Clinical and Prognostic Value of Immunogenetic Characteristics in Anti-LGI1 Encephalitis

Abstract

ObjectiveAntibodies against leucine-rich glioma-inactivated 1 (LGI1-Abs) characterize a limbic encephalitis (LE) strongly associated with HLA-DRB1*07:01, although some patients lack LGI1-Abs in CSF or do not carry this allele. Whether they represent a different subtype of disease or have different prognoses is unclear.MethodsRetrospective analysis of clinical features, IgG isotypes, and outcome according to LGI1-Ab CSF positivity and DRB1*07:01 in a cohort of anti-LGI1 LE patients.ResultsPatients with LGI1-Abs detected in both CSF and serum (105/134, 78%) were compared with those who were CSF negative (29/134, 22%). Both groups had similar clinical features and serum levels, but CSF-positive patients had shorter diagnostic delay, more frequently hyponatremia, inflammatory CSF, and abnormal MRI (p < 0.05). Human leukocyte antigen (HLA) genotyping was performed in 72/134 (54%) patients and 63/72 (88%) carried DRB1*07:01. Noncarriers (9/72, 12%) were younger, more commonly women, and had less frequently psychiatric and frontal symptoms (p < 0.05). No difference in IgG isotypes according to CSF positivity or HLA was found (p > 0.05). HLA and IgG isotypes were not associated with poor outcome (mRS >2 at last follow-up) in univariate analyses; CSF positivity was only identified as a poor outcome predictor in the multivariate analysis including the complete follow-up, whereas age and female sex also remained when just the first year was considered.ConclusionsLE without CSF LGI1-Abs is clinically indistinguishable and likely reflects just a lesser LGI1-Ab production. HLA association is sex and age biased and presents clinical particularities, suggesting subtle differences in the immune response. Long-term outcome depends mostly on demographic characteristics and the intensity of the intrathecal synthesis.

Positive LGI1 Antibodies in CSF and Relapse Relate to Worse Outcome in Anti-LGI1 Encephalitis

“…However, our patients had a relatively lower detection rate of LGI1 antibodies in CSF and better functional outcome compared to some other studies (2-4). Consistent with our findings, positive LGI1 antibodies in CSF were found to correlate with increased neuronal excitability (11) and poor outcome recently (8). Similarly, an elevated LGI1-IgG CSF index was reported to predict unfavorable neurological outcome (7), indicating that intrathecal antibody synthesis may lead to more severe neuronal impairment.…”

“…Consistent with previous studies (2-5), our patients showed typical manifestations such as seizures (particularly FBDS) and cognitive deficit, and some patients had hippocampal T2/FLAIR hyperintense signals or hippocampal atrophy/sclerosis. This is because LGI1 antibodies [mainly of IgG4 subclass (2,7,8)] are believed to alter K v 1.1 subunit of VGKC as well as AMPA receptors, causing neuronal hyperexcitability and reducing longterm synaptic plasticity in the hippocampus (1,9). HLA class II was reported to relate with anti-LGI1 encephalitis, particularly HLA-DRB1*07:01 (8,10).…”

“…This is because LGI1 antibodies [mainly of IgG4 subclass (2,7,8)] are believed to alter K v 1.1 subunit of VGKC as well as AMPA receptors, causing neuronal hyperexcitability and reducing longterm synaptic plasticity in the hippocampus (1,9). HLA class II was reported to relate with anti-LGI1 encephalitis, particularly HLA-DRB1*07:01 (8,10). However, the exact mechanisms that underlie the effects of anti-LGI1 antibodies remain to be investigated.…”

The Role of IgG4 in Autoimmunity and Rheumatic Diseases

“…What matters in the context of the topic under discussion in autoimmune diseases of the central and peripheral nervous system with importance of CASPR2, CASPR1, LGI1, or neurofascin 155 antibodies is that the shared feature is the predominance of antigen-specific antibodies of the IgG4 subclass ( 30 , 31 ).…”

Current Status of Biomarkers in Anti-N-Methyl-D-Aspartate Receptor Encephalitis

“…The heterogeneity of the environmental factors described in anti-NMDAR encephalitis could potentially interplay with an eventual genetic predisposition. The human leukocyte antigen (HLA) is the main genetic factor related to autoimmunity, with several associations in neurological diseases driven by neural antibodies [ 90 ], being especially strong between DRB1*07:01 and limbic encephalitis (LE) with antibodies against leucine-rich glioma inactivated 1 [ 91 , 92 , 93 , 94 ] and between DRB1*11:01 and LE with antibodies against contactin-associated protein-like 2 (CASPR2) [ 93 , 95 ]. On the contrary, a first study including a small cohort of patients with anti-NMDAR encephalitis found no association with HLA [ 91 ].…”