Department of Neurology, University of California Irvine, Irvine, California, USA.

Author Of 1 Presentation

Neuromyelitis Optica and Anti-MOG Disease Oral Presentation

PS15.03 - Optical coherence tomography in aquaporin-4-IgG positive neuromyelitis optica spectrum disorders: a collaborative multi-center study

Abstract

Background

Optic neuritis (ON) is a frequent manifestation in aquaporin-4 antibody (AQP4-IgG) seropositive neuromyelitis optica spectrum disorders (NMOSD). Due to limited samples, existing optical coherence tomography (OCT) studies are inconsistent regarding retinal changes in eyes with a history of ON (NMO-ON) and without a history of ON (NMO-NON), and their functional relevance.

Objectives

The CROCTINO (Collaborative Retrospective Study on retinal OCT in Neuromyelitis Optica) project aims to reveal correlates of retinal pathology and to generate hypotheses for prospective OCT studies in NMOSD. The objective of this study was to analyze retinal changes of AQP4-IgG seropositive NMO-ON and NMO-NON eyes in an international cross-sectional OCT dataset.

Methods

Of 656 subjects, we enrolled 283 AQP4-IgG seropositive NMOSD patients and 72 healthy controls (HC) from 22 international expert centers. OCT data was acquired with Spectralis SD-OCT, Cirrus HD-OCT and Topcon 3D OCT-1. Mean thickness for the combined ganglion cell and inner plexiform layer (GCIP) and inner nuclear layer (INL) were calculated from macular volume scans. Clinical, functional and laboratory testing were performed at discretion of each center.

Results

We compared NMO-ON eyes (N = 260), NMO-NON eyes (N = 241) and HC eyes (N = 136). GCIP was reduced in NMO-ON (57.4 ± 12.2 µm) compared with NMO-NON (75.9 ± 7.7 µm; p < 0.001) and HC (81.4 ± 5.7 µm; p < 0.001). NMO-NON had thinner GCIP (p < 0.001) compared with HC. INL was thicker in NMO-ON (40.3 ± 3.9 µm) compared with NMO-NON (38.6 ± 3.9µm; p < 0.001), but not HC (39.4 ± 2.6 µm). Microcystic macular edema were visible in 6.6 % of NMOSD eyes.

Conclusions

AQP4-IgG seropositive NMOSD is characterized by a functionally relevant loss of retinal neuroaxonal content and a - probably inflammatory - increase of INL after ON. Our study further supports the existence of attack-independent damage in the visual system of patients with AQP4-IgG seropositive NMOSD.

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Author Of 5 Presentations

Imaging Late Breaking Abstracts

LB1177 - PAMRINO: International MRI and clinical data repository for neuromyelitis optica spectrum disorder (ID 469)

Abstract

Background

Neuromyelitis optica spectrum disorders (NMOSD) encompasses a group of rare inflammatory diseases which primarily target the optic nerves, spinal cord, and brain. Typically, magnetic resonance imaging (MRI) data from single-center studies comprise 20-50 patients, limiting statistical power for outcomes research. Using retrospective data from the PArallel MRI in NmOsd (PAMRINO) study, a novel prospective NMOSD image repository (NMOsDIR) representing multiple international sites was coordinated by Charité-Universitätsmedizin Berlin and the Medical Image Analysis Center (Basel).

Objectives

The PAMRINO study aimed to investigate and analyze retrospective MRIs collected from NMOSD-specialized centers, potentially for the evaluation of disease-related brain and spinal cord changes. NMOsDIR serves as an international imaging research resource (comprising standardized retinal optical coherence tomography and MRI scans) and clinical data hub for prospective studies in NMOSD. Linking imaging and clinical data, as well as enabling analysis pipelines for each modality, will facilitate multi-centered studies using sufficient data and statistical power to advance outcomes research in this rare disease.

Methods

For clinical data collection in PAMRINO, a Research Electronic Data Capture (REDCap) platform was used, where participating centers entered data relevant for NMOSD patient monitoring. An image database (XNAT) was established for image uploads. This large collection of MRI data is currently being analyzed in a joint international effort of NMOSD clinical neuroradiologists and scientists.

Results

Brain, spinal cord, and optic nerve MRI scans with associated clinical data were collected from 514 NMOSD patients and 56 healthy controls from 17 international centers. Roughly 20,000 individual MRI scans from patients and healthy controls were collected. Of these, 78% had T1-weighted cerebral MRIs (55% with 3D scans), 80% had T2-weighted cerebral MRIs (54% with 3D scans), 86% had T2-weighted spinal cord MRIs (55% with 3D scans), and 35% had optic nerve MRIs.

Conclusions

We successfully established PAMRINO, an international collaborative retrospective MRI and clinical data repository. The knowledge gained during this process provided important new insights, where the initial analysis of the dataset has underscored the large degree of heterogeneity in image and clinical data collection in NMOSD-specialized centers. Thus, calling for more standardized methods of data acquisition and imaging analysis, as not to limit research opportunities. The new longitudinal, prospective NMOsDIR will help us to answer many pressing - yet open - questions regarding patients seropositive for aquaporin-4-IgG+, myelin oligodendrocyte glycoprotein-IgG+ and other autoimmune-related diseases. In turn, such a strategy will strengthen future capabilities in research, diagnosis, monitoring and improving NMOSD patient care.

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Biomarkers and Bioinformatics Poster Presentation

P0153 - Serum neurofilament light chain and retinal layer thickness measurements are complementary predictors of disease activity in early multiple sclerosis. (ID 1808)

Speakers
Presentation Number
P0153
Presentation Topic
Biomarkers and Bioinformatics

Abstract

Background

Serum neurofilament light chain (sNfL) and retinal optical coherence tomography (OCT) measurements have individually been shown to be promising biomarkers for future disease activity in multiple sclerosis (MS).

Objectives

To investigate the complementary value of sNfL and retinal OCT measurements for predicting disease activity in patients with early MS at a stable disease state.

Methods

We retrospectively screened patients with early MS or clinically isolated syndrome (CIS) from a prospective cohort study (Berlin CIS cohort). The baseline sNfL (single-molecule array (SimoaTM) assay) were determined between 12 and 24 months after initial disease onset. Inclusion criteria were the availability of baseline sNfL, OCT measurements, clinical and MRI follow-up data (new relapses, expanded disability status scale (EDSS), new T2 lesions, composing the no evidence of disease activity (NEDA-3) criteria) over a period of at least 365 days. Exclusion criteria were concomitant eye diseases interfering with OCT and a relapse within 120 days before baseline visit. For Cox regression hazard models, patients were grouped with regards to their sNfL level (abnormal/normal: ≥/< 95th percentile of age-matched reference value) and their peripapillary retinal nerve fiber layer (pRNFL: >/≤ 100 µm) and ganglion cell and inner plexiform layer (GCIP: >/≤ 1.99 mm3) in non-optic neuritis eyes. Analysis was censored after 760 days.

Results

We included 78 patients (50 females, age: 36.4 ± 7.6 years) with a median follow-up of 728 days (range: 709 – 751 days). Patients with abnormal sNfL at baseline showed a significantly higher risk for developing a new relapse (Hazard Ratio (HR): 3.33, 95% confidence interval (CI): 1.43 – 7.71, p = 0.003), a new lesion (HR: 2.64, CI: 1.35 – 5.18, p = 0.003) and violating NEDA-3 (HR: 3.22, CI: 1.73 – 6.01. p < 0.001). Patients with both thinner pRNFL and abnormal sNfL value had a greater risk for developing a new relapse (HR: 8.12, CI: 2.17 – 30.46, p = 0.002) and violating NEDA-3 criteria (HR: 4.28, CI: 1.81 – 10.14, p < 0.001) than patients with only one of the risk factors. Meanwhile, patients with thinner GCIP and abnormal sNfL not only yielded greater risk for new relapse (HR: 6.51, CI 2.06 – 20.63, p = 0.001) and NEDA-3 violation (HR: 4.48, CI: 2.11 – 9.50, p < 0.001), but also for new lesion (HR: 3.11, CI: 1.42 – 6.80, p = 0.004).

Conclusions

In patients with early MS, presence of both abnormal sNfL and OCT measurements may be a stronger risk factor for future disease activity than presence of each risk factor alone.

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Prognostic Factors Poster Presentation

P0509 - Utility of NEDA-3 status as a predictor of future disease activity (ID 1643)

Speakers
Presentation Number
P0509
Presentation Topic
Prognostic Factors

Abstract

Background

No evidence of disease activity (NEDA) is viewed as an important goal in relapsing multiple sclerosis (MS) and has been advocated as a benchmark for treatment decisions. However, NEDA status is maintained only by a minority of MS patients over prolonged periods, regardless of disease-modifying treatment. The predictive value and utility of NEDA in guiding individual therapy remains unclear.

Objectives

To investigate the association of NEDA-3 status and criteria subitems in a one-year reference period with subsequent disease activity.

Methods

We included 113 patients (age 35 ± 10 years, 67 (59.3%) female) with relapsing remitting MS who had annual clinical and MRI follow-up visits. There were no restrictions on disease-modifying therapy. The first year of follow-up was considered the reference period. Patients had a median of 2.8 years follow-up time (interquartile range 1.1 - 4.0 years) after the reference period. NEDA-3 status was established based on relapse assessment, 1-point increase in the expanded disability status scale (EDSS, unrelated to relapse activity) and the appearance of new T2-weighted or contrast-enhancing lesions.

Results

Patients who failed NEDA-3 criteria during the reference period had an increased rate of subsequent NEDA-3 failure (Hazard ratio (HR) 1.84, 95% confidence interval (CI) 1.12-3.02, p=0.0165). Attacks and new lesions during the reference period were associated with a new relapse (HR 2.872, CI 1.31-6.30, p=0.00843) or a new lesion (HR 2.57, CI 1.49-4.43, p=0.000691) during subsequent follow-up, respectively. An EDSS increase in the reference period was not predictive of a future failure of NEDA-3.

Conclusions

Relapses and new lesions increase the risk of future disease activity in relapsing-remitting MS, irrespective of disease-modifying therapy. Relapse-independent disability progression appears to be less useful in predicting future disease activity.

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Pathogenesis – the Blood-Brain Barrier Poster Presentation

P0945 - Brain choroid plexus volume in Multiple Sclerosis versus Neuromyelitis Optica Spectrum Disease (ID 1476)

Abstract

Background

Neuromyelitis optica spectrum disease (NMOSD) and multiple sclerosis (MS) have a different pathophysiology. Accumulating evidence suggests that the choroid plexus plays a pivotal role in the pathogenesis of MS. However, MRI data comparing the choroid plexus volume between MS and NMOSD are scarce.

Objectives

To compare the choroid plexus volume in MS vs. NMOSD in vivo using high-resolution 3D MRI data. Migraine patients and healthy individuals served as control groups.

Methods

We included 95 MS patients [45% secondary progressive (SP); mean age 51.0±11.5 years; disease duration 20.8±10.4 years, 62% female; median Expanded Disability Status Scale (EDSS) 4.0], 43 NMOSD patients [28/43 anti-aquaporin 4 antibody positive; 11/43 anti-myelin oligodendrocyte glycoprotein antibody positive; 87% female; mean age 50.0±13.8 years; disease duration 6.8±7.3 years, median EDSS 3.0], 38 migraine patients [mean age 39±13 years, 79% female; 15/38 migraine with aura] and 65 healthy individuals [HCs, mean age 41±17 years, 48% female]. The choroid plexus of the lateral ventricles and T2-weighted (T2w) white matter lesions (WMLs) were segmented fully automated on T1-weighted (T1w) magnetization-prepared rapid gradient echo (MPRAGE) images and fluid attenuated inversion recovery sequences (FLAIR, voxel size of both sequences 1x1x1 mm3), respectively, using a supervised deep learning algorithm (multi-dimensional gated recurrent units). Total intracranial volume (TIV) and lateral ventricle volumes were assessed fully automated using Freesurfer. All outputs were reviewed and manually corrected (if necessary) using 3D-Slicer by trained raters who were blinded to the clinical information. Group differences were analyzed using multivariable generalized linear models (GLMs) adjusted for age, gender, TIV and lateral ventricle volume. Cohens’ d was used to calculate the standardized difference between the respective groups. Given p-values are adjusted for multiple comparisons (Bonferroni).

Results

Mean choroid plexus was larger in MS compared to NMOSD (1907±455 vs. 1467±408 µl; p<0.001, d=0.86), HCs (1663±424 µl; p=0.007, d=1.17) and migraine (1527±366 µl; p=0.02, d=0.72). There was no statistical difference in the choroid plexus volume between NMOSD, migraine and HCs. The choroid plexus was marginally larger in RRMS than SPMS (1959±482 vs. 1875±476 µl; p=0.28; d=0.17) and in untreated MS patients compared to MS patients on disease modifying therapy (2111±382 vs. 1876±459 µl; p=0.36). However, these differences did not reach statistical significance after correction for multiple comparisons. There was no association between the choroid plexus volume and total T2w WML volume in MS.

Conclusions

Patients with MS have larger choroid plexus than HCs, migraine and NMOSD patients. Further studies are warranted to investigate the respective roles of the choroid plexus in the pathogenesis of MS and NMOSD.

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Pediatric MS Poster Presentation

P1079 - Optic nerve head volume decreases in pediatric multiple sclerosis but not in pediatric MOG-related disorders (ID 1357)

Speakers
Presentation Number
P1079
Presentation Topic
Pediatric MS

Abstract

Background

Children with multiple sclerosis (MS) and myelin oligodendrocyte glycoprotein (MOG)-associated syndromes exhibit changes in the retinal nerve fiber layer thickness (RNFL) and ganglion cell inner plexiform layer thickness (GCIPL), but knowledge about abnormalities in the optic nerve head (ONH) morphology in these groups is lacking. Previous studies have characterized deformations of the ONH structures associated with glaucoma and increased raised intracranial pressure and others demonstrated the utility of the assessment of these 3D parameters in the management of adults with aquaporin-4-related NMOSD and acute optic neuritis. No information regarding the utility of these measures in childhood demyelinating syndromes is available.

Objectives

To compare 3D ONH characteristics of pediatric multiple sclerosis and MOG-associated syndromes to healthy controls (HC).

Methods

Standardized OCT data (Cirrus HD-OCT (Carl Zeiss Meditec, Dublin, CA)) were collected on HC [n=27(16 female); median age at OCT of 15.0 years (13.7-16.3)], pediatric MS patients [n=17(11 female), median age at diagnosis of 16.9 years(15.4-18.4); median disease duration of 2.6 years(0.2-5.4)] and children with MOG-related disorders [ n=13( 11 female); median age at diagnosis of 11.5 years (7.3-15.7), median disease duration of 1.7 years(0.4-3)]. ONH parameters (total ONH volume (TV), Bruch’s membrane opening (BMO), region volume (BMO-Vol), and BMO minimal rim width (BMO-MRW)) were computed by triangulated 3D surface reconstruction. Mean peripapillary RNFL and GCIPL were derived from manufacturer’s fully-automated segmentation software, and results were reviewed with manual correction where necessary. Multivariable mixed effects models were used to model the 5 OCT parameters between groups, accounting for age at OCT, eye-specific number of optic neuritis episodes, and a subject-specific random intercept. Results were Bonferroni adjusted for multiple comparisons (p = 0.01).

Results

MS patients showed lower ONH TV (-.241, SE.073; p=.002), BMO-Vol (-.217, SE.083; p=.012), and BMO-MRW (-0.42 dMRW, SE.014; p=.004) compared to HC. ONH parameters were not different in MOG patients compared to controls. Neither RNFL nor GCIPL were significantly different between HC and MS. GCIPL was lower in MOG than HC (-7.9, SE 3.045; p.012).

Conclusions

Our analysis showed ONH volume loss in pediatric MS despite no significant differences in RNFL or GCIPL compared to HC. These changes were not observed in MOG patients. ONH analysis may therefore be superior to RNFL and GCIPL in detecting anterior visual pathway injury in children with MS early in the disease course. Larger studies are needed to confirm these associations.

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