Cell-surface central nervous system autoantibodies: clinical relevance and emerging paradigms

Abstract

The recent discovery of several potentially pathogenic autoantibodies has helped identify patients with clinically distinctive central nervous system diseases that appear to benefit from immunotherapy. The associated autoantibodies are directed against the extracellular domains of cell-surface-expressed neuronal or glial proteins such as LGI1, N-methyl-D-aspartate receptor, and aquaporin-4. The original descriptions of the associated clinical syndromes were phenotypically well circumscribed. However, as availability of antibody testing has increased, the range of associated patient phenotypes and demographics has expanded. This in turn has led to the recognition of more immunotherapy-responsive syndromes in patients presenting with cognitive and behavioral problems, seizures, movement disorders, psychiatric features, and demyelinating disease. Although antibody detection remains diagnostically important, clinical recognition of these distinctive syndromes should ensure early and appropriate immunotherapy administration. We review the emerging paradigm of cell-surface-directed antibody-mediated neurological diseases, describe how the associated disease spectrums have broadened since the original descriptions, discuss some of the methodological issues regarding techniques for antibody detection and emphasize considerations surrounding immunotherapy administration. As these disorders continue to reach mainstream neurology and even psychiatry, more cell-surface-directed antibodies will be discovered, and their possible relevance to other more common disease presentations should become more clearly defined.

Figure 1

(A) Transfected cells or tissue (neuronal cultures or brain sections) may be labeled with patient antibody and then a secondary, dye/enzyme-conjugated antibody to allow visualization. Graphic courtesy of Dr T. Moloney. (B, C) Cell-based assay. Enhanced green fluorescent protein (EGFP)-tagged antigen (in this case contactin-associated protein 2 [CASPR2]; B; green) is bound by patient immunoglobulin (Ig) G (C; red). (D) Hippocampal neuronal cultures labeled with leucine-rich glioma-inactivated 1 (LGI1)-IgG (green) and intracellularly stained with microtubule-associated protein 2, a neuronal marker (red; image courtesy of Dr L. Zuliani). (E) Sagittal rat brain section showing hippocampal staining with patient serum N-methyl-D-aspartate receptor–IgG (image from Irani et al46). (F) Depiction of the voltage-gated potassium channel (VGKC) complex labeled with radioiodinated dendrotoxin (DTX). Antibodies bind the extracellular domains of LGI1 (in patients with limbic encephalitis, faciobrachial dystonic seizures [FBDS], and, less so, Morvan syndrome [MoS]) and CASPR2 (in patients with MoS more frequently than in neuromyotonia (NMT) or LE). Contactin-2 antibodies are rare. Some antibodies may bind the intracellular domains of some molecules within the VGKC complex (blue antibody): these antibodies may precipitate the VGKC-complex but only those directed against extracellular epitopes are likely to be pathogenic. HEK = human embryonic kidney.

Figure 2

(A) The phenotype spread of voltage-gated potassium channel (VGKC) complex, leucine-rich glioma-inactivated 1 (LGI1), and contactin-associated protein 2 (CASPR2) antibodies. The relative proportions of patients with LGI1 and CASPR2 antibodies and those who remain without a known cell-surface antigenic target (Neuroglial cell-surface antibody [NGSAb] unknown) are depicted in the gradient bars. Movement disorders include ataxia, chorea, and parkinsonism.,, A number of patients, especially those with cramp fasciculation syndrome–neuromyotonia (CFS-NMT; high frequency discharges shown) and epilepsy (excluding faciobrachial dystonic seizures [FBDS]) currently have no defined antigenic target (NGSAb unknown), although their sera precipitate VGKC complexes in the radioimmunoassay. (B) High levels of glutamic acid decarboxylase (GAD) antibodies are associated with a variety of syndromes, including cerebellar ataxia, stiff-person syndrome (SPS), variant SPS (vSPS), progressive encephalomyelitis with rigidity and myoclonus (PERM), limbic encephalitis (LE), and epilepsy. Glycine-alpha1 receptor antibodies have been reported in patients with PERM, vSPS, and SPS in order of decreasing frequency; dipeptidyl peptidase IV–related protein (DPPX) antibodies in some patients with vSPS/PERM; and antibodies against γ-aminobutyric acid_B receptor (GABA_BR) and α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid receptor (AMPAR) in some patients with GAD antibodies and LE but not to date in cases with epilepsy alone. Their relative frequencies, and those of the NGSAb unknown patients, are depicted in the gradient bars, where a darker color implies a higher chance of finding that antibody.

Figure 3

(A) The epidemiology of patients with voltage-gated potassium channel (VGKC) complex antibodies in published series that reported >3 cases since the first publication in 2001 and 2013. There have been trends toward fewer males (p = 0.068) and tumors (p = 0.397). (B) The epidemiology of patients with N-methyl-D-aspartate (NMDA)-receptor antibodies in series that reported >3 cases since the first publication in 2007 and 2013. There have been significant reductions in tumors over time (p = 0.044) and a trend toward an increasing number of males, whereas the frequency of affected children has not altered. (C) Differences in the features of adults and children with VGKC-complex antibodies. Significant differences were seen in percentage of males (**p = 0.006) and presence of leucine-rich glioma-inactivated 1 (LGI1)/contactin-associated protein 2 (CASPR2) antibodies (Ab; *p = 0.036); there were nonsignificant differences for serum hyponatremia (↓Na⁺; p = 0.21) and tumors (p = 0.51; Mann–Whitney U tests). (D) Modified Rankin score in 64 patients with nonparaneoplastic LGI1-antibody–associated encephalopathy at peak of illness (pink) and latest follow-up (black). Data were modified from Irani et al. Patients were treated with corticosteroids (ST), with or without intravenous immunoglobulins (IVIG) and/or plasma exchange (PLEX). One patient died in the ST + IVIG + PLEX group. Median follow-up was for 48 months (range = 19–95) with no differences between groups (p = 0.77, Kruskal–Wallis test).