{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,17]],"date-time":"2026-09-17T01:39:20Z","timestamp":1789609160272,"version":"build-2803163510"},"reference-count":39,"publisher":"BMJ","issue":"4","funder":[{"DOI":"10.13039\/100004440","name":"Wellcome Trust","doi-asserted-by":"publisher","award":["104079\/Z\/14\/Z"],"award-info":[{"award-number":["104079\/Z\/14\/Z"]}],"id":[{"id":"10.13039\/100004440","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000295","name":"Epilepsy Research UK","doi-asserted-by":"publisher","award":["P1201"],"award-info":[{"award-number":["P1201"]}],"id":[{"id":"10.13039\/501100000295","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000374","name":"British Medical Association","doi-asserted-by":"publisher","award":["Vera Down"],"award-info":[{"award-number":["Vera Down"]}],"id":[{"id":"10.13039\/501100000374","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["bmj.com"],"crossmark-restriction":true},"short-container-title":["J Neurol Neurosurg Psychiatry"],"accepted":{"date-parts":[[2016,11,30]]},"published-print":{"date-parts":[[2017,4]]},"abstract":"<jats:sec><jats:title>Objectives<\/jats:title><jats:p>Autoantibodies against the extracellular domains of the voltage-gated potassium channel (VGKC) complex proteins, leucine-rich glioma-inactivated 1 (LGI1) and contactin-associated protein-2 (CASPR2), are found in patients with limbic encephalitis, faciobrachial dystonic seizures, Morvan's syndrome and neuromyotonia. However, in routine testing, VGKC complex antibodies without LGI1 or CASPR2 reactivities (double-negative) are more common than LGI1 or CASPR2 specificities. Therefore, the target(s) and clinical associations of double-negative antibodies need to be determined.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Sera (n=1131) from several clinically defined cohorts were tested for IgG radioimmunoprecipitation of radioiodinated \u03b1-dendrotoxin (<jats:sup>125<\/jats:sup>I-\u03b1DTX)-labelled VGKC complexes from mammalian brain extracts. Positive samples were systematically tested for live hippocampal neuron reactivity, IgG precipitation of<jats:sup>125<\/jats:sup>I-\u03b1DTX and<jats:sup>125<\/jats:sup>I-\u03b1DTX-labelled Kv1 subunits, and by cell-based assays which expressed Kv1 subunits, LGI1 and CASPR2.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>VGKC complex antibodies were found in 162 of 1131 (14%) sera. 90 of these (56%) had antibodies targeting the extracellular domains of LGI1 or CASPR2. Of the remaining 72 double-negative sera, 10 (14%) immunoprecipitated<jats:sup>125<\/jats:sup>I-\u03b1DTX itself, and 27 (38%) bound to solubilised co-expressed Kv1.1\/1.2\/1.6 subunits and\/or Kv1.2 subunits alone, at levels proportionate to VGKC complex antibody levels (r=0.57, p=0.0017). The sera with LGI1 and CASPR2 antibodies immunoprecipitated neither preparation. None of the 27 Kv1-precipitating samples bound live hippocampal neurons or Kv1 extracellular domains, but 16 (59%) bound to permeabilised Kv1-expressing human embryonic kidney 293T cells. These intracellular Kv1 antibodies mainly associated with non-immune disease aetiologies, poor longitudinal clinical\u2013serological correlations and a limited immunotherapy response.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>Double-negative VGKC complex antibodies are often directed against cytosolic epitopes of Kv1 subunits and occasionally against non-mammalian \u03b1DTX. These antibodies should no longer be classified as neuronal-surface antibodies. They consequently lack pathogenic potential and do not in themselves support the use of immunotherapies.<\/jats:p><\/jats:sec>","DOI":"10.1136\/jnnp-2016-314758","type":"journal-article","created":{"date-parts":[[2017,1,24]],"date-time":"2017-01-24T02:46:01Z","timestamp":1485225961000},"page":"353-361","update-policy":"https:\/\/doi.org\/10.1136\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":140,"title":["Intracellular and non-neuronal targets of voltage-gated potassium channel complex 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