Autoimmune encephalitis (AIE) comprises a group of rare, immune-mediated conditions where an individual’s immune system produces autoantibodies that target cells of the central nervous system (CNS) resulting in neuronal dysfunction, neuroinflammation, and cell-death (1). Multiple autoantibodies have been identified in individuals with AIE over the last two decades. The most prevalent are the anti-N-methyl-D-aspartate receptor (NMDAR), anti-myelin oligodendrocytic glycoprotein (MOG), anti-leucine-rich glioma inactivated 1 (LGI1), anti-contactin-associated protein 2 (CASPR2), anti-α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR), anti-gamma-aminobutyric acid A receptor (GABA_AR), anti-metabotropic glutamate receptor (mGluR) and anti-glycine receptor (GlyR) autoantibodies, and some of them are often related with neoplasms (paraneoplastic autoantibodies) while others are not (2–4). The clinical manifestations of AIE are heterogenous and are temporally dependent on the location of the antigenic target in the CNS. Broadly, symptoms can include abnormal movements, behavioral changes, catatonia, cognitive dysfunction, confusion, memory loss, psychosis, and seizures (5), all of which could also be indicative of different autoimmune, neurologic or psychiatric conditions (1, 3). Aside from NMDAR-AIE, which is relatively well-characterized, similarities in imaging and laboratory findings make diagnosis and subtype determination of AIE challenging (3, 5). In addition to antibody-positive AIE, there is growing recognition of antibody-negative AIE, which includes cases of AIE that occur without any identifiable pathogenic antibody and present with similar clinical presentation as antibody-positive AIE (6).

Compared with adults, children with AIE may have different symptoms, paraclinical findings, comorbidities, treatment responses, and prognosis (4). The symptoms of AIE are also poorly characterized in children although important clinical differentiators have emerged. Children with AIE more frequently present with seizures, movement disorders, encephalopathy and multifocal neuropsychiatric symptoms, rather than insidious neurologic and psychiatric phenotypes (4, 5). Moreover, unlike adults, who often experience more subtle and fluctuant disease onset, children with AIE more frequently present as previously healthy with acute onset of neuropsychiatric symptoms (4, 5, 7).

Studies reporting the incidence and prevalence of AIE in children are scarce. This could in part be due to the challenges associated with the diagnosis of AIE in children, which relies on a combination of clinical history consistent with pediatric AIE and paraclinical and antibody testing (4). In antibody testing, both false-positive and false-negative results are possible, highlighting the importance of not relying solely on laboratory test results (8). As such, clinicians must synthesize a greater amount of data resulting in delays in diagnosis and treatment. Critically, these delays are associated with poorer long-term functional and cognitive outcomes, including worse verbal and visuospatial episodic memory scores (9–11). Early identification and diagnosis of AIE to avoid delays in treatment would therefore increase the likelihood of better longer-term outcomes.

A better understanding of the epidemiology of pediatric AIE and AIE subtypes could provide an estimate of the burden and distribution of AIE. This in turn could inform research, health policy, clinical decision-making guidelines, and allocation of resources. It can also aid more accurate diagnosis, for example by avoiding misdiagnosing patients with diseases that mimic AIE that are more prevalent in the general population (12, 13). Therefore, this systematic literature review (SLR) was conducted to identify published studies reporting epidemiological data on AIE (of any subtype) in children.

This SLR was conducted based on a prespecified protocol, in accordance with stringent methodological principles of conduct for SLRs (14, 15).

A Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) diagram displaying the flow of records through each stage of the review process is presented in Figure 1. A total of 4,058 records were retrieved by the electronic database searches. After exclusion of duplicate studies, 3,056 titles/abstracts (75.3%) were reviewed against the pre-specified eligibility criteria. Following this, 415 full-text articles (10.2%) were reviewed in full. Of these, 39 (1.0%) ultimately fulfilled the eligibility criteria for inclusion in the SLR. Supplementary searches yielded four additional records that fulfilled the eligibility criteria. In total, 43 publications reporting on 41 unique studies were included in the SLR.

Ten studies reported data on age of onset and/or presenting symptoms specific to the pediatric population with AIE (17–26). Age of onset of AIE ranged from 8 to 16 years for AIE overall, whereas age of onset for NMDAR-AIE ranged from 3.5–17 years in the identified studies. Age of onset was not reported for other AIE subtypes. The most common presenting symptoms, irrespective of AIE subtype, were seizures and behavioral change in combination with other neuropsychiatric features (17–25). These findings highlight the heterogenous presentation of AIE with little distinction among the different subtypes in the key presenting features.

This SLR identified a distinct lack of published data on the epidemiology of pediatric-onset AIE. Only nine studies reporting incidence data were identified (18, 20, 25, 27–32), of which, only one reported incidence rates of definite AIE in a full pediatric population in children of all ages (20). Two studies reporting incidence estimates for NMDAR-AIE reported only on children in specific ancestral or ethnic subpopulations (30, 32). Only three studies reported results for specific AIE subtypes, including GAD-65 AIE and antibody-negative AIE (18); post-herpes simplex virus (HSV) infection AIE in children with seizures under 3 years (27), and Bickerstaff brainstem encephalitis (29). Reporting was sparse and disparate across geographies, with no incidence studies from the US, South America, Africa or Central Asia. Moreover, the quality of the evidence base was limited, with factors such as different periods of data collection and small sample size resulting in high between-study heterogeneity and thus limiting the confidence in the results. Although studies that reported proportion data for AIE were used to calculate further incidence estimates, these calculations were based on several assumptions, including the application of incidence rates from one country to another country, and thus only constitute crude estimates. As the symptoms of AIE have been found to be poorly-characterized in children, coupled with the reporting and severity bias associated with the studies included in this SLR, the calculated incidences are likely to be an underestimation of the true incidence of AIE (4).

One potential reason for the scarcity of data is that AIE in children may be under-recognized (39). Limited data on the condition’s epidemiology could be attributed to several reasons, including lack of clinical awareness, along with difficulties in AIE diagnosis and testing. In addition to its broad clinical phenotype, diagnosing AIE in children is difficult owing to the complexity of behavioral changes and the limited capacity of children to describe their symptoms (4). The diagnostic process is complex and requires comprehensive assessment, including clinical workup, neuroimaging, electroencephalogram (EEGs), neoplasia screening, and the collection of samples for testing, which can involve costly and invasive procedures which require sedation to obtain (3, 4). Moreover, antibody testing is generally associated with a number of limitations, and can result in both false-positive and false-negative results (8). Two studies identified in this SLR stated that they found no association between antibody positivity and presenting clinical phenotypes, with antibody negative groups presenting with similar clinical phenotypes to antibody positive groups (11, 27). This finding may be a result of delays between clinical presentation and antibody testing, or a reflection of the number of neural autoantibodies and their pathogenic mechanisms associated with AIE which have yet to be identified (4, 40). Given the growth of antibody testing panels in the past decade, it is critical to combine antibody tests with thorough clinical evaluation as the potential capture of novel autoantibodies may increase over time (4, 40).

Another important factor that may relate to the lack of published incidence data is the limited number of centers offering a dual antibody testing approach, which includes initial screening for antibodies using immunofluorescent assays followed by testing for specific antibodies using antibody titer assays and immunoblots, which provides an accurate diagnosis. However, this approach is currently only used by a limited number of international sites in the US and Europe and is not used for antibody testing in a number of other countries. Published information on exact costs for testing is difficult to obtain, but costs are known to differ by facility and region. Clinicians from other regions not offering testing (particularly Asia, South America, Africa) would be required to ship samples for long distances to these testing facilities that utilize more stringent methods for antibody detection or rely solely on the results of commercially available assays. This aligns with the studies identified in this SLR, with the majority using commercial testing kits rather than samples being tested at a specialized facility offering this dual testing. Concerns have been raised regarding false negative results in certain commercial assays and antibody kits, especially when CSF alone is used as a sample. This is more predominantly seen for LGI1, GABABR and AMPAR antibodies. This highlights the fact that any inferences made on the incidence of AIE from these studies might not be as accurate (41). A substantial number of healthcare institutions face barriers in accessing these testing facilities, which can result in patients going with unconfirmed or inaccurate AIE diagnoses, thereby contributing to the paucity of epidemiological data on antibody-mediated AIE.

Finally, there may be differences in the approach taken to treat AIE in children. The 2020 guidelines for differential diagnosis of AIE in children by Cellucci et al. (4) highlights the importance of starting therapy while awaiting the results of antibody testing among children suspected to have AIE. Expert consensus is consistent with this recommendation; in a 2018 report on the expert opinion of three AIE specialists from three different continents (US, UK, and India) regarding the challenges of AIE diagnosis and the role of antibody testing, the experts emphasized the importance of starting treatment for suspected AIE cases while awaiting the results of antibody testing, without being over reliant on test results (42). However, awareness of this urgency to initiate treatment may be lacking among less experienced or non-specialist clinicians. A worldwide survey of 1,333 neurologists from 94 countries asked questions on their approach to dealing with AIE cases (43). In response to clinical questions about a patient strongly suspected of AIE, the majority of clinicians responded that they would treat the patient empirically for presumed AIE, while 11% would wait for antibody test results. However, for ambiguous cases that had partial phenotypes, only 40% of respondents said that they would consider empiric immunotherapy, and 28% would only do so on confirmatory antibody test results. Unsurprisingly, these decisions were found to be associated with the number of AIE cases seen annually by the treating physician, where more experienced physicians chose to start treatment early. This finding highlights the rarity of AIE and how this impacts the ability of physicians to recognize and treat the condition appropriately. It also emphasizes the importance of epidemiological data in gaining a deeper understanding of the disease burden and how this affects clinical decision-making. Physician likelihood-to-treat discrepancies due to not seeing patients with AIE frequently are thus compounded by the limitations in access to autoantibody testing and by cognitive biases to not treat individuals who do not have known autoantibody mediated AIE. Multiple studies have found that delays in diagnosis, including waiting times for antibody test results, can result in unnecessary delays in treatment, which has been found to be associated with poorer long-term outcomes (9–11). To improve the odds of favorable outcomes for patients, there is a critical need for earlier diagnosis and aggressive treatment of AIE. Given the emphasis on early treatment initiation prior to antibody test confirmation, clinicians should prioritize prompt initiation of immunosuppressive therapy for AIE while waiting for antibody confirmation. Following the receipt of antibody testing results, the treatment strategy could be altered or refined to suit the patient’s needs (5). This approach should be utilized until further real-world data on the epidemiology of AIE becomes available to better inform treatment strategies. A deeper understanding of the epidemiology of AIE is also essential to inform research, health policies and clinical decision-making guidelines at a global scale.

One of the best examples of how epidemiological data can be instrumental in making decisions for better allocation of resources for prevention and treatment of diseases is the recent COVID-19 pandemic. Epidemiological studies published in the months following the outbreak of the virus highlighted that worse COVID-19-related outcomes were positively correlated with people aged ≥ 60 years old and those with underlying co-morbidities (44–46). This identified a vulnerable population to be prioritized for vaccination drives, implementation of stricter regulations for self-isolation and distancing. Epidemiological data were also considered when deciding which patients should be fully escalated to invasive mechanical ventilation or other types of organ support. Furthermore, research into the epidemiology of anti-NMDAR encephalitis following the condition’s discovery increased clinician awareness of the disease phenotype and aided in treatment decision making for patients presenting with symptoms including rapidly progressive psychiatric symptoms or cognitive impairment, seizures, abnormal movements, or coma of unknown cause (47).

Overall, the findings of this SLR support that pediatric AIE is very rare. However, given the multiple biases present in the reported literature included in this SLR, the calculated incidence estimates presented here likely underestimate the true incidence of AIE in children. Further research at a national/international level, across a wider breadth of countries is critically necessary. With broader awareness and identification of AIE in clinical practice extracted from these types of studies, earlier diagnosis and treatment may lead to improved long-term outcomes in this unique patient population. Moreover, epidemiological data will play an instrumental role in informing research, health policies, clinical decision-making and also to better understand the worldwide burden of disease.

The original contributions presented in the study are included in the article/Supplementary material, further inquiries can be directed to the corresponding author.

JS: Conceptualization, Formal analysis, Investigation, Methodology, Supervision, Visualization, Writing – review & editing, Writing – original draft. PD: Conceptualization, Investigation, Methodology, Supervision, Visualization, Writing – review & editing, Writing – original draft. SH: Conceptualization, Formal analysis, Investigation, Methodology, Visualization, Writing – original draft, Writing – review & editing, Project administration. SK: Conceptualization, Formal analysis, Investigation, Methodology, Visualization, Writing – original draft, Writing – review & editing, Project administration. MM: Conceptualization, Formal analysis, Investigation, Methodology, Supervision, Visualization, Writing – original draft, Writing – review & editing. FT: Conceptualization, Formal analysis, Investigation, Methodology, Supervision, Visualization, Writing – review & editing, Writing – original draft, Funding acquisition. CH: Conceptualization, Formal analysis, Investigation, Methodology, Supervision, Visualization, Writing – review & editing, Writing – original draft.