SOP: antibody-associated autoimmune encephalitis

Abstract

Background: Antibody-mediated and paraneoplastic autoimmune encephalitides (AE) present with a broad spectrum of clinical symptoms. They often lead to progressing inflammatory changes of the central nervous system with subacute onset and can cause persistent brain damage. Thus, to promptly start the appropriate and AE-specific therapy, recognition of symptoms, initiation of relevant antibody diagnostics and confirmation of the clinical diagnosis are crucial, in particular as the diseases are relatively rare.

Aim: This standard operating procedure (SOP) should draw attention to the clinical presentation of AE, support the diagnostic approach to patients with suspected AE and guide through the necessary steps including therapeutic decisions, tumour screening and exclusion of differential diagnoses.

Method: Based on existing diagnostic algorithms, treatment recommendations and personal experiences, this SOP gives an overview of clinical presentation, diagnostic procedures and therapy in AE. Additional information is provided within an accompanying text and a table describing the most important autoantibodies and their characteristics.

Results: The initial steps of the AE flow chart are based on clinical symptoms and the patient's history. Assignment to paraneoplastic or antibody-mediated AE is sometimes clinically possible. Diagnostics should include MRI, EEG and CSF analysis with antibody panel diagnostic. Definite AE can be diagnosed if the underlying antibody is compatible with the clinical presentation. Classification of probable AE may be possible even with negative anti-neuronal autoantibodies if the clinical presentation and laboratory abnormalities are highly suggestive of AE. The confirmed AE diagnosis requires immediate initiation of immunotherapy.

Conclusion: The SOP facilitates the recognition of patients with AE and presents the necessary diagnostic and therapeutic steps.

Keywords: Antibody; Autoimmune; Encephalitis; Limbic encephalitis; NMDAR; Paraneoplastic.

Fig. 1

Flow chart for the diagnosis of suspected autoimmune encephalitis. AE: Autoimmune encephalitis, PNS: paraneoplastic neurological syndrome, CSF: cerebrospinal fluid, FLAIR: fluid attenuated inversion recovery, MTX: methotrexate, MMF: mycophenolat mofetil, IVIG: intravenous immunoglobulin, NMO: neuromyelitis optica, MS: multiple sclerosis, ADEM: acute disseminated encephalomyelitis

Fig. 2

Detection of anti-neuronal autoantibodies for the diagnosis of autoimmune encephalitis. a The current gold standard for established surface antibodies is the cell-based assay (CBA), in which diverse target antigens (in this example NMDAR) are recombinantly expressed on the surface of cultured cells. Binding of patient antibodies from CSF or serum samples can be visualized with fluorescent dyes. b The same CSF sample of a patient with NMDAR encephalitis shows strong binding on a mouse hippocampus section with the characteristic NMDAR distribution. c Autoantibodies to GABAbR also show strong binding to hippocampus tissue, but with a clearly distinguishable pattern. d Antibodies to onconeural antigens can be visualized by staining of line blots (not shown) or by their intracellular binding on brain sections, here Yo antibody-positive Purkinje neurons on a mouse cerebellum section. e GAD antibodies show a punctate pattern around cerebellar granule cells and Purkinje neurons. f Immunohistochemistry using brain sections also allows the detection of antibodies targeting glia cells, such as against GFAP. The methodology further permits detection of as yet undetermined anti-brain antibodies in research laboratories. D and E modified from “Prüss et al. 2017, Neurotransmitter”