Patients with multiple sclerosis demonstrate reduced subbasal corneal nerve fibre density.

BACKGROUND: Many studies in multiple sclerosis (MS) have investigated the retina. Little, however, is known about the effect of MS on the cornea, which is innervated by the trigeminal nerve. It is the site of neural-immune interaction with local dendritic cells reacting in response to environmental stimuli. OBJECTIVE: This study aims to investigate the effect of MS on corneal nerve fibres and dendritic cells in the subbasal nerve plexus using in vivo confocal microscopy (IVCM). METHODS: We measured the corneal nerve fibre and dendritic cell density in 26 MS patients and matched healthy controls using a Heidelberg Retina Tomograph with cornea module. Disease severity was assessed with the Multiple Sclerosis Functional Composite, Expanded Disability Status Scale, visual acuity and retinal optical coherence tomography. RESULTS: We observed significant reduction in total corneal nerve fibre density in MS patients compared to controls. Dendritic cell density was similar in both groups. Reduced total nerve fibre density was associated with worse clinical severity but not with previous clinical trigeminal symptoms, retinal neuro-axonal damage, visual acuity or disease duration. CONCLUSION: Corneal nerve fibre density is a promising new imaging marker for the assessment of disease severity in MS and should be investigated further.

Intraretinal Layer Segmentation Using Cascaded Compressed U-Nets.

Reliable biomarkers quantifying neurodegeneration and neuroinflammation in central nervous system disorders such as Multiple Sclerosis, Alzheimer's dementia or Parkinson's disease are an unmet clinical need. Intraretinal layer thicknesses on macular optical coherence tomography (OCT) images are promising noninvasive biomarkers querying neuroretinal structures with near cellular resolution. However, changes are typically subtle, while tissue gradients can be weak, making intraretinal segmentation a challenging task. A robust and efficient method that requires no or minimal manual correction is an unmet need to foster reliable and reproducible research as well as clinical application. Here, we propose and validate a cascaded two-stage network for intraretinal layer segmentation, with both networks being compressed versions of U-Net (CCU-INSEG). The first network is responsible for retinal tissue segmentation from OCT B-scans. The second network segments eight intraretinal layers with high fidelity. At the post-processing stage, we introduce Laplacian-based outlier detection with layer surface hole filling by adaptive non-linear interpolation. Additionally, we propose a weighted version of focal loss to minimize the foreground-background pixel imbalance in the training data. We train our method using 17,458 B-scans from patients with autoimmune optic neuropathies, i.e., multiple sclerosis, and healthy controls. Voxel-wise comparison against manual segmentation produces a mean absolute error of 2.3 µm, outperforming current state-of-the-art methods on the same data set. Voxel-wise comparison against external glaucoma data leads to a mean absolute error of 2.6 µm when using the same gold standard segmentation approach, and 3.7 µm mean absolute error in an externally segmented data set. In scans from patients with severe optic atrophy, 3.5% of B-scan segmentation results were rejected by an experienced grader, whereas this was the case in 41.4% of B-scans segmented with a graph-based reference method. The validation results suggest that the proposed method can robustly segment macular scans from eyes with even severe neuroretinal changes.

Spinocerebellar ataxia type 14: refining clinicogenetic diagnosis in a rare adult-onset disorder.

OBJECTIVES: Genetic variant classification is a challenge in rare adult-onset disorders as in SCA-PRKCG (prior spinocerebellar ataxia type 14) with mostly private conventional mutations and nonspecific phenotype. We here propose a refined approach for clinicogenetic diagnosis by including protein modeling and provide for confirmed SCA-PRKCG a comprehensive phenotype description from a German multi-center cohort, including standardized 3D MR imaging. METHODS: This cross-sectional study prospectively obtained neurological, neuropsychological, and brain imaging data in 33 PRKCG variant carriers. Protein modeling was added as a classification criterion in variants of uncertain significance (VUS). RESULTS: Our sample included 25 cases confirmed as SCA-PRKCG (14 variants, thereof seven novel variants) and eight carriers of variants assigned as VUS (four variants) or benign/likely benign (two variants). Phenotype in SCA-PRKCG included slowly progressive ataxia (onset at 4-50 years), preceded in some by early-onset nonprogressive symptoms. Ataxia was often combined with action myoclonus, dystonia, or mild cognitive-affective disturbance. Inspection of brain MRI revealed nonprogressive cerebellar atrophy. As a novel finding, a previously not described T2 hyperintense dentate nucleus was seen in all SCA-PRKCG cases but in none of the controls. INTERPRETATION: In this largest cohort to date, SCA-PRKCG was characterized as a slowly progressive cerebellar syndrome with some clinical and imaging features suggestive of a developmental disorder. The observed non-ataxia movement disorders and cognitive-affective disturbance may well be attributed to cerebellar pathology. Protein modeling emerged as a valuable diagnostic tool for variant classification and the newly described T2 hyperintense dentate sign could serve as a supportive diagnostic marker of SCA-PRKCG.

Normative Data and Minimally Detectable Change for Inner Retinal Layer Thicknesses Using a Semi-automated OCT Image Segmentation Pipeline.

Neurodegenerative and neuroinflammatory diseases regularly cause optic nerve and retinal damage. Evaluating retinal changes using optical coherence tomography (OCT) in diseases like multiple sclerosis has thus become increasingly relevant. However, intraretinal segmentation, a necessary step for interpreting retinal changes in the context of these diseases, is not standardized and often requires manual correction. Here we present a semi-automatic intraretinal layer segmentation pipeline and establish normative values for retinal layer thicknesses at the macula, including dependencies on age, sex, and refractive error. Spectral domain OCT macular 3D volume scans were obtained from healthy participants using a Heidelberg Engineering Spectralis OCT. A semi-automated segmentation tool (SAMIRIX) based on an interchangeable third-party segmentation algorithm was developed and employed for segmentation, correction, and thickness computation of intraretinal layers. Normative data is reported from a 6 mm Early Treatment Diabetic Retinopathy Study (ETDRS) circle around the fovea. An interactive toolbox for the normative database allows surveying for additional normative data. We cross-sectionally evaluated data from 218 healthy volunteers (144 females/74 males, age 36.5 ± 12.3 years, range 18-69 years). Average macular thickness (MT) was 313.70 ± 12.02 µm, macular retinal nerve fiber layer thickness (mRNFL) 39.53 ± 3.57 µm, ganglion cell and inner plexiform layer thickness (GCIPL) 70.81 ± 4.87 µm, and inner nuclear layer thickness (INL) 35.93 ± 2.34 µm. All retinal layer thicknesses decreased with age. MT and GCIPL were associated with sex, with males showing higher thicknesses. Layer thicknesses were also positively associated with each other. Repeated-measurement reliability for the manual correction of automatic intraretinal segmentation results was excellent, with an intra-class correlation coefficient >0.99 for all layers. The SAMIRIX toolbox can simplify intraretinal segmentation in research applications, and the normative data application may serve as an expandable reference for studies, in which normative data cannot be otherwise obtained.

Active contour method for ILM segmentation in ONH volume scans in retinal OCT.

The optic nerve head (ONH) is affected by many neurodegenerative and autoimmune inflammatory conditions. Optical coherence tomography can acquire high-resolution 3D ONH scans. However, the ONH's complex anatomy and pathology make image segmentation challenging. This paper proposes a robust approach to segment the inner limiting membrane (ILM) in ONH volume scans based on an active contour method of Chan-Vese type, which can work in challenging topological structures. A local intensity fitting energy is added in order to handle very inhomogeneous image intensities. A suitable boundary potential is introduced to avoid structures belonging to outer retinal layers being detected as part of the segmentation. The average intensities in the inner and outer region are then rescaled locally to account for different brightness values occurring among the ONH center. The appropriate values for the parameters used in the complex computational model are found using an optimization based on the differential evolution algorithm. The evaluation of results showed that the proposed framework significantly improved segmentation results compared to the commercial solution.

Optic nerve head three-dimensional shape analysis.

We present a method for optic nerve head (ONH) 3-D shape analysis from retinal optical coherence tomography (OCT). The possibility to noninvasively acquire in vivo high-resolution 3-D volumes of the ONH using spectral domain OCT drives the need to develop tools that quantify the shape of this structure and extract information for clinical applications. The presented method automatically generates a 3-D ONH model and then allows the computation of several 3-D parameters describing the ONH. The method starts with a high-resolution OCT volume scan as input. From this scan, the model-defining inner limiting membrane (ILM) as inner surface and the retinal pigment epithelium as outer surface are segmented, and the Bruch's membrane opening (BMO) as the model origin is detected. Based on the generated ONH model by triangulated 3-D surface reconstruction, different parameters (areas, volumes, annular surface ring, minimum distances) of different ONH regions can then be computed. Additionally, the bending energy (roughness) in the BMO region on the ILM surface and 3-D BMO-MRW surface area are computed. We show that our method is reliable and robust across a large variety of ONH topologies (specific to this structure) and present a first clinical application.

CuBe: parametric modeling of 3D foveal shape using cubic Bézier.

Optical coherence tomography (OCT) allows three-dimensional (3D) imaging of the retina, and is commonly used for assessing pathological changes of fovea and macula in many diseases. Many neuroinflammatory conditions are known to cause modifications to the fovea shape. In this paper, we propose a method for parametric modeling of the foveal shape. Our method exploits invariant features of the macula from OCT data and applies a cubic Bézier polynomial along with a least square optimization to produce a best fit parametric model of the fovea. Additionally, we provide several parameters of the foveal shape based on the proposed 3D parametric modeling. Our quantitative and visual results show that the proposed model is not only able to reconstruct important features from the foveal shape, but also produces less error compared to the state-of-the-art methods. Finally, we apply the model in a comparison of healthy control eyes and eyes from patients with neuroinflammatory central nervous system disorders and optic neuritis, and show that several derived model parameters show significant differences between the two groups.

Optical coherence tomography for the diagnosis and monitoring of idiopathic intracranial hypertension.

The objectives of the study were to investigate the value of optical coherence tomography in detecting papilledema in patients with idiopathic intracranial hypertension (IIH), a disease which is difficult to monitor and which can lead to permanent visual deficits; to analyze retinal changes over time. In this non-interventional case-control study, spectral-domain optical coherence tomography (SD-OCT) was used to analyze the retinal and optic nerve head (ONH) morphology of 21 patients with IIH and 27 age- and sex-matched healthy controls over time. We analyzed the ONH volume using a custom-made algorithm and employed semi-automated segmentation of macular volume scans to assess the macular retinal nerve fiber layer (RNFL) and ganglion cell layer and inner plexiform layer complex as well as the total macular volume. In IIH patients, the ONH volume was increased and correlated with cerebrospinal fluid (CSF) pressure. The ONH volume decreased after the initiation of treatment with acetazolamide. The macular RNFL volume decreased by 5% in 3.5 months, and a stepwise multivariate regression analysis identified CSF pressure as the main influence on macular RNFL volume at diagnosis. The only factor predicting macular RNFL volume loss over time was ONH volume. SD-OCT can non-invasively monitor changes in retinal and ONH morphology in patients with IIH. Increased ONH volume leads to retinal atrophy in the form of macular RNFL volume loss, presumably due to mechanic jamming of the optic nerve at the disc and subsequent axonal loss.

No Evidence for Retinal Damage Evolving from Reduced Retinal Blood Flow in Carotid Artery Disease.

INTRODUCTION: Carotid artery disease (CAD) comprising high-grade internal carotid artery stenosis (CAS) or carotid artery occlusion (CAO) may lead to ipsilateral impaired cerebral blood flow and reduced retinal blood supply. OBJECTIVE: To examine the influence of chronic CAD on retinal blood flow, retinal morphology, and visual function. METHODS: Patients with unilateral CAS ≥ 50% (ECST criteria) or CAO were grouped according to the grade of the stenosis and to the flow direction of the ophthalmic artery (OA). Retinal perfusion was measured by transorbital duplex ultrasound, assessing central retinal artery (CRA) blood flow velocities. In addition, optic nerve and optic nerve sheath diameter were measured. Optical coherence tomography (OCT) was performed to study retinal morphology. Visual function was assessed using high- and low-contrast visual paradigms. RESULTS: Twenty-seven patients were enrolled. Eyes with CAS ≥ 80%/CAO and retrograde OA blood flow showed a significant reduction in CRA peak systolic velocity (no-CAD side: 0.130 ± 0.035 m/s, CAS/CAO side: 0.098 ± 0.028; p = 0.005; n = 12). OCT, optic nerve thicknesses, and visual functional parameters did not show a significant difference. CONCLUSION: Despite assessable hemodynamic effects, chronic high-grade CAD does not lead to gaugeable morphological or functional changes of the retina.

Comparison of Standard Versus Wide-Field Composite Images of the Corneal Subbasal Layer by In Vivo Confocal Microscopy.

PURPOSE: To evaluate whether the densities of corneal subbasal nerves and epithelial immune dendritiform cells (DCs) are comparable between a set of three representative standard images of in vivo confocal microscopy (IVCM) and the wide-field mapped composite IVCM images. METHODS: This prospective, cross-sectional, and masked study included 110 eyes of 58 patients seen in a neurology clinic who underwent laser-scanning IVCM (Heidelberg Retina Tomograph 3) of the central cornea. Densities of subbasal corneal nerves and DCs were compared between the average of three representative standard images and the wide-field mapped composite images, which were reconstructed by automated mapping. RESULTS: There were no statistically significant differences between the average of three representative standard images (0.16 mm2 each) and the wide-field composite images (1.29 ± 0.64 mm2) in terms of mean subbasal nerve density (17.10 ± 6.10 vs. 17.17 ± 5.60 mm/mm2, respectively, P = 0.87) and mean subbasal DC density (53.2 ± 67.8 vs. 49.0 ± 54.3 cells/mm2, respectively, P = 0.43). However, there were notable differences in subbasal nerve and DC densities between these two methods in eyes with very low nerve density or very high DC density. CONCLUSIONS: There are no significant differences in the mean subbasal nerve and DC densities between the average values of three representative standard IVCM images and wide-field mapped composite images. Therefore, these standard images can be used in clinical studies to accurately measure cellular structures in the subbasal layer.

Retinal pathology in idiopathic moyamoya angiopathy detected by optical coherence tomography.

OBJECTIVE: To investigate whether patients with moyamoya angiopathy without obvious retinal pathologies such as retinal infarctions or the congenital morning glory anomaly may have subtle subclinical retinal changes. METHODS: In this cross-sectional study, spectral domain optical coherence tomography was used to analyze the retinal morphology of 25 patients with idiopathic moyamoya angiopathy and 25 age- and sex-matched healthy controls. We analyzed the retinal vasculature with blue laser autofluorescence, lipofuscin deposits with MultiColor confocal scanning laser ophthalmoscopy, and the optic nerve head (ONH) volume with a custom postprocessing algorithm. In addition to the total retinal thickness, semiautomated segmentation was used for segmentation of retinal layers in macular cross scans, macular volume scans, and peripapillary ring scans. RESULTS: The main finding was a pronounced reduction of the ONH volume in moyamoya angiopathy compared with controls (0.76 ± 0.45 mm(3) and 1.47 ± 0.50 mm(3), respectively; p < 0.0001), which was associated with a less pronounced reduction of the retinal nerve fiber layer in macular volume scans (0.97 ± 0.11 mm(3) and 1.10 ± 0.10 mm(3), respectively; p < 0.001). Autofluorescence and MultiColor confocal scanning laser ophthalmoscopy images revealed no pathologies except for one branch retinal artery occlusion. CONCLUSION: Our results indicate that even patients with moyamoya angiopathy who do not have obvious retinal abnormalities have retinal abnormalities. These can be detected by spectral domain optical coherence tomography, and the association of ONH abnormalities with the vascular changes may suggest that idiopathic moyamoya angiography is a systemic disease involving abnormalities of the early mesodermal development.

Dynamic formation of macular microcysts independent of vitreous traction changes.

OBJECTIVE: To test the assumption of vitreous traction as a cause of macular microcysts in neuroinflammatory diseases and to establish a testable model to quantify vitreous traction changes. METHODS: Retrospective cohort study including 9 patients with neuroinflammatory diseases and macular microcysts that were longitudinally analyzed using optical coherence tomography. A mechanical model was developed to test the theory of vitreous traction vs macular swelling. This model was applied to one case presenting with dynamic microcyst evolution over 2 years with 4 visits. RESULTS: None of the patients' eyes with microcysts showed any signs of vitreous traction upon qualitative meticulous optical coherence tomographic analysis. The longitudinal changes analyzed in one patient were in the opposite direction as predicted by the mechanical model involving vitreous traction. CONCLUSIONS: Vitreous traction does not appear to be a causative factor in macular microcyst formation. Quantitative analysis in one case shows even a reduced traction caused by an increase in macular thickness leading to vitreous impingement by the macular wall. The presented model might also serve as a quantification approach in other studies investigating macular microcysts.

Optical Coherence Tomography Reveals Distinct Patterns of Retinal Damage in Neuromyelitis Optica and Multiple Sclerosis.

BACKGROUND: Neuromyelitis optica (NMO) and relapsing-remitting multiple sclerosis (RRMS) are difficult to differentiate solely on clinical grounds. Optical coherence tomography (OCT) studies investigating retinal changes in both diseases focused primarily on the retinal nerve fiber layer (RNFL) while rare data are available on deeper intra-retinal layers. OBJECTIVE: To detect different patterns of intra-retinal layer alterations in patients with NMO spectrum disorders (NMOSD) and RRMS with focus on the influence of a previous optic neuritis (ON). METHODS: We applied spectral-domain OCT in eyes of NMOSD patients and compared them to matched RRMS patients and healthy controls (HC). Semi-automatic intra-retinal layer segmentation was used to quantify intra-retinal layer thicknesses. In a subgroup low contrast visual acuity (LCVA) was assessed. RESULTS: NMOSD-, MS- and HC-groups, each comprising 17 subjects, were included in analysis. RNFL thickness was more severely reduced in NMOSD compared to MS following ON. In MS-ON eyes, RNFL thinning showed a clear temporal preponderance, whereas in NMOSD-ON eyes RNFL was more evenly reduced, resulting in a significantly lower ratio of the nasal versus temporal RNFL thickness. In comparison to HC, ganglion cell layer thickness was stronger reduced in NMOSD-ON than in MS-ON, accompanied by a more severe impairment of LCVA. The inner nuclear layer and the outer retinal layers were thicker in NMOSD-ON patients compared to NMOSD without ON and HC eyes while these differences were primarily driven by microcystic macular edema. CONCLUSION: Our study supports previous findings that ON in NMOSD leads to more pronounced retinal thinning and visual function impairment than in RRMS. The different retinal damage patterns in NMOSD versus RRMS support the current notion of distinct pathomechanisms of both conditions. However, OCT is still insufficient to help with the clinically relevant differentiation of both conditions in an individual patient.

Optic nerve head quantification in idiopathic intracranial hypertension by spectral domain OCT.

OBJECTIVE: To evaluate 3D spectral domain optical coherence tomography (SDOCT) volume scans as a tool for quantification of optic nerve head (ONH) volume as a potential marker for treatment effectiveness and disease progression in idiopathic intracranial hypertension (IIH). DESIGN AND PATIENTS: Cross-sectional pilot trial comparing 19 IIH patients and controls matched for gender, age and body mass index. Each participant underwent SDOCT. A custom segmentation algorithm was developed to quantify ONH volume (ONHV) and height (ONHH) in 3D volume scans. RESULTS: Whereas peripapillary retinal nerve fiber layer thickness did not show differences between controls and IIH patients, the newly developed 3D parameters ONHV and ONHH were able to discriminate between controls, treated and untreated patients. Both ONHV and ONHH measures were related to levels of intracranial pressure (ICP). CONCLUSION: Our findings suggest 3D ONH measures as assessed by SDOCT as potential diagnostic and progression markers in IIH and other disorders with increased ICP. SDOCT may promise a fast and easy diagnostic alternative to repeated lumbar punctures and could therefore ease monitoring of treatment or disease progression.