Anti-NMDAR encephalitis is the most common type of autoimmune encephalitis.Some clinical features are different between children and adult with anti-NMDAR encephalitis. And they may vary from regions and racial. Besides most published papers focused on adult patients. Our study focused on children with anti-NMDAR encephalitis and had relatively large cases in southern China to provide more practical information and guidance.
There were some differences in demographic data of patients comparing with the previous studies. According to previous studies, pediatric anti-NMDAR encephalitis in China and other countries was more common in children aged around 8–12 years[3, 12–16]. While in our study, the mean age at onset was 6.3 ± 3.1 years old which was slightly younger (See Additional file 1: Table S1). In addition, the onset age of boys in our study was younger than that of girls, which was different from the outcomes of UK and Thailand studies [13, 12]. These differences suggested that the demographics feature of age might range from regions and nations. The gender ratio in our study was 50:57 (male: female), which was similar to the outcomes of previous studies in Asia including studies from different regions of China in which the ratio of female ranged from 50–70% (See Additional file 1: Table S1)[17–19, 13, 15, 16, 14, 20]. While in studies from western country female was moderately predominate (higher than 70%). And the gender ratio was also various in different age, with the age increase, proportion of female patient increase[14, 20, 15]. One reason for the predominance of female is teratomas which are more common in female more than 14 years old. Therefore, we presumed the dissimilarity of gender ratio in our patients was likely to racial, region and age differences.
Some common neurological and psychological symptoms are present in anti-NMDAR encephalitis. And symptoms presentation varied between children and adult. In our pediatric study, the proportion of seizures (39.2%, 42/107) among initial symptoms was similar to others’ studies, whereas the movement disorder (29.9%, 32/107) was more common than other studies and psychiatric symptoms (18.7%, 20/107) was less than other studies[17, 3, 10, 20, 16, 14, 15] (See Additional file 1: Table S1). The distribution of symptoms during whole course was similar to other studies[17, 3, 10, 20, 16, 14, 15].
The initial symptoms were various in the different age. Previous studies found that in adult and children older than 12 years old, psychiatric symptoms were the most common initial presentation[17, 10, 15, 14]. However, in children younger than 12 years old, the proportion of psychiatric symptoms at initial symptoms was nearly equal to that of seizures, but more common than that of movement disorder[10, 15, 21]. It remained unclear why there existed age differences on the initial symptoms of anti-NMDAR encephalitis. In general speaking, the manifestation of anti-NMDAR encephalitis associated with NMDAR dysfunction in neurobiology. One hypothesis for explaining the anti-NMDAR clinical features is that psychiatric symptom which is more common in adults is caused by NMDAR hypofunction resulted from antibody mediated NMDAR internalized, while neurological symptoms like seizures and movement disorders as initial symptoms are caused by agonist effect of NMDAR, extrasynaptic NMDAR hyperfunction or neuronal network imbalance with impaired intraneuronal activity[6, 1]. Extrasynaptic NMDAR is more commonly in GluN1/2B, while synaptic NMDAR is more commonly in GluN1/2A. And during development from juvenile to adult, NMDAR subunit switch from GluN2B to GluN2A. In future, more researches about the NMDAR function network in physiology, disease during development need to do in order to elucidate the pathological mechanism of anti-NMDAR encephalitis.
The EEG abnormalities were not specific, and the proportion of EEG abnormalities was similar to other studies[23, 24, 8, 17]. Delta brush was relatively rare among the EEG examinations in current study, if compared to the EEG outcomes of Zhang et al study from north of China (See Additional file 1: Table S1), which might be related to the time of EEG monitoring for patients. Though the MRI change of anti-NMDAR was non-specific, we found some abnormalities suggesting an association with other auto-antibodies, so called “antibody overlapping syndrome”. The outcomes of MRI scan in 7 cases in our previous studies showed the abnormal of multiple demyelination lesions, among which 5 cases having MOG antibody positive. And among other 3 cases with MRI abnormalities of leptomeninges enhancement, one case had GFAP antibody positive.
Some patients with anti-NMDAR encephalitis have prodromal events. 48.6% of anti-NMDAR encephalitis patients in our study had prodromal events. 92.9% of these patients with prodromal events of intracranial infection was HSV encephalitis. Anti-NMDAR encephalitis is a major constitution of autoimmune encephalitis after HSV encephalitis and patients aged 4 years or younger are more likely to develop to autoimmune encephalitis after HSV encephalitis and develop movement disorder and worse condition, whereas older children develop behavioral and psychiatric manifestations predominated[9, 25, 15, 10]. The pathophysiology of anti-NMDAR encephalitis after HSV encephalitis is still unclear. In vitro model of the blood-brain barrier, HSV can reduce the cell-cell barrier resistance lead to a viability loss of the infected endothelial cells. Blood-brain barrier disruption provides a convenient for entry of complement and other pro-inflammatory molecules. And complement may be involved in the pathological process of anti-NMDAR encephalitis and cause neuronal degeneration which is different from the other anti-NMDAR encephalitis[1, 27]. That’s a hypothesis for why young children with anti-NMDAR encephalitis after HSV encephalitis are worse than others with classical encephalitis. Analysis of the prodromal events is helpful for further mechanism study of anti-NMDAR encephalitis.
The relapse rate of anti-NMDAR encephalitis ranges from 0.0–25%[15, 10, 20, 16, 14] (See Additional file 1: Table S1). And it was 12.1% in our study. The relapse rate may be associated with duration of follow-up. The fatality rate of anti-NMDAR encephalitis ranges from 0–12.5%[10, 28, 29, 20, 16, 14, 15] (See Additional file 1: Table S1). While it was 1.8% in current study, that was similar to studies from other region of China[20, 16, 14, 15], which ranged from 0.0–2.3% (See Additional file 1: Table S1), being relatively low. A systematic review of reported cases which involved studies of pediatric and adult anti-NMDAR encephalitis showed that patients who died had an older onset age than patients who survived, and pediatric patients had a better outcome than the adult. This might be an explanation for the lower fatality rate in our study and studies form other regions of China.
The ratio of patients with good prognosis in our study was 76.6% which similar to other study[30, 16, 10, 14, 12]. The predictors of poor outcome in previous study including decrease consciousness, speech disorder, longer hospital day, higher initial mRS, and treatment with RTX were consistent with the outcomes of our study[30, 16, 10, 14, 12, 31]. Byrne et al found the patients who recovered completely had shorter interval (15 days) between onset and initiation of treatment than that of those who did not recovered completely (21 days). Similarly, we found a longer duration (more than 14 days) served as a predictor of poor outcome, in consistent with the general value of “early treatment with good outcome”. Male, lesions in brain MRI and autonomic dysfunction served as predictors of poor outcome in our study, although previous study did not[30, 16, 10, 14, 12, 31]. We found patients aged 3 years or younger was a risk factor for outcome. The previous study involved both pediatric and adult anti-NMDAR encephalitis, found the younger age was a predictor of poor outcome, although the study only concentrating on pediatric patients did not found [16, 14, 12]. In our study, we found prodromal event was also associated with poor outcome that is rarely analyzed in previous studies. Prodromal events could play an important role in epigenetic change in patients. For now, epigenetic mechanisms for NMDAR receptor hypofunction in schizophrenia provided new insights into understanding of its neuropathophysiology and early interventions.
Besides boys occurred onset at younger age, we also found boys were more likely to have fever, longer hospital day, higher mRS score after treatment and needed more course of steroid treatment compared with girls. And male was an independent risk factor of poor outcome.
While no difference of initial mRS, level of CSF anti-NDMAR titer, ratio of abnormal MRI, initial mRS, RTX treatment and relapse between boys and girls was found. And these difference between boys and girls in our study might suggest though no difference of severity at initial onset, boys might more likely recover slower and have poor outcomes than girls. One study from UK which involved 31 pediatric patients with anti-NMDAR encephalitis also found partial phenotypes were different between girls and boys and boys were more likely to present predominant movement. But in contrast to one study from Thailand which only involved 14 pediatric patients with anti-NMDAR encephalitis found that there was no difference of duration hospitalization between boys and girls and the ratio of fever in boys was tend to be higher than girls but this difference didn’t have statistical significance and as a result, male was not a risk factor of poor outcome. The difference of results between ours and other study might be caused by the sample size. And the sample size in our study was relatively large.