Ultrahigh-resolution Optical Coherence Tomography Research Articles

Advances in Imaging Technology of Anterior Segment of the Eye.

Advances in imaging technology and computer science have allowed the development of newer assessment of the anterior segment, including Corvis ST, Brillouin microscopy, ultrahigh-resolution optical coherence tomography, and artificial intelligence. They enable accurate and precise assessment of structural and biomechanical alterations associated with anterior segment disorders. This review will focus on these 4 new techniques, and a brief overview of these modalities will be introduced. The authors will also discuss the recent advances in research regarding these techniques and potential application of these techniques in clinical practice. Many studies on these modalities have reported promising results, indicating the potential for more detailed comprehensive understanding of the anterior segment tissues.

Relationship between corneal biomechanical parameters and corneal sublayer thickness measured by Corvis ST and UHR-OCT in keratoconus and normal eyes

BackgroundTo explore the relationship between corneal biomechanical parameters and corneal sublayer thickness using corneal visualization Scheimpflug technology (Corvis ST) and ultrahigh-resolution optical coherence tomography (UHR-OCT) in clinical and suspected keratoconus and normal eyes.MethodsCross-sectional prospective study. A total of 94 eyes of 70 participants were recruited. Twenty five eyes of 19 keratoconus patients, 52 eyes of 34 patients showing high risk of developing keratoconus according to the Belin/Ambrosio Enhanced Ectasia Display, and each eye of 17 normal subjects were enrolled. All participants underwent Corvis ST, Pentacam, and UHR-OCT examinations at the same time. Stiffness parameter A1 (SP-A1), deformation amplitude ratio (DA ratio), and other biomechanical parameters were recorded using Corvis ST. The vertical and horizontal thickness profiles of central 3 mm corneal epithelium, Bowman’s layer, and stroma as measured by the perpendicular distance between the neighboring interfaces were generated using UHR-OCT. The flat keratometry and steep keratometry were obtained using Pentacam. Analysis of correlation was applied to explore the association between variables.ResultsMost of the biomechanical parameters and corneal sublayer thickness profiles showed statistical differences among three groups. A statistically significant linear relationship was noted between SP-A1 and DA ratio in all three groups. SP-A1 was found to be positively correlated with epithelial and Bowman’s layer thickness in the keratoconus (KC) group, and with stromal thickness in all three groups. In the normal and suspected keratoconus (SKC) groups, only stromal thickness was included in the stepwise linear regression to predict SP-A1, whereas in the KC group, steep keratometry and Bowman’s layer thickness were included.ConclusionsSignificant and different correlations were noted between corneal stiffness and corneal sublayer thickness in different groups, indicating that corneal sublayers may play different roles in maintaining corneal biomechanical stability between keratoconus and normal eyes.

Issue Information

The cover image is based on the Letter to the Editor In vivo characterization of extramammary Paget's disease by ultra-high cellular resolution optical coherence tomography by Jen-Yu Wanget al., https://doi.org/10.1111/srt.12914.

The Association between Tear Film Thickness as Measured with OCT and Symptoms and Signs of Dry Eye Disease: A Pooled Analysis of 6 Clinical Trials

Purpose: To determine the association between tear film thickness (TFT) as measured with ultra-high resolution optical coherence tomography (UHR-OCT) and signs and symptoms of dry eye disease (DED). Methods: A total of 450 eyes from 225 patients with DED from six different randomized clinical trials were included in this pooled analysis. In all subjects, TFT was measured with a custom-built UHR-OCT system. Symptoms of DED were quantified using a standardized Ocular Surface Disease Index (OSD)I questionnaire and clinical signs including tear film break up time (TFBUT) and Schirmer I test were assessed. Associations of the average TFT with OSDI, TFBUT, and Schirmer I test were calculated using a linear regression analysis. Results: The average TFT of the included sample (mean age, 45.0 ± 13.3 years; 65% female) was 4.2 ± 0.5 µm and the OSDI 36.2 ± 10.4. A significant negative correlation was found between TFT and OSDI (r = −0.36 to −0.31; p < 0.001). Tear break up time and Schirmer I test were not correlated with OSDI. Significant albeit weak correlations were found between TFT and TFBUT (r = 0.17 to 0.25; p < 0.01) as well as Schirmer I (r = 0.36 to 0.37; p < 0.001). Subgroup analysis revealed that the correlation was stronger in the subjects with abnormal Schirmer I (<15 mm; r = 0.50 to 0.54; p < 0.001). Conclusions: The present study demonstrates an objective measurement of TFT using a novel OCT approach for DED that correlates with symptoms and signs of DED. Our data are consistent with the idea that TFT represents the aqueous-deficient component of DED.

Towards ultrahigh resolution OCT based endoscopical pituitary gland and adenoma screening: a performance parameter evaluation.

Ultrahigh resolution optical coherence tomography (UHR-OCT) for differentiating pituitary gland versus adenoma tissue has been investigated for the first time, indicating more than 80% accuracy. For biomarker identification, OCT images of paraffin embedded tissue are correlated to histopathological slices. The identified biomarkers are verified on fresh biopsies. Additionally, an approach, based on resolution modified UHR-OCT ex vivo data, investigating optical performance parameters for the realization in an in vivo endoscope is presented and evaluated. The identified morphological features–cell groups with reticulin framework–detectable with UHR-OCT showcase a promising differentiation ability, encouraging endoscopic OCT probe development for in vivo application.

Evaluation of ultrahigh-resolution optical coherence tomography for basal cell carcinoma, seborrheic keratosis, and nevus.

Basal cell carcinoma, seborrheic keratosis, and nevus are common skin conditions. Though most of the skin diseases can be distinguished from each other by physician's naked eyes, the diagnostic accuracy is not 100%. The accurate diagnosis and assessment of three diseases make a big difference on the clinical management. Nowadays, biopsy is still the gold standard for diagnosis even it is invasive, time-consuming, and painful. Ultrahigh-resolution optical coherence tomography is an emerging technology that can produce in situ, cellular-resolution, real-time, continuous, 3D images in a noninvasive way. In our study, four basal cell carcinoma patients, five seborrheic keratosis patients, and 10 nevus patients who were diagnosed by histology were studied by ultrahigh-resolution optical coherence tomography after visual examination by experienced dermatologists. Cellular contrast was utilized to clearly identify the features of the three skin diseases. The features including such as hyperkeratosis (horn pseudocysts), papillomatosis, intraepidermal nests, elongated, and expanded rete ridge can be visualized in seborrheic keratosis. Tumor nodular, mucin surrounding with tumor (retraction space in histopathology), tumor subtype, and necrosis were featured in basal cell carcinoma. Pigment was characterized in epidermis and dermis. The comparison of ultrahigh-resolution optical coherence tomography images reveals a strong correlation with histological images. Ultrahigh-resolution optical coherence tomography can complement existing diagnostic techniques for investigating seborrheic keratosis, basal cell carcinoma and nevus, and show enormous potential in vivo applications for the three skin diseases in the future.

Machine learning helps improve diagnostic ability of subclinical keratoconus using Scheimpflug and OCT imaging modalities

PurposeTo develop an automated classification system using a machine learning classifier to distinguish clinically unaffected eyes in patients with keratoconus from a normal control population based on a combination of Scheimpflug camera images and ultra-high-resolution optical coherence tomography (UHR-OCT) imaging data.MethodsA total of 121 eyes from 121 participants were classified by 2 cornea experts into 3 groups: normal (50 eyes), with keratoconus (38 eyes) or with subclinical keratoconus (33 eyes). All eyes were imaged with a Scheimpflug camera and UHR-OCT. Corneal morphological features were extracted from the imaging data. A neural network was used to train a model based on these features to distinguish the eyes with subclinical keratoconus from normal eyes. Fisher’s score was used to rank the differentiable power of each feature. The receiver operating characteristic (ROC) curves were calculated to obtain the area under the ROC curves (AUCs).ResultsThe developed classification model used to combine all features from the Scheimpflug camera and UHR-OCT dramatically improved the differentiable power to discriminate between normal eyes and eyes with subclinical keratoconus (AUC = 0.93). The variation in the thickness profile within each individual in the corneal epithelium extracted from UHR-OCT imaging ranked the highest in differentiating eyes with subclinical keratoconus from normal eyes.ConclusionThe automated classification system using machine learning based on the combination of Scheimpflug camera data and UHR-OCT imaging data showed excellent performance in discriminating eyes with subclinical keratoconus from normal eyes. The epithelial features extracted from the OCT images were the most valuable in the discrimination process. This classification system has the potential to improve the differentiable power of subclinical keratoconus and the efficiency of keratoconus screening.

High-Speed, Ultrahigh-Resolution Spectral-Domain OCT with Extended Imaging Range Using Reference Arm Length Matching.

PurposeTo develop high-speed, extended-range, ultrahigh-resolution spectral-domain optical coherence tomography (UHR SD-OCT) and demonstrate scan protocols for clinical retinal imaging.MethodsA UHR SD-OCT operating at 840-nm with 150-nm bandwidths was developed. The axial imaging range was extended by dynamically matching reference arm length to the retinal contour during acquisition. Two scan protocols were demonstrated for imaging healthy participants and patients with dry age-related macular degeneration. A high-definition raster protocol with intra–B-scan reference arm length matching (ReALM) was used for high-quality cross-sectional imaging. A cube volume scan using horizontal and vertical rasters with inter–B-scan ReALM and software motion correction was used for en face and cross-sectional imaging. Linear OCT signal display enhanced visualization of outer retinal features.ResultsUHR SD-OCT was demonstrated at 128- and 250-kHz A-scan rates with 2.7 µm axial resolution and a 1.2-mm, 6-dB imaging range in the eye. Dynamic ReALM was used to maintain the retina within the 6-dB imaging range over wider fields of view. Outer retinal features, including the rod and cone interdigitation zones, retinal pigment epithelium, and Bruch's membrane were visualized and alterations observed in age-related macular degeneration eyes.ConclusionsTechnological advances and dynamic ReALM improve the imaging performance and clinical usability of UHR SD-OCT.Translational RelevanceThese advances should simplify clinical imaging workflow, reduce imaging session times, and improve yield of high quality images. Improved visualization of photoreceptors, retinal pigment epithelium, and Bruch's membrane may facilitate diagnosis and monitoring of age-related macular degeneration and other retinal diseases.

Multi-modal Anterior Eye Imager Combining Ultra-High Resolution OCT and Microvascular Imaging for Structural and Functional Evaluation of the Human Eye

To establish complementary information for the diagnosis and evaluation of ocular surface diseases, we developed a multi-modal, non-invasive optical imaging platform by combining ultra-high resolution optical coherence tomography (UHR-OCT) with a microvascular imaging system based on slit-lamp biomicroscopy. Our customized UHR-OCT module achieves an axial resolution of ≈2.9 μm in corneal tissue with a broadband light source and an A-line acquisition rate of 24 kHz with a line array CCD camera. The microvascular imaging module has a lateral resolution of 3.5 μm under maximum magnification of ≈187.5× with an imaging rate of 60 frames/s, which is sufficient to image the conjunctival vessel network and record the movement trajectory of clusters of red blood cells. By combining the imaging optical paths of different modules, our customized multi-modal anterior eye imaging platform is capable of performing real-time cross-sectional UHR-OCT imaging of the anterior eye, conjunctival vessel network imaging, high-resolution conjunctival blood flow videography, fluorescein staining and traditional slit-lamp imaging on a single device. With self-developed software, a conjunctival vessel network image and blood flow videography were further analyzed to acquire quantitative morphological and hemodynamics parameters, including vessel fractal dimensions, blood flow velocity and vessel diameters. The ability of our multi-modal anterior eye imager to provide both structural and functional information for ophthalmic clinical applications was demonstrated on a healthy human subject and a keratitis patient.

Shortened Pattern Electroretinogram Latency and Impaired Autoregulatory Dynamics to Steady-State Stimuli in Patients With Multiple Sclerosis.

The steady-state pattern electroretinogram (PERG) is a sensitive measure of retinal ganglion cell (RGC) function that includes within-test progressive changes-adaptation-reflecting RGC autoregulatory dynamics. Comprehensive PERG assessment in patients with multiple sclerosis (MS) (with or without optic neuritis [ON]) may provide unique information about RGC dysfunction and its progression, as well as a comparison between functional loss and structural loss as measured by optical coherence tomography (OCT). The goal of this project was to measure steady-state PERG components and their associations with intraretinal layer thicknesses in MS. One hundred forty eyes of 70 patients with relapsing-remitting MS and 126 eyes of 63 age- and sex-matched healthy control subjects (HC) were investigated using a new-generation PERG method and ultrahigh-resolution OCT. Of MS eyes, there were 30 eyes with ON (MSON), 22 non-ON fellow eyes (MSFE), and 88 non-ON MS eyes (MSNON). PERG amplitude, phase (latency), and adaptation of amplitude and phase were measured and correlated with OCT-determined thicknesses of intraretinal layers. The average PERG amplitude in MSON eyes was significantly lower than MSFE (P = 0.007), MSNON (P = 0.002), and HC (P < 0.001). The PERG amplitude in MSFE eyes was also significantly lower than HC (P = 0.039). The PERG latency in MSON eyes was significantly shorter than in MSFE (P = 0.001), MSNON (P = 0.002), and HC (P < 0.001). The PERG latency in MSFE (P = 0.007) and MSNON (P = 0.002) was significantly shorter than in HC. However, no significant differences were found between MSFE and MSNON (P > 0.05). PERG adaptation of amplitude in MSON was significantly lower than that in MSNON (P = 0.039) and HC (P = 0.037). Both the amplitude and latency in the MS eyes were significantly correlated with the thicknesses of the macular retinal nerve fiber layer (mRNFL) and ganglion cell-inner plexiform layer (GCIPL). Shortened PERG latency and impaired autoregulatory dynamics occurred in MS, suggesting preferential dysfunction of small, slower RGC axons and decreased ability of RGC to autoregulate their gain in response to PERG stimulus. The established relations of PERG measurements with intraretinal thickness measurements suggested that PERG losses were primarily associated with GCIPL and mRNFL thinning.

Interferometer-in-Spectrometer for High-Resolution Optical Coherence Tomography

Ultrahigh-resolution optical coherence tomography provides an axial resolution of 1-2 μm for resolving cellular structures of biological tissues critical for the diagnosis of diseases. However, it requires a relatively large spectral bandwidth which is not supported by the key components of the imaging system. We propose a novel spectral-domain OCT design, termed interferometer-in-spectrometer, which is able to compensate the bandwidth limitations of the grating and the line scan sensor by spectral shaping without compromising the signal intensity and adding the system cost. The advantage of axial resolution and ranging depth over the standard design is experimentally validated using the standard testing method and fresh swine cornea ex vivo. Moreover, opportunities that opened up by this new scheme for improving the performances of spectral-domain OCT are also discussed.

Wavelet Features of the Thickness Map of Retinal Ganglion Cell-Inner Plexiform Layer Best Discriminate Prior Optic Neuritis in Patients With Multiple Sclerosis

The goal of this study was to analyze wavelet features of topographic thickness maps of the retinal ganglion cell-inner plexiform layer (GCIPL) and evaluate their discrimination ability in patients with multiple sclerosis (MS) and a history of optic neuritis (ON). Twenty-nine patients with relapsing-remitting MS and a history of ON were recruited together with 63 age- and sex-matched controls (HC). There were 33 eyes with a history of ON (MSON), 25 non-ON fellow eyes (MSFE) and 63 HC eyes. Ultrahigh-resolution optical coherence tomography was used to image the macula of each participant, and the volumetric dataset was segmented to yield a topographic thickness map of the GCIPL. The thickness map was analyzed using discrete wavelet transform to extract useful features, which were further analyzed with three machine learning methods, including logistic regression (LR), logistic regression regularized with the elastic net penalty (LR-EN), and support vector machine (SVM), for classification between groups. LR-EN with nested leave-one-out cross-validation resulted in 94% (83%) sensitivity and 100% (97%) specificity in discriminating MSON (MSFE) eyes from HC eyes in the training data and 88% (64%) sensitivity and 94% (94%) specificity in discriminating MSON (MSFE) eyes from HC eyes in the validation data, which were similar to or better than those resulting from LR and SVM. LR-EN improved the sensitivity and specificity of discriminating prior ON and MSFE eyes in patients with MS from HC eyes compared with traditional thickness analysis. It may be promising in facilitating the diagnosis of subclinical ON in patients with MS.

Ultra-High-Resolution (UHR) Optical Coherence Tomography (OCT) in the Upper Airways: Aspect of Combined High-Speed Films and UHR OCT in the Larynx

Ultra-High-Resolution (UHR) Optical Coherence Tomography (OCT) in the Upper Airways: Aspect of Combined High-Speed Films and UHR OCT in the Larynx

Focal Thickness Reduction of the Ganglion Cell-Inner Plexiform Layer Best Discriminates Prior Optic Neuritis in Patients With Multiple Sclerosis.

PurposeThe goal was to visualize topographic thickness maps of the intraretinal layers and evaluate their discrimination abilities and relationships with clinical manifestations in patients with multiple sclerosis (MS) and a history of optic neuritis (ON).MethodsThirty patients with relapsing-remitting MS (34 eyes with a history of ON [MSON] and 26 non-ON fellow eyes [MSFE]) were recruited together with 63 age- and sex-matched controls (HC). Ultrahigh resolution optical coherence tomography was used to image the macula and the volumetric data set was segmented to yield six intraretinal layers. Topographic thickness maps were aligned and averaged for the visualization. The thickness maps were partitioned using the Early Treatment Diabetic Retinopathy Study (ETDRS) and related to Sloan low-contrast letter acuity (LCLA), Expanded Disability Status Scale (EDSS), and disease duration.ResultsFocal thickness reduction occurred in the macular retinal nerve fiber layer (mRNFL) and ganglion cell-inner plexiform layer (GCIPL), with the most profound reduction occurring in MSON eyes (P < 0.05). A horseshoe-like thickness reduction pattern (U Zone) in the GCIPL appeared in MSON. The thickness of the U Zone had better discrimination power than the ETDRS partitions (area under the curve = 0.97) and differentiated 96% of MSON from HC. The thickness of the U Zone was positively correlated to 2.5% LCLA (r = 0.38, P < 0.05) and 1.25% LCLA (r = 0.57, P < 0.05).ConclusionsThe horseshoe-like thickness reduction of the GCIPL appeared to be an ON-specific focal thickness alteration with the highest discrimination power of prior ON.

In vivo corneal endothelium imaging using ultrahigh resolution OCT.

We investigate the influence of optical coherence tomography (OCT) system resolution on high-quality in vivo en face corneal endothelial cell images of the monkey eye, to allow for quantitative analysis of cell density. We vary the lateral resolution of the ultrahigh resolution (UHR) OCT system (centered at 850 nm) by using different objectives, and the axial resolution by windowing the source spectrum. By suppressing the motion of the animal, we are able to obtain a high-quality en face corneal endothelial cell map in vivo using UHR OCT for the first time with a lateral resolution of 3.1 µm. Increasing lateral resolution did not result in a better image quality but a smaller field of view (FOV), and the axial resolution had little impact on the visualization of corneal endothelial cells. Quantitative analysis of cell density was performed on in vivo en face OCT images of corneal endothelial cells, and the results are in agreement with previously reported data. Our study may offer a practical guideline for designing OCT systems that allow for in vivo corneal endothelial cell imaging with high quality.

Ultrahigh-resolution optical coherence tomography/angiography with an economic and compact supercontinuum laser

In this study, a Q-switch pumped supercontinuum laser (QS-SCL) is used as a light source for in vivo imaging via ultrahigh-resolution optical coherence tomography and angiography (UHR-OCT/OCTA). For this purpose, an OCT system based on a spectral-domain detection scheme is constructed, and a spectrometer with a spectral range of 635 - 875 nm is designed. The effective full-width at half maximum of spectrum covers 150 nm, and the corresponding axial and transverse resolutions are 2 and 10 µm in air, respectively. The relative intensity noise of the QS-SCL and mode-locked SCL is quantitatively compared. Furthermore, a special processing algorithm is developed to eliminate the intrinsic noise of QS-SCL. This work demonstrates that QS-SCLs can effectively reduce the cost and size of UHR-OCT/OCTA instruments, making clinical applications feasible.

Corneal epithelial thickness profile in dry-eye disease.

To characterize and evaluate the use of corneal epithelial profile maps generated by an ultrahigh-resolution optical coherence tomography (UHR-OCT) in the diagnosis and management of dry-eye disease (DED). This prospective, interventional case-control study included 115 eyes of 71 subjects (52 DED and 19 controls) imaged using an UHR-OCT. Average, maximum, and minimum, range of corneal epithelial thicknesses were extracted from epithelial profile maps. Surface regularity was quantified using the range and variance of the epithelial thickness measured along a horizontal UHR-OCT scan. The variance of thickness measurements along a scan was named epithelial irregularity factor (EIF). Symptoms of 31 DED patients (55 eyes) were quantified by questionnaire and correlated to epithelial profile findings, fluorescein staining, tear breakup time, and Schirmer's test. Twenty-one DED eyes were administered autologous serum drops and follow-up UHR-OCT images were captured. DED patients had a highly irregular corneal epithelial surface compared with controls. Epithelial thickness profile variance (EIF) and range were significantly higher in DED as compared with controls (5.79 vs. 0.77, p < 0.001 and 7.6 vs. 4.6 μm, p < 0.001). Both parameters were highly significantly correlated with questionnaire scores (EIF: r = 0.778; p < 0.001, range: r = 0.737; p < 0.001). Follow-up showed a statistically significant reduction in epithelial thickness profile variance and range of treated patients ( p < 0.001). DED patients have irregular epithelial surface that can be quantified using UHR-OCT generated CEP maps. Epithelial thickness profile range and EIF correlate accurately with patients' symptoms and could be used to follow-up patients and response to treatment.

Characterization of dry eye disease in a mouse model by optical coherence tomography and fluorescein staining.

A custom-built ultrahigh-resolution optical coherence tomography (UHR-OCT) system and fluorescein staining were employed for investigation of a scopolamine induced dry eye mouse model. Acquired data was used to evaluate common and complementary findings of the two modalities. Central corneal thickness as measured by UHR-OCT increased significantly over the study period of 24 hours, from 89.0 ± 3.57 µm to 92.2 ± 4.07 µm. Both techniques were able to show corneal lesions with a large range of severity. Localized fluorescein staining was detected in 5% and diffuse staining in 45% of cases where no epithelial damage was visible with OCT. However, OCT revealed stromal defects in 6% and endothelial defects in 18% of the cases, which could not be visualized via fluorescein staining. Thus, while fluorescein staining widely detected defects of the corneal surface in a mouse model of dry eye disease, OCT non-invasively revealed additional information about defect depth and involvement of particular layers.

Fully Automated Postlumpectomy Breast Margin Assessment Utilizing Convolutional Neural Network Based Optical Coherence Tomography Image Classification Method

The purpose of this study was to develop a deep learning classification approach to distinguish cancerous from noncancerous regions within optical coherence tomography (OCT) images of breast tissue for potential use in an intraoperative setting for margin assessment. A custom ultrahigh-resolution OCT (UHR-OCT) system with an axial resolution of 2.7 μm and a lateral resolution of 5.5 μm was used in this study. The algorithm used an A-scan-based classification scheme and the convolutional neural network (CNN) was implemented using an 11-layer architecture consisting of serial 3 × 3 convolution kernels. Four tissue types were classified, including adipose, stroma, ductal carcinoma in situ, and invasive ductal carcinoma. The binary classification of cancer versus noncancer with the proposed CNN achieved 94% accuracy, 96% sensitivity, and 92% specificity. The mean five-fold validation F1 score was highest for invasive ductal carcinoma (mean standard deviation, 0.89 ± 0.09) and adipose (0.79 ± 0.17), followed by stroma (0.74 ± 0.18), and ductal carcinoma in situ (0.65 ± 0.15). It is feasible to use CNN based algorithm to accurately distinguish cancerous regions in OCT images. This fully automated method can overcome limitations of manual interpretation including interobserver variability and speed of interpretation and may enable real-time intraoperative margin assessment.

This issue of Acta

This issue of Acta