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Stop Testing for Autoantibodies to the VGKC-Complex: Only Request LGI1

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Stop Testing for Autoantibodies to the VGKC-Complex: Only Request LGI1 REVIEW Stop testing for autoantibodies to Pract Neurol: first published as 10.1136/practneurol-2019-002494 on 28 June 2020. Downloaded from the VGKC-complex: only request LGI1 and CASPR2 Sophia Michael,1,2 Patrick Waters ,1 Sarosh R Irani 1,2 1Oxford Autoimmune Neurology ABSTRACT This prediction was directly tested with Group, Nuffield Department of Autoantibodies to leucine-rich glioma-inactivated 1 alpha-dendrotoxin (α-DTX), a neurotoxin Clinical Neurosciences, University of Oxford, Oxford, UK (LGI1) and contactin-associated protein like-2 derived from green mamba snake venom. α- 2Department of Neurology, John (CASPR2) are associated with clinically distinctive DTX labels Kv1.1, 1.2 and 1.6 potassium Radcliffe Hospital, Oxford syndromes that are highly immunotherapy channels and was radioiodinated to label University Hospitals NHS Foundation Trust, Oxford, UK responsive, such as limbic encephalitis, faciobrachial soluble mammalian brain extracts upon dystonic seizures, Morvan’ssyndromeand establishment of the VGKC antibody radio- Correspondence to neuromyotonia. These autoantibodies target immunoassay. This radioimmunoassay Prof Sarosh R Irani, Oxford Autoimmune Neurology Group, surface-exposed domains of LGI1 or CASPR2, and detected serum or cerebrospinal fluid auto- Nuffield Department of Clinical appear to be directly pathogenic. In contrast, antibodies that precipitated iodinated α- Neurosciences, University of voltage-gated potassium channel (VGKC) antibodies DTX. Hence, these autoantibodies were ori- Oxford, Oxford OX3 9DU, UK; 23 [email protected] that lack LGI1 or CASPR2 reactivities (‘double- ginallythoughttobindVGKCs, and some negative’) are common in healthy controls and have reports even showed IgG from patients Accepted 30 April 2020 no consistent associations with distinct syndromes. binding directly to oocyte or HEK293T- 2–4 These antibodies target intracellular epitopes and cell-expressed VGKCs. During this series lack pathogenic potential. Moreover, the clinically of molecular observations, VGKC antibo- important LGI1 and CASPR2 antibodies comprise dies were also identified in patients with ’ only ~15% of VGKC-positive results, meaning that Morvan s syndrome (neuromyotonia with most VGKC-antibody positive results mislead rather characteristic central nervous system 4 5–7 than help. Further, initial VGKC testing misses some manifestations) and limbic encephalitis. cases that have LGI1 and CASPR2 antibodies. These Importantly, patients with these syndromes collective observations confirm that laboratories improved markedly following immunother- should stop testing for VGKC antibodies and apy. Overall, these serological discoveries http://pn.bmj.com/ instead, test only for LGI1 and CASPR2 antibodies. helped to describe and classify a potentially reversible set of autoimmune neurological This change in practice will lead to significant patient conditions. benefit. Subsequently,these findings were rapidly disseminated through the neurology com- munity. To avoid missing a potentially VGKC ANTIBODIES: ORIGINS OF immunotherapy-responsive condition, on October 2, 2021 by guest. Protected copyright. A DIAGNOSTIC TEST VGKC antibodies were requested in patients The initial clinical insights describing an with a wider spectrum of clinical features. autoimmune basis for acquired neuro- This led to a large number of positive VGKC myotonia (Isaacs’ syndrome), a form of antibody results, in broad-ranging pheno- peripheral nerve hyperexcitability, types. Many of these syndromes were not emerged in Oxford around 30 years ago. immunotherapy-responsive or intuitively A patient with severe disease, refractory to immune-mediated. This non-distinctive set sodium channel blocking medications, of syndromes led us to question how anti- ©Author(s)(ortheir showed almost complete symptom resolu- bodies to a single protein family could cause employer(s)) 2020. Re-use tion after plasma exchange.1 Moreover, such a variety of diseases (Figure 1). permitted under CC BY. this patient’s purified IgG induced muscle Published by BMJ. hyperexcitability in phrenic nerve–dia- SPLITTING THE COMPLEX: To cite: Michael S, Waters P, phragm preparations. These findings sug- IDENTIFICATION OF LGI1 AND CASPR2, Irani SR. Pract Neurol Epub gested an underlying autoantibody-driven AND CLINICAL ASSOCIATIONS ahead of print: [please include Day Month Year]. mechanism for neuromyotonia, with vol- Biochemical interrogation of proteins doi: 10.1136/ tage-gated potassium channels (VGKCs) complexed to VGKCs identified that leu- practneurol-2019-002494 considered a likely antigenic target. cine-rich glioma-inactivated 1 (LGI1) Michael S, et al. Pract Neurol 2020;0:1–8. doi:10.1136/practneurol-2019-002494 1 REVIEW Pract Neurol: first published as 10.1136/practneurol-2019-002494 on 28 June 2020. Downloaded from Figure 1 LGI1 and CASPR2—but not double-negative VGKC—autoantibodies predict characteristic, immunotherapy-responsive syn- dromes. Pathogenic antibodies (shown in purple) bind to the surface-exposed domains of LGI1 and CASPR2. Also, some autoantibodies against LGI1 bind to the domain which docks with its receptors, a disintegrin and metalloproteases (especially ADAM22/23). Autoantibodies that bind extracellular protein domains are pathogenic, manifesting with characteristic clinical syndromes including faciobrachial dystonic seizures, limbic encephalitis and neuromyotonia. Both LGI1- and CASPR2-antibody mediated syndromes classically affect elderly men in their sixth decade, who improve markedly with immunotherapies. HLA-DRB1*07:01 is strongly linked to patients with LGI1 antibodies, and HLA-DRB1*11:01 to patients with CASPR2 antibodies. The non-pathogenic antibodies (shown in red) have been shown to bind the intracellular domain of VGKCs, and some bind the I125-α-dendrotoxin (α-DTX) used in the original VGKC radio- immunoassays. The targets of other double-negative antibodies are unknown, but likely to be other intracellular epitopes. Double-negative VGKC antibodies are found in a wide array of clinical syndromes, including epilepsies, dementias and primary psychiatric conditions, which span wide age ranges and lack either a clear immunotherapy response or a specific HLA association. CASPR2, contactin-associated protein like-2; HLA, human leukocyte antigen; LGI1, leucine-rich glioma-inactivated 1; VGKC, voltage- gated potassium channel. http://pn.bmj.com/ and contactin-associated protein like-2 (CASPR2) were resistant to antiseizure medications but respond well to the actual targets of patient autoantibodies in the immunotherapies, often within a few days. They provide immunotherapy-responsive syndromes: limbic encepha- an excellent example of a distinctive phenotype with litis, Morvan’s syndrome and neuromyotonia.89Also, a robust response to immunotherapies whose character- a few patients had contactin-2 antibodies.8 Crucially, the istics translate to the other frequent focal seizure semiol- on October 2, 2021 by guest. Protected copyright. extracellular-exposed domains of these proteins were the ogiesinpatientswithLGI1-antibodies.24 25 direct antigenic epitopes. Table 1 describes the character- CASPR2 is a neurexin family protein with a large istics of these molecules, plus the LGI1 receptors extracellular domain. Patients with CASPR2 autoanti- ADAM22 and 23. bodies are very often elderly males (Table 2). CASPR2 LGI1 is a secreted neuronal protein, known to link pre- antibody–positive patients often have neuromyotonia and post-synaptic terminals, akin to a molecular or Morvan’s syndrome, and some have forms of scaffold.19 Patients with LGI1 antibodies are typically limbic encephalitis as well as neuropathic pain syn- aged over 60, with a 2:1 male to female predominance. dromes. All typically respond to immunotherapy. LGI1 antibodies are prominent in patients with limbic Also, in patients with neuromyotonia and, especially, encephalitis, found in many with Morvan’s syndrome, Morvan’s syndrome there is an association with andinafewwithneuromyotonia.8923In addition, tumours, typically thymomas.8923Importantly, around 50% of patients with LGI1-antibodies show LGI1 or CASPR2 specificities are rare outside of a highly specific seizure semiology—termed faciobrachial these syndromes. Taken together, LGI1 and CASPR2 dystonic seizures.24 Faciobrachial dystonic seizures typi- antibodies have strong and specific clinical associa- cally begin before the onset of the cognitive impairment tions, and unequivocal clinical value in accurately that characterises limbic encephalitis and are largely detecting treatable syndromes. 2 Michael S, et al. Pract Neurol 2020;0:1–8. doi:10.1136/practneurol-2019-002494 REVIEW Pract Neurol: first published as 10.1136/practneurol-2019-002494 on 28 June 2020. Downloaded from Table 1 Molecular characteristics of LGI1, CASPR2, and associated proteins Molecular evidence LGI1 CASPR2 ADAM22/23 Contactin-2 Genetic mutations Autosomal dominant partial Homozygous mutations Heterozygous mutations cause Homozygous epilepsy with auditory features10 cause epilepsy, early infantile epileptic mutations cause intellectual disability and encephalopathy with cortical autosomal recessive autism11 atrophy12 familial cortical myoclonic tremor and epilepsy13 Neural expression Central nervous system (CNS): CNS: stratum radiatum of CNS: ADAM22 predominantly CNS: cerebellum, CA1 strongly expressed within mossy CA3 layer of within the cerebellum, and CA3 hippocampal fibre CA3 layer of hippocampus hippocampus and hippocampus, amygdala, and pyramidal cells,
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