Investigation of LGI1 as the antigen in limbic encephalitis previously attributed to potassium channels: a case series

Abstract

Summary Background Voltage-gated potassium channels are thought to be the target of antibodies associated with limbic encephalitis. However, antibody testing using cells expressing voltage-gated potassium channels is negative; hence, we aimed to identify the real autoantigen associated with limbic encephalitis. Methods We analysed sera and CSF of 57 patients with limbic encephalitis and antibodies attributed to voltage-gated potassium channels and 148 control individuals who had other disorders with or without antibodies against voltage-gated potassium channels. Immunohistochemistry, immunoprecipitation, and mass spectrometry were used to characterise the antigen. An assay with HEK293 cells transfected with leucine-rich, glioma-inactivated 1 (LGI1) and disintegrin and metalloproteinase domain-containing protein 22 (ADAM22) or ADAM23 was used as a serological test. The identity of the autoantigen was confirmed by immunoabsorption studies and immunostaining of Lgi1-null mice. Findings Immunoprecipitation and mass spectrometry analyses showed that antibodies from patients with limbic encephalitis previously attributed to voltage-gated potassium channels recognise LGI1, a neuronal secreted protein that interacts with presynaptic ADAM23 and postsynaptic ADAM22. Immunostaining of HEK293 cells transfected with LGI1 showed that sera or CSF from patients, but not those from control individuals, recognised LGI1. Co-transfection of LGI1 with its receptors, ADAM22 or ADAM23, changed the pattern of reactivity and improved detection. LGI1 was confirmed as the autoantigen by specific abrogation of reactivity of sera and CSF from patients after immunoabsorption with LGI1-expressing cells and by comparative immunostaining of wild-type and Lgi1-null mice, which showed selective lack of reactivity in brains of Lgi1-null mice. One patient with limbic encephalitis and antibodies against LGI1 also had antibodies against CASPR2, an autoantigen we identified in some patients with encephalitis and seizures, Morvan’s syndrome, and neuromyotonia. Interpretation LGI1 is the autoantigen associated with limbic encephalitis previously attributed to voltage-gated potassium channels. The term limbic encephalitis associated with antibodies against voltage-gated potassium channels should be changed to limbic encephalitis associated with LGI1 antibodies, and this disorder should be classed as an autoimmune synaptic encephalopathy. Funding National Institutes of Health, National Cancer Institute, and Euroimmun.

The Emerging Link Between Autoimmune Disorders and Neuropsychiatric Disease

“…Leucine-rich glioma-inactivated 1 (LGI1) is a secreted protein that interacts with presynaptic ADAM23 and postsynaptic ADAM22 to create a trans -synaptic protein complex, which also includes potassium channels and AMPA-type glutamate receptors. 29,30 Mutations in LGI1 are known to cause autosomal-dominant partial epilepsy with auditory features, 31 a syndrome characterized by temporal lobe seizures with prominent auditory hallucinations (Table 1). 32 A classic limbic encephalitis previously thought to be caused by autoantibodies recognizing voltage-gated potassium channels (VGKC) is now known to result from autoantibodies targeting LGI1.…”

“…32 A classic limbic encephalitis previously thought to be caused by autoantibodies recognizing voltage-gated potassium channels (VGKC) is now known to result from autoantibodies targeting LGI1. 30,33 As described in detail as encephalitis attributed to anti-VGKC antibodies, 34 anti-LGI1 patients present most prominently with seizures, memory loss, and confusion. Other symptoms can include autonomic dysfunction (hyperhidrosis, hypersalivation) and behavioral changes such as apathy and irritability.…”

“…30,33 Contactin-associated protein-like 2 (Caspr2) has a role in clustering VGKC at the paranodal regions of myelinated axons. 36 Caspr2 is a member of the neurexin superfamily, which mediates cell–cell interactions in the CNS and in which mutations have been associated with schizophrenia, autism, and mental retardation.…”

Elevated LGI1‐IgG CSF index predicts worse neurological outcome

“…Autoantibodies targeting the leucine‐rich glioma inactivated 1(LGI1) protein, an extracellular component of the voltage‐gated Kv1 potassium channel‐complex (VGKC), have potential to cause neurological autoimmunity with both central and peripheral nervous system manifestations 1, 2. Most cases are immunotherapy‐responsive 3, 4, 5.…”

Neuronal antibodies in pediatric epilepsy: Clinical features and long‐term outcomes of a historical cohort not treated with immunotherapy

“…Patients present with memory loss, confusion, and seizures in limbic encephalitis with predominantly LGI1 antibodies3, 4 and neuropsychiatric features, movement, and autonomic symptoms in NMDAR‐Ab (antibody) encephalitis 5, 6. However, the recent characterization of faciobrachial dystonic seizures (FBDS) in patients with LGI1 antibodies has widened the phenotype to include patients presenting with seizure predominance 7, 8.…”