Anti-NMDA Receptor Encephalitis and Mycoplasma pneumoniae Infection With Demyelination

While most children with anti-N-methyl-d-aspartate (NMDA) receptor encephalitis (NMDARE) have normal brain magnetic resonance imaging (MRI) [1], 3% have demyelinating lesions on MRI [2]. We describe a patient who had NMDARE and MRI lesions resembling multiple sclerosis (MS).

This 16-year-old girl with a history of major depressive disorder presented with 1 month of altered behavior with hyper-religiosity and insomnia. She was admitted to an inpatient psychiatric facility and was started on antipsychotic and antidepressant medications without improvement and was transferred to our facility. On presentation, she was awake but would not regard. She was nonverbal and did not follow commands, had full strength and normal reflexes, and withdrew to noxious stimuli bilaterally.

Brain MRI with contrast revealed multifocal T2/fluid-attenuated inversion recovery (FLAIR) hyperintense lesions with some enhancement (Figure 1), meeting the McDonald imaging criteria for MS [3]. While some demyelinating syndromes such as myelin oligodendrocyte glycoprotein (MOG) antibody disease (MOGAD) can present with psychosis, psychosis is not a typical MS presentation, so additional evaluation was pursued.

She subsequently developed acute respiratory distress and was transferred to the intensive care unit. Serum Mycoplasma pneumoniae IgM and IgG were positive by immunofluorescent assay. Routine bloodwork including blood counts, chemistry panels, inflammatory markers, and nutritional labs were unrevealing. Cerebrospinal fluid studies were unremarkable except for an elevated IgG index (2.5). Oligoclonal bands were negative. Serum testing for anti-MOG and aquaporin-4 antibodies were negative for MOGAD and neuromyelitis optica spectrum disorder (NMOSD), respectively. Anti-NMDA antibodies were positive in the cerebrospinal fluid (1:80) and serum (1:160), consistent with a diagnosis of NMDARE.

She was treated with high dose of intravenous steroids, plasmapheresis, intravenous immunoglobulin, and rituximab. She received azithromycin to treat an acute M. pneumoniae infection. She improved during the next year on maintenance intravenous immunoglobulin and rituximab. On follow-up imaging 1 year later, most lesions had improved or resolved except for one persistent lesion.

NMDARE is a common cause of pediatric encephalitis and can present with psychiatric symptoms, seizures, movement disorders, or altered consciousness [4]. Definitive diagnosis includes at least one characteristic symptom and positive anti-NMDA autoantibodies [4]. We assessed for autoimmune encephalitis in this patient due to the atypical clinical presentation for a demyelinating disease. Demyelinating features can occur in 3% of patients with NMDARE, with some meeting criteria for MOGAD or NMOSD. However, overlap between MS and NMDARE is not common [2]. While coexistent MS and NMDARE has been described, such patients typically have clinical symptoms consistent with MS [5]. Our patient presented with encephalitis without prior clinical demyelinating episodes.

Interestingly, our patient also had positive M. pneumoniae IgG and IgM serologies. M. pneumoniae has been associated with encephalitis, but it also overlaps with NMDARE [6]. M. pneumoniae IgM can stay positive for more than a year [7], but the presence of IgM via immunofluorescent assay with concurrent respiratory symptoms in our patient is consistent with an acute infection.

The pathogenesis of M. pneumoniae–associated encephalitis has potential direct pathogen-mediated and indirect immune-mediated pathways [8]. Encephalitis attributed to M. pneumoniae in children with neurological symptoms and positive serologies has been reported [6], including demyelination in M. pneumoniae–associated encephalitis [9, 10]. However, whether M. pneumoniae can cause neuroinflammation is debated. It is possible M. pneumoniae infection contributed to the MRI findings in our patient. She will continue to undergo at least yearly MRI monitoring to assess for new lesions.

We highlight a patient whose MRI findings resembled MS but who had NMDARE with concurrent M. pneumoniae infection. Additional studies are needed to elucidate the role of M. pneumoniae in pediatric encephalitis and the overlap between MS and NMDARE.

Leah Loerinc: conceptualization, investigation, writing–original draft, methodology, writing–review and editing, data curation. Jenny Lin: methodology, validation, writing–review and editing, data curation, visualization. David S. Wolf: investigation, writing–review and editing. Grace Gombolay: supervision, writing–review and editing, conceptualization, investigation, methodology, validation, visualization, data curation.

We adhere to the ethics and integrity policies as indicated for the Annals of the Child Neurology Society.

Dr. Gombolay serves as an associate editor for Annals of the Child Neurology Society and part-time CDC consultant for acute flaccid myelitis case review. The other authors declare no conflicts of interest.