drusen and geographic atrophy in order to evaluate the performance of the described methods. PS-OCT appears as a promising imaging modality for three-dimensional retinal imaging and ranging with additional contrast based on the structures’ tissue-inherent polarization properties.
optical coherence tomography; polarization sensitive devices; medical imaging; ophthalmology; algorithms; segmentation; age-related macular degeneration
Spectral-domain optical coherence tomography (SD-OCT) provides new insights into the understanding of age-related macular degeneration (AMD) but limited information on the nature of hyperreflective tissue at the level of the retinal pigment epithelium. Therefore, polarization-sensitive (PS) SD-OCT was used to identify and characterize typical RPE findings in AMD.
Forty-four eyes of 44 patients with AMD were included in this prospective case series representing the entire AMD spectrum from drusen (n = 11), geographic atrophy (GA; n = 11), neovascular AMD (nAMD; n = 11) to fibrotic scars (n = 11). Imaging systems were used for comparative imaging. A PS-SD-OCT instrument was developed that was capable of recording intensity and polarization parameters simultaneously during a single scan.
In drusen, PS-SD-OCT identified a continuous RPE layer with focal elevations. Discrete RPE atrophy (RA) could be observed in two patients. In GA, the extension of the RA was significantly larger. Residual RPE islands could be detected within the atrophic zone. PS-SD-OCT identified multiple foci of RPE loss in patients with nAMD and allowed recognition of advanced RPE disease associated with choroidal neovascularization. Wide areas of RA containing residual spots of intact retinal pigment epithelium could be identified in fibrotic scars.
PS-SD-OCT provided precise identification of retinal pigment epithelium in AMD. Recognition of these disease-specific RA patterns in dry and wet forms of AMD is of particular relevance to identify the status and progression of RPE disease and may help to better estimate the functional prognosis of AMD.
We present a new method for identifying and segmenting the retinal pigment epithelium (RPE) in polarization sensitive optical coherence tomography (PS-OCT) images of the human retina. Contrary to previous, intensity based segmentation algorithms, our method uses an intrinsic tissue property of the RPE: its depolarizing, or polarization scrambling effect on backscattered light. Two different segmentation algorithms are presented and discussed: a simpler algorithm based on retardation data, and a more sophisticated algorithm based on local variations of the polarization state calculated from averaged Stokes vector elements. By using a state of the art spectral domain PS-OCT instrument, we demonstrate the method in healthy and diseased eyes.
Polarization sensitive OCT has recently been shown to provide tissue specific contrast, enabling direct identification of retinal layers based on the intrinsic properties of their interaction with light. However, the capabilities of displaying and analyzing 3D datasets in scientific publications were rather limited. Within the framework of the Interactive Science Publishing project, we present new ways of displaying and analyzing 3D sets of various polarization parameters recorded in healthy and diseased human retinas. These datasets can be interactively explored by the reader. Furthermore, we provide data of the 3D distribution of backscattered Stokes vectors to allow the reader to develop and test their own data processing algorithms.
Recently the reduction of the retinal nerve fibre layer (RNFL) was suggested to be associated with diffuse axonal damage in the whole CNS of multiple sclerosis (MS) patients. However, several points are still under discussion. (1) Is high resolution optical coherence tomography (OCT) required to detect the partly very subtle RNFL changes seen in MS patients? (2) Can a reduction of RNFL be detected in all MS patients, even in early disease courses and in all MS subtypes? (3) Does an optic neuritis (ON) or focal lesions along the visual pathways, which are both very common in MS, limit the predication of diffuse axonal degeneration in the whole CNS? The purpose of our study was to determine the baseline characteristics of clinical definite relapsing-remitting (RRMS) and secondary progressive (SPMS) MS patients with high resolution OCT technique.
Forty-two RRMS and 17 SPMS patients with and without history of uni- or bilateral ON, and 59 age- and sex-matched healthy controls were analysed prospectively with the high resolution spectral-domain OCT device (SD-OCT) using the Spectralis 3.5mm circle scan protocol with locked reference images and eye tracking mode. Furthermore we performed tests for visual and contrast acuity and sensitivity (ETDRS, Sloan and Pelli-Robson-charts), for color vision (Lanthony D-15), the Humphrey visual field and visual evoked potential testing (VEP).
All 4 groups (RRMS and SPMS with or without ON) showed significantly reduced RNFL globally, or at least in one of the peripapillary sectors compared to age-/sex-matched healthy controls. In patients with previous ON additional RNFL reduction was found. However, in many RRMS patients the RNFL was found within normal range. We found no correlation between RNFL reduction and disease duration (range 9–540 months).
RNFL baseline characteristics of RRMS and SPMS are heterogeneous (range from normal to markedly reduced levels).
To determine the reproducibility among readers of two independent certified centres, the Vienna Reading Center (VRC) and the University of Wisconsin-Madison Reading Center (UW-FPRC) for optical coherence tomography (OCT) images in age-related macular degeneration (AMD).
Fast macular thickness scans and 6 mm cross hair scans were obtained from 100 eyes with all subtypes of AMD using Stratus OCT. Consensus readings were performed by two certified OCT readers of each reading center using their grading protocol. Common variables of both grading protocols, such as presence of cystoid spaces, subretinal fluid, vitreomacular traction and retinal pigment epithelial detachment, were compared using κ statistics. In addition, the intraclass correlation coefficient (ICC) was calculated for centre point thickness (CPT) of values re-measured manually in the presence of alignment errors.
The reproducibility was dependent on the variable measured with a κ value of 0.81 for the presence of cystoid spaces, 0.78 for the presence of subretinal fluid and 0.795 for the presence of vitreomacular traction. The lowest reproducibility was found for the presence of retinal pigment epithelial detachment with a κ value of 0.51. The CPT was re-measured in 29 out of 100 scans at both sites with an ICC of the re-measured thicknesses of 0.92.
OCT scan data are crucial in monitoring treatment efficacy in AMD clinical trials. For comparison of results obtained by different reading centers, the inter-reading center reproducibility is essential. Although the reproducibility is generally high, the reliability depends on the selected morphological parameters.
Cataract in diabetic patients is a major cause of blindness in developed and developing countries. The pathogenesis of diabetic cataract development is still not fully understood. Recent basic research studies have emphasized the role of the polyol pathway in the initiation of the disease process.
Population-based studies have greatly increased our knowledge concerning the association between diabetes and cataract formation and have defined risk factors for the development of cataract. Diabetic patients also have a higher risk of complications after phacoemulsification cataract surgery compared to nondiabetics. Aldose-reductase inhibitors and antioxidants have been proven beneficial in the prevention or treatment of this sightthreatening condition in in vitro and in vivo experimental studies.
This paper provides an overview of the pathogenesis of diabetic cataract, clinical studies investigating the association between diabetes and cataract development, and current treatment of cataract in diabetics.
To evaluate the effect of systemic bevacizumab (Avastin®) therapy on pigment epithelial detachment (PED) secondary to age‐related macular degeneration (AMD) and to identify prognostic factors for PED regression and improvement in best corrected visual acuity (BCVA).
Prospective uncontrolled pilot study.
Nine patients (nine eyes) received three systemic bevacizumab treatments at 2 week intervals and were examined at baseline, weeks 1, 2, 4, 6 and month 3 by using optical coherence tomography (Stratus OCT™, Carl Zeiss© Meditec, Dublin, California, USA). Changes in maximum PED height and greatest linear diameter (GLD) were planimetrically analysed by using Adobe Photoshop CS and correlated with retinal morphological changes and changes in BCVA.
Systemic bevacizumab therapy was well tolerated. Mean maximum PED height decreased significantly by 21% as early as 1 week (−96 µm (SD 48.8), p<0.01). At 3 months follow‐up, two PEDs resolved completely, mean maximum PED height decreased significantly by 39% (−179 µm (SD 178), p = 0.02) and mean PED GLD by 24% (−714 µm (SD 1010), p = 0.07). Mean BCVA improved significantly by week 2 (+8.7 letters (SD 5.7), p<0.01) and at 3 months with 12.7 letters (SD 6.4) (p<0.01).
In the examined nine patients, systemic bevacizumab therapy showed evidence for an effect on PED secondary to neovascular AMD in terms of a decrease in lesion height and diameter. A high PED at baseline was found to be a negative predictive factor for visual outcome.
AMD; PED; VEGF; bevacizumab; OCT
Age-related macular degeneration (AMD) is still referred to as the leading cause of severe and irreversible visual loss world-wide. The disease has a profound effect on quality of life of affected individuals and represents a major socioeconomic challenge for societies due to the exponential increase in life expectancy and environmental risks. Advances in medical research have identified vascular endothelial growth factor (VEGF) as an important pathophysiological player in neovascular AMD and intraocular inhibition of VEGF as one of the most efficient therapies in medicine. The wide introduction of anti-VEGF therapy has led to an overwhelming improvement in the prognosis of patients affected by neovascular AMD, allowing recovery and maintenance of visual function in the vast majority of patients. However, the therapeutic benefit is accompanied by significant economic investments, unresolved medicolegal debates about the use of off-label substances and overwhelming problems in large population management. The burden of disease has turned into a burden of care with a dissociation of scientific advances and real-world clinical performance. Simultaneously, ground-breaking innovations in diagnostic technologies, such as optical coherence tomography, allows unprecedented high-resolution visualisation of disease morphology and provides a promising horizon for early disease detection and efficient therapeutic follow-up. However, definite conclusions from morphologic parameters are still lacking, and valid biomarkers have yet to be identified to provide a practical base for disease management. The European Society of Retina Specialists offers expert guidance for diagnostic and therapeutic management of neovascular AMD supporting healthcare givers and doctors in providing the best state-of-the-art care to their patients.
Trial registration number
To evaluate efficacy and safety of intravitreal aflibercept (IVT-AFL) in Japanese patients with wet age-related macular degeneration (wAMD) from the VIEW 2 trial.
In this double-masked study, patients were randomised to: 0.5 mg IVT-AFL every 4 weeks (0.5q4); 2 mg IVT-AFL every 4 weeks (2q4); 2 mg IVT-AFL every 8 weeks (2q8) after 3 monthly injections; or 0.5 mg ranibizumab every 4 weeks (Rq4). Main efficacy outcomes included vision maintenance and best-corrected visual acuity (BCVA) at week 52.
At week 52, all Japanese patients in the IVT-AFL groups (n=70) maintained vision, compared with 96% of Japanese patients (n=23/24) treated with ranibizumab. Japanese patients in all treatment groups showed improvement in BCVA after treatment. The Rq4, 2q4 and 2q8 groups experienced similar gains in BCVA from baseline. The 0.5q4 group had higher gains due to an unexpected drop in BCVA between screening and baseline. Central retinal thickness and mean area of choroidal neovascularisation decreased in all treatment groups with similar magnitude. Ocular treatment-emergent adverse events were balanced across treatment groups.
IVT-AFL was effective and well tolerated in Japanese patients. Outcomes in this population were consistent with those in the overall VIEW 2 population.
Trial registration number
Angiogenesis; Clinical Trial; Macula; Neovascularisation; Retina