VGKC-complex/LGI1-antibody encephalitis: Clinical manifestations and response to immunotherapy

https://doi.org/10.1016/j.jneuroim.2013.10.005Get rights and content

Highlights

  • FDG-PET is the most sensitive test in detecting intracranial pathology.

  • FDG-PET showed similar rate of medial temporal and basal ganglia hypermetabolism.

  • FDG-PET findings may be associated with therapeutic outcome.

  • Combination therapy might be superior to monotherapy in getting symptom-free status.

  • Second-line immunotherapy can be effective in refractory cases.

Abstract

Leucine-rich glioma inactivated 1 (LGI1) was recently identified as a target protein in autoimmune synaptic encephalitis, a rare condition associated with autoantibodies against structures in the neuronal synapse. Studies dealing with LGI1 are small in number and the various outcomes of different therapeutic regimens are not well studied. Here, we analyzed clinical characteristics of 14 patients with LGI1 antibodies, and outcomes according to therapeutic strategies. Most patients exhibited abnormal brain positron emission tomography and that patients treated with steroids alone were more likely to relapse and had less favorable outcomes than those treated with steroids and intravenous immunoglobulins.

Introduction

Autoimmune synaptic encephalitis (ASE) is a disorder that is associated with antibodies targeting the cell surface or synaptic proteins. Reported symptoms of ASE include seizure, memory dysfunction, abnormal behavior, and decreased consciousness. The known neuronal autoantigens associated with ASE include N-methyl-d-aspartate receptor (NMDAR), α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR), γ-aminobutyric acid receptor-B (GABAB-R), leucine-rich glioma-inactivated 1 (LGI1), contactin-associated protein-like 2 (CASPR2), contactin-2, glycine receptor (GlyR), and metabotropic glutamate receptor 5 (mGluR5) (Bien and Scheffer, 2011, Vincent et al., 2011, Lancaster and Dalmau, 2012, Rubio-Agusti et al., 2013). Interestingly, it has recently come to light that LGI1, CASPR2 and, less frequently, contactin-2 are specific targets of voltage-gated potassium channel (VGKC)-complex antibodies (Irani et al., 2010, Lai et al., 2010, Vincent and Irani, 2010, Lancaster et al., 2011a, Lancaster et al., 2011b, Paterson et al., in press).

Ever since anti-NMDAR encephalitis was first recognized, many patients with idiopathic encephalitis have been diagnosed with ASE (Dalmau et al., 2007). However, aside from the discovery of several antibodies associated with the disorder, a general lack of knowledge about ASE limits our understanding of the disease's characteristics and therapeutic outcome. The benefit of early therapy and of immunotherapy responsiveness has addressed in previous studies of VGKC-complex associated encephalitis (Thieben et al., 2004, Vincent et al., 2004, Irani et al., 2008, Tan et al., 2008, Quek et al., 2012). However, no study has compared outcomes in patients with LGI1 antibodies after immunotherapy between initial monotherapy and combination therapy. Additionally, to our knowledge, there has only been 1 study evaluating fluorodeoxyglucose positron emission tomography (FDG-PET) findings of VGKC-complex associated encephalitis with only LGI1 antibodies (Irani et al., 2011). Here, we present 14 cases of VGKC-complex/LGI1-antibody encephalitis, including an evaluation of the FDG-PET findings, and a description of the overall treatment outcome.

Section snippets

Methods

This study comprised of 631 consecutive patients who were suspected of having autoimmune encephalitis between June 2012 and May 2013. Clinical features, electroencephalogram (EEG), brain magnetic resonance image (MRI), laboratory findings, cerebrospinal fluid (CSF) profile, whole-body and brain FDG-PET, and other radiologic screenings for a systemic neoplasm were reviewed. Clinical information was obtained by the authors or provided by referring physicians.

In the majority of patients,

Clinical features of anti-LGI encephalitis

Among the 125 patients (19.8%) who showed positive results, NMDAR antibodies were identified in 80 patients (64% of positive cases), GABAB-R antibodies were present in 4 patients (3.2%), and AMPA1, AMPA2, and CASPR2 antibodies were found in 1 patient (0.8%) each. Additionally, classic paraneoplastic antibodies were found in 19 patients (15.2%).

LGI1 antibodies were identified in 14 patients (11.2%) ranging in age from 41 to 78 years (median, 60.5 years), with a male to female ratio of 4:3. All

Discussion

LGI1 is a glycoprotein secreted from presynaptic terminals that interacts with presynaptic ADAM22 and postsynaptic ADAM23, and influences synaptic transmission by regulating presynaptic kv.1 channels and postsynaptic AMPA receptors (Lai et al., 2010). It is accepted that mutations in the LGI1 gene are responsible for autosomal dominant partial epilepsy with auditory features (Kalachikov et al., 2002), and knock-out mice void of LGI1 expression develop lethal epilepsy (Fukata et al., 2010). The

Acknowledgment

This study was supported by a grant from the Ministry of Health and Welfare (A120480-1201-0000100). S.K.L. was supported by Seoul National University Hospital (0420130580). K.H.J. was supported by Seoul National University Hospital (0420131120, 0420120990). The authors thank Hong-Il Seo, Yoo-Jin Lee, Duk-Soo Park, Sang-Won Yoo, and Hyunjin Kim for providing clinical information of the patients.

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    The first two authors contributed equally to this work.

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