Antibodies to Kv1 potassium channel-complex proteins leucine-rich, glioma inactivated 1 protein and contactin-associated protein-2 in limbic encephalitis, Morvan’s syndrome and acquired neuromyotonia

Abstract

Antibodies that immunoprecipitate 125I-α-dendrotoxin-labelled voltage-gated potassium channels extracted from mammalian brain tissue have been identified in patients with neuromyotonia, Morvan’s syndrome, limbic encephalitis and a few cases of adult-onset epilepsy. These conditions often improve following immunomodulatory therapies. However, the proportions of the different syndromes, the numbers with associated tumours and the relationships with potassium channel subunit antibody specificities have been unclear. We documented the clinical phenotype and tumour associations in 96 potassium channel antibody positive patients (titres >400 pM). Five had thymomas and one had an endometrial adenocarcinoma. To define the antibody specificities, we looked for binding of serum antibodies and their effects on potassium channel currents using human embryonic kidney cells expressing the potassium channel subunits. Surprisingly, only three of the patients had antibodies directed against the potassium channel subunits. By contrast, we found antibodies to three proteins that are complexed with 125I-α-dendrotoxin-labelled potassium channels in brain extracts: (i) contactin-associated protein-2 that is localized at the juxtaparanodes in myelinated axons; (ii) leucine-rich, glioma inactivated 1 protein that is most strongly expressed in the hippocampus; and (iii) Tag-1/contactin-2 that associates with contactin-associated protein-2. Antibodies to Kv1 subunits were found in three sera, to contactin-associated protein-2 in 19 sera, to leucine-rich, glioma inactivated 1 protein in 55 sera and to contactin-2 in five sera, four of which were also positive for the other antibodies. The remaining 18 sera were negative for potassium channel subunits and associated proteins by the methods employed. Of the 19 patients with contactin-associated protein-antibody-2, 10 had neuromyotonia or Morvan’s syndrome, compared with only 3 of the 55 leucine-rich, glioma inactivated 1 protein-antibody positive patients (P < 0.0001), who predominantly had limbic encephalitis. The responses to immunomodulatory therapies, defined by changes in modified Rankin scores, were good except in the patients with tumours, who all had contactin-associated-2 protein antibodies. This study confirms that the majority of patients with high potassium channel antibodies have limbic encephalitis without tumours. The identification of leucine-rich, glioma inactivated 1 protein and contactin-associated protein-2 as the major targets of potassium channel antibodies, and their associations with different clinical features, begins to explain the diversity of these syndromes; furthermore, detection of contactin-associated protein-2 antibodies should help identify the risk of an underlying tumour and a poor prognosis in future patients.

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

“…Cell‐based assays (CBAs) were used to detect antibodies to the NMDAR, alpha amino‐3‐hydroxy‐5‐methyl‐4‐isoxazolepropionic acid receptor (AMPAR), LGI1, CASPR2, and contactin‐2. These tests were scored on a visual scale: 0, no binding; 1, low but specific binding; to 4, strong binding to all transfected cells by two independent observers as previously described3, 5 and in use for routine diagnostics. All positive samples were confirmed, and then tested blind by LW as part of a routine antibody service, with dilutions to assess the titer; the positives samples were also tested for binding to the surface of live hippocampal neurons in culture, prepared from P0 Sprague‐Dawley rat pups as described previously 23, 24…”

“…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.…”

The Emerging Link Between Autoimmune Disorders and Neuropsychiatric Disease

“…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.…”