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 froma 6mmEarly 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 from218 healthy volunteers (144 females/74males, 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

Afferent visual system damage after optic neuritis in MOG-IgG-seropositive versus AQP4-IgG-seropositive patients

Background Antibodies against myelin oligodendrocyte glycoprotein (MOG-IgG) have been reported in patients with aquaporin-4 antibody (AQP4-IgG)-negative neuromyelitis optica spectrum disorders (NMOSD). The objective of this study was to describe optic neuritis (ON)-induced neuro-axonal damage in the retina of MOG-IgG-positive patients in comparison with AQP4-IgG-positive NMOSD patients. Methods Afferent visual system damage following ON was bilaterally assessed in 16 MOG-IgG-positive patients with a history of ON and compared with that in 16 AQP4-IgG-positive NMOSD patients. In addition, 16 healthy controls matched for age, sex, and disease duration were analyzed. Study data included ON history, retinal optical coherence tomography, visual acuity, and visual evoked potentials. Results Eight MOG-IgG-positive patients had a previous diagnosis of AQP4-IgG-negative NMOSD with ON and myelitis, and eight of (mainly recurrent) ON. Twenty-nine of the 32 eyes of the MOG-IgG-positive patients had been affected by at least one episode of ON. Peripapillary retinal nerve fiber layer thickness (pRNFL) and ganglion cell and inner plexiform layer volume (GCIP) were significantly reduced in ON eyes of MOG- IgG-positive patients (pRNFL = 59 ± 23 μm; GCIP = 1.50 ± 0.34 mm3) compared with healthy controls (pRNFL = 99 ± 6 μm, p < 0.001; GCIP = 1.97 ± 0.11 mm3, p < 0.001). Visual acuity was impaired in eyes after ON in MOG-IgG-positive patients (0.35 ± 0.88 logMAR). There were no significant differences in any structural or functional visual parameters between MOG-IgG-positive and AQP4 -IgG-positive patients (pRNFL: 59 ± 21 μm; GCIP: 1.41 ± 0.27 mm3; Visual acuity = 0.72 ± 1.09 logMAR). Importantly, MOG-IgG-positive patients had a significantly higher annual ON relapse rate than AQP4-IgG-positive patients (median 0.69 vs. 0.29 attacks/year, p = 0.004), meaning that on average a single ON episode caused less damage in MOG-IgG-positive than in AQP4-IgG- positive patients. pRNFL and GCIP loss correlated with the number of ON episodes in MOG-IgG-positive patients (p < 0.001), but not in AQP4-IgG- positive patients. Conclusions Retinal neuro-axonal damage and visual impairment after ON in MOG-IgG-positive patients are as severe as in AQP4-IgG- positive NMOSD patients. In MOG-IgG-positive patients, damage accrual may be driven by higher relapse rates, whereas AQP4-IgG-positive patients showed fewer but more severe episodes of ON. Given the marked damage in some of our MOG-IgG-positive patients, early diagnosis and timely initiation and close monitoring of immunosuppressive therapy are important

Reliability of Intra-Retinal Layer Thickness Estimates

Purpose Measurement of intra-retinal layer thickness using optical coherence tomography (OCT) has become increasingly prominent in multiple sclerosis (MS) research. Nevertheless, the approaches used for determining the mean layer thicknesses vary greatly. Insufficient data exist on the reliability of different thickness estimates, which is crucial for their application in clinical studies. This study addresses this lack by evaluating the repeatability of different thickness estimates. Methods Studies that used intra-retinal layer segmentation of macular OCT scans in patients with MS were retrieved from PubMed. To investigate the repeatability of previously applied layer estimation approaches, we generated datasets of repeating measurements of 15 healthy subjects and 13 multiple sclerosis patients using two OCT devices (Cirrus HD-OCT and Spectralis SD-OCT). We calculated each thickness estimate in each repeated session and analyzed repeatability using intra-class correlation coefficients and coefficients of repeatability. Results We identified 27 articles, eleven of them used the Spectralis SD-OCT, nine Cirrus HD-OCT, two studies used both devices and two studies applied RTVue-100. Topcon OCT-1000, Stratus OCT and a research device were used in one study each. In the studies that used the Spectralis, ten different thickness estimates were identified, while thickness estimates of the Cirrus OCT were based on two different scan settings. In the simulation dataset, thickness estimates averaging larger areas showed an excellent repeatability for all retinal layers except the outer plexiform layer (OPL). Conclusions Given the good reliability, the thickness estimate of the 6mm-diameter area around the fovea should be favored when OCT is used in clinical research. Assessment of the OPL was weak in general and needs further investigation before OPL thickness can be used as a reliable parameter

Afferent Visual Pathway Affection in Patients with PMP22 Deletion-Related Hereditary Neuropathy with Liability to Pressure Palsies

Background The PMP22 gene encodes a protein integral to peripheral myelin. Its deletion leads to hereditary neuropathy with liability to pressure palsies (HNPP). PMP22 is not expressed in the adult central nervous system, but previous studies suggest a role in CNS myelin development. The objective of this study was to identify potential structural and functional alterations in the afferent visual system in HNPP patients. Methods Twenty HNPP patients and 18 matched healthy controls (HC) were recruited in a cross-sectional study. Participants underwent neurological examination including visual acuity, visual evoked potential (VEP) examination, optical coherence tomography (OCT), and magnetic resonance imaging with calculation of brain atrophy, regarding grey and white matter, and voxel based morphometry (VBM), in addition answered the National Eye Institute’s 39-item Visual Functioning Questionnaire (NEI- VFQ). Thirteen patients and 6 HC were additionally examined with magnetic resonance spectroscopy (MRS). Results All patients had normal visual acuity, but reported reduced peripheral vision in comparison to HC in the NEI-VFQ (p = 0.036). VEP latency was prolonged in patients (P100 = 103.7±5.7 ms) in comparison to healthy subjects (P100 = 99.7±4.2 ms, p = 0.007). In OCT, peripapillary retinal nerve fiber layer thickness RNFL was decreased in the nasal sector (90.0±15.5 vs. 101.8±16.5, p = 0.013), and lower nasal sector RNFL correlated with prolonged VEP latency (Rho = -0.405, p = 0.012). MRS revealed reduced tNAA (731.4±45.4 vs. 814.9±62.1, p = 0.017) and tCr (373.8±22.2 vs. 418.7±31.1, p = 0.002) in the visual cortex in patients vs. HC. Whole brain volume, grey and white matter volume, VBM and metabolites in a MRS sensory cortex control voxel did not differ significantly between patients and HC. Conclusion PMP22 deletion leads to functional, metabolic and macro- structural alterations in the afferent visual system of HNPP patients. Our data suggest a functional relevance of these changes for peripheral vision, which warrants further investigation and confirmation

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 mm 2 each) and the wide-field composite images (1.29 6 0.64 mm 2 ) in terms of mean subbasal nerve density (17.10 6 6.10 vs. 17.17 6 5.60 mm/mm 2 , respectively, P ¼ 0.87) and mean subbasal DC density (53.2 6 67.8 vs. 49.0 6 54.3 cells/mm 2 , respectively, P ¼ 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

MOG-IgG in NMO and related disorders: a multicenter study of 50 patients. Part 4: Afferent visual system damage after optic neuritis in MOG-IgG-seropositive versus AQP4-IgG-seropositive patients

Background: Antibodies against myelin oligodendrocyte glycoprotein (MOG-IgG) have been reported in patients with aquaporin-4 antibody (AQP4-IgG)-negative neuromyelitis optica spectrum disorders (NMOSD). The objective of this study was to describe optic neuritis (ON)-induced neuro-axonal damage in the retina of MOG-IgG-positive patients in comparison with AQP4-IgG-positive NMOSD patients. Methods: Afferent visual system damage following ON was bilaterally assessed in 16 MOG-IgG-positive patients with a history of ON and compared with that in 16 AQP4-IgG-positive NMOSD patients. In addition, 16 healthy controls matched for age, sex, and disease duration were analyzed. Study data included ON history, retinal optical coherence tomography, visual acuity, and visual evoked potentials. Results: Eight MOG-IgG-positive patients had a previous diagnosis of AQP4-IgG-negative NMOSD with ON and myelitis, and eight of (mainly recurrent) ON. Twenty-nine of the 32 eyes of the MOG-IgG-positive patients had been affected by at least one episode of ON. Peripapillary retinal nerve fiber layer thickness (pRNFL) and ganglion cell and inner plexiform layer volume (GCIP) were significantly reduced in ON eyes of MOG-IgG-positive patients (pRNFL = 59 ± 23 μm; GCIP = 1.50 ± 0.34 mm3) compared with healthy controls (pRNFL = 99 ± 6 μm, p < 0.001; GCIP = 1.97 ± 0.11 mm3, p < 0.001). Visual acuity was impaired in eyes after ON in MOG-IgG-positive patients (0.35 ± 0.88 logMAR). There were no significant differences in any structural or functional visual parameters between MOG-IgG-positive and AQP4-IgG-positive patients (pRNFL: 59 ± 21 μm; GCIP: 1.41 ± 0.27 mm3; Visual acuity = 0.72 ± 1.09 logMAR). Importantly, MOG-IgG-positive patients had a significantly higher annual ON relapse rate than AQP4-IgG-positive patients (median 0.69 vs. 0.29 attacks/year, p = 0.004), meaning that on average a single ON episode caused less damage in MOG-IgG-positive than in AQP4-IgG-positive patients. pRNFL and GCIP loss correlated with the number of ON episodes in MOG-IgG-positive patients (p < 0.001), but not in AQP4-IgG-positive patients. Conclusions: Retinal neuro-axonal damage and visual impairment after ON in MOG-IgG-positive patients are as severe as in AQP4-IgG-positive NMOSD patients. In MOG-IgG-positive patients, damage accrual may be driven by higher relapse rates, whereas AQP4-IgG-positive patients showed fewer but more severe episodes of ON. Given the marked damage in some of our MOG-IgG-positive patients, early diagnosis and timely initiation and close monitoring of immunosuppressive therapy are important

Corneal changes in neurodegenerative diseases

Viele Studien über Multiple Sklerose (MS) haben bisher die Retina untersucht. Allerdings ist wenig über den Einfluss der MS auf die Cornea, welche durch den Nervus trigeminus innerviert wird, bekannt. Die Cornea ist diejenige Stelle im Körper, an welcher die neuronale Immunreaktion lokaler dendritischer Zellen auf Umwelteinflüsse stattfindet. Zielstellung Ziel dieser Studie ist es, die Wirkung der MS auf die kornealen Nervenfasern und die dendritischen Zellen des subbasalen Nervenplexus mittels in vivo Konfokalmikroskopie (IVCM) zu untersuchen. Methodika Mit dem Heidelberg Retina Tomographen® mit Rostock Cornea Modul wurden bei 26 MS-Patienten und dazu hinsichtlich Alter und Geschlecht gematchten gesunden Kontrollen die Dichte der kornealen Nervenfasern und die der dendritischen Zellen gemessen. Zusätzlich wurde die Schwere der MS-Erkrankung mit dem Multiple Sclerosis Functional Composite (MSFC) und der Expanded Disability Status Scale (EDSS) ermittelt. Des Weiteren wurde die Sehschärfe und retinalen Parameter mittels Optischen Kohärenztomographie (OCT) erhoben. Ergebnisse Es konnte eine signifikante Reduktion der kornealen Nervenfaserdichte der MSPatienten im Vergleich zu den gesunden Kontrollen festgestellt werden. Hingegen war die Dichte der dendritischen Zellen bei beiden Gruppen ähnlich. Des Weiteren wurde ein Zusammenhang zwischen reduzierter kornealer Nervenfaserdichte und einem erhöhten Behinderungsgrad infolge der MS, ermittelt mit dem EDSS festgestellt. Kein Zusammenhang bestand hingegen zwischen reduzierter kornealer Nervenfaserdichte und dem früheren Auftreten von klinischen Symptomen am N. trigeminus, einer mittels OCT gemessenen neuroaxonaler Schädigung der Netzhaut, einer veränderter Sehschärfe oder der Krankheitsdauer. Schlussfolgerung Die korneale Nervenfaserdichte könnte eine vielversprechende neue bildgebende Methode für die Bewertung der Krankheitsschwere der MS sein und sollte weiter untersucht werden.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 age and gender 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 neuroaxonal 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

Robust Optic Nerve Head Analysis Based On 3D Optical Coherence Tomography

"Many conditions such as glaucoma (GD), optic neuritis (ON), multiple sclerosis (MS) or idiopathic intracranial hypertension (IIH) affect the optic nerve head (ONH). Optical coherence tomography (OCT) allows 3D ONH imaging. However, current ONH analysis methods work in only atrophic or in swollen ONH but not both. Manual steps for masking Bruch's membrane opening (BMO) or ONH center are regularly required. Our objective was to develop a robust and fully automatic ONH quantification algorithm applicable in atrophic, normal and swollen conditions.

Explanation of different thickness estimates used for the simulation of repeatability.

<p>The red areas or points on the fundus images indicate the values that were averaged to generate the layer thickness estimates. The text to the right of each image refers to (top-to-bottom): 1) the used OCT device 2) the applied scan as elucidated in <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0137316#pone.0137316.g001" target="_blank">Fig 1</a>; 3) the (subset of) B-scans used for the thickness estimate; 4) the procedure used to calculate the thickness estimates; 5) the program used for calculating the thickness estimate. The last column indicated the article(s) in which the layer estimated was applied. For a detailed overview of the segmentation methods applied in the retrieved articles, see Table B in <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0137316#pone.0137316.s002" target="_blank">S1 File</a>. Note: the number and spacing of B-scans on the fundus image for the thickness estimates C and E are not correct due to space limitations.</p

Intraclass correlation coefficients (ICC) for different thickness estimates and retinal layers in MS/CIS patients and healthy controls.

<p>Intraclass correlation coefficient (ICC) for the distinct cohorts of healthy controls (HC) and patients (MS) ordered for (A) the twelve thickness estimates (<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0137316#pone.0137316.g003" target="_blank">Fig 3</a>) and (B) the seven retinal layers. Abbreviations: mRNFL = macular retinal nerve fiber layer, GCL = ganglion cell layer, IPL = inner plexiform layer, GICP = combined GCL and IPL, INL = inner nuclear layer, OPL = outer plexiform layer, ONL = outer nuclear layer.</p