Anti-NMDAR encephalitis is a type of severe autoimmune encephalitis. Clinical routine MRI findings are either normal or with mild changes in most patients with acute anti-NMDAR encephalitis (John et al., 2019). Moreover, >75% of patients still suffer from prolonged cognitive deficits, even with timely access to adequate immunotherapy (McKeon et al., 2021; McKeon et al., 2018), indicating that these patients may have cerebral functional and/or structural changes. Indeed, most patients in this study showed normal routine clinical MRI results. However, we found structural and functional changes in some brain regions with high-resolution structural MRI and rs-fMRI.
Patients with anti-NMDAR encephalitis showed significant gray matter atrophy in bilateral triIFG and PCUN.R compared with NCs. Additionally, the RSFCs between triIFG.L and HES.L/HES.R, between triIFG.R and HES.R, and between PCUN.R and left CERE.L were significantly reduced in patients with anti-NMDAR encephalitis compared to NCs, yet the opposite was true for the RSFC between triIFG.R and SFG.L as assessed using seed-to-whole-brain voxel analyses. Additionally, decreased gray matter volume and RSFC were associated with memory deficits and disease duration. These findings suggest that these typical gray matter atrophies and altered RSFCs may represent key structural alterations related to the cognitive symptoms of anti-NMDAR encephalitis, and that combined multi-MRI and cognitive assessment are potentially valuable to assess prognosis and treatment efficacy.
Significant gray matter atrophy was observed in both triIFG.R and triIFG.L. These results were similar to the findings of our previous studies, which demonstrated decreased cerebral blood flow in both triIFG.R and triIFG.L in 15 patients with anti-NMDAR encephalitis compared with 15 NCs(Guo Y et al., 2020). The IFG is considered sensitive to auditory and phonological information and, consequently, related to verbal working memory (Zhu et al., 2020). Indeed, decreased gray matter volume in the IFG has been observed in patients with neurological diseases characterized by deficits in higher-order cognition, such as multiple sclerosis, Alzheimer’s disease, and mild cognitive impairment (Rossi et al., 2016; Toko et al., 2021; Whitwell et al., 2008). Consistently with previous studies(Irish et al., 2014), we demonstrated that the decreased gray matter volume in triIFG.R was positively correlated with AVLT_DR scores and marginally correlated with AVLT_IR scores in patients with anti-NMDAR encephalitis, controlling for age, sex, and education. The AVLT score is used to assess verbal working memory (Xu et al., 2019) and was significantly decreased in the patients in this study compared with NCs. Moreover, we found that decreased gray matter volume in triIFG.R was marginally related to disease duration. Briefly, we presumed that the IFGs may be key contributors to anti-NMDAR encephalitis pathogenesis. Additionally, we identified significant decreases in gray matter volume in PCUN.R in patients with anti-NMDAR encephalitis compared with NCs, and this result is consistent with previous studies. Compared with NCs, patients with anti-NMDAR encephalitis were reported to have decreased white matter volume, amplitude of low frequency fluctuations (ALFF), and hypometabolism in PCUN (Cai et al., 2020; Liang et al., 2020; Wegner et al., 2014). Although no relationship between PCUN.R cortical atrophy and cognitive scores has been demonstrated, we cannot exclude their association since PCUN has been reported to be involved in the processing of working memory, and patients with cognitive deficits usually show hypoperfusion and disruptions of functional connectivity within PCUN (Ferri et al., 2016; Jia et al., 2018).
Brain structure atrophy may be accompanied by functional impairment. For example, altered gray matter volume and RSFC were observed in patients with neurological and psychiatric diseases, such as Parkinson’s disease, major depression, and bipolar disorder, compared with NCs (Chen et al., 2018; Droby et al., 2021). Using the clusters derived from the VBM analysis of seed regions, we observed altered RSFCs between several regions in patients with anti-NMDAR encephalitis, indicating functional impairment in these brain areas. We primarily found decreased RSFC between triIFG.L and HES.L/HES.R and between triIFG.R and HES.R in patients with anti-NMDAR encephalitis compared with NCs. Previously, decreased HES RSFC has been observed in autoimmune diseases such as multiple sclerosis (Fu et al., 2019), and another report has demonstrated extensive damage to HES in patients with status epilepticus following viral meningoencephalitis (P.Pillion et al., 2014). Patients with seizures have been reported to be seizure-free following HES resection (Ferri et al., 2014). Additionally, an MRI study has found that patients with schizophrenia demonstrated significantly decreased RSFC between HES and IFG (Guo et al., 2014). Epileptic seizures and psychosis are two of the most typical clinical manifestations of anti-NMDAR encephalitis (Dalmau et al., 2008).
We demonstrated a significant correlation between decreased RSFC and AVLT scores, which are used to assess verbal working memory (Xu et al., 2019). As we know, verbal working memory is divided into phonological store and articulatory rehearsal (Baddeley, 1992). The Heschl gyrus is a major component of the superior temporal gyrus and forms the primary auditory region (Fernandez et al., 2020); the IFG is also considered to play an important role in auditory and visual verbal information processing (Liu X et al., 2012; Zhu et al., 2020). Therefore, these two brain regions are both related to verbal working memory, thus supporting our observations.
Additionally, compared with NCs, patients with anti-NMDAR encephalitis had decreased RSFC between PCUN.R and left CERE.L. Previous studies have indicated that CERE showed high NMDAR expression besides the frontal lobe and hippocampus (Moscato et al., 2014; Skowronska et al., 2019; Wang and Xiao, 2020). Decreased ALFF were also observed in CERE and PCUN in patients with anti-NMDAR encephalitis (Cai et al., 2020), indicating functional impairment in these brain regions. Even though we did not find a direct link between the RSFC between these two regions and the memory performance, the disrupted connectivity between PCUN and CERE is an interesting finding for the pathological basis of anti-NMDAR encephalitis. Besides decreased RSFC in several brain regions, we also found increased RSFC between triIFG.R and SFG.L in patients with anti-NMDAR encephalitis compared with NCs. Moreover, a previous study has demonstrated a hyperintense lesion in SFG in a patient who tested positive for both anti-myelin oligodendrocyte glycoprotein and anti-NMDAR antibodies (Nagata et al., 2018), supporting the results of this study. Increased RSFC is considered a compensation after acute inflammatory injury or a result of the proliferation of glial cells during recovery (Cai et al., 2020). As the neural activity requires cerebral blood perfusion to supply oxygen and nutrients, elevated perfusion tends to induce increased neural activity (Poornima et al., 2016). Moreover, increased cerebral blood perfusion was also observed in patients with anti-NMDAR encephalitis due to the increased permeability of the blood-brain barrier (Guo Y et al., 2020; Suárez et al., 2016).
This study has several limitations. First, its small sample size limited statistical efficiency, and more patients are still needed to verify our results. Second, abnormal MRI findings with different lesions were identified in nearly 50% of patients at onset, and their potential effects are concerning. Third, the the results of this study were limited by its cross-sectional design; longitudinal studies further exploring the neural mechanism of anti-NMDAR encephalitis are warranted.