CSF and blood signatures support classification of limbic encephalitis subtypes.

Autoimmune limbic encephalitis (ALE) represents a heterogeneous disease associated with antibodies targeting extracellular (ALEextra) epitopes, intracellular (ALEintra) epitopes, anti-glutamic acid decarboxylase65 ALE (ALEGAD65), and ALE without detectable antibodies (ALEabneg). Combining analysis of cellular parameters, investigated by flow cytometry, and soluble parameters in the blood and cerebrospinal fluid (CSF) from a large cohort of 148 ALE patients (33 ALEextra, 12 ALEintra, 28 ALE-GAD65, 37 ALEabneg) in comparison to paradigmatic examples for neuro-inflammatory (51 relapsing remitting MS patients (RRMS)), and neuro-degenerative (34 Alzheimer's disease patients (AD)) diseases revealed discrete immune signatures in ALE subgroups. Identification of ALE-subtype specific markers facilitated classification of rare ALE-associated tumors, which may prompt further diagnostic efforts in clinical practice. While ALEintra exhibited features of neuro-inflammation, ALEextra displayed features of neuro-inflammation as well as neuro-degeneration. Moreover, ALEGAD65 and ALEabneg lacked hallmarks of inflammation. This may explain the low efficacy of anti-inflammatory treatment regimens in ALEGAD65 and presumably also ALEabneg.