Autoantibodies to leucine-rich glioma-inactivated 1 (LGI1) and contactin-associated protein like-2 (CASPR2) are associated with clinically distinctive syndromes that are highly immunotherapy responsive, such as limbic encephalitis, faciobrachial dystonic seizures, Morvan’s syndrome and neuromyotonia. These autoantibodies target surface-exposed domains of LGI1 or CASPR2, and appear to be directly pathogenic. In contrast, voltage-gated potassium channel (VGKC) antibodies that lack LGI1 or CASPR2 reactivities (‘double-negative’) are common in healthy controls and have no consistent associations with distinct syndromes. These antibodies target intracellular epitopes and lack pathogenic potential. Moreover, the clinically important LGI1 and CASPR2 antibodies comprise only ~15% of VGKC-positive results, meaning that most VGKC-antibody positive results mislead rather than help. Further, initial VGKC testing misses some cases that have LGI1 and CASPR2 antibodies. These collective observations confirm that laboratories should stop testing for VGKC antibodies and instead, test only for LGI1 and CASPR2 antibodies. This change in practice will lead to significant patient benefit.
- NMDA receptor
- Movement disorders
- Neuromyelitis optica
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Contributors SRI and SM drafted the original manuscript. All authors designed the figures, and reviewed and edited the final manuscript.
Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.
Competing interests SRI and PW are coinventors on ‘A Diagnostic Strategy to improve specificity of CASPR2 antibody detection.’ Ref. JA94536P. SRI is a co-applicant and receives royalties on patent application WO/2010/046716 (U.K. patent no. PCT/GB2009/051441) entitled ‘Neurological Autoimmune Disorders’. The patent has been licensed for the development of assays for LGI1 and other VGKC-complex antibodies. He has received honoraria from UCB, MedImmune, ADC Therapeutics and MedLink Neurology, and research funding from UCB, ONO and CSL Pharmaceuticals. PW is a named inventor on patents for antibody assays and has received royalties. He has received honoraria from Biogen Idec, Mereo BioPharma, Retrogenix and UBC; travel grants from the Guthy-Jackson Charitable Foundation.
Patient consent for publication Not required.
Provenance and peer review Commissioned; externally peer reviewed by Mike andi, London, UK.
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