Abstract
Introduction:
Myelin oligodendrocyte glycoprotein antibodies (MOG-abs) are associated with demyelinating diseases. Leptomeningeal enhancement occurs in 6% of adult MOG-abs patients but rates in pediatric MOG-abs patients are unknown.
Methods:
Retrospective review of pediatric MOG-abs patients was performed.
Results:
Twenty-one patients (7 boys, 14 girls) were included with an average age of 8.6 years (range 2-15 years). Seven of 21 (33%) pediatric MOG-abs patients had leptomeningeal enhancement. Two patients’ relapses were manifested by leptomeningeal enhancement alone and another patient presented with seizures, encephalopathy, and aseptic meningitis without demyelinating lesions. Cerebrospinal fluid pleocytosis was seen in both leptomeningeal (4/7 patients) and nonleptomeningeal enhancement (10/14 patients). Interestingly, 3 patients with leptomeningeal enhancement had normal cerebrospinal fluid white blood cell count. Cortical edema was more likely in patients with leptomeningeal enhancement (P = .0263).
Conclusion:
We expand the clinical spectrum of anti-MOG antibody–associated disorder. Patients with recurrent leptomeningeal enhancement without demyelinating lesions should be tested for MOG antibodies.
Keywords: leptomeningeal enhancement, aseptic meningitis, myelin oligodendrocyte glycoprotein, MOG, MOG antibody associated disorder, demyelinating disease, pediatric, multiple sclerosis
Myelin oligodendrocyte glycoprotein (MOG) antibodies have been associated with causing demyelinating diseases of different phenotypes including neuromyelitis optica spectrum disorders, recurrent demyelinating disease mimicking multiple sclerosis, acute disseminated encephalomyelitis, and optic neuritis. The clinical phenotype has expanded to include encephalitistype features including seizures and has been suggested to be named MOG antibody–associated disorder.1,2 Leptomeningeal enhancement has been identified as a feature of MOG antibody-associated disorder.3 One cohort found leptomeningeal enhancement in 6% of adult MOG patients4 but rates of leptomeningeal enhancement have not been reported in children. Here we report on the rates of leptomeningeal enhancement in our cohort of pediatric MOG antibody–associated disorder. We also expand upon the clinical spectrum of MOG antibody–associated disorder to highlight other manifestations of this disease.
Methods
A retrospective chart review was performed on pediatric patients with positive anti-MOG antibody testing who were seen at the hospitals or clinics associated with a single institution from October 2017 until April 2020. Clinical information collected on patients included demographics, clinical symptoms, and cerebrospinal fluid results. All magnetic resonance images (MRIs) were obtained before lumbar puncture except for 3 patients. Cerebrospinal fluid studies were associated with MRI findings if obtained within 24 hours of MRI. All patients who were MOG seropositive were tested by a cell-based assay performed through the Mayo Clinic. An event was defined as new clinical symptom and/or new radiologic lesion and/or enhancement more than 30 days apart. Relapsing disease was defined as having more than 1 event. One patient has been previously published.5 A single neuroradiologist (JG) reviewed the images for demyelinating images and for leptomeningeal enhancement. Descriptive statistics, Student t test, and Fisher exact test were used (Stata 16, 2019).
Results
Table 1 presents the demographic characteristics of our patient cohort. Twenty-one patients (7 boys, 14 girls) were included in this study with a total of 37 neurologic events. The average age of our cohort was 8.6 years with an age range from 2 to 15 years at the time of the first neurologic event. Average age was the same between patients with leptomeningeal vs without leptomeningeal enhancement (Student t test). The most common initial presentations included encephalopathy (42.9%), optic neuritis (42.9%), and new-onset seizures (28.5%).
Table 1.
Demographic Information of MOG Antibody Positive Pediatric Patients.
| All patients (N = 21) | With LME (n = 7) | Without LME (n = 14) | P value | |
|---|---|---|---|---|
| Age, y, mean (SD) | 8.6 (4.1) | 9.1 (4.3) | 8.4 (4.2) | .696 |
| Male-female ratio | 7:14 | 2:5 | 5:9 | >.99 |
| Cerebrospinal fluid pleocytosis, n (%) | 14 (66.7) | 4 (57.1) | 10 (71.4) | .638 |
| Oligoclonal bands, n (%) | 5 (23.8) | 1 (14.3) | 4 (28.6) | .624 |
| Relapsing disease, n (%) | 11 (52.3) | 6 (85.7) | 5 (35.7) | .063 |
| Number of events, total n | 37 | 19 | 18 | |
| Demyelinating lesions only, n (%) | 21 (56.8) | 6 (31.6) | 15 (83.3) | |
| LME only, n (%) | 3 (8.1) | 3 (15.8) | 0 (0) | |
| LME + demyelinating lesions, n (%) | 10 (27.0) | 10 (52.6) | 0 (0) |
Abbreviations: LME, leptomeningeal enhancement; SD, standard deviation.
Demyelinating phenotypes included 6 of 21 (28.5%) with acute disseminated encephalomyelitis, 6 of 21 (28.5%) with optic neuritis, 3 of 21 (14.3%) with recurrent demyelinating disease, 2 of 21 (9.5%) with neuromyelitis optica spectrum disorders, 1 of 21 (4.8%) with transverse myelitis, and 3 of 21 (14.3%) aseptic meningitis (with 1 of the 3 aseptic meningitis patients presenting with strokelike symptoms). Five of 21 patients (23.8%) had cerebrospinal fluid oligoclonal bands, with no differences between the 2 groups (Table 1). On imaging, 7 of 21 (33.3%) patients had evidence of optic neuritis, 16 of 21 (76.2%) patients had brain lesions, and 6 of 21 (28.6%) had spinal cord lesions (Table 2).
Table 2.
Imaging Features in MOG Antibody Positive Pediatric Patients With and Without Leptomeningeal Enhancement (LME).
| All patients, n (%) (N = 21) | With LME, n (%) (n = 7) | Without LME, n (%) (n = 14) | P value | |
|---|---|---|---|---|
| Demyelinating disease phenotype | .443 | |||
| Acute disseminated encephalomyelitis | 7 (33.3) | 1 (14.3) | 6 (42.9) | |
| Optic neuritis | 6 (28.6) | 1 (14.3) | 5 (35.7) | |
| Recurrent demyelinating disease | 3 (10) | 1 (14.3) | 2 (14.3) | |
| Neuromyelitis optica spectrum disorders | 2 (9.5) | 1 (14.3) | 1 (7.1) | |
| Aseptic meningitis | 2 (9.5) | 2 (28.6) | 0 (0) | |
| Acute transverse myelitis | 1 (4.7) | 1 (14.3) | 0 (0) | |
| Demyelinating lesions on MRI | 19 (90.5) | 5 (71.4) | 14 (100) | .1 |
| Optic neuritis on MRI | 7 (33.3) | 2 (28.6) | 5 (35.7) | >.99 |
| Brain lesions | 16 (76.2) | 5 (71.4) | 11 (78.6) | >.99 |
| Spinal cord lesions | 6 (28.6) | 2 (28.6) | 4 (28.6) | >.99 |
| Cortical edema | 3 (14.3) | 3 (42.9) | 0 (0) | .0263 |
Abbreviations: LME, leptomeningeal enhancement; MRI, magnetic resonance imaging.
Leptomeningeal enhancement was present in 7 of 21 (33.3%) of patients. Thirteen of 37 (35.1%) neurologic events were associated with leptomeningeal enhancement, whereas 3 of 37 (8.1%) events had pure leptomeningeal enhancement without any demyelinating lesions (Table 1). Cortical edema was more likely in patients with leptomeningeal enhancement (42.9% vs 0%, P = .0263). One patient’s initial presentation included new-onset seizures, headache, and back pain at the age of 11 years. MRI demonstrated cortical lesions (Figure 1) that resolved on repeat imaging 3 months later. Ten months later, he had recurrent seizures and MRI demonstrated new T2 lesions with leptomeningeal enhancement (Figure 2). Cerebrospinal fluid pleocytosis (cerebrospinal fluid white cells > 5 per mm3) was seen in both leptomeningeal (in 4 of 7 or 57.1% of patients) and nonleptomeningeal enhancement (10 of 14 or 71.5% of patients). Interestingly, 3 patients with leptomeningeal enhancement had normal cerebrospinal fluid white blood cell count. Three patients had lumbar puncture prior to MRI. Of those patients, 2 had no leptomeningeal enhancement; one patient had focal leptomeningeal enhancement unlikely due to lumbar puncture. Eleven of 21 patients (52.3%) had relapsing disease with relapses occurring in 6/7 (85.7%) patients with leptomeningeal enhancement compared with 5 of 14 (35.7%) with a monophasic illness, which trended toward significance (P = .063). The single patient with transverse myelitis did not have abnormal enhancement. Treatments included steroids, intravenous immunoglobulin, mycophenolate mofetil, and rituximab.
Figure 1.
Initial axial T2-weighted MR images of an 11-year-old boy show abnormal T2 hyperintensity in the cortex of the left cingulate gyrus (arrow) and in the bilateral parasagittal frontal lobe cortex (arrowheads). MR, magnetic resonance.
Figure 2.
Eleven-year-old boy presents 10 months after initial presentation with relapse. Axial T2 FLAIR MR images demonstrate new abnormal T2 FLAIR hyperintensity in (A) the right frontal cortex and in (B) the inferior left frontal cortex with associated leptomeningeal enhancement in (C) the right frontal lobe on postcontrast axial T1. Follow-up imaging performed 6 months later demonstrates decrease of the prior abnormal T2 FLAIR hyperintensity in (D) the right frontal cortex and in (E) the inferior left frontal cortex. There is also decrease of the prior leptomeningeal enhancement in (F) the right frontal lobe on postcontrast axial T1. This patient was diagnosed with recurrent demyelinating disease. FLAIR, fluid-attenuated inversion recovery.
Discussion
Leptomeningeal enhancement can occur in MOG antibody–associated disorder, including spinal leptomeningeal enhancement,6 and aseptic meningitis with demyelinating lesions.7,8 MOG antibodies are more likely to occur in children as compared to adults.1 Moreover, phenotypic presentations are different as children are more likely to present with encephalopathy or acute disseminated encephalomyelitis, whereas adults are more likely to have optic neuritis-myelitis.1 Radiographic features in pediatric MOG antibody–associated disorder have included different types of gray and white matter lesions in both the brain and spinal cord,9-11 but the rate of leptomeningeal enhancement has not been reported in pediatric patients. Leptomeningeal enhancement has been reported in 6% of adults,4 but in our pediatric cohort, 33% of patients have leptomeningeal enhancement. Currently it is unclear as to why pediatric patients may have a higher frequency of leptomeningeal enhancement as compared to adults but is likely related to age. Children are more likely to have inflammatory activity as evidenced by increased relapse rates12 and increased leptomeningeal enhancement.
Leptomeningeal enhancement is reflective of blood-brain barrier breakdown,13 which may be mediated by different aspects of the immune system in MOG antibody–associated disorder. The MOG protein is accessible to the immune system because of its location on the myelin sheath surface.14 Although the exact mechanism for blood-brain barrier breakdown in MOG antibody–associated disorder is unknown, blood-brain barrier breakdown is implicated in MOG antibody–associated disorder mediated by anti-MOG antibodies and central nervous system–specific T cells.15,16 In our study, leptomeningeal enhancement trended toward being associated with increased relapses and thus reflective of increased inflammation, which should be investigated further in larger cohorts.
Limitations of this study include a small sample size and selection bias, as these are patients at 1 institution. Further studies will be helpful to see if leptomeningeal enhancement is more common in children as compared to adults with MOG antibody–associated disorder. Moreover, only patients with neurologic demyelinating disease are being screened for MOG antibodies.
In conclusion, patients with leptomeningeal enhancement may also be MOG seropositive. Thus, in patients with aseptic meningitis with recurrent or persistent leptomeningeal enhancement, MOG antibody–associated disorder should be considered even without the presence of demyelinating lesions as immunotherapy treatment may be warranted in those patients.
Funding
The authors received no financial support for the research, authorship, and/or publication of this article.
Declaration of Conflicting Interests
The authors declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: GG receives salary support from the Centers for Disease Control and Prevention for review of acute flaccid myelitis cases for surveillance.
Footnotes
Prior Publication
This work has not been presented in part or in whole at any meeting.
Ethical Approval
Institutional review board approval (IRB00000209) was obtained for this study.
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