Neuropsychiatric Disorders Due to Limbic Encephalitis: Immunologic Aspect

Abstract

Limbic encephalitis (LE) is a rare cause of encephalitis presenting as an acute and subacute onset of neuropsychiatric manifestations, particularly with memory deficits and confusion as core features, along with seizure occurrence, movement disorders, or autonomic dysfunctions. LE is caused by neuronal antibodies targeting the cellular surface, synaptic, and intracellular antigens, which alter the synaptic transmission, especially in the limbic area. Immunologic mechanisms involve antibodies, complements, or T-cell-mediated immune responses in different degree according to different autoantibodies. Sensitive cerebrospinal fluid markers of LE are unavailable, and radiographic findings may not reveal a typical mesiotemporal involvement at neurologic presentations; therefore, a high clinical index of suspicions is pivotal, and a neuronal antibody testing is necessary to make early diagnosis. Some patients have concomitant tumors, causing paraneoplastic LE; therefore, tumor survey and treatment are required in addition to immunotherapy. In this study, a review on the molecular and immunologic aspects of LE was conducted to gain awareness of its peculiarity, which we found quite different from our knowledge on traditional psychiatric illness.

Keywords: limbic encephalitis; neuronal cell-surface antibody; neuropsychiatric; onconeural antibody; paraneoplastic neurologic syndrome.

Figure 1

Antibodies and their pathogenic effects in limbic encephalitis. The pathologic effects of antibodies include blocking of receptors or ion channels, disruption of interaction with neighboring molecules, and crosslinking and internalization of receptors from cell surface. (1) CASPR2 and contactin2 antibodies inhibit the interaction between these proteins and reduce the clustering and surface expression of VGKC; (2) LGI1 antibody disrupts interaction between protein components such as LGI1 to ADAM22/23, downregulates VGKC and reduces AMPAR clustering and synaptic transmission; (3) AMPAR antibody causes cross-linking and receptor internalization; (4) NMDAR* antibody causes cross-linking and receptor internalization; (5) mGluR5 antibody causes decreased synaptic mGluR5 cluster density; (6) GAD antibodies target mostly the GAD65 subunits but also the GAD67 subunits, disrupting GABAergic signaling; (7) GABA-BR antibody prevents ligand binding to the receptor and alters receptor function; (8) GlyR antibody probably acts as antagonist to disrupt receptor function. Ab: antibody; ADAM: a disintegrin and metalloproteinase; AMPAR: α-amino-3-hydroxy-5-methyl-4-isoxazolepropionate receptor; CASPR2: contactin associated protein-like 2; GABA-AR: γ-aminobutyric acid-A receptor; GABA-BR: γ-aminobutyric acid-B receptor, GAD: glutamic acid decarboxylase; GlyR: glycine receptor; LGI1: leucine-rich, glioma inactivated 1; mGluR5: metabotropic glutamate receptor 5; NMDAR: N-methyl-D-asparate receptor; PSD-95: postsynaptic density protein 95; VGKC: voltage-gated potassium channels.

Figure 2

Diagnostic algorithm of limbic encephalitis. NMDAR antibody (*) generally causes autoimmune encephalitis but rarely causes limbic encephalitis. Nevertheless, it should be included in neuronal antibody survey for limbic encephalitis due to clinical similarity. GAD (**) is a synaptic enzyme.