Brain Metabolite Levels in the Post-Acute Stage of Anti-NMDA Receptor Encephalitis and Schizophrenia: A Longitudinal Case-Control Study

Abstract

Background: In vivo assessment of glutamatergic metabolites in patients with anti-NMDA receptor (anti-NMDAR) encephalitis compared with schizophrenia may help increase understanding of the pathophysiology of both conditions.

Methods: This 24-month prospective case-control study included participants ages 12 to 60 years with anti-NMDAR encephalitis during the post-acute stage and age- and sex-matched individuals with schizophrenia and healthy control participants (HCs). Single-voxel magnetic resonance spectroscopy was used to estimate brain concentrations of glutamatergic metabolites, myo-inositol, and N-acetylaspartate+N-acetylaspartylglutamate (tNAA) in the left dorsomedial prefrontal region (dmPF) and medial temporal lobe. The effect of group and time on metabolite levels and the relationship between metabolite levels and psychiatric and cognitive features were tested with multilevel linear mixed models.

Results: Thirty-two participants with anti-NMDAR encephalitis (84% women), 27 participants with schizophrenia (63% women), and 36 HCs (72% women) were included. In the dmPF, levels of glutamate and glutamate+glutamine were significantly lower in patients with anti-NMDAR encephalitis than in participants with schizophrenia (Cohen's d = -0.87 and d = -0.80, respectively) and HCs (d = -0.73 and d = -0.71). Myo-inositol levels were significantly higher in both participants with anti-NMDAR encephalitis (d = 0.91) and patients with schizophrenia (d = 1.07) than in HCs. Group differences remained stable over time. Metabolite levels were not associated with psychiatric or cognitive symptoms.

Conclusions: This is the first report of hypoglutamatergia in the left dmPF in anti-NMDAR encephalitis and of increased levels of myo-inositol in both anti-NMDAR encephalitis and schizophrenia. The findings suggest persistent alterations in glutamatergic neurotransmission during the post-acute stage of anti-NMDAR encephalitis and overlapping neuroinflammatory processes between anti-NMDAR encephalitis and schizophrenia.