Steroid-responsive aseptic meningitis with raised intracranial pressure syndrome associated with myelin oligodendrocyte glycoprotein autoantibodies.

Abstract

Aseptic meningitis is a syndrome of meningitis with a negative gram stain and bacterial culture.1 Aetiologies include viruses, fungi, parasites, post-infectious causes, drugs, systemic disease and malignancy.1 Identifying the cause of aseptic meningitis is often challenging. Anti-myelin oligodendrocyte glycoprotein (MOG) antibodies are associated with several steroid-responsive paediatric neuroinflammatory diseases, with acute disseminated encephalomyelitis (ADEM) being the commonest in children.2 Recently, aseptic meningitis has been described as a presentation of anti-MOG antibody-associated disease (MOGAD) in childhood.3-5 Given the steroid-responsive nature of MOGAD, it is an important diagnosis to consider paediatric aseptic meningitis. We report three children who presented with aseptic meningitis and raised intracranial pressure (ICP) who progressed to ADEM and other encephalomyelitis phenotypes 2–5 weeks later; these patients were found to be MOG antibody positive. Patient A was a 5-year-old female who presented with fever and headache but no encephalopathy or focal neurological signs. Cerebrospinal fluid (CSF) showed 6 × 106/L polymorphs (normal < 1 × 106/L), 10 × 106/L mononuclear cells (normal < 6 × 106/L), protein 0.27 g/L (0.15–0.42 g/L), neopterin 56.96 nmol/L (6–30 nmol/L) and negative gram stain, culture and PCR for bacterial and viral pathogens (Table S1). CSF opening pressure was >40 cm CSF (normal ≤ 25 cm CSF). Magnetic resonance imaging (MRI) brain and spine were normal (Fig. 1a1). Due to worsening headache and ongoing fever, CSF was repeated 1 week later and showed 610 × 106/L polymorphs, 241 × 106/L mononuclear cells, protein 1.18 g/L, neopterin 287.43 nmol/L and no growth on bacterial culture. Tuberculosis meningitis was suspected as she migrated from India 4 months prior. She was treated with antituberculosis medications and prednisolone 2 mg/kg daily with a weaning schedule. Fevers settled and she was discharged home 6 weeks after symptom onset. She re-presented 10 days later with severe headache, Glasgow coma scale (GCS) score of 11, irritability, restricted right eye abduction, dysphasia and dysarthria, on prednisolone 10 mg daily and antituberculosis medications. Repeat CSF showed 1 × 106/L polymorphs, 9 × 106/L mononuclear cells and an elevated opening pressure 33.5 cm CSF. Investigations for tuberculosis remained negative and antitubercular drugs were stopped. Repeat MRI brain showed meningeal enhancement and T2/FLAIR hyperintensities with patchy enhancement of the basal ganglia, subcortical white matter and right cerebellar hemisphere (Fig. 1a2), and with the clinical progression, was consistent with ADEM. She was mycoplasma IgM positive and treated with azithromycin. She received intravenous methylprednisolone (30 mg/kg daily for 5 days) with oral prednisolone tapering from 1 mg/kg over 2 months with resolution of symptoms. Within 24 hours of starting treatment, GCS improved to 15. Serum MOG antibody was positive. After 2 months, she was asymptomatic with almost complete resolution of previous MRI changes. She remains well 18 months after discharge. Patient B was a healthy 4-year-old female who presented to another institution with a 20-min seizure with fever preceded by 5 days of abdominal pain and vomiting. She was treated with ceftriaxone for 2 days and discharged. After 10 days, she had further seizures controlled with levetiracetam. After an ultrasound showing features of appendicitis, she underwent a laparoscopic appendicectomy and lumbar puncture (LP). Although macroscopic appearances of the appendix were normal, microscopic analysis was consistent with appendicitis. CSF showed 1 × 106/L polymorphs, 6 × 106/L mononuclear cells, protein 0.39 g/L and negative gram stain, culture and PCR for bacterial and viral pathogens (Table S1). CSF opening pressure was >32 cm CSF. MRI brain showed subtle bright FLAIR signal in the right frontoparietal cortex/subcortical white matter with associated meningeal enhancement (Fig. 1b1). She was treated for infective meningoencephalitis with antibiotics and acyclovir but deteriorated with high fevers, drowsiness and irritability. Repeat CSF showed 125 × 106/L polymorphs, 108 × 106 mononuclear cells, protein 0.8 g/L, neopterin 371.37 nmol/L and negative gram stain with no growth. The patient was started on oral prednisolone 2 mg/kg with resolution of fever for 48 h before becoming febrile again. Repeat MRI brain (2.5 weeks into her illness) showed multifocal T2/FLAIR hyperintensities (Fig. 1b2) consistent with ADEM. A speckled ANA pattern was detected at a titre of 80. Anti-dsDNA antibodies and ENA screen were negative. She was treated with intravenous methylprednisolone (30 mg/kg daily for 5 days) and intravenous immunoglobulin 2 g/kg over 2 days. She defervesced within hours of starting methylprednisolone. Her drowsiness and irritability were resolved by completion of her methylprednisolone course. She was continued on a tapering prednisolone from 2 mg/kg daily over 4 months and discharged home after a 2.5-week admission. Serum MOG antibody was positive. She remains asymptomatic and well 4 months after discharge. Patient C was a well 12-year-old girl who initially was admitted with an afebrile seizure and discharged after a normal electroencephalogram and head computed tomography. She was readmitted 10 days later with headache and papilloedema. The rest of the neurological examination was normal, including visual fields and visual acuity. Lumbar puncture opening pressure was 60 cm CSF. CSF showed 34 × 106/L polymorphs, 113 × 106/L mononuclear cells, protein 0.7 g/L, negative infection screen (Table S1) and neopterin 256.4 nmol/L. MRI brain was normal (Fig. 1c1). She was diagnosed with aseptic meningitis, treated with acetazolamide and discharged after 10 days of antibiotics and resolution of her headache. She was readmitted 1 week later (1 month after the initial seizure) with ataxia, lower limb paraesthesia, intention tremor and urinary retention. Repeat LP showed 18 × 106 polymorphs, 27 × 106 mononuclear cells, 0.71 g/L protein, no growth and neopterin 151.9 nmol/L. MRI spine showed extensive T2 signal throughout the spinal cord consistent with longitudinally extensive transverse myelitis. MRI brain showed patchy, multifocal high T2 signal in the subcortical white matter and thalami suggestive of ADEM (Fig. 1c2). Speckled ANA pattern was detected at a titre of 320. ANCA, ENA screen, rheumatoid factor, anti-dsDNA antibodies and anti-GM1 antibodies were negative. She was treated with intravenous methylprednisolone (30 mg/kg daily for 5 days), followed by prednisolone tapering from 1 mg/kg daily over 6 weeks with clinical and radiological resolution by completion of steroids. She was serum MOG antibody positive. She remains symptom-free 7 years after presentation. We present three cases of anti-MOG-associated aseptic meningitis preceding the development of ADEM or encephalomyelitis between 2 weeks and 2 months later. Initial brain MRIs were normal (2/3) or marginally abnormal. The diagnosis remained unclear until they developed clinical and radiological evidence of ADEM. Patients A and B briefly responded to prednisolone (2 mg/kg) but all patients progressed to ADEM or encephalomyelitis. Anti-MOG antibody testing results became available weeks to years after initial presentations. These cases add to two reports of paediatric MOGAD presenting with aseptic meningitis with progression to ADEM (Table 1).3, 4 All five patients rapidly responded to high-dose methylprednisolone followed by weaning prednisolone. Our three patients had complete resolution without relapse (follow-up between 4 months and 7 years). A recent article reported a further two children presenting with MOG-associated aseptic meningitis and leptomeningeal enhancement, but clinical details were not published.5 45 mononuclear cells, 11 polymorphs Protein 67.9 g/L Multifocal enhancing and non-enhancing lesions in the subcortical white matter, left cerebellar peduncle, and spinal cord Intravenous methylprednisolone (30 mg/kg daily) for 5 days Although ADEM is the commonest presentation of paediatric MOGAD, other syndromes include optic neuritis, transverse myelitis, aquaporin-negative neuromyelitis optica spectrum disease and non-ADEM encephalitis.2, 6 Seizures preceding radiological identification of demyelination have been reported, as in our cases.7 MOGAD is typically steroid responsive but has an increased risk of relapse with rapid steroid weaning and can be associated with permanent neurological sequelae if inadequately treated.8 However, there is no evidence available to direct the duration of the steroid wean and represents an area for future research. Thus, early recognition and adequate steroid therapy are critical. Earlier, high-dose steroid treatment in our cases may have prevented progression to ADEM, given their rapid improvements after treatment. Aseptic meningitis presents a diagnostic dilemma for clinicians due to the variable aetiologies. A cause is not found in up to 80% of cases and investigations are typically limited to infectious testing and, in some cases, neuroimaging.1 The main focus of management is excluding culture-negative bacterial meningitis.1 Our case series identifies anti-MOG-associated neuroinflammation as a rare, but treatable cause of aseptic meningitis. Aseptic meningitis with raised ICP is an important early clinical biomarker of MOG antibody-associated neuroinflammation. Given steroid responsiveness, empiric treatment with high-dose corticosteroids and testing for anti-MOG antibodies should be considered in children with persisting aseptic meningitis. Informed consent was obtained from all patients and their families for inclusion in this report. Open access publishing facilitated by The University of Sydney, as part of the Wiley - The University of Sydney agreement via the Council of Australian University Librarians. Table S1 Microbial testing which was all negative on cerebrospinal fluid for patients A, B and C Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.