Sonja Kosek: Autoimmune Encephalitis: Epidemiology, Clinical Characteristics, and Biomarkers

Abstract

Autoimmune encephalitis (AE) and paraneoplastic neurological syndromes (PNS) are immune-mediated disorders of the nervous system, often associated with neuronal antibodies detectable in blood or cerebrospinal fluid (CSF). Most neuronal antibodies and their associated disorders were identified within the past two decades, substantially improving patient outcomes. This thesis aims to expand our understanding of AE and PNS regarding epidemiology, clinical features, and potential biomarkers.

First, incidence rates of AE and PNS in Healthcare Region Mid Sweden were estimated, and nationwide trends in neuronal antibody testing were analyzed. Between 2015-2019, the annual incidence of AE and PNS increased in parallel with expanding antibody testing, while the proportion of positive results declined slightly. Notably, only about one-third of patients with positive antibody tests fulfilled diagnostic criteria.

Second, clinical features of confirmed AE or PNS cases were characterized. Findings largely mirrored international cohorts, except for an unexpected older age distribution among anti-NMDAR encephalitis cases. Despite hallmark symptoms, diagnoses were often delayed, highlighting the need for greater clinical awareness. Additionally, the onset of non-tumor-related AE primarily occurred during the warm seasons, suggesting a possible seasonal trigger such as viral infections.

Third, a systematic review of studies reporting individual-level brain FDG-PET findings in AE revealed that FDG-PET abnormalities were more frequently detected than MRI abnormalities. Patterns varied by antibody, with medial temporal lobe hypermetabolism typical in some AE subtypes, while others showed complex combinations of hyper- and hypometabolism across multiple anatomical regions. These results underscore the need for refined interpretation strategies, including the selection of appropriate reference regions.

Finally, targeted proteomic profiling of serum and CSF in anti-NMDAR encephalitis revealed distinct, compartment-specific protein signatures involving microglial activation, synaptic dysfunction, and systemic protease activity. Caspase-8 (CASP-8) was significantly elevated in both serum and CSF, particularly in early disease, and dynamic changes correlated with clinical deterioration, suggesting potential utility as a biomarker of disease activity.

In summary, this thesis addresses key challenges encountered in the early stages of identifying a new disease group and contributes to the growing body of knowledge on potential disease biomarkers. The results aim to improve clinical awareness and stimulate further research in AE.