Leucine‐Rich Glioma‐Inactivated 1 versus Contactin‐Associated Protein‐like 2 Antibody Neuropathic Pain: Clinical and Biological Comparisons

Abstract

Pain is a under‐recognized association of leucine‐rich glioma‐inactivated 1 (LGI1) and contactin‐associated protein‐like 2 (CASPR2) antibodies. Of 147 patients with these autoantibodies, pain was experienced by 17 of 33 (52%) with CASPR2‐ versus 20 of 108 (19%) with LGI1 antibodies ( p = 0.0005), and identified as neuropathic in 89% versus 58% of these, respectively. Typically, in both cohorts, normal nerve conduction studies and reduced intraepidermal nerve fiber densities were observed in the sampled patient subsets. In LGI1 antibody patients, pain responded to immunotherapy ( p = 0.008), often rapidly, with greater residual patient‐rated impairment observed in CASPR2 antibody patients ( p = 0.019). Serum CASPR2 antibodies, but not LGI1 antibodies, bound in vitro to unmyelinated human sensory neurons and rodent dorsal root ganglia, suggesting pathophysiological differences that may underlie our clinical observations. ANN NEUROL 2021;90:683–690

Patient-derived recombinant autoantibodies reveal the subcellular neuroglial distribution and heterogeneous interactome of leucine-rich glioma-inactivated 1

“…The single transmembrane domain protein Caspr2 is an axonal protein that interacts extracellularly with TAG1 and binds MPP2 and CASK [28] that were co- immunoprecipitated in this study. These observations may concur with phenotypic overlaps observed in patients who have Caspr2-directed antibodies [62] and provide a molecular link to hypomyelination reported in Lgi1 -/- mice [71]. Our data also suggest that Caspr2/ADAM22/23 complexes [27] as well as LGI1/ADAM22/23 occur in association with Kv1 at the AIS and/or glutamatergic synapses.…”

Phenotypic Spectrum of CASPR2 and LGI1 Antibodies Associated Neurological Disorders in Children

“…To date, no more than 70 cases of double-positive antibodies have been reported in adults and children ( 2 , 6 , 15 , 16 ). In the study, we describe two pediatric Morvan syndrome with LGI1-CASPR2 double-positive and present the results of the first systematic literature review on pediatric LGI1-CASPR2 double-positive cases.…”

Autoimmune Neurological Disorders with IgG4 Antibodies: a Distinct Disease Spectrum with Unique IgG4 Functions Responding to Anti-B Cell Therapies

“…LGI1 and CASPR2 are expressed in both the CNS and PNS, including peripheral nerves and dorsal root ganglia. Sera from patients with CASPR2-but not LGI1antibodies bind in vitro to unmyelinated human sensory neurons and rodent dorsal root ganglia [25], suggesting peripheral pathophysiological differences among the two that impact on their clinical symptomatology especially the association with neuropathic pain, as recently highlighted [25]. Increased titers of LGI1 antibodies are also present in the serum and CSF.…”

“…Although patients with anti-LGI-1 and CASPR2 antibodies have clinical heterogeneity, they also exhibit significant overlapping clinical symptomatology; the antibodies to LGI1 are most commonly associated with limbic encephalitis and epilepsy while the antibodies to CASPR2 with Morvan syndrome, neuromyotonia, and neuropathic pain [1,5,8,9,25]. Refractory epilepsy, and mental and behavioral abnormalities are variably present.…”

“…In several retrospective but small series, the first-line immunotherapy for those patient subsets presented with encephalitis and epilepsy has been steroids and IVIG with either encouraging or inconsistent responses [63,64]. Although some LGI1 antibody-positive patients with epilepsy and especially pain respond to immunotherapies [25,64], greater residual patient-rated impairment was more prominent in CASPR2 antibody patients [63]. In one retrospective series, rituximab was used in some patients with worse outcome and, although used only as second-line therapy, 3 of 4 patients reported improvement [65].…”