A fully automatic nerve segmentation and morphometric parameter quantification system for early diagnosis of diabetic neuropathy in corneal images

Diabetic Peripheral Neuropathy (DPN) is one of the most common types of diabetes that can affect the cornea. An accurate analysis of the nerve structures can assist the early diagnosis of this disease. This paper proposes a robust, fast and fully automatic nerve segmentation and morphometric parameter quantification system for corneal confocal microscope images. The segmentation part consists of three main steps. First, a preprocessing step is applied to enhance the visibility of the nerves and remove noise using anisotropic diffusion filtering, specifically a Coherence filter followed by Gaussian filtering. Second, morphological operations are applied to remove unwanted objects in the input image such as epithelial cells and small nerve segments. Finally, an edge detection step is applied to detect all the nerves in the input image. In this step, an efficient algorithm for connecting discontinuous nerves is proposed. In the morphometric parameters quantification part, a number of features are extracted, including thickness, tortuosity and length of nerve, which may be used for the early diagnosis of diabetic polyneuropathy and when planning Laser-Assisted in situ Keratomileusis (LASIK) or Photorefractive keratectomy (PRK). The performance of the proposed segmentation system is evaluated against manually traced ground-truth images based on a database consisting of 498 corneal sub-basal nerve images (238 are normal and 260 are abnormal). In addition, the robustness and efficiency of the proposed system in extracting morphometric features with clinical utility was evaluated in 919 images taken from healthy subjects and diabetic patients with and without neuropathy. We demonstrate rapid (13 seconds/image), robust and effective automated corneal nerve quantification. The proposed system will be deployed as a useful clinical tool to support the expertise of ophthalmologists and save the clinician time in a busy clinical setting

Novel medical imaging technologies for processing epithelium and endothelium layers in corneal confocal images. Developing automated segmentation and quantification algorithms for processing sub-basal epithelium nerves and endothelial cells for early diagnosis of diabetic neuropathy in corneal confocal microscope images

Diabetic Peripheral Neuropathy (DPN) is one of the most common types of diabetes that can affect the cornea. An accurate analysis of the corneal epithelium nerve structures and the corneal endothelial cell can assist early diagnosis of this disease and other corneal diseases, which can lead to visual impairment and then to blindness. In this thesis, fully-automated segmentation and quantification algorithms for processing and analysing sub-basal epithelium nerves and endothelial cells are proposed for early diagnosis of diabetic neuropathy in Corneal Confocal Microscopy (CCM) images. Firstly, a fully automatic nerve segmentation system for corneal confocal microscope images is proposed. The performance of the proposed system is evaluated against manually traced images with an execution time of the prototype is 13 seconds. Secondly, an automatic corneal nerve registration system is proposed. The main aim of this system is to produce a new informative corneal image that contains structural and functional information. Thirdly, an automated real-time system, termed the Corneal Endothelium Analysis System (CEAS) is developed and applied for the segmentation of endothelial cells in images of human cornea obtained by In Vivo CCM. The performance of the proposed CEAS system was tested against manually traced images with an execution time of only 6 seconds per image. Finally, the results obtained from all the proposed approaches have been evaluated and validated by an expert advisory board from two institutes, they are the Division of Medicine, Weill Cornell Medicine-Qatar, Doha, Qatar and the Manchester Royal Eye Hospital, Centre for Endocrinology and Diabetes, UK

Development of Novel Diagnostic Tools for Dry Eye Disease using Infrared Meibography and In Vivo Confocal Microscopy

Dry eye disease (DED) is a multifactorial disease of the ocular surface where tear film instability, hyperosmolarity, neurosensory abnormalities, meibomian gland dysfunction, ocular surface inflammation and damage play a dedicated etiological role. Estimated 5 to 50% of the world population in different demographic locations, age and gender are currently affected by DED. The risk and occurrence of DED increases at a significant rate with age, which makes dry eye a major growing public health issue. DED not only impacts the patient’s quality of vision and life, but also creates a socio-economic burden of millions of euros per year. DED diagnosis and monitoring can be a challenging task in clinical practice due to the multifactorial nature and the poor correlation between signs and symptoms. Key clinical diagnostic tests and techniques for DED diagnosis include tearfilm break up time, tear secretion – Schirmer’s test, ocular surface staining, measurement of osmolarity, conjunctival impression cytology. However, these clinical diagnostic techniques are subjective, selective, require contact, and are unpleasant for the patient’s eye. Currently, new advances in different state-of-the-art imaging modalities provide non-invasive, non- or semi-contact, and objective parameters that enable objective evaluation of DED diagnosis. Among the different and constantly evolving imaging modalities, some techniques are developed to assess morphology and function of meibomian glands, and microanatomy and alteration of the different ocular surface tissues such as corneal nerves, immune cells, microneuromas, and conjunctival blood vessels. These clinical parameters cannot be measured by conventional clinical assessment alone. The combination of these imaging modalities with clinical feedback provides unparalleled quantification information of the dynamic properties and functional parameters of different ocular surface tissues. Moreover, image-based biomarkers provide objective, specific, and non / marginal contact diagnosis, which is faster and less unpleasant to the patient’s eye than the clinical assessment techniques. The aim of this PhD thesis was to introduced deep learning-based novel computational methods to segment and quantify meibomian glands (both upper and lower eyelids), corneal nerves, and dendritic cells. The developed methods used raw images, directly export from the clinical devices without any image pre-processing to generate segmentation masks. Afterward, it provides fully automatic morphometric quantification parameters for more reliable disease diagnosis. Noteworthily, the developed methods provide complete segmentation and quantification information for faster disease characterization. Thus, the developed methods are the first methods (especially for meibomian gland and dendritic cells) to provide complete morphometric analysis. Taken together, we have developed deep learning based automatic system to segment and quantify different ocular surface tissues related to DED namely, meibomian gland, corneal nerves, and dendritic cells to provide reliable and faster disease characterization. The developed system overcomes the current limitations of subjective image analysis and enables precise, accurate, reliable, and reproducible ocular surface tissue analysis. These systems have the potential to make an impact clinically and in the research environment by specifying faster disease diagnosis, facilitating new drug development, and standardizing clinical trials. Moreover, it will allow both researcher and clinicians to analyze meibomian glands, corneal nerves, and dendritic cells more reliably while reducing the time needed to analyze patient images significantly. Finally, the methods developed in this research significantly increase the efficiency of evaluating clinical images, thereby supporting and potentially improving diagnosis and treatment of ocular surface disease

Classification of Corneal Nerve Images Using Machine Learning Techniques

Recent research shows that small nerve fiber damage is an early detector of neuropathy. These small nerve fibers are present in the human cornea and can be visualized through the use of a corneal confocal microscope. A series of images can be acquired from the subbasal nerve plexus of the cornea. Before the images can be quantified for nerve loss, a human expert manually traces the nerves in the image and then classifies the image as having neuropathy or not. Some nerve tracing algorithms are available in the literature, but none of them are reported as being used in clinical practice. An alternate practice is to visually classify the image for neuropathy without quantification. In this paper, we evaluate the potential of various machine learning techniques for automating corneal nerve image classification. First, the images are down-sampled using discrete wavelet transform, filtering and a number of morphological operations. The resulting binary image is used for extracting characteristic features of the image. This is followed by training the classifier on the extracted features. The trained classifier is then used for predicting the state of the nerves in the images. Our experiments yield a classification accuracy of 0.91 reflecting the effectiveness of the proposed method

3D confocal laser-scanning microscopy for large-area imaging of the corneal subbasal nerve plexus

The capability of corneal confocal microscopy (CCM) to acquire high-resolution in vivo images of the densely innervated human cornea has gained considerable interest in using this non-invasive technique as an objective diagnostic tool for staging peripheral neuropathies. Morphological alterations of the corneal subbasal nerve plexus (SNP) assessed by CCM have been shown to correlate well with the progression of neuropathic diseases and even predict future-incident neuropathy. Since the field of view of single CCM images is insufficient for reliable characterisation of nerve morphology, several image mosaicking techniques have been developed to facilitate the assessment of the SNP in large-area visualisations. Due to the limited depth of field of confocal microscopy, these approaches are highly sensitive to small deviations of the focus plane from the SNP layer. Our contribution proposes a new automated solution, combining guided eye movements for rapid expansion of the acquired SNP area and axial focus plane oscillations to guarantee complete imaging of the SNP. We present results of a feasibility study using the proposed setup to evaluate different oscillation settings. By comparing different image selection approaches, we show that automatic tissue classification algorithms are essential to create high-quality mosaic images from the acquired 3D dataset

An automatic corneal subbasal nerve registration system using FFT and phase correlation techniques for an accurate DPN diagnosis

yesConfocal microscopy is employed as a fast and non-invasive way to capture a sequence of images from different layers and membranes of the cornea. The captured images are used to extract useful and helpful clinical information for early diagnosis of corneal diseases such as, Diabetic Peripheral Neuropathy (DPN). In this paper, an automatic corneal subbasal nerve registration system is proposed. The main aim of the proposed system is to produce a new informative corneal image that contains structural and functional information. In addition a colour coded corneal image map is produced by overlaying a sequence of Cornea Confocal Microscopy (CCM) images that differ in their displacement, illumination, scaling, and rotation to each other. An automatic image registration method is proposed based on combining the advantages of Fast Fourier Transform (FFT) and phase correlation techniques. The proposed registration algorithm searches for the best common features between a number of sequenced CCM images in the frequency domain to produce the formative image map. In this generated image map, each colour represents the severity level of a specific clinical feature that can be used to give ophthalmologists a clear and precise representation of the extracted clinical features from each nerve in the image map. Moreover, successful implementation of the proposed system and the availability of the required datasets opens the door for other interesting ideas; for instance, it can be used to give ophthalmologists a summarized and objective description about a diabetic patient’s health status using a sequence of CCM images that have been captured from different imaging devices and/or at different time

Novel methods for subcellular in vivo imaging of the cornea with the Rostock Cornea Module 2.0

The Rostock Cornea Module transforms a confocal laser scanning ophthalmoscope into a corneal confocal laser scanning microscope. In this thesis, an improved version, the Rostock Cornea Module 2.0, and its achieved results were demonstrated. These include a concave contact cap design to attenuate eye movements to improve 3D volume reconstruction, an oscillating focal plane to improve mosaicking of the subbasal nerve plexus, the integration of simultaneous optical coherence tomography, multiwavelength corneal imaging, the clinical usage, and the automated morphological characterization

Neuropathy Classification of Corneal Nerve Images Using Artificial Intelligence

Nerve variations in the human cornea have been associated with alterations in the neuropathy state of a patient suffering from chronic diseases. For some diseases, such as diabetes, detection of neuropathy prior to visible symptoms is important, whereas for others, such as multiple sclerosis, early prediction of disease worsening is crucial. As current methods fail to provide early diagnosis of neuropathy, in vivo corneal confocal microscopy enables very early insight into the nerve damage by illuminating and magnifying the human cornea. This non-invasive method captures a sequence of images from the corneal sub-basal nerve plexus. Current practices of manual nerve tracing and classification impede the advancement of medical research in this domain. Since corneal nerve analysis for neuropathy is in its initial stages, there is a dire need for process automation. To address this limitation, we seek to automate the two stages of this process: nerve segmentation and neuropathy classification of images. For nerve segmentation, we compare the performance of two existing solutions on multiple datasets to select the appropriate method and proceed to the classification stage. Consequently, we approach neuropathy classification of the images through artificial intelligence using Adaptive Neuro-Fuzzy Inference System, Support Vector Machines, Naïve Bayes and k-nearest neighbors. We further compare the performance of machine learning classifiers with deep learning. We ascertained that nerve segmentation using convolutional neural networks provided a significant improvement in sensitivity and false negative rate by at least 5% over the state-of-the-art software. For classification, ANFIS yielded the best classification accuracy of 93.7% compared to other classifiers. Furthermore, for this problem, machine learning approaches performed better in terms of classification accuracy than deep learning

NerveFormer: A Cross-Sample Aggregation Network for Corneal Nerve Segmentation

The segmentation of corneal nerves in corneal confocal microscopy (CCM) is of great to the quantification of clinical parameters in the diagnosis of eye-related diseases and systematic diseases. Existing works mainly use convolutional neural networks to improve the segmentation accuracy, while further improvement is needed to mitigate the nerve discontinuity and noise interference. In this paper, we propose a novel corneal nerve segmentation network, named NerveFormer, to resolve the above-mentioned limitations. The proposed NerveFormer includes a Deformable and External Attention Module (DEAM), which exploits the Transformer-based Deformable Attention (TDA) and External Attention (TEA) mechanisms. TDA is introduced to explore the local internal nerve features in a single CCM, while TEA is proposed to model global external nerve features across different CCM images. Specifically, to efficiently fuse the internal and external nerve features, TDA obtains the query set required by TEA, thereby strengthening the characterization ability of TEA. Therefore, the proposed model aggregates the learned features from both single-sample and cross-sample, allowing for better extraction of corneal nerve features across the whole dataset. Experimental results on two public CCM datasets show that our proposed method achieves state-of-the-art performance, especially in terms of segmentation continuity and noise discrimination

Fully automated computer system for diagnosis of corneal diseases. Development of image processing technologies for the diagnosis of Acanthamoeba and Fusarium diseases in confocal microscopy images

Confocal microscopy demonstrated its value in the diagnosis of Acanthamoeba and fungal keratitis which considered sight-threatening corneal diseases. However, it can be difficult to find and train confocal microscopy graders to accurately detect Acanthamoeba cysts and fungal filaments in the images. Use of an automated system could overcome this problem and help to start the correct treatment more quickly. Also, response to treatment can be difficult to assess in infectious keratitis using clinical examination alone, but there is evidence that the morphology of filaments and cysts may change over time with the use of correct treatment. An automated system to analyse confocal microscopy images for such changes would also assist clinicians in determining whether the ulcer is improving, or whether a change of treatment is needed. This research proposes a fully automated novel system with GUI to detect cysts and hyphae (filaments) and measure useful quantitative parameters for them through many stages; Image enhancement, image segmentation, quantitative analysis for detected cysts and hyphae, and registration and tracking of ordered sequence of images. The performance of the proposed segmentation procedure is evaluated by comparing between the manual and the automated traced images of the dataset that was provided by the Manchester Royal Eye Hospital. The positive predictive values rate of cysts for Acanthamoeba images was 76%. For detected hyphae in Fusarium images, many standard measurements were computed. The accuracy of their values was quantified by calculating the percent error rate for each measurement and which ranged from 23% to 49%