Frequency of New Silent MRI Lesions in Myelin Oligodendrocyte Glycoprotein Antibody Disease and Aquaporin-4 Antibody Neuromyelitis Optica Spectrum Disorder

IMPORTANCE In multiple sclerosis, magnetic resonance imaging (MRI) new silent lesions contribute to the diagnostic criteria, have prognostic value, and are used in treatment monitoring; but in aquaporin-4 antibody neuromyelitis optica spectrum disorder (AQP4-NMOSD), they are rare between attacks. Their frequency and their association with relapses in adults with myelin oligodendrocyte glycoprotein antibody disease (MOGAD) are still unclear. OBJECTIVE To examine the frequency and characteristics of MRI new silent lesions in MOGAD and AQP4-NMOSD. DESIGN, SETTING, AND PARTICIPANTS This retrospective cohort study analyzed clinical and MRI data of 404 patients with MOGAD or AQP4-NMOSD between February 1, 1994, and April 1, 2021; data were prospectively recorded on the Oxford NMOSD clinical database under follow-up. The study was conducted at the Oxford National Referral Center for NMOSD. Participants included patients with MOGAD and AQP4-NMOSD who were treated within the Oxford National NMO Specialist Service. EXPOSURES Seropositive MOGAD and AQP4-NMOSD patients who had MRIs during attacks and the remission phase of their disease. MAIN


Findings
Meaning These findings suggest that new silent lesions are rare in MOGAD and AQP4-NMOSD during remission and appear to precede imminent relapses.

Introduction
Myelin oligodendrocyte glycoprotein antibody disease (MOGAD) is a relatively newly described demyelinating disease of the central nervous system, without predominance by sex or racial category. 1It is characterized by serum MOG IgG1 autoantibodies whose pathogenetic role has not been proven yet.Its clinical phenotype is broad, most frequently presenting with unilateral or bilateral optic neuritis, but also transverse myelitis, brain and brainstem attacks, and a rarer cortical syndrome with seizure. 1,2In children, MOGAD accounts for approximately 50% of acute disseminated encephalomyelitis cases. 3Approximately 50% of patients have a relapsing course, 2 although this appears less in children. 3 Conversely, aquaporin-4 antibody neuromyelitis optica spectrum disorder (AQP4-NMOSD) is a relapsing astrocytopathy affecting preferentially non-White female individuals and requiring long-term immunosuppression to reduce the high rate of relapserelated disability.AQP4-NMOSD may present with severe optic neuritis, longitudinally extensive transverse myelitis, and area postrema, brainstem, diencephalic, and cerebral syndromes. 1,4The prompt distinction between MOGAD, AQP4-NMOSD, and multiple sclerosis (MS) may be challenging for clinicians because the diseases share some clinical and magnetic resonance imaging (MRI) characteristics, which may hamper the treatment of patients.
The appearance of new asymptomatic (silent) T2 hyperintense lesions on interval MRI outside of relapses is a characteristic feature used in the diagnosis of MS, 5 and their absence is one of the treatment goals. 6Although MRI silent lesions during attacks have been reported in both the antibody diseases 7,8 and new brain interattack asymptomatic lesions have been rarely found in AQP4-NMOSD, 9 the role of new brain and spinal cord silent lesions outside of relapses is unclear in MOGAD, with only a single pediatric study noting they occur in a minority of children with MOGAD. 10 In this retrospective analysis, we aimed to assess the frequency of new brain and spinal cord silent lesions on clinical MRIs and their association with relapses in a large cohort of patients with MOGAD and AQP4-NMOSD across all ages.

Population
This cohort study retrospectively included patients [11][12][13] with clinically and serologically diagnosed MOGAD or AQP4-NMOSD who were treated within the Oxford National NMO Specialist Service.Data on race and ethnicity were not collected from all patients because this was not considered a focus of the study, and the collected data were not sufficient to conduct any analysis by race and ethnicity.
Participating patients signed a written informed consent to collect their clinical and imaging data according to the Oxford Research Ethics, and the study was approved by the South Central-Oxford C Research Ethics Committee.Data analyzed had been collected from February 1, 1994, to April 1, 2021.

JAMA Network Open | Neurology
Frequency of New Silent Lesions on MRI in MOGAD and AQP4-NMOSD This study followed the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) reporting guideline.

Clinical Data Collection
We collected demographic and clinical information from the Oxford NMOSD database: sex, date of birth, age at disease onset, age at MOG or AQP4 antibody detection, follow-up duration, total number of clinical demyelinating events (attacks), MRI dates for each patient, date of the last attack before the considered MRI, immunotherapy at the time of the MRI scan, and date of the first clinical relapse after the considered MRI.

MRI Data Collection and New Lesion Analysis
Magnetic resonance images at 1.5 and 3 T were assessed according to the local respective neuroscience department protocols at the time.All the brain MRI protocols included T2-weighted imaging/fluid-attenuated inverse recovery, T1-weighted imaging, and diffusion-weighted imaging sequences.Whole spinal cord MRIs were acquired, including T2-weighted imaging, T1-weighted imaging, and short tau inversion recovery sequences.Gadolinium contrast was administered variably according to the local protocols and clinical scenario.All the scans were reviewed by the Oxford NMOSD expert neurologists (M.I.L. and J.P.) and neuroradiologists (T.H. and W.K.) and data were recorded on the Oxford NMO database.The MRI scans were classified as attack MRIs if performed during the clinical demyelinating events and as remission MRIs if performed at least 3 months from the last attack and the patient was completely free of new symptoms.The latter were arranged to "rebaseline" the appearances for future comparison and were not performed at regular intervals after the last inflammatory attack.We compared lesions on the MRI to the last reference MRI.On the attack MRIs, we identified new (T2-weighted imaging/fluid-attenuated inverse recovery) attack silent lesions as those unrelated to the clinical symptoms and signs.All brain and brainstem lesions were assumed to be symptomatic when it was not possible to distinguish whether they were symptomatic, such as in acute disseminated encephalomyelitis.
On remission MRIs (all had to have been performed at least 3 months from the last attack and all patients had to be completely free of new symptoms), we identified new (T2-weighted imaging/ fluid-attenuated inverse recovery) remission lesions (ie, remission silent lesions), and they were classified as probable if compared with a reference attack MRI and as definite if compared with a reference MRI performed at least 4 weeks after last attack onset.The "definite" category was added to avoid the inclusion of new lesions evolving during the acute attack but after the attack MRI.Some imaging sessions scanned both brain and spinal cord and some either brain or spinal cord regions according to the anatomic areas affected during the previous relapses.Finally, we recorded time from remission MRI to the next relapse.

Statistical Analysis
We described continuous variables by using medians and IQRs or ranges and categorical variables by using proportions and percentages.Proportions were compared with the χ 2 test.Kaplan-Meier curves were used for depicting time from remission MRIs to next relapse, and group comparison was evaluated by log-rank test and Cox proportional hazard ratio.We assessed the Cox proportional hazard assumptions with Schoenfeld residuals.The analysis was conducted with Stata version 14 (StataCorp LLC) in June 2021.Significance was determined at 2-sided P = .05.

MRI Findings
Within a cohort of 182 patients with MOGAD and 222 with AQP4-NMOSD, a total of 663 MOGAD clinical MRIs were available, 416 performed during an attack (296 sessions) and 247 during remission (167 sessions from 107 patients), and a total of 1048 AQP4-NMOSD MRIs were available, 669 during an attack (470 sessions) and 379 during remission (269 sessions from 136 patients) (Table 1).
Follow-up orbital imaging was rare, so data from brain and spinal cord images only were included.

Limitations
The main limitation of our study was its retrospective design analyzing remission MRIs performed with different MRI scanners with variable magnetic field intensity and intervals.Moreover, we may have missed some optic nerve silent lesions because they were not scanned regularly.This was not a prospective study, and thus the various intervals between remission MRIs could have affected new remission lesion accumulation, which would be important if lesion accumulation were used as an outcome in a clinical trial (such as in a phase 2 MS clinical treatment study).However, these findings are relevant in actual clinical practice these 2 diseases are currently managed.The shorter median interval for MOGAD remission MRIs and the greater tendency for lesions to resolve in MOGAD 14 could have led to an underestimation of new lesions compared with that in AQP4-NMOSD, but the opposite effect might also be true, because more AQP4-NMOSD patients were treated.Only a prospective study performing regular-interval MRI scans with patients not receiving treatments or receiving identical treatments would fairly compare the 2 treatment groups.Additionally, none of these observations remove the conclusion that lesion activity is rare in these antibody diseases within current clinical practice and would not be an appropriate outcome in a clinical trial nor useful in routine monitoring of treatments; nevertheless, new remission lesions, when they do occur, would be a cause for concern.
In this cohort study of 404 patients with MOGAD or AQP4-NMOSD, new remission (silent) T2 lesions occurred in 5 of 167 MOGAD and 7 of 269 AQP4-NMOSD nonrelapse imaging sessions.Median time from magnetic resonance imaging to next relapse was shorter in the presence of new magnetic resonance imaging remission (silent) lesions (2 and 5 months) than in their absence (73 and 85 months) in both MOGAD and AQP4-NMOSD cohorts, respectively.
Figure.Association Between New Silent T2 Lesions at Remission MRIs and Time to Next Relapse in MOGAD and AQP4-NMOSD

Table 1 .
Cohort Characteristics b Denominators are the number of remission MRI sessions (167 for MOGAD and 269 for AQP4-NMOSD) instead of the total cohort of patients.cIncluded patients receiving subtherapeutic doses of immunosuppression (eg, <5 mg oral prednisolone daily, azathioprine <2.5 mg/kg/d).

Table 2 .
Characteristics of Remission MRI New Silent LesionsAbbreviations: adt, alternate days; AQP4-NMOSD, aquaporin-4 antibody neuromyelitis optica spectrum disorder; AZA, azathioprine; CNS, central nervous system; definite, new SL found by a remission MRI compared with a reference MRI performed at least 4 weeks after an attack onset; DMT, disease-modifying therapy; DWI, diffusion-weighted imaging; gad, gadolinium contrast; IVIG, intravenous immunoglobulin; MMF, mycophenolate mofetil; MOGAD, myelin oligodendrocyte glycoprotein antibody disease; pred, prednisolone; probable, new SL found by a remission MRI compared with a reference MRI performed at onset or nadir of last clinical attack; r-MRI, remission magnetic resonance imaging (performed at least 3 months from last attack and all had to be completely free of new symptoms); RTX, rituximab; SL, silent lesion.
a Number of patients with definite or probable new remission silent lesions either in MOGAD or in AQP4-NMOSD.