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Advanced Neurology The diagnosis and treatment of anti-LGI1 autoimmune encephalitis

the elderly, affecting more males than females. Its clinical A
manifestations are characterized by faciobrachial dystonic
seizure (FBDS), cognitive disorders, mental disorders, and
refractory hyponatremia.
2. Etiology and pathogenesis

LGI1 is a glycoprotein secreted by the presynaptic membrane.
It is mainly expressed in the hippocampus and temporal
cortex but is also weakly expressed in the basal ganglia
and the inner cerebral cortex [3,4] . It connects presynaptic B C
voltage-gated potassium channels (VGKC) and postsynaptic
α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid
receptor (AMPAR) [5,6] . LGI1 antibody inhibits the binding
of LGI1 protein to A Disintegrin And Metalloproteinase
22/23 (ADAM22/23) , a metalloproteinase in the synaptic
[7]
space, through its epitempin (EPTP) domain, and reduces
the AMPAR function of inhibitory interneurons. In
the hippocampus, inhibitory interneurons constitute a
strong feedback or feed forward inhibition loop; thus, the
decreased activity of inhibitory interneurons may lead to
[8]
over-excitation of the whole network , resulting in the
occurrence of FBDS. It has been found that the knockout
[5]
of LGI1 gene may cause autosomal dominant lateral
temporal epilepsy (ADLTE) [9,10] .
Fukata et al. showed that the LGI1-ADAM22 Figure 1. (A-C) LGI1 gene structure and interaction. (Adapted from
[11]
complex can form a cross-synaptic heterodimer complex, Fels et al., 2021, Role of LGI1 protein in synaptic transmission: From
physiology to pathology, Neurobiol Dis, 160: 105537. http://doi.
which is composed of three major parts: the presynaptic org/10.1016/j.nbd.2021.105537).
part, which includes ADAM23 and the Kv1 channel; the
synaptic cleft part, which includes LGI1 protein; and the and ADAM22 increased Kv1.1 current . In addition,
[18]
postsynaptic part, which includes ADAM22, postsynaptic it has been shown that LGI1 antibodies can induce the
density protein 95 (PSD-95), regulatory protein Stargazin, internalization of Kv1 channel and its protein complex .
[19]
and AMPAR (Figure 1) . In the physiological state, These may be the possible mechanisms of FBDS in
[12]
the Kv1 channel that is located in the presynaptic patients with antibody-LGI1 autoimmune encephalitis
membrane is activated at the membrane potential near the (anti-LGI1 AE).
discharge threshold of neuron , which limits and delays
[13]
the discharge of neuron, thus inhibiting the secretion of the Multiple studies have shown that anti-LGI1 AE is
excitatory neurotransmitter glutamate. Glutamate activates related to human leukocyte antigen (HLA) [20-25] , and Ding
AMPAR in the postsynaptic membrane, and the opening et al. have reported a familial case supporting this genetic
[26]
of the sodium (Na ) influx channel mediates postsynaptic association . To date, several studies have conducted
+
excitatory current . Several studies have shown that the HLA genotyping and genome-wide association studies
[14]
loss of LGI1 increases excitatory synaptic transmission, (GWAS) on anti-LGI1 AE patients in different populations,
whereas the overexpression of LGI1 decreases glutamate including the Caucasian population [22,23,25,27] , Korean
[21]
[24]
synaptic transmission [15-17] . In a study, Schulte et al. population , and Southwest Han population , revealing
transfected oocytes with plasmids expressing Kv1.1, Kv1.4, significant associations between unique HLA subtypes and
and Kvβ1 channels and electrophysiologically recorded anti-LGI1 AE. A genome-wide association study (GWAS)
potassium currents in the presence of endogenous LGI1. that was conducted in Germany has found that anti-LGI1
[23]
They observed that LGI1 prevented the rapid inactivation AE is associated with 27 single nucleotide polymorphisms
of Kv1.1 channel via the Kvβ1 subunit. Therefore, it was (SNPs) that are located in the major histocompatibility
speculated that LGI1 antibody may mediate the rapid complex II (MHC II) gene region (between HLA-DRB1
inactivation of Kv1 channel. Lancaster et al. have also and HLA-DQA1) and that DRB1*07:01 and DQA1*02:01
demonstrated that independent ADAM22 alone had always appeared in all patients. In addition, a study in
no effect on Kv1.1 current, while the presence of LGI1 South Korea has found a high frequency of B*44:03 and

Volume 1 Issue 3 (2022) 2 https://doi.org/10.36922/an.v1i3.237