Abstract
Introduction
Anti-myelin oligodendrocyte glycoprotein (MOG) antibody disease (MOGAD) is a type of acquired demyelinating disease that is distinct from multiple sclerosis (MS) and aquaporin-4 antibody neuromyelitis optica spectrum disorder (AQP4-NMOSD). Leptomeningeal enhancement (LME) has been reported in children and adults with MOGAD, and in adults with MS and AQP4-NMOSD, but less is known about LME in pediatric-onset MS (POMS) and pediatric AQP4-NMOSD. Here we compare rates of LME in children with MOGAD, POMS, and AQP4-NMOSD.
Methods
Retrospective chart review was performed in patients with MOGAD, POMS, and AQP4-NMOSD who presented to our institution. Clinical characteristics, imaging features, and relapsing data were included. Descriptive statistics were used, including chi-square or Fischer’s exact test to compare proportions. The Benjamini-Hochberg procedure was used to correct for multiple comparisons.
Results
A total of 42 children were included: 16 POMS, 6 AQP4-NMOSD and 20 MOGAD. Brain LME was only observed in the MOGAD group (6/20=30%) as compared to 0 (0%) POMS and AQP4-NMOSD (p=0.012). Relapsing disease occurred in 9/20 (45%), but LME did not associate with relapse.
Discussion
LME is only observed in pediatric MOGAD and not in POMS or pediatric AQP4-NMOSD. LME did not predict relapses in MOGAD. Further work is needed to determine the clinical significance of LME in pediatric MOGAD.
Keywords: MOG, MOGAD, myelin oligodendrocyte glycoprotein associated disorder, pediatric, multiple sclerosis, neuromyelitis optica spectrum disorder, NMO, NMOSD
Introduction
Anti-myelin oligodendrocyte glycoprotein (MOG) antibody disease (MOGAD) is a neuroinflammatory disorder that occurs in up to 50% of cases of childhood demyelinating disease1. MOGAD is characterized by positive anti-MOG antibodies in specific clinical and radiological syndromes, including optic neuritis (ON), acute disseminated encephalomyelitis (ADEM), transverse myelitis (TM), neuromyelitis optica spectrum disorder (NMOSD), and cerebral cortical encephalitis2.
MOGAD can also present with leptomeningeal enhancement (LME) even in the absence of demyelination and MOGAD may not be suspected until after demyelinating disease occurs3. LME has been reported in 6% of adults,4 33% in children,5 and 46% in a mixed pediatric and adult cohort with MOGAD.6 LME is also observed in 5–8% of adults with MS7 and has been reported in adults with NMOSD.8 However, rates of LME in other pediatric demyelinating diseases such as pediatric onset multiple sclerosis (POMS) or aquaporin-4 antibody positive NMOSD (AQP4-NMOSD) are lesser known.9 Here we compare rates of LME in pediatric MOGAD as compared to POMS and pediatric AQP4-NMOSD, as well as the association with clinical or additional imaging findings.
Methods
Patient cohort and characteristics
Institutional Review Board Approval was obtained for this study; informed consent was waived as this was a retrospective study. Pediatric patients under the age of 18 at the time of symptom onset who presented to Children’s Healthcare of Atlanta, a tertiary children’s hospital, from January 1, 2017 to December 30, 2020 were included. Data from some of these patients have been previously published.3,5,10–12
Patients included in this study were those who were diagnosed with multiple sclerosis (MS) based on the 2017 McDonald Criteria,13 AQP4-NMOSD as by international consensus diagnostic criteria for NMOSD,14 or MOGAD by the International MOGAD Panel criteria.2 AQP4 and MOG serum antibodies were based on a cell-based assay (Mayo Clinic, Rochester, Minnesota, USA).
Data Collection
Clinical and demographic information was obtained from retrospective chart review. MR images obtained at initial presentation as a part of routine clinical care were retrospectively reviewed by a board-certified neuroradiologist with subspecialty training in pediatric neuroradiology (A.G-Y). The MOGAD subjects were first reviewed to determine if leptomeningeal enhancement (LME) was a potential phenotype in these patients. All cases were then reviewed at a later date (at least 6 months), including the MOGAD cases along with the MS and NOMSD cases, blinded to the final diagnosis and serology. LME was defined on postcontrast T1-weighted and/or T2 FLAIR images. Since LME was only observed in the MOGAD patients, we then investigated whether any clinical variables or imaging characteristics are associated with LME.
Statistical Methods
Descriptive statistics were used for clinical characteristics, including mean and standard deviation (SD) or median and interquartile range (IQR) for continuous variables when appropriate, and proportions for categorical variables. One-way ANOVA, including non-parametric ANOVA (Kruskal-Wallis), was used to compare continuous variables among the three groups. Corrections for multiple comparisons were performed using the Benjamini-Hochberg method. Chi-square analysis or Fischer’s exact test, when appropriate, was used to compare proportions. Statistical analysis was performed using SAS 16.0 (Cary, North Carolina, USA).
Results
Clinical characteristics
Our initial cohort included a total of 18 POMS, 6 AQP4-NMOSD, one double seronegative (negative for AQP4 and MOG antibodies) NMOSD, and 21 patients with positive MOG antibodies. Two patients with POMS, the patient with double seronegative NMOSD and one patient with MOG antibodies were excluded. The final number of patients in each group included: 16 POMS, 6 AQP4- NMOSD, and 20 MOGAD (Figure 1).
Figure 1:
Flow diagram of patient cohort included in this study. POMS: pediatric onset multiple sclerosis, AQP4-NMOSD: aquaporin-4 neuromyelitis optica spectrum disorder, MOG: myelin oligodendrocyte glycoprotein, MOGAD: MOG antibody disease, MRI: magnetic resonance imaging.
Univariate analyses
We first compared the clinical characteristics of our cohort by diagnosis (Table 1). The following characteristics were different among the three cohorts, even when corrected for multiple comparisons using the Benjamini Hochberg method. A difference was observed in age of onset (p= 0.0357), in that POMS patients were older (median age 15.0 years, IQR 12.3–15.8) than the MOGAD cohort (median 8.0, IQR 5.0–12.0). MOGAD patients were also more likely to present with seizures (6/20=30%) as compared to POMS (0/16 =0%) and AQP4-NMOSD (1/6=17%) (p= 0.027). Oligoclonal bands (OCBs) were also elevated in the POMS (12/12=100%), as compared to 0% of the AQP4-NMOSD and 5/18 (28%) of MOGAD patients (p<0.0001). Also a difference in follow up time was observed between POMS (median 13.7 months, IQR 9.1–23.6) and AQP4-NMOSD (median 27.3 months, IQR 23.7–49.0) (p=0.021), but no significant differences in follow up time were noted compared to MOGAD.
Table 1:
Clinical characteristics of this pediatric-onset neuroinflammatory disease cohort
| Entire cohort (N=42) | MS (N= 16) | NMOSD (N = 6) | MOGAD (N = 20) | p-value | |
|---|---|---|---|---|---|
| Age at disease onset, y median (IQR) | 11.9 (7.0, 15.0) | 15.0 (12.3, 15.8) | 11.6 (9.8, 14.6) | 8.0 (5.0, 12.0) | 0.036 |
| Sex, Female, N (%) | 32 (76) | 12 (75) | 6 (100) | 14 (70) | 0.32 |
| Seizure at time of presentation, N (%) | 7 (18)2 | 0 (0)2 | 1 (17) | 6 (30) | 0.027 |
| CSF white cell count, cells/uL, median (IQR) | 8 (3, 19)5 | 6 (2, 17)5 | 19 (3, 33) | 8.5 (3.0, 19.0) | 0.49 |
| Elevated CSF OCBs, N (%) | 17 (47)7 | 12 (100)4 | 0 (0)1 | 5 (28)2 | <0.001 |
| Leptomeningeal enhancement, N (%) | 6 (15) | 0 (0)1 | 0 (0) | 6 (30) | 0.012 |
| Follow up time, months, median (IQR) | 15.4 (10.5, 26.6) | 13.7 (9.1, 23.6) | 27.3 (23.7, 49.0) | 15.3 (10.1, 25.6) | 0.021 |
MS: multiple sclerosis, NMOSD: neuromyelitis optica spectrum disorder, MOGAD: anti-myelin oligodendrocyte glycoprotein antibody disease, IVIG: intravenous immunoglobulin, CSF: cerebrospinal fluid, NA: not applicable, IQR: interquartile range; SD: standard deviation, uL: microliter
missing data in 1 patient
missing data in 2 patients
missing data in 4 patients
missing data in 5 patients
missing data in 7 patients
Interestingly, brain LME was only observed in the MOGAD group (6/20=30%) as compared to 0 (0%) of POMS and 0 (0%) of AQP4-NMOSD (p=0.012, Table 1). Of note, the retrospective review did not differ significantly from the initial radiology reports. Most patients with LME or cortical involvement were observed on initial presentation, with the exception of one patient who developed cortical encephalitis 9 months from initial onset. No patients had spine LME in our cohort.
Characterization of MOGAD with LME versus without LME
Since LME was only observed in the MOGAD patients, we then investigated whether any clinical variables or imaging characteristics are associated with LME (Table 2). No clinical characteristics, including relapses and the CSF to serum albumin ratio, were associated with LME. Relapse was observed in 9/20 (45%) but LME did not associate with relapsing disease in our cohort (p=0.17).
Table 2:
MOGAD characteristics by presence or absence of leptomeningeal enhancement on the initial brain MRI.
| MOGAD with LME (N=6) | MOGAD without LME (N=14) | p-value | |
|---|---|---|---|
| Clinical characteristics | |||
| Age at disease onset, y median (IQR) | 11.0 (7.0, 12.0) | 7.0 (5.0, 12.0) | 0.38 |
| Sex, Female, N (%) | 5 (83) | 9 (64) | 0.61 |
| Seizure at time of presentation, N (%) | 2 (33) | 4 (29) | 1.00 |
| Relapse, N (%) | 6 (67) | 3 (27) | 0.17 |
| Ancillary test results | |||
| CSF white cell count, cells/uL, median (IQR) | 13 (3, 34) | 8 (3, 15) | 0.53 |
| Elevated CSF OCBs, N (%) | 2 (40)1 | 3 (23)1 | 0.58 |
| CSF to serum albumin ratio, median (IQR) | 4.0 (2.5, 6.9) | 3.3 (2.3, 3.9) | 0.22 |
| MRI features, N (%) | |||
| Brain MRI | |||
| Lesion number | 0.40 | ||
| None | 1 (17) | 5 (36) | |
| 1–10 | 3 (50) | 6 (43) | |
| > 10 | 2 (33) | 3 (21) | |
| Lesion size | 0.21 | ||
| 0–2 cm | 1 (20) | 8 (62) | |
| > 2 cm | 2 (40) | 2 (15) | |
| Both | 2 (40) | 3 (21) | |
| Lesion Location | |||
| Basal ganglia | 2 (40) | 4 (31) | 1.00 |
| Thalamus | 2 (40) | 3 (23) | 0.58 |
| Corpus callosum | 2 (40) | 3 (23) | 0.58 |
| Periventricular white matter | 2 (40) | 5 (38) | 1.00 |
| Brainstem | 2 (40) | 4 (31) | 1.00 |
| Cerebellum | 2 (40) | 3 (23) | 0.58 |
| Supratentorial lesions | 0.21 | ||
| None | 0 (0) | 4 (31) | |
| 1–10 | 3 (60) | 6 (46) | |
| >10 | 2 (40) | 3 (23) | |
| Infratentorial lesions | 0.85 | ||
| None | 3 (60) | 8 (62) | |
| 1–10 | 2 (40) | 4 (31) | |
| >10 | 0 (0) | 1 (8) | |
| Confluent | 4 (80) | 5 (38) | 0.29 |
| Well demarcated | 2 (40) | 5 (38) | 1.00 |
| Poorly demarcated | 5 (86) | 7 (50) | 0.35 |
| T1 hypointense | 0 (0) | 0 (0) | -- |
| Cortical lesion | 3 (50) | 0 (0) | 0.018 |
| MS-like | 2 (40) | 2 (15) | 0.53 |
| Gadolinium enhancement | 4 (80) | 6 (46) | 0.31 |
| Diffusion restriction | 1 (20) | 0 (0) | 0.28 |
| Optic neuritis | 1 (25)2 | 6 (67)7 | 0.27 |
| Spinal cord | |||
| Any lesion | 2 (50) | 1 (9) | 0.15 |
| Cervical | 2 (33) | 1 (7) | 0.20 |
| Thoracic | 1 (17) | 0 (0) | 0.30 |
| Conus | 0 (0) | 0 (0) | -- |
| Gray matter | 2 (33) | 1 (7) | 0.20 |
| White matter | 1 (17) | 1 (7) | 0.52 |
| Mixed | 0 (0) | 0 (0) | -- |
| Single short segment | 0 (0) | 0 (0) | -- |
| Multiple short segment | 0 (0) | 0 (0) | -- |
| LETM | 2 (33) | 1 (7) | 0.20 |
| Spine LME | |||
| Edema | 1 (17) | 1 (7) | 1.00 |
| Syrinx | 2 (33) | 0 (0) | 0.40 |
MOGAD: anti-myelin oligodendrocyte glycoprotein antibody disease, CSF: cerebrospinal fluid, OCBs: oligoclonal bands, NA: not applicable, IQR: interquartile range; SD: standard deviation, uL: microliter, LME: leptomeningeal enhancement, LETM: longitudinally extensive transverse myelitis, MS: multiple sclerosis, cm = centimeters
Missing data in 1 patient
Missing data in 2 patients
Missing data in 7 patients
Missing data in 9 patients
Discussion
Leptomeningeal enhancement
In this study we find that LME is only seen in MOGAD, and not in POMS or AQP4-NMOSD but LME does not appear to be a factor for relapse in our cohort. LME is a marker of leptomeningeal blood-brain barrier (BBB) breakdown. We also examined the CSF to serum albumin ratio as a marker for blood-brain-barrier breakdown, as CSF albumin increases if the integrity of the BBB is perturbed. The CSF to serum albumin ratio did not correlate with LME in this cohort. Another study found that BBB was more impaired in AQP4-NMOSD than MOGAD but this finding may not be significant if corrected for multiple comparisons.15 In contrast, our study suggests that another serum and/or CSF biomarker is needed to assess LME. For instance, studies have assessed the role of neurofilament light chain (NfL), which is a marker for axonal injury that can be elevated with increased BBB permeability in MS.16 Serum NfL levels did not differ in children with MOGAD, MS, and other demyelinating diseases, which included NMOSD.17 Moreover, anti-glucose-regulated protein 78 (GRP78) antibodies affecting the NF-kB and oxidative stress pathways have also been associated with increased BBB permeability in MOGAD.18
Limited neuropathological studies may provide evidence for why LME is often observed in MOGAD as neuroinflammation in MOGAD differs from MS or AQP4-NMOSD. One difference may be cortical and/or meningeal inflammation. In a mixed cohort of children and adults with MOGAD who had brain specimens available for histopathology (N = 22, median 10 years old), 5/16 (31%) had LME on MRI, with 6/7 (86%) demonstrating meningeal inflammation on histopathology19. While MOGAD subjects had observed meningeal inflammation on histopathology, this number may have ascertainment bias as this proportion was observed from patients with biopsies available19. However, meningeal inflammation was observed in the two MOGAD patients with histopathology performed at autopsy. Interestingly, subpial cortical demyelination is observed in both MOGAD and MS, with MOGAD patients having a higher representation of intracortical demyelinating lesions as compared to those with MS19. However, limited studies are available and thus future studies should explore the immune signaling pathways and migration of immune cells that lead to LME. While LME did not predict relapse in our cohort, larger studies in understanding what features predict relapse will be helpful in MOGAD, and could use methods including a Cox proportional hazards model to account for follow up time.
Advanced neuroimaging techniques may be useful in future studies to interrogate the underlying pathophysiology and morbidity of MOGAD and LME. For example, future studies could also use advanced neuroimaging techniques to assess BBB permeability, such as dynamic contrast enhanced perfusion,20 arterial spin label perfusion,21 or Dynamic Glucose-Enhanced imaging.22 Additional MRI techniques could be used to determine if the glymphatic system and leptomeningeal lymphatics are affected with LME in MOGAD.23 Therefore, advanced neuroimaging techniques will play a crucial role in elucidating the pathophysiology of MOGAD and predicting prognosis.
Limitations
Limitations of this study include inherent constraints of a retrospective design. Additionally, patients are obtained from a single institution. The sample size is also relatively small; however, we are still able to demonstrate differences in LME despite the small sample size. Follow up times were also different among the groups which would affect relapse rates, and the duration of follow up may not have captured all relapses over time in MOGAD.
Conclusions
LME may be a neuroradiological marker that distinguishes a subset of children with MOGAD from those with other diagnoses, including MS or AQP4-NMOSD. Future studies should investigate the role of LME in MOGAD in larger cohorts and examine the pathophysiology of LME in MOGAD. Moreover, additional studies are needed to see whether LME can predict relapsing disease, or determine other predictors for relapse in MOGAD.
Figure 2:
Axial T2 FLAIR (A) and contrast-enhanced T1-weighted (B) images demonstrate leptomeningeal enhancement within left frontotemporal sulci (arrow) without any parenchymal lesions identified. Axial T2 FLAIR (C) and contrast-enhanced T1-weighted (D) images demonstrate cortical edema in the posterior frontal lobe (arrow) with associated leptomeningeal enhancement (arrowhead). Axial T2 FLAIR (E) and contrast-enhanced T1-weighted (F) images demonstrate multiple small T2 hyperintense white matter lesions (arrowheads) in the periventricular, juxtacortical and deep white matter, as well as the corpus callosum, with associated incomplete rim of enhancement on one (thin arrow). Axial T2 FLAIR (G) and contrast-enhanced T1-weighted (H) images demonstrate nonenhancing T2 hyperintense signal in the area postrema (arrow). MOGAD: MOG antibody associated disease, MS: multiple sclerosis, AQP4+ NMOSD: aquaporin-4 antibody positive neuromyelitis optica spectrum disorder, C+ -post contrast study
Funding
This work was supported by the National Center for Advancing Translational Sciences (NCATS) of the National Institutes of Health (NIH) under Award Numbers UL1TR002378 and KL2TR002381.
Declaration of Competing Interest
A.G-Y. and A.L. have no conflicts of interest. G.G. receives part-time salary support from the Centers of Disease Control and Prevention for acute flaccid myelitis case review, and an honorarium as Media Editor for Pediatric Neurology.
Footnotes
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Data Availability Statement
Data will be available to qualified researchers upon reasonable request.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Data Availability Statement
Data will be available to qualified researchers upon reasonable request.