Our case followed a classic clinical picture of anti-NMDAR encephalitis resulting from the loss of NR1 subunit of NMDA receptors as presented in the current literatures, including psychotic behavior, disruption of dopaminergic pathway (orofacial movement), dysautonomia (cardiac dysrhythmia, hypersalivation, central hypoventilation) and memory deficits are similar to those obtained with models of genetic or pharmacologic attenuation of NMDA receptors function [8–10]. High titers of serum anti-TPO antibodies suggested comorbid diagnosis of Hashimoto encephalopathy (HE) requires further attentions. The presence of serum EBV-VCA-IgM (not previously described in patients with anti-NMDAR encephalitis) provides further evidence that anti-NMDAR encephalitis is not merely a paraneoplastic disorder, but that a probable postinfectious autoimmue process contributes to disease presentation.
HE is a steroid-responsive encephalopathy associated with elevated blood concentrations of anti-thyroid antibodies and euthyroid or mildly hypothyroid function. Alink summarized 25 pediatric HE cases mainly with acute manifestations, among which the most frequent symptoms were seizures (80%), confusion (52%), hallucinations (32%), and only half of the patients develop abnormal neuroimaging . The diagnosis of HE requires both detection of high concentrations of anti-TPO antibodies in serum, and exclusion of other toxic-metabolic encephalopathies. From above mentioned aspects, the current case met the diagnostic criteria for HE  until both the ovary immature teratoma and anti-NMDAR antibodies were identified. In the present case, serum anti-TPO antibodies remained elevated one year after discharge, despite resolution of clinical symptoms, further suggesting that the likely diagnosis in this case was anti-NMDAR encephalitis. Although, anti-TPO antibodies directed at microsomes and released from damaged thyroid cells were found in all HE cases, they have also been found in autoimmmue diseases ranging from type 1 diabetes mellitus to rheumatoid arthritis [13, 14], even in euthyroid individuals . Hence, clinicians should be cautioned against accepting HE as the sole explanation for an encephalitic illness, after excluding conventional metabolic, infectious or vascular etiologies, and merely based on anti-TPO test. On the other hand, with evolving case studies of anti-NMDAR encephalitis, more and more authors regard HE as an important differential diagnosis [16–20]. Recently, Tüzün and colleagues compared serum autoantibodies to neuronal surface antigens in serum thyroid antibody-positive and -negative limbic encephalitis, suggesting patients with anti-thyroid antibodies are inclined to develop anti-neuronal immune responses and autoimmune encephalitis such as anti-NMDAR encephalitis, which supported the notion that neuronal and thyroid autoimmunities might represent a pathogenic spectrum . Interestingly, although prednisone is known to reduce thyroid antibodies titers, several courses of immunotherapy had no effect on sera anti-TPO antibodies reduction in current case. Her serum anti-TPO antibodies were still elevated when she was discharged and had persisted for a year after dismissal, which suggested a propensity for autoimmunity in anti-NMDAR encephalitis.
A high incidence of prodromal hyperthermia and viral-like symptoms during the course of anti-NMDAR encephalitis frequently lead to extensive studies to rule out infections [2, 22]. Although some positive infectious serology has been reported in anti-NMDAR encephalitis cases, not a common pathogen has been identified even in cases without tumors . The preceding active EBV infection or reactivation suggested by EBV-VCA-IgM in this case hasn't been previously reported.
In developing countries like China, primary EBV infection is usually asymptomatic and occurs through close contacts between parents and children within the first 3 years of life . Therefore, given lack of typical EBV infection symptoms and blood lymphoctosis, EBV-VCA-IgM seropositivity of current adolescent case on admission was not due to primary EBV infection but probably recent EBV reactivation. In addition, evidence of acute hepatitis A virus or HIV infections, which had been reported to have false positive reactions of the EBV-VCA-IgM ELISA was absent in this patient . Follow-up EBV-VCA-IgM seroreversion proved by both ELISA and indirect immunofluorescence assay which is known as gold standard for highly sensitive and monospecific antibody detection , further excluded the persisting EBV-VCA-IgM seropostive status and reinforced the credibility of our conventional ELISA methodology. It is well acknowledged that the titer of CSF anti-NMDAR antibodies appears to correlate more closely with the clinical outcome than serum antibodies and prolonged follow-up studies have found anti-NMDAR antibodies in CSF and serum [2, 3, 27, 28]. Depriving NR1 as autoantigen with teratoma and reducing anti-NMDAR antibody titers by previous immunotherapies may explain the prolonged symptom-free intervals in those cases. Taking into account different EBV-VCA-IgM serostatus from admission to one year follow-up, we proposed the prodromal EBV reactivation and following cascade may also contribute to triggering and boosting the immune response or facilitate autoantibodies crossing the blood-brain barrier in our patient one year ago . Controlled studies are expected to compare the concomitant infectious or inflammatory status of patients with and without prodromal flu-like symptoms and may shed new light on the pathophysiology of anti-NMDAR encephalitis.
In chronic aspects, persistence and reactivation of EBV is presumed to elicit autoimmunity in multiple sclerosis, systemic lupus erythematosus, rheumatoid arthritis, myasthenia gravis, Hashimoto thyroiditis, etc [24, 29, 30], but hasn't been linked with anti-NMDAR encephalitis up to now. Following primary infection, EBV latency is maintained by expression of a set of viral proteins that deliver activation, growth, and survival signals to infected B cells. These B cells are able to cross the blood-brain barrier, and are believed to undergo restimulation, antigen-driven affinity maturation, clonal expansion, and differentiation into antibody-secreting plasma cells which may cause damage in self-tissues . EBV has also been associated with numerous cancers such as Burkitt's lymphoma, Hodgkin lymphoma, nasopharyngeal carcinoma, gastric adenocarcinoma and even breast cancer , the latent EBV infection in this immature teratoma proved by EBER ISH may either suggest oncogenicity of EBV in teratoma or underlying EBV related immunopathogenesis of anti-NMDAR encephalitis as we proposed previously.
The improvement in the clinical presentation with therapies also can be correlated to the resolution of the EEG changes (Figure 1A-D). Although the patient was lack of severe stressors and functioned very well in daily life before falling ill, she presented clinical spectrum of seizures, agitation, autonomic instability and hypoventilation compatible with a catatonic disorder [32, 33]. Nevertheless, without aggressive management of the observable symptoms of catatonia, the most profound improvements in psychiatric and behavioral symptoms occurred after the teratoma had been resected. Unlike recently reported two non-tumor associated anti-NMDAR encephalitis cases with anti-TPO and infectious serology concurrence , the patient had complete clinical recovery both on discharge and one year later, which may also due to timely tumor resection. However, controlled studies and more cases are still necessary to prove the real effectiveness of IV immunoglobulin and IV steroids recommended as first line immunotherapies by some authors [19, 26] in anti-NMDAR encephalitis. Factors related to the surgery including anesthetics or induction of sleep may not be account for patient's clinical improvements, for propofol and midazolam administered during endotracheal intubation hadn't change the course of her illness.