LGI1, CASPR2 and related antibodies: a molecular evolution of the phenotypes

Abstract

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.

Keywords: autoimmune encephalitis; epilepsy; limbic system; neuroimmunology; paraneoplastic syndrome.

Figure 1

Clinical features of patients with antibodies to LGI1, CASPR2, both LGI1 and CASPR2 and double-negatives. Double-negatives are patients with VGKC complex antibodies, but without LGI1 or CASPR2 reactivities. Figure shows binding of LGI1 and CASPR2 antibodies to the extracellular domains of their respective proteins, whereas the likely intracellular binding of double-negative antibodies, as proven for those that target the intracellular domains of VGKCs themselves. Relative frequency of various features and conditions in association with each pattern of antibody reactivity denoted by - through ++++. Patient at computer shown during FBDS, medical temporal lobe hyperintensities and neuromyotonic discharges shown. We are grateful to Dr M Symmonds, Oxford, for the neuromyotonic trace. The patient consented to their photograph being used for scientific publications. CASPR2, contactin-associated protein 2; CNS, central nervous system; FBDS, faciobrachial dystonic seizures; LGI1, leucine-rich glioma-inactivated 1; PNS, peripheral nervous system; VGKCs, voltage-gated potassium channels.

Figure 2

Clinical and serological features of patients with LGI1 and CASPR2 antibodies. (A) Daily frequency of faciobrachial dystonic seizures as recorded prospectively by the patient in figure 1 and the online video. Days 4–12 not recorded by patient (dotted line). His FBDS began with a frequency of 10 per day and rose to 200 per day, with a fall after corticosteroid initiation to around 150 per day. The remainder of his clinical progress is shown in figure 2A and suggests a marked improvement after PLEX. (B) Live LGI1 antibody cell based assay in the patient (from A) with FBDS and a healthy control (HC) showing human IgG deposition on the surface of HEK 293 T cells transfected with membrane-tethered EGFP-tagged LGI1 (LGI1-EGFP). (C) Levels of human IgG bound to surface-expressed LGI1-EGFP may also be quantified by flow cytometry. Five clouds of cells showing increasing IgG binding, left to right. (D) From patients with limbic encephalitis and autoimmune epilepsies, VGKC complex antibody determination misses some patients with LGI1 antibodies proven by flow cytometry. Both cut-offs determined as mean plus 3 SD. (E) CASPR2-IgG deposition in the sural nerve of a patient with peripheral nerve symptoms and CASPR2 antibodies who shows normal sural nerve morphology (F) by morphometric analysis in both large (8–12 µm) and small (<5 µm) nerve fibre density (G). This supports a neurophysiological disruption at the node with potential for reversibility. Thermal sweat test using alizarin red powder; face not tested, loss of sweat in yellow and sweating in blue with normalisation after immunotherapy (panel H compared with panel I. Panels (E–I) reproduced with permissions. CASPR2, contactin-associated protein 2; EGFP, enhanced green flourescent protein; FBDS, faciobrachial dystonic seizures; IVMP, 3 days of 1 g intravenous methylprednisolone; LGI1, leucine-rich glioma-inactivated 1; Pred, prednisolone; PLEX, plasma exchange; VGKC, voltage-gated potassium channel.

Figure 3

The evolution of LGI1 antibody disease. Schematic diagram to show the likely risk factors for developing LGI1 antibody encephalitis, possible midlife events, followed by the development of antibody positivity and onset of a prodrome of seizures, including FBDS and cognitive alterations. As these worsen into a full-blown encephalitic syndrome, medial temporal lobe hyperintensities are often noted. After immunotherapies, the disease often resolves to leave persistent cognitive deficits and hippocampal atrophy. Human leucocyte antigen (HLA) diagram reproduced with permissions. EGFP, enhanced green flourescent protein; FBDS, faciobrachial dystonic seizures; LGI1, leucine-rich glioma-inactivated 1.