Anti-N-methyl-d-aspartate receptor (NMDAR) encephalitis is an autoimmune disorder that develops as a rapidly progressive encephalopathy. The incidence of NMDAR encephalitis is increasing globally with the popularization of antibody testing for autoimmune encephalitis [1]. This encephalitis may be associated with neoplasms or secondary to viral infection [2]. Anti-NMDAR encephalitis is a severe and treatable disease. Being able to assess prognosis early, timely, and accurately can help to individualize treatment plans. To provide the basis for early identification and diagnosis, we retrospectively analyzed the clinical symptoms and laboratory data of anti-NMDAR encephalitis in Shenzhen People’s Hospital, a single center in Shenzhen, China.

This study shows that anti-NMDAR encephalitis more frequently occurs at a young age. Previous studies have demonstrated that the age of onset of NMDAR encephalitis is younger than 35 years, with a median age of onset between 21 and 28 years [4, 5]. Shenzhen, one of the fastest growing cities in China, is dominated by young people. As the population increases, the incidence of anti-NMDAR encephalitis is increasing in Shenzhen. In this study, the proportion of anti-NMDAR encephalitis was equal between men and women, and the median age of onset was 31 years, which may be due to the fact it typically occurs in younger adults. Furthermore, we found that psychosis and cognition defects were the most common symptoms, which is consistent with the results of previous data [4, 6], remaining that mental and cognitive symptoms anti-NMDAR encephalitis should be cause for concern. In addition, behavioral disorders such as stress disorder, emotional instability, and agitation are more prominent in anti-NMDAR encephalitis patients [7, 8], compared with primary psychiatric patients. Psychobehavioral disorders and cognitive dysfunction can be long-term coexistence [9, 10, 11]. The severity of other psychiatric symptoms of anti-NMDAR encephalitis varies. Most symptoms such as personality changes, anxiety and irritability are mild, but can also be accompanied by persistent depression that may even lead to suicide [12, 13]. Therefore, it is necessary to conduct rigorous neuropsychological monitoring of these patients after immunotherapy and pay attention to distinguishing patients from relapsed patients.

Tumors are one of the important causes of anti-NMDAR encephalitis, and the prevalence of tumors varies in different studies. Thirty-eight percent of patients have been reported to have tumors, and 45% of Asian patients are more likely to have teratomas [4]. Guan et al. [14] reported that only 19.5% of patients have tumors and 29.4% of the females have ovarian teratomas. In our study, only 16.1% of patients have tumors and 25% of females had ovarian teratomas. Studies in Asia also reported low prevalence of tumors [15, 16]. The differences between the studies may be due to sample size, as well as or selection bias, which require further investigation. Besides tumors, it has been reported that herpes simplex virus (HSV) infection is another possible trigger. One case of anti-NMDAR encephalitis in our study was clearly diagnosed as HSV infection 6 months before onset by next-generation sequencing. However, the gold standard for a definitive diagnosis of infection is polymerase chain reaction testing. For this validation is relatively expensive and time-consuming, empirical treatment is started prior to confirmation of a definitive diagnosis of HSV infection in most patients. As a result, anti-NMDAR encephalitis after HSV could not be evaluated in our study due to the number of cases and the intensity of exclusion.

Notably, Guan et al. [14] reported that 5% of patients with anti-NMDAR encephalitis have overlapping demyelination, besides tumor and infection factors. Maarten et al. [17] reported the overlap of anti-NMDAR encephalitis and demyelinating diseases. Demyelinating diseases can occur before or after anti-NMDAR encephalitis, or at the same time. These finding suggest the existence of two simultaneously active immune mechanisms at the same time. We found two cases of overlapping syndrome in our study, one with MS [18], and the other with a positive MOG antibody. Demyelination-related diseases, including AQP-4 antibody and MOG antibody-related and MS, may be a potential cause of anti-NMDAR encephalitis. Among these patients, immunological studies usually show that these diseases are independent, but co-existing immune mechanisms, such as AQP4 and MOG antibodies, are related to NMDAR antibodies. In addition, the outcome data indicate that compared with anti-NMDAR encephalitis, demyelination episodes are more difficult to be treated, often leading to residual defects, highlighting the importance of timely diagnosis and treatment. ANA antibodies are associated with autoimmune diseases, which may be related to the disease activity of MS [19] and NMOSD [20]. Our research showed that some patients have elevated levels of SSA, Ro52, antinuclear antibodies, TPOAB, and TGAB, and the relationship between antibodies and disease activities still needs further investigation.

The findings of brain MRI further confirm that anti-NMDAR encephalitis is a “diffuse encephalopathy” [6]. Guan et al. [14] reported that 35.9% of patients have abnormal signals, mainly in the temporal, frontal, parietal, and occipital lobes. In our study, 35.5% of patients had abnormal signals mainly in the temporal and frontal regions. Other brain areas affected by anti-NMDAR encephalitis were the cerebellum, brainstem, frontal, parietal, and occipital cortices, and diencephalon. Abnormal EEG is one of the criteria for the diagnosis of anti-NMDAR encephalitis, and the change in EEG is closely related to brain injury severity. The most the common EEG manifestations of anti-NMDAR encephalitis are diffuse slow waves [3, 21]. It is a possible that NMDAR specifically binds to anti-NMDAR antibodies played a role in the mechanism, leading to cell depolarization shorten [22], and causing diffuse slow waves. Meanwhile, another important cause is that the loss of afferent impulses in the cortex lead by subcortical lesions [14]. In our study, abnormal EEG findings were found in 16 (51.6%) patients, including 14 (45.2%) patients, showing no significant differences compared with males and females. The proportion of slow waves is slightly lower than that reported in literature [23], which may be related to the severity of the disease.

Previous studies had shown that intravenous immunoglobulin was common chosen following glucocorticoids. In addition, therapies including at least 2 forms of immunotherapy had a higher efficacy rate than therapy using only one form [24]. In our study, repeated first-line immunotherapy occurred frequently in the treatment of anti-NMDAR encephalitis. However, only a minority of patients received second-line immunotherapy because of the cost, hospitalization requirements, concerns about adverse effects, and the off-label drug use of RTX in China, similar to previous reports [14]. In a cohort study, Titulaer et al. [4] reported that 435 of 563 patients (75%) with mRS scores $\ge$4 were admitted to the ICU, whereas Guan et al. [14] reported that 68 of 133 patients (51.1%) with severe disease (mRS score $\ge$4) were admitted to the ICU. In our study, because of limited medical resources and cost concerns, only 7 of 23 (30.4%) critically ill patients (mRS score $\ge$4) were admitted to the ICU. The hospitalization costs for good and poor outcomes were 0.45 [0.31–0.93] and 1.61 [0.83–4.40] (10,000 dollars) [25], respectively, while ours was 5.05 [3.13–11.10] (10,000 yuan). In this study, the average time from symptom onset to confirmative diagnosis was 15 days (IQR, 7–26). Our diagnosis is timely because of the rapid detection of third-party companies. Once the diagnosis was established, immunological therapy was starts immediately, and sometimes empirical treatment begins even before the diagnosis. The median hospitalization stay was 22 (IQR, 14–32) days. However, severe patients requiring intensive care were hospitalized for up to 75 days. With a combination of enhanced first-line therapy and long-term immunotherapy, 29 patients (93.5%) achieved satisfying clinical outcomes. At more than 12 months of follow-up, the median mRS score decreased from 4 to 0. Compared with other reports [4, 6, 16, 26], we observed more satisfactory clinical results.

The relapse rates were approximately 36.3% reported by Guan et al. [14] and 12.9% (4/31) in this study, which was significantly lower than that reported in the literature. This may be associated with the absence of a unified standard for the definition of relapse. Some studies are based on clinical findings. Nevertheless, a thorough examination is required to rule out other diseases and confirm the diagnosis. At present, there is no ideal clinical index to detect and evaluate the recurrence of anti-NMDAR encephalitis, for MRI is usually inconspicuous and serum antibody titers did not match the disease severity perfectly [25]. What’s more, some recurrent antibodies only could be tested in the CSF [25], which is difficult to achieve continuous CSF during follow-up.

The limitations of this study include its small sample size, and single center and retrospective nature. We have only a few patients undergoing dynamic monitoring of NMDA antibody concentration. More rigorous research is needed to study the relationship between the changes in antibody concentration, recurrence and therapeutic effects. Investigating and validating more clinical features are necessary in large sample sizes and prospective multicenter studies in the future.

In this study, we describe the clinical features, immunology treatment protocol, clinical outcomes, and long-term prognosis of patients with single-center anti-NMDAR encephalitis in Shenzhen, China. Patients with anti-NMDAR encephalitis in China had high rates of psychosis and seizures, with a low rate of underlying neoplasms. A higher proportion of female patients required mechanical ventilation. Complications with other positive autoimmune antibodies were a common clinical symptoms of anti-NMDAR encephalitis. Majority of the patients obtained satisfactory outcomes in combination with early first-line and long-term immunization therapy. Although recurrences are relatively common, most of treatment outcomes are satisfactory.

QHX: Conceptualization, Data Curation, Formal Analysis, Writing—Original Draft. YZ, QW, JH, FJM, SLZ, SYC, CYZ, MG, ZWL, XGL: Data Curation, Validation. XJF, YH: Conceptualization, Data Curation, Writing—Review & Editing.

Written informed consent was obtained from each subject. The study was approved by the Research Ethics Committee of Shenzhen People’s Hospital, code ID: LL-KY-2021646.

Not applicable.

This research received no external funding.

The authors declare no conflict of interest.