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Delayed diagnosis and treatment may cause progression to more severe phenotypes.
Abstract
Background
Myelin oligodendrocyte glycoprotein (MOG) antibodies mediate inflammatory demyelinating diseases of the central nervous system. This study aimed to understand the clinical characteristics of MOG antibody-associated aseptic meningitis (MOGAM).
Methods
Here, we report the cases of two children with MOGAM. A systematic literature review was conducted and included patients who had MOGAM only, without neurological parenchymal lesions. The clinical characteristics that may have affected the outcome were statistically analyzed.
Results
We reviewed 12 cases of MOGAM; male: female = 9: 3. Prolonged fever lasting over 7 days (11/12) was the most frequent symptom, followed by headache (10/12), vomiting (5/12), and seizures (4/12). None of the patients had focal neurological manifestations or parenchymal lesions on imaging. Cerebrospinal fluid (CSF) leukocytosis was observed in all patients (12/12), and blood leukocytosis and elevated CSF pressure was observed in all patients who had corresponding results (9/9 and 4/4, respectively). Seizures occurrence was lower than that of MOG antibody-associated cortical encephalitis. Seven cases progressed to other MOG antibody-associated diseases (MOGADs) in the later phase of MOGAM. Patients who did not progress to other MOGADs had a shorter disease duration from onset to the initiation of intravenous methylprednisolone than those who did. All the patients achieved full recovery after steroid treatment. One patient had relapses.
Conclusions
MOGAM without inflammatory demyelination is a rare but distinct phenotype of MOGAD, with fewer clinical manifestations mimicking bacterial or viral meningitis/encephalomeningitis. Delayed diagnosis and treatment may induce the progression to other severe MOGADs. Early recognition of this unique autoimmune aseptic meningitis may contribute to early diagnosis, treatment, and better outcomes.
Myelin oligodendrocyte glycoprotein (MOG) antibodies mediate inflammatory demyelinating diseases of the central nervous system (CNS) with diverse phenotypes. According to previous studies, inflammatory demyelinating lesions of the CNS are the core imaging and pathological features of MOG antibody-associated disease (MOGAD). In recent years, the phenotypic spectrum of MOGAD has expanded. In addition to acute disseminated encephalomyelitis (ADEM), optic neuritis (ON), neuromyelitis optica spectrum disorder (NMOSD), transverse myelitis (TM), and encephalitis, MOGAD may also manifest as cortical encephalitis without white matter demyelination and involving only the cerebral cortex (
). We report here two cases of MOG antibody-associated aseptic meningitis (MOGAM) without positive imaging of the CNS parenchyma or optic nerves and systematically review the literature to summarize its clinical characteristics and facilitate further recognition of this unique phenotype of MOGAD.
2. Case report
2.1 Case 1
A 13-year-old boy was hospitalized with intermittent fever, headache, and infrequent vomiting for 12 days. He did not have any mental changes, seizures, limb weakness, limb sensory disturbance, or decreased vision. Complete blood cell count (CBC) showed leukocytosis (17 × 109/L), and elevated erythrocyte sedimentation rate (ESR) at 33 mm/h, while procalcitonin and C-reactive protein (CRP) levels were normal. Cerebrospinal fluid (CSF) analysis revealed leukocytosis (392 × 106/L, monocyte 59%), slightly elevated protein at 566.7 mg/L, and an elevated opening pressure of 260 mmH2O.
Detailed tests for pathogens were negative, including serological analysis for anti-streptolysin O; Widal test; and immunoglobulin M (IgM) antibodies against herpes simplex virus, Epstein-Barr virus, Mycoplasma pneumoniae, and Chlamydia. Swab polymerase chain reaction (PCR) for influenza A and B, respiratory syncytial virus, and adenovirus yielded negative results. CSF PCR was used to detect herpes simplex virus types 1 and 2, Epstein-Barr virus, Mycoplasma pneumoniae, and tuberculosis, all of which were negative. Bacterial cultures of the blood and CSF were negative. Routine serum autoantibodies, including ANCA, ANA, rheumatoid factor, anti-SSA, and anti-SSB, were negative. Electroencephalography was normal. Brain magnetic resonance imaging (MRI), angiography (MRA), and venography (MRV) findings were normal on the 13th day after onset.
After admission, the boy was empirically treated with ceftriaxone and acyclovir, and the antibiotics were upgraded to meropenem and linezolid; however, his condition did not improve. He still had a low fever and headache, which was relieved after the administration of low-dose dexamethasone but reoccurred upon withdrawal of the drug. On the 24th day from onset, a cell-based assay for serum MOG immunoglobulin G (IgG) was performed, and the results were positive (1:100), while AQP4-IgG and MBP-IgG were negative. On the 27th day, repeat brain MRI were performed, which revealed no parenchymal abnormality but a slight enhancement of the leptomeninges (Fig. 1). The visual evoked potential (VEP) was normal.
Fig. 1Brain magnetic resonance imaging of case 1 with MOG antibody-associated aseptic meningitis. Day 13 after onset, on axial T2-weighted fluid-attenuated inversion recovery (T2-FLAIR) imaging pre-gadolinium, no abnormalities were seen (A–D). Day 27 after onset, no parenchymal abnormality was found in repeat brain MRI (E–H) and DWI (I–J). Slight leptomeningeal enhancement could be seen (K–L). Ten months after onset, the patient relapsed and presented as ADEM, and T2-FLAIR imaging revealed hyperintense lesions in the right cerebellum (M, arrow), left cerebral peduncle (N, arrow), and bilateral thalamus (O, arrows). At 3.5 years after onset, T2-FLAIR imaging demonstrated hyperintense lesions in periventricular white matter and the corpus callosum (P, arrow).
Intravenous methylprednisolone (500 mg/day) was administered for 3 days, followed by oral prednisone (60 mg/day). The fever and headache were completely relieved on the first day of methylprednisolone administration. After discharge, prednisone was gradually reduced to 30 mg/day over 2 months. Seven months after onset, the serum MOG-IgG titer decreased to 1:32, and the oral prednisone dose was reduced to 10 mg/day.
Ten months after onset, the patient developed fever and headache again. Brain MRI showed a high T2 flair signal in the bilateral thalamus and basal ganglia. The serum MOG-IgG titer significantly increased to 1:640. The boy received plasma exchange three times and IVIG (1 g/kg), high-dose methylprednisolone 15 mg/kg pulse therapy for 3 days, followed by oral prednisone (60 mg/day) and mycophenolate mofetil. The symptoms subsided, but he still had an intermittent headache. For the next 4 years, he had several relapses, during which seizures, paralysis, decreased visual acuity, and sudden right eye blindness developed. Three and a half years after the onset, the serum MOG-IgG titer was 1:32. At the last follow-up five years after onset, the patient was still taking mycophenolate mofetil, low-dose oral prednisone, and antiseizure medications.
2.2 Case 2
A five-year-old boy was hospitalized with persistent headache for 10 days. He had decreased appetite, fatigue, and infrequent vomiting, but no fever, vision loss, or limb paralysis. Neurological examination revealed no abnormalities. Blood tests showed leukocytosis (18 × 109/L), and a slightly elevated CRP level (18 mg/L). CSF examination revealed elevated leukocyte (44 × 106/L, 75% monocytes) and pressure (300 mmH2O) levels, whereas protein and glucose levels were normal. Bacterial culture and PCR in the CSF for herpes simplex virus type 1 and type 2, Epstein-Barr virus, Mycoplasma pneumoniae, and tuberculosis were all negative. Metagenomic next‐generation sequencing of DNA and RNA microorganisms in the blood and CSF was negative. After admission, ceftriaxone and acyclovir were administered; however, his condition did not improve. Brain and spinal MRI revealed no parenchymal lesions, except for diffuse and slight enhancement of the leptomeninges (Fig. 2). On the 13th day after onset, antibodies associated with inflammatory demyelinating diseases of the CNS were detected, and the results for serum MOG-IgG through cell-based assays and tissue-based assays were positive (1:100) and positive in the CSF (1:1), while AQP4-IgG and MBP-IgG were negative. The CSF oligoclonal band (OCB) was negative as Type 4 pattern. VEP was normal. Methylprednisolone pulse therapy (20 mg/kg/day for three days) was administered, followed by prednisone at 1 mg/kg/day. In addition, high-dose IVIG (2 g/kg divided into 5 days) was administered for further anti-inflammatory effects. Subsequently, the boy's symptoms were completely relieved. At the 1-month follow-up MRI, no abnormalities were observed in the brain, spine, or orbit. No relapse occurred within 3 months of follow-up.
Fig. 2Magnetic resonance imaging of case 2 with MOG antibody-associated aseptic meningitis. Day 13 after onset, on brain axial T2-weighted fluid-attenuated inversion recovery (T2-FLAIR) imaging pre-gadolinium (A, E) and axial diffusion-weighted imaging (C, G), no abnormalities were seen. On axial T1-weighted imaging post-gadolinium, slight diffuse leptomeningeal enhancement was seen (B, F). Day 18 after onset, sagittal T2-weighted imaging revealed no abnormalities in the spinal cord (D, H).
We reviewed the case reports of aseptic meningitis associated with MOG antibody before April 6, 2022, searching PubMed for ‘[meningitis] AND [MOG]’, ‘[intracranial infection] AND [MOG]’, ‘[encephalitis] AND [MOG]’, and ‘[encephalomeningitis] AND [MOG]’. Patients were included if they (a) had aseptic meningitis based on symptoms and CSF tests; (b) did not have symptoms indicating focal lesions in the CNS or optic nerves, including visual impairment, limb paralysis, dysuria, etc.; (c) did not have positive examinations indicating optic or spinal involvement, including MRI and VEP examination; (d) MRI revealed no brain parenchymal lesions; and (e) serum MOG-IgG antibodies were positive based on cell-based assays. We retrieved all the articles and manually reviewed as many potential cases as possible. All searches were performed independently by two authors (SFL and WWL).
SPSS version 28.0 (IBM Corp., Armonk, NY, USA) was used for all analyses. The median was used for continuous variables. Differences between discrete variables were analyzed using a Fisher's exact test where appropriate. When discrete variables followed the normal distribution, the t-test was used for two-group comparison. The binomial test was used to compare the proportion of the sample in this study with a proportion from reference. The significance level for all tests was p = 0.05.
This study was approved by the Ethics Committee of Shenzhen Children's Hospital, China (2,022,007). Informed consent was obtained from the parents or legal guardians of each patient.
4. Results
Ten cases of aseptic meningitis associated with MOG antibodies in seven published studies were included in our analysis (
Children suspected of having intracranial infection with normal brain magnetic resonance imaging may be associated with the myelin oligodendrocyte glycoprotein antibody.
). The clinical characteristics of the 12 patients (including the two cases reported in this study) are listed in Table 1. The mean age was 12.0 ± 8.7 (range 2.5–25) years, and 9/12 (75%) were male.
Table 1Clinical characteristics of the patients with MOG antibody-associated aseptic meningitis without neurological parenchymal lesions.
All (12/12) patients had meningitis symptoms, including intermittent and prolonged fever lasting over 7 days or even several weeks (11/12), headache (10/12), vomiting (5/12), and seizures (4/12). Nine patients had results of peripheral blood leukocytes, 8 with CRP, 6 with ESR, 5 with OCB, and 4 with opening CSF pressure. Laboratory examination on admission showed elevated peripheral blood leukocytes (9/9), elevated ESR (4/6), and elevated CRP level (2/8). CSF tests revealed leukocytosis (12/12), elevated opening pressure (4/4), and negative OCB (5/5). All 12 patients were previously healthy.
All patients (12/12) received antibiotics empirically and (or) antiviral treatment before diagnosis. After the diagnosis was confirmed by positive serum MOG-IgG, 12 of 12 patients received steroid therapy (8 patients received high-dose methylprednisolone pulse therapy, including 6 patients receiving sequential oral prednisone, while no details were obtained from the other 4 patients). Eleven patients were steroid-responsive, and their symptoms were completely relieved upon steroids. One patient still had relapses while on intravenous methylprednisolone (no details on dosage were available), but he no longer relapsed after the diagnosis of MOGAD was confirmed at 6 months from onset and being treated with rituximab, azathioprine, and low-dose prednisone. Six patients were followed up for more than 6 months, of which one case (case 1) had relapses. Case 1 had multiple relapses during the 5-year follow-up with persistently positive serum MOG-IgG, and he received long-term oral immunosuppressants.
There was a male predominance (male: female = 9: 3) in patients with MOGAM, which is different from the equal or even slight female predominance (57%) of MOGAD reported in previous research (
) (p = 0.03, Binomial test). Intermittent and prolonged fever lasting over 7 days or even several weeks was the most common manifestation of MOGAD, which was observed in 11/12 cases. The duration of fever was 15–42 days. Seizures occurred in four cases (33.3%), which did not differ from the seizure occurrence of MOGAD (19.6%) (
Encephalitis is an important clinical component of myelin oligodendrocyte glycoprotein antibody associated demyelination: a single-center cohort study in Shanghai, China.
) (p = 0.47, Fisher's exact test). Recently, two studies on MOG antibody-associated cortical encephalitis with a relatively larger number of patients reported that the seizure occurrence was 17/20 (85%) and 7/11 (63.5%), respectively (
Unilateral cortical FLAIR-hyperintense Lesions in Anti-MOG-associated Encephalitis with Seizures (FLAMES): characterization of a distinct clinico-radiographic syndrome.
), and the combined seizure occurrence was 24/31(77.4%), which was higher than the seizure occurrence of MOGAM in this study (p = 0.02, Fisher's exact test).
Except for one case (case 12) who had a second attack as ADEM three months after full recovery from the first attack as MOGAM, seven patients progressed to other phenotypes of MOGAD from aseptic meningitis, but four did not. The median time from onset to the initiation of intravenous methylprednisolone was 19.3 ± 4.4 (range: 13–24) days in the group that did not progress to other phenotypes, and 27.0 ± 4.8 (range: 17–32) days in the group with progression. The group without progression had a shorter duration from onset to the initiation of intravenous methylprednisolone than the group with progression (p = 0.08, t-test).
5. Discussion
In the present study, we report the cases of two children with MOGAM and systematically review 10 cases in the literature, focusing on clinical features and related risk factors. The imaging manifestations of different phenotypes of MOGAD are diverse, including the white matter, cortex, subcortical white matter, optic nerve, deep nucleus (thalamus, basal ganglia), brainstem, and long or short spinal segments (
). MOG-related encephalitis is the most common autoimmune encephalitis in children, accounting for 34% of all cases of autoimmune encephalitis except ADEM (
Associations of paediatric demyelinating and encephalitic syndromes with myelin oligodendrocyte glycoprotein antibodies: a multicentre observational study.
). In contrast to our two cases, most of the reported cases had symptoms related to focal lesions in the nervous system, such as visual impairment, limb paralysis, sensory disturbance, and urinary retention. In addition, they already had abnormalities related to demyelination in the brain parenchyma, optic nerve, or spinal cord at the first MRI examination. In this study, we reviewed 12 patients with MOGAM with normal early MRI findings and no focal neurological symptoms, including the two children reported in this study. All patients had symptoms associated with meningitis, including fever, headache, vomiting, and seizure. Laboratory examinations revealed leukocytosis in the blood and CSF and elevated CRP levels and ESR. All four patients who had CSF pressure results reported high CSF pressure. Unlike other MOGAD cases, our cases did not have clinical or imaging manifestations of inflammatory demyelination in the early phase, which led to misdiagnosis of bacterial meningitis/encephalomeningitis or viral encephalitis/encephalomeningitis after hospitalization and the administration of empirical antibiotics or antiviral therapy.
MOGAM was more common in males (75%) in the studies that we reviewed, whereas previous studies showed no sex predominance in MOGAD, or reported a slight female predominance (
). The patients’ age ranged from 2.5 to 25 years at presentation, including five cases below 5 years of age, indicating that MOGAM may affect children and young people more often than older people, while previous studies showed conflicting results, including a broad age of onset in MOGAD (
Unilateral cortical FLAIR-hyperintense Lesions in Anti-MOG-associated Encephalitis with Seizures (FLAMES): characterization of a distinct clinico-radiographic syndrome.
). In this study, we did not observe differences in seizure occurrence between ADEM associated with MOG and MOGAM. In recent years, MOG antibody-related cortical encephalitis, a rare phenotype, has been reported. Although MOGAM has clinical features similar to those of MOG antibody-associated cortical encephalitis, including headache, vomiting, and leukocytosis in the blood and CSF, seizure occurrence in MOGAM (33.3%) is lower than that of MOG antibody-associated cortical encephalitis (77.4%) (
Unilateral cortical FLAIR-hyperintense Lesions in Anti-MOG-associated Encephalitis with Seizures (FLAMES): characterization of a distinct clinico-radiographic syndrome.
). In addition, unilateral or bilateral cortical hyperintensities in the T2-FLAIR sequence are distinct imaging features of cortical encephalitis, whereas the 12 patients with aseptic meningitis in this study had no brain parenchymal involvement. Of note, in view of the small sample size of this study, the results of the statistical analysis need to be confirmed in the future in studies with larger sample sizes.
Patients with MOGAM may progress to other phenotypes of MOGAD with CNS demyelination if they are not correctly diagnosed and receive immunotherapy on time. Seven patients progressed from aseptic meningitis to other phenotypes of MOGAD, including three cases of ADEM, two cases of optic neuritis, and one case of cortical encephalitis plus myelitis. The median duration from onset to the initiation of intravenous methylprednisolone of the four patients without progression was 19.3 days, which was shorter than that of the seven patients with progression (27 days), suggesting that delayed diagnosis and steroid therapy may induce the development of other phenotypes with more severe clinical manifestations. Different phenotypes may present in different phases of the same autoimmune disease, and the phenotype of aseptic meningitis may be an early phase of MOGAD. Case 12 had a full recovery and did not progress to other phenotype from MOGAM, but she had a relapse as ADEM three months after the remission of meningitis, which probably resulted from insufficient steroid therapy. Therefore, for patients with meningitis-like manifestations of unknown etiology who respond poorly to anti-infection therapy, and whose clinical symptoms include prolonged fever, headache, vomiting, leukocytosis in the blood and CSF, and elevated CSF pressure, MOGAM should be considered, even though there is no inflammatory demyelination on initial imaging. Early diagnosis and treatment may help prevent the occurrence of CNS demyelination and the progression to other phenotypes of MOGAD, thus improving prognosis.
Patients with MOGAM responded well to steroid therapy, similar to other phenotypes of MOGAD. In addition to high-dose methylprednisolone, the first-line therapy includes high-dose intravenous gamma globulin (IVIG) and plasma exchange. Case 1 had multiple relapses with a positive but fluctuating titer of serum MOG-IgG during the 5-year follow-up, suggesting that persistently positive serum MOG-IgG was related to relapses. For cases of relapse, long-term immunosuppressants should be considered, including mycophenolate mofetil, azathioprine, and monthly IVIG.
Our study was limited by its small sample size and lack of data on long-term follow-ups for many cases, and statistical analysis in this study need to be confirmed with larger studies . Future prospective studies with a larger sample size and a multicenter research design could help to further characterize the clinical presentations and outcomes of MOGAM.
6. Conclusions
In contrast to other MOGAD phenotypes, patients with MOGAM have no symptoms or imaging features related to focal neurological lesions in the CNS parenchyma or optic nerves. Prolonged fever and headache were the most prominent clinical symptoms, with elevated inflammatory markers. Due to atypical clinical manifestations, patients are usually misdiagnosed with CNS infections, which lead to delayed administration of steroids and progression to more severe phenotypes. Early recognition of this unique autoimmune-related aseptic meningitis may contribute to early diagnosis and treatment.
CRediT authorship contribution statement
Sufang Lin assessed the patients, reviewed the neuroimaging, performed the review of the literature, and drafted and revised the manuscript, figures, and tables (Conceptualization, Methodology, Investigation, Resources, Writing and Editing). Weiwei Long assessed the patients, performed the review of the literature, and revised the manuscript and figures (Investigation, Writing Original Draft). Jialun Wen assessed the patient, reviewed the neuroimaging, and revised the manuscript (Investigation, Resources). Qiru Su performed the statistical analysis (Formal analysis). Jianxiang Liao assessed the patient, reviewed the neuroimaging, and revised the manuscript (Review & Editing Draft, Funding acquisition). Zhanqi Hu assessed the patient and revised the manuscript. All authors read and approved the final version of this manuscript (Resources).
Data availability
Data about the two pediatric cases presented here are not publicly available due to patient confidentiality. Datasets will be made available to researchers upon reasonable request.
Declaration of Competing Interest
The authors declare that there is no conflict of interest.
Acknowledgments
The authors wish to thank the patients and the families for their participation. We thank Xiuwei Zhuo from Beijing Children's Hospital for her help with the review of the MR images.
Funding
This research was supported by the grants from the Sanming Project of Medicine in Shenzhen (no. SZSM201812005) and the Shenzhen Key Medical Discipline Construction Fund (no. SZXK033).
Associations of paediatric demyelinating and encephalitic syndromes with myelin oligodendrocyte glycoprotein antibodies: a multicentre observational study.
Unilateral cortical FLAIR-hyperintense Lesions in Anti-MOG-associated Encephalitis with Seizures (FLAMES): characterization of a distinct clinico-radiographic syndrome.
Children suspected of having intracranial infection with normal brain magnetic resonance imaging may be associated with the myelin oligodendrocyte glycoprotein antibody.
Encephalitis is an important clinical component of myelin oligodendrocyte glycoprotein antibody associated demyelination: a single-center cohort study in Shanghai, China.
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