Recent biochemical observations have helped redefine antigenic components within the
voltage-gated potassium channel (VGKC) complex. The related
autoantibodies may be now divided into likely pathogenic entities, which target the extracellular domains of
leucine-rich
glioma-inactivated 1 (LGI1) and contactin-associated
protein-like 2 (CASPR2), and species that target intracellular neuronal components and are likely non-pathogenic. This distinction has enhanced clinical practice as direct determination of LGI1 and CASPR2
antibodies offers optimal sensitivity and specificity. In this review, we describe and compare the clinical features associated with pathogenic LGI1 and CASPR2
antibodies, illustrate emerging laboratory techniques for antibody determination and describe the immunological mechanisms that may mediate antibody-induced pathology. We highlight marked clinical overlaps between patients with either LGI1 or CASPR2
antibodies that include frequent
focal seizures, prominent
amnesia,
dysautonomia,
neuromyotonia and
neuropathic pain. Although occurring at differing rates, these commonalities are striking and only faciobrachial dystonic
seizures reliably differentiate these two conditions. Furthermore, the coexistence of both LGI1 and CASPR2
antibodies in an individual occurs surprisingly frequently. Patients with either antibody respond well to
immunotherapies, although systematic studies are required to determine the magnitude of the effect beyond placebo. Finally, data have suggested that CASPR2 and LGI1 modulation via genetic or autoimmune mechanisms may share common intermediate molecules. Taken together, the biochemical distinction of antigenic targets has led to important clinical advances for patient care. However, the striking syndrome similarities, coexistence of two otherwise rare
antibodies and molecular insights suggest the VGKC complex may yet be a common functional effector of antibody action. Hence, we argue for a molecular evolution alongside a clinical and phenotypic re-evaluation.