Strukturelle und funktionelle Veränderungen des afferenten visuellen Systems bei Patienten mit Neuromyelitis optica-Spektrum-Erkrankungen

Neuromyelitis optica-Spektrum-Erkrankungen (NMOSD) bezeichnen eine inflammatorische Autoimmunerkrankung des zentralen Nervensystems (ZNS), die vorwiegend durch Optikusneuritis (ON) und/oder Myelitis gekennzeichnet ist. In der Mehrzahl der Betroffenen sind pathogene Serumantikörper gegen Aquaporin-4 (AQP4-IgG) nachweisbar. In einem Teil der AQP4-IgG-seronegativen NMOSD-Patienten sowie in Patienten mit rezidivierender ON oder Myelitis konnten Antikörper gegen Myelin-Oligodendrozyten-Glykoprotein (MOG-IgG) nachgewiesen werden. Patienten mit MOG-IgG-assoziierter Enzephalomyelitis (MOG-EM) wurden häufig klinisch als milderer Phänotyp mit besserer Remission und Langzeitprognose im Vergleich zu AQP4-IgG-positiven NMOSD-Patienten beschrieben. Ziel dieser Arbeit war die Charakterisierung der strukturellen und funktionellen Schädigung des afferenten visuellen Systems bei NMOSD und MOG-EM. In einer multimodalen Magnetresonanztomographie-Untersuchung zeigten NMOSD-Patienten im Vergleich zu gesunden Kontrollen keine signifikanten Verminderungen der grauen und weißer Substanz sowie kortikaler Dicken. Mit Hilfe von Diffusions-Tensor-Bildgebung und optischer Kohärenztomographie (OCT) konnte allerdings gezeigt werden, dass es bei NMOSD zu einer Abnahme der fraktionellen Anisotropie in der Sehstrahlung kommt, welche mit einer Verdünnung der retinalen Nervenfaserschicht (RNFL) assoziiert ist. Bei AQP4-IgG-positiven NMOSD-Patienten kam es auch ohne vorherige ON zu einer solchen Abnahme. Zudem zeigten diese Patienten auch eine Reduktion der fovealen Dicke. Bei AQP4-IgG-positiven NMOSD-Patienten war zudem die funktionelle Konnektivität der visuellen Netzwerke erhöht, was auf einen maladaptiven plastischen Prozess hindeutet. Es wurde gezeigt, dass Blutgefäße in der inneren Retina OCT-Dickenmessungen der RNFL bei NMOSD beeinflussen, wobei bei dünnerer RNFL der Einfluss ausgeprägter ist. Eine multizentrische Untersuchung zeigte, dass es bei MOG-EM und AQP4-IgG-positiven NMOSD-Patienten bei vergleichbarer Erkrankungsdauer in ähnlicher Dimension zu ON-assoziierter neuro-axonaler Schädigung der Retina kommt. Allerdings hatten MOG-EM-Patienten eine deutlich höhere ON-Schubrate als die NMOSD Patienten. Daraus schlussfolgerten wir, dass es bei MOG-EM durch die akkumulierte Schädigung - trotz besserer Remission beim einzelnen Schub - zu ähnlicher Schädigung kommt wie bei AQP4-IgG-positiven NMOSD-Patienten mit weniger, aber dafür schwereren Schüben. Mit Hilfe eines Fragebogens (NEI-VFQ) wurde die sehbezogene Lebensqualität von Patienten mit NMOSD untersucht. Dabei wurde festgestellt, dass diese eine signifikant niedrigere sehbezogene Lebensqualität haben als Patienten mit multipler Sklerose (MS). Dies erklärte sich dadurch, dass NMOSD-Patienten schwerwiegendere ON-Episoden durchliefen, die zudem häufiger beide Augen betrafen, als MS-Patienten. Zusammengefasst führt ON bei NMOSD-Patienten neben retinalem neuro-axonalen Schaden zu anterograder Neurodegeneration der Sehstrahlung, möglicherweise maladaptiver Reorganisation des visuellen Netzwerks und eingeschränkter sehbezogener Lebensqualität. Inwieweit es schubunabhängig zu einer direkten, möglicherweise gegen AQP4 gerichteten ZNS-Schädigung kommt, muss noch näher untersucht werden.Neuromyelitis optica spectrum disorders (NMOSD) describe an autoimmune disease of the central nervous system (CNS), predominantly characterized by optic neuritis (ON) and/or myelitis. In the majority of patients pathogenic serum antibodies against aquaporin-4 (AQP4-IgG) can be detected. In a subset of AQP4-IgG seronegative NMOSD patients, as well as in patients with recurrent ON or myelitis, antibodies against myelin oligodendrocyte glycoprotein (MOG-IgG) could be detected. Patients with MOG-IgG associated encephalomyelitis (MOG-EM) have been described as a milder phenotype with better remission and long-term outcomes as compared to AQP4-IgG positive NMOSD patients. The objective of this work was the characterization of structural and functional afferent visual system damage in NMOSD and MOG-EM. A multimodal magnetic resonance imaging study did not show a reduction of either grey or white matter, nor cortical thicknesses in NMOSD patients in comparison to healthy controls. However, diffusion tensor imaging and optical coherence tomography showed that fractional anisotropy of the optic radiation was reduced in NMOSD patients, which was associated with thinner retinal nerve fiber layer (RNFL). Even AQP4-IgG positive NMOSD patients without previous ON showed this reduction, and, additionally, reduced 7 foveal thickness. Furthermore, the functional connectivity of the visual networks was shown to be increased in AQP4-IgG positive NMOSD patients, indicating a maladaptive process. We showed that blood vessels of the inner retina influenced OCT-derived thickness measurements in NMOSD, with a more pronounced effect in thinner RNFL. A multicenter study showed similar retinal neuro-axonal damage in MOG-EM and AQP4- IgG positive NMOSD patients with comparable disease duration. However, MOG-EM patients had a significantly higher ON relapse rate than NMOSD patients. We concluded that accumulative damage in MOG-EM patients, despite better remission in a single attack, leads to similar damage as in AQP4-IgG positive NMOSD patients with less, but more severe attacks. Applying a questionnaire (NEI-VFQ), we investigated vision-related quality of life in patients with NMOSD. We found that NMOSD patients have a significantly reduced vision-related quality of life compared to patients with multiple sclerosis (MS). This could be explained by more severe ON episodes in NMOSD, that present more frequently in both eyes, compared to MS. To conclude, besides retinal neuro-axonal damage, ON in NMOSD leads to anterograde neurodegeneration of the optic radiation, potentially maladaptive reorganization of the visual networks and impairment in vision-related quality of life. To what extent an attack-independent and direct, potentially AQP4-targeted CNS damage occurs in these patients has to be further investigated

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

Imaging markers of disability in aquaporin-4 immunoglobulin G seropositive neuromyelitis optica: a graph theory study

Neuromyelitis optica spectrum disorders lack imaging biomarkers associated with disease course and supporting prognosis. This complex and heterogeneous set of disorders affects many regions of the central nervous system, including the spinal cord and visual pathway. Here, we use graph theory-based multimodal network analysis to investigate hypothesis-free mixed networks and associations between clinical disease with neuroimaging markers in 40 aquaporin-4-immunoglobulin G antibody seropositive patients (age = 48.16 ± 14.3 years, female:male = 36:4) and 31 healthy controls (age = 45.92 ± 13.3 years, female:male = 24:7). Magnetic resonance imaging measures included total brain and deep grey matter volumes, cortical thickness and spinal cord atrophy. Optical coherence tomography measures of the retina and clinical measures comprised of clinical attack types and expanded disability status scale were also utilized. For multimodal network analysis, all measures were introduced as nodes and tested for directed connectivity from clinical attack types and disease duration to systematic imaging and clinical disability measures. Analysis of variance, with group interactions, gave weights and significance for each nodal association (hyperedges). Connectivity matrices from 80% and 95% F-distribution networks were analyzed and revealed the number of combined attack types and disease duration as the most connected nodes, directly affecting changes in several regions of the central nervous system. Subsequent multivariable regression models, including interaction effects with clinical parameters, identified associations between decreased nucleus accumbens (β = −0.85, P = 0.021) and caudate nucleus (β = −0.61, P = 0.011) volumes with higher combined attack type count and longer disease duration, respectively. We also confirmed previously reported associations between spinal cord atrophy with increased number of clinical myelitis attacks. Age was the most important factor associated with normalized brain volume, pallidum volume, cortical thickness and the expanded disability status scale score. The identified imaging biomarker candidates warrant further investigation in larger-scale studies. Graph theory-based multimodal networks allow for connectivity and interaction analysis, where this method may be applied in other complex heterogeneous disease investigations with different outcome measures

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

Retinal Optical Coherence Tomography in Neuromyelitis Optica

Retina; Pérdida visualRetina; Visual lossRetina; Pèrdua visualBackground and Objectives To determine optic nerve and retinal damage in aquaporin-4 antibody (AQP4-IgG)-seropositive neuromyelitis optica spectrum disorders (NMOSD) in a large international cohort after previous studies have been limited by small and heterogeneous cohorts. Methods The cross-sectional Collaborative Retrospective Study on retinal optical coherence tomography (OCT) in neuromyelitis optica collected retrospective data from 22 centers. Of 653 screened participants, we included 283 AQP4-IgG–seropositive patients with NMOSD and 72 healthy controls (HCs). Participants underwent OCT with central reading including quality control and intraretinal segmentation. The primary outcome was thickness of combined ganglion cell and inner plexiform (GCIP) layer; secondary outcomes were thickness of peripapillary retinal nerve fiber layer (pRNFL) and visual acuity (VA). Results Eyes with ON (NMOSD-ON, N = 260) or without ON (NMOSD-NON, N = 241) were assessed compared with HCs (N = 136). In NMOSD-ON, GCIP layer (57.4 ± 12.2 μm) was reduced compared with HC (GCIP layer: 81.4 ± 5.7 μm, p < 0.001). GCIP layer loss (−22.7 μm) after the first ON was higher than after the next (−3.5 μm) and subsequent episodes. pRNFL observations were similar. NMOSD-NON exhibited reduced GCIP layer but not pRNFL compared with HC. VA was greatly reduced in NMOSD-ON compared with HC eyes, but did not differ between NMOSD-NON and HC. Discussion Our results emphasize that attack prevention is key to avoid severe neuroaxonal damage and vision loss caused by ON in NMOSD. Therapies ameliorating attack-related damage, especially during a first attack, are an unmet clinical need. Mild signs of neuroaxonal changes without apparent vision loss in ON-unaffected eyes might be solely due to contralateral ON attacks and do not suggest clinically relevant progression but need further investigation.Guthy-Jackson Charitable Foundation (GJCF) and German Research Foundation (DFG)