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

Functional and structural testing of the afferent visual system in neuroinflammatory diseases

Multiple sclerosis (MS) and neuromyelitis optica spectrum disorders (NMOSD) are both inflammatory autoimmune diseases of the central nervous system associated with damage to the afferent visual system through neuro-axonal loss and demyelination. The aim of this work was to investigate dynamic visual function in MS and NMOSD using two tests with regard to their relationship to established functional and structural parameters of the afferent visual system: critical flicker frequency (CFF), a test of temporal visual resolution, and Numbers from Motion (NFM) testing of motion vision. First, a retinal optical coherence tomography (OCT) segmentation pipeline was developed to determine structural damage, and a normative database of retinal layers was assembled and analysed. In a cross-sectional study of CFF in patients with MS, CFF was shown to be lower in MS patients than in healthy subjects. There was no difference between eyes with previous optic neuritis (ON) and eyes without ON (NON). No association was observed with high contrast visual acuity (HCVA), low contrast visual acuity (LCLA), visual evoked potentials (VEP), OCT thickness of the peripapillary retinal nerve fibre layer (pRNFL) and combined ganglion cell and inner plexiform layer (GCIPL). However, CFF showed an association with the Expanded Disability Status Scale (EDSS) and tonic alertness, a component of attention measured with the Test Battery for Attention Testing (TAP) but not with the Paced Auditory Serial Addition Tests (PASAT), a measure of information processing speed. The NFM score was lower in MS and NMOSD patients than in healthy subjects. In NMOSD but not MS, NFM scores were lower after ON. In MS and NMOSD, a lower NFM scores were associated with lower HCVA, LCLA, thinner pRNFL and GCIPL, but not with prolonged VEP latencies. In a second MS cohort, low NFM scores were associated with thinner pRNFL and prolonged multifocal VEP (mfVEP) latencies. In conclusion, CFF is a marker of overall disease progression and possibly cortical damage in MS. Neuro-axonal damage to the visual pathway, measured by retinal OCT, is the driving force behind impaired motion vision in MS and NMOSD.Multiple Sklerose (MS) und Neuromyelitis optica-Spektrum-Erkrankungen (NMOSD) sind beides inflammatorische Autoimmunerkrankungen des zentralen Nervensystems, welche mit Schaden des afferenten visuellen Systems durch neuro-axonalen Untergang und Demyelinisierung einhergehen. Ziel dieser Arbeit war die Untersuchung der dynamischen Sehfunktion bei MS und NMOSD mittels zweier Testverfahren und deren Zusammenhang mit etablierten funktionellen und strukturellen Parametern des afferenten visuellen Systems: Die kritische Flimmerfrequenz (CFF), ein Testverfahren der zeitlichen visuellen Auflösung, und die Testung des Bewegungssehens mittels Numbers from Motion (NFM). Zunächst wurde zur Bestimmung des strukturellen Schadens eine Segmentierungspipeline für retinale optische Kohärenztomographie (Optical coherence tomography, OCT) entwickelt und eine normative Datenbank der Netzhautschichten aufgebaut und analysiert. In einer Querschnittsuntersuchung der CFF in Patient*innen mit MS wurde gezeigt, dass die CFF in MS-Patient*innen niedriger als in gesunden Kontrollproband*innen war. Es bestand kein Unterschied zwischen Augen mit vorheriger Optikusneuritis (ON) und Augen ohne ON (NON). Ein Zusammenhang mit dem Hochkontrastvisus (HCVA), dem Niedrigkontrastsehen (LCLA), den visuell evozierten Potenzialen (VEP) sowie der mittels OCT bestimmten Dicke der peripapillären retinalen Nervenfaserschicht (pRNFL) und der kombinierten Ganglienzell- und inneren plexiformen Schicht (GCIPL) wurde nicht beobachtet. Jedoch zeigte die CFF eine Assoziation mit der Expanded Disability Status Scale (EDSS) Skala und der tonischen Alertness, eine Komponente der Aufmerksamkeit, gemessen mit der Testbatterie für Aufmerksamkeitsprüfung (TAP) aber nicht mit dem Paced Auditory Serial Addition Tests (PASAT), einer Messung der Informationsverarbeitungsgeschwindigkeit. Der NFM-Score zeigte sich in MS- und NMOSD Patient*innen niedriger als in gesunden Kontrollproband*innen. In NMOSD aber nicht MS kam es nach ON zu niedrigeren NFM-Scores. In beiden Krankheitsentitäten ging ein niedriger NFM-Score mit niedriger HCVA, LCLA, dünnerer pRNFL und GCIPL, jedoch nicht mit verlängerten VEP-Latenzen einher. In einer zweiten MS-Kohorte waren niedrige NFM-Scores mit dünnerer pRNFL und verlängerter multifokalen VEP (mfVEP)-Latenzen assoziiert. Zusammenfassend ist die CFF ein Marker für allgemeinen Krankheitsprogress und möglicherweise auch kortikalen Schaden in MS. Neuro-axonaler Schaden der Sehbahn, gemessen mittels retinalem OCT, ist die treibende Kraft hinter eingeschränktem Bewegungssehen in MS und NMOSD