Author Of 2 Presentations
PS15.03 - Optical coherence tomography in aquaporin-4-IgG positive neuromyelitis optica spectrum disorders: a collaborative multi-center study
- F. Oertel
- S. Specovius
- H. Zimmermann
- C. Chien
- S. Motamedi
- L. Cook
- M. Lana-Peixoto
- M. Fontenelle
- H. Kim
- J. Hyun
- J. Palace
- A. Roca-Fernandez
- F. Ashtari
- R. Kafieh
- L. Pandit
- A. D'Cunha
- O. Aktas
- M. Ringelstein
- E. May
- C. Tongco
- L. Leocani
- M. Pisa
- M. Radaelli
- E. Martinez-Lapiscina
- H. Stiebel-Kalish
- S. Siritho
- J. De Seze
- T. Senger
- J. Havla
- R. Marignier
- E. Nerrant
- A. Cobo Calvo
- D. Bichuetti
- I. Tavares
- N. Asgari
- K. Soelberg
- A. Altintas
- U. Tanriverdi
- A. Jacob
- S. Huda
- Z. Rimler
- Y. Mao-Draayer
- I. Soto De Castillo
- A. Green
- M. Yeaman
- T. Smith
- A. Brandt
- F. Paul
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.
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.
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.
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.
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.
Presenter Of 1 Presentation
Invited Speaker Of 1 Presentation
Author Of 5 Presentations
P0155 - Serum neurofilament light chain levels correlate with attack-related disability in neuromyelitis optica spectum disorder (ID 1291)
Pathogenic autoantibodies against aquaporin 4 (AQP4) in neuromyelitis optica spectrum disorder (NMOSD) cause central nervous system injury, with subsequent release of astroglial and neuronal proteins such as glial fibrillary acidic protein (GFAP), neurofilament light chain (NfL), ubiquitin carboxyl-terminal hydrolase L1 (UCH-L1) and Tau into the circulation. N-MOmentum is a randomized, placebo-controlled, double-masked trial of inebilizumab, a B-cell-depleting monoclonal antibody (NCT02200770).
Investigate relationships of NfL, UCH-L1, Tau and serum (s)GFAP to disease activity and Expanded Disability Status Scale (EDSS) disability in N-MOmentum trial participants with either AQP4-immunoglobulin G (IgG) seropositive or seronegative NMOSD.
Serum biomarkers NfL, UCH-L1, Tau and sGFAP were measured using the single molecular array (SIMOA; Quanterix) in 1260 serial and attack-related samples from N-MOmentum participants (n=215) and healthy controls (HC; n=25).
At baseline, biomarkers were elevated in subsets of patients with NMOSD (NfL, 16%; UCH-L1, 6%; Tau, 12%; sGFAP, 29%); NfL and UCH-L1 levels correlated with sGFAP (r=0.53 [p<0.001] and 0.18 [p=0.007]). Baseline elevations were significantly associated with increased attack risk (NfL, hazard ratio [HR] 2.5, p=0.01; UCH-L1, HR 2.8, p=0.039; Tau, HR 2.6, p=0.01; sGFAP, HR 3.03, p<0.001). After controlling for baseline sGFAP in Cox regressions, the other markers were not independently associated with attack risk (all HR <2; p>0.05). In the total cohort, a greater proportion of patients had an attack with placebo than inebilizumab (39% vs 12%). All biomarker levels increased after attacks and median-fold increases from baseline (95% confidence interval) trended higher with placebo than inebilizumab, reaching significance with sGFAP (NfL, 1.49 [0.93–3.37] vs 1.30 [0.84–2.14], p=0.4; UCH-L1, 6.70 [1.59–52.4] vs 1.85 [0.89–23], p=0.12; Tau, 2.19 [0.96–9.46] vs 1.09 [0.40–3.7], p=0.23; sGFAP, 20.2 [4.4–98] vs 1.11 [0.75–24.6], p=0.037). Following attacks, NfL correlated with EDSS score at attack assessments (R=0.55; p<0.001); other biomarkers did not correlate with EDSS score after controlling for NfL levels.
In NMOSD, serum NfL, UCH-L1 and Tau levels were higher than in HC; increased baseline sGFAP levels were associated with greater attack risk. Although sGFAP levels showed the greatest increase following attacks, NfL correlated with attack-related disability.
P0189 - AQP4-IgG seronegative patient outcomes in the N-MOmentum trial of inebilizumab in neuromyelitis optica spectrum disorder (ID 1288)
The N-MOmentum trial of inebilizumab included patients with aquaporin 4-IgG seropositive (AQP4+) or seronegative (AQP4−) neuromyelitis optica spectrum disorder (NMOSD).
To report AQP4− participant outcomes in N-MOmentum. .......................................................
Medical histories and screening data for AQP4− patients were assessed independently by 3 clinical experts before enrollment. Majority decision confirmed diagnoses using the 2006 criteria. Myelin oligodendrocyte glycoprotein-IgG (MOG) serology and annualized attack rates (AARs) were tested post hoc. These observations do not account for bias in estimates of effects on the AAR caused by regression to the mean, introduced by inclusion criteria requiring attacks during the 1 to 2 years before study entry.
Only 18/50 AQP4− patients (36%) were eligible for randomization; 17 were randomized, 4 to placebo (1 MOG+) and 13 to inebilizumab (6 MOG+). Reasons for not enrolling prospective AQP4− NMOSD participants were mainly related to lack of fulfillment of MRI findings required by the 2006 criteria.
Owing to limited patient numbers, we compared the on-study to the pre-study AAR for treated participants to assess treatment effects.
For AQP4− participants (n=17), 40 attacks occurred in 23 patient-years of pre-study follow-up with mean AAR (95% confidence interval) of 1.72 (1.23–2.33). For MOG+ participants (n=7), 16 attacks occurred in 8.3 patient-years of pre-study follow-up with an AAR of 1.93 (1.11–3.14). For double-seronegative participants (n=10), 24 attacks occurred in 15 patient-years of pre-study follow-up with an AAR of 1.60 (1.02–2.38).
After receiving inebilizumab, AARs declined in all groups by the end of the randomized controlled period: AQP4− participants (n=13), 0.09 (0.02–0.26), or 3 attacks in 34.2 patient-years; MOG+ participants (n=6), 0.08 (0.002–0.464), or 1 attack in 12 patient-years; double-seronegative participants (n=7), 0.09 (0.011–0.326), or 2 attacks in 22 patient-years.
The benefit was sustained with longer-term inebilizumab exposure. At 120 days into the open-label period (OLP), during which all participants received inebilizumab, the AAR in AQP4− participants (n=17) remained low (0.069 [0.014–0.202]). No attacks were seen in any AQP4−, MOG+ or double seronegative patient during the OLP.
The N-MOmentum trial provides clinically important insight on the difficulty of correctly diagnosing AQP4− NMOSD and suggests that inebilizumab may have a benefit on AAR in these patients.
P0229 - Quiescent MRI activity in neuromyelitis optica spectrum disorder: results from the N-MOmentum randomized placebo-controlled trial (ID 1292)
Magnetic resonance imaging (MRI) findings in patients with neuromyelitis optica spectrum disorder (NMOSD) have not previously been studied with data from a prospective, randomized controlled study. During N-MOmentum, longitudinal MRIs were performed systematically.
To characterize MRI findings in patients with NMOSD in the N-MOmentum study of inebilizumab. .....................
MRIs of the spinal cord, optic nerve and brain were performed at baseline, within 8 days of an NMOSD attack and at the end of the randomized controlled period (RCP; month 6.5). MRIs were read centrally by two independent, blinded-to-treatment neuroradiologists for new gadolinium-enhancing (Gd)-T1 enhancement events. Attacks were adjudicated by an expert committee.
Complete MRI data were available for 192 (83%) of 230 participants, 42 of whom had an adjudicated attack (22 myelitis, 14 optic neuritis, 6 multi-domain). The remaining 38 patients did not have valid post-baseline MRI scans available for analysis. Inter-rater agreement between the two neuroradiologists for gadolinium-enhancing lesions was 98% for brain, 95% for spinal cord and 90% for optic nerve.
At the time of acute adjudicated NMOSD attacks, new Gd-T1 MRI enhancement corresponding to the affected clinical domain was present in 19/22 myelitis attacks (86%) and 11/14 optic neuritis attacks (79%). At the time of acute optic neuritis attacks, asymptomatic, new Gd-T1 enhancement was simultaneously observed in 4/14 spinal cord MRIs (29%) and 1/14 brain MRIs (7%). At the time of acute myelitis attacks, asymptomatic, new Gd-T1 enhancement was simultaneously observed in 6/22 optic nerve MRIs (27%) and 3/22 brain MRIs (14%).
In the 150 participants without an adjudicated attack, new Gd-T1 MRI enhancements compared with baseline readings were observed in the brain, spinal cord and optic nerve in 3%, 18% and 51% of patients at the end of the RCP, respectively.
At the time of attack, MRI enhancements were highly correlated to the clinical presentations. However, asymptomatic Gd-T1 enhancements were detected outside the symptomatic attack domain in about one-third of cases. Furthermore, subclinical Gd-T1 enhancements were observed in many patients who did not experience clinically overt attacks. Subclinical blood–brain barrier breakdown, particularly in the optic nerve, may be a frequent phenomenon in patients with active NMOSD.
P0253 - Gaps in characterization of bladder dysfunction in clinical care and research (ID 1934)
Neurogenic bladder dysfunction (BD) affects up to 90% of patients with multiple sclerosis (MS) at some point during the disease course and is a highly debilitating symptom. Despite its prevalence, there are no consensus guidelines for screening and ascertaining BD. These discrepancies could underrepresent the impact of BD on neurological decline.
In a cohort of women with MS, we compared clinical notes and research registry scores pertaining to BD. We secondarily evaluated how often Bowel/Bladder Functional System (B/B FS) scores reflected the severity of bladder (rather than bowel) scores.
For 100 adult women with MS in the University of California, San Francisco longitudinal observational EPIC cohort (epicstudy.ucsf.edu), we retrospectively extracted data on bladder and bowel symptoms and treatments from prospectively collected clinical notes in the electronic medical record and compared them with research-grade B/B FS scores annually collected in the EPIC registry. We performed descriptive statistics to evaluate agreement between the clinical notes (BD) and research B/B FS scores at matching timepoints (within 6 months). Finally, seeking to understand whether the severity of BD could be inferred by the B/B FS, we calculated the frequency that bladder (vs. bowel) symptoms drove a higher B/B FS.
We included 89 women, aged 37 to 77, with at least one matching clinical and research visit; a total of 316 visits were examined. Overall, 63 of the 89 participants (70.7%) experienced BD symptoms per clinical notes. BD symptoms were described in 284 of the 316 visits (89.9%), and research B/B FS scores were available for 283 of these. The severity of BD symptoms matched the research B/B FS in 203 (71.5%) of visits. For the rest, BD symptoms were more severe than research B/B FS for 46 visits and less severe for 34. BD severity “drove” the overall B/B FS score in 280 (98.6%); in contrast, in only 4 visits (1.4%) bowel symptoms were more severe.
We noted moderate discrepancy between clinical notes and research B/B FS; in 10% visits, BD symptoms were not ascertained; and in 16.3% research evaluations, BD symptoms were underscored. Inconsistencies in screening for both clinical care and research point to the need for consensus around consistency of BD symptom ascertainment and B/B FS scoring. Of relevance to interpreting B/B FS in the context of understanding the impact of BD on clinical course, B/B FS in most cases reflected the severity of bladder symptoms.
P1113 - Underutilization of Physical Therapy Resources for Symptomatic Women with MS During and Following Pregnancy (ID 1240)
Patients with MS continue to have symptoms of their disease even when inflammatory activity is reduced by DMTs. Although this activity is reduced during pregnancy - especially in the third trimester – women with MS can experience ongoing symptoms during pregnancy, or new ones in the immediate post-partum period, that degrade quality of life. Many MS-related and postpartum symptoms can be improved with physical therapy (PT), but there are no guidelines on pregnancy-related rehabilitation in MS.
To evaluate the prevalence of PT-amenable symptoms and patterns of PT referrals in a cohort of UCSF MS Clinic patients who became pregnant.
Data collected prospectively between 09-2005 to 08-2019 were retrospectively extracted from electronic medical records (EMR) for the year before conception, during pregnancy, and year postpartum. This included clinical visits, MS therapies and symptoms (as defined by the National MS Society). PT and pelvic floor PT orders and notes were also extracted.
We included 142 live birth pregnancies from 118 women. During the course of their pregnancy and within the year postpartum, 107 women (75.4%) reported at least one PT-amenable symptom. A total of 30 (28.0%) referrals were made to PT, with attendance confirmed for 10 (33.3%). Symptoms most commonly triggering a referral for PT evaluation were numbness and urinary incontinence. Falls were reported after 10 of the pregnancies; 4 resulted in a referral to PT. Forty-one women reported urinary incontinence: 11 (26.8%) were referred to PT, and 2 to pelvic floor PT. Nineteen women experienced a documented relapse during pregnancy and/or postpartum: 11 received a PT referral, and 4 attended PT.
While women with MS recorded at least 1 PT-amenable during or following 75.4% of their pregnancies, only 28% of these were referred to PT – and only a third attended PT. Of significance was the 4.9% referral rate for pelvic floor PT in postpartum women with a record of urinary incontinence. Pelvic floor PT is a mainstay of general postpartum care in many European countries. These data illustrate critical gaps in rehabilitation referral, access and use at the intersection of neurological conditions and pregnancy in a large US-based MS clinic. They lend support for quality improvement efforts to improve care pathways and for telerehabilitation innovations to reduce barriers to access and improve synergistic care between PT, MD and urologic care.