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  • Updated 09.27.2023
  • Released 05.08.2018
  • Expires For CME 09.27.2026

Anti-LGI1 encephalitis



In 2010, antibodies to leucine-rich glioma inactivated 1 (LGI1) were first described as a distinct serological entity. In this review, we evaluate the historical and diagnostic evolution of this condition as well as the potential immunological and genetic contributors to disease pathogenesis. Firstly, we discuss the common epilepsy presentations in these patients, with particular attention to the faciobrachial dystonic seizures, a pathognomonic association of this condition, as well as other associated seizure semiologies. Although cognitive impairment may be a presenting feature or, more commonly, follow the development of faciobrachial dystonic seizures, it also remains the most significant residual disability that can impair patients’ ability to return to functional independence. Therefore, secondly, we also explore the cognitive profiles of these patients and measures of their quality of life. Thirdly, although there are characteristic peripheral, CSF, and MRI findings in a subgroup of patients with LGI1-antibody autoimmune encephalitis, in many patients these investigations can be normal and, hence, noncontributory to diagnosis. Finally, the majority of patients are responsive to immunotherapy. Early recognition and institution of immunotherapy and achieving seizure control is crucial to optimize long-term outcomes and should be a major future therapeutic goal.

Key points

• LGI1-antibody seropositivity is most commonly associated with limbic encephalitis, with a high incidence of seizures and cognitive impairment.

• Faciobrachial dystonic seizures are exclusively associated with LGI1 antibodies and may predate the onset of cognitive impairment.

• Although typical findings on investigation include hyponatremia and medial temporal lobe hyperintensity or swelling on MRI, more than half the patients with LGI1 antibodies may have unremarkable findings.

• Laboratories should stop testing VGKC-antibodies as VGKC-antibody positivity, in the absence of antibodies to LGI1 and CASPR2, is unlikely to be of clinical significance

• The majority of patients appear to be immunotherapy-responsive to first-line treatment, including one or more of the following: corticosteroids, intravenous immunoglobulin, and plasma exchange. Efficacy of second-line therapy remains to be systematically evaluated.

• Delay in initiation of immunotherapy, delay in controlling faciobrachial dystonic seizures, and the presence of relapses are associated with poorer outcomes.

Historical note and terminology

Clinico-serological correlations. Autoimmune encephalitis is an increasingly recognized and understood clinical entity; many patients are found to have antibodies targeting domains of extracellular neuronal surface antigens, such as the N-methyl-D-aspartate (NMDA) receptor, the alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor, the gamma-aminobutyric acid (GABA) receptor, the glycine receptor, leucine-rich glioma inactivated 1 (LGI1) protein, and contactin-associated protein 2 (CASPR2), as well as numerous other less common targets (07; 56; 41). These antigens are thought to play a critical role in central nervous system synaptic transmission; hence, disruption of these targets is likely to result in cognitive and psychiatric manifestations as well as seizures. These neuronal surface antibody syndromes share some common paradigms: the target epitope is extracellular in location, and autoantibody binding is conformationally-sensitive. Hence, the native antigen is accessible to circulating autoantibodies. Also, the antibodies may alter the density and function of receptors; the clinical manifestations may be severe but are typically responsive to immunotherapy; and finally, the clinical phenotypes may be reminiscent of animal models of pharmacological or genetic dysfunction of the specific antigen in question.

Antibodies targeting the voltage-gated potassium channel, a transmembrane ion channel, were previously identified in 3 primary neurologic syndromes: limbic encephalitis, neuromyotonia, and Morvan syndrome (21). Limbic encephalitis is a CNS condition characterized by confusion and psychiatric changes, amnesia, seizures, and in several cases, hippocampal swelling on brain MRI. Neuromyotonia is a peripheral nervous system disorder characterized by peripheral nerve hyperexcitability that manifests as muscle cramps and stiffness. Morvan syndrome has features of both peripheral nervous system hyperexcitability and CNS disturbance with encephalopathy as well as autonomic dysfunction and insomnia (21). Neuromyotonia and Morvan syndrome have paraneoplastic associations, mostly with thymomas, particularly in Morvan syndrome (21). These 3 disorders share a commonality in that they are often subacute in onset, patients share overlapping features, and they often respond to immunotherapy (21; 33).

Revision of the underlying biochemistry. Antibody binding to the VGKC was previously detected using the pattern of immunostaining in rodent brain tissue and, most commonly, a radioimmunoprecipitation assay employing alpha-dendrotoxin-labelled VGKC channels from mammalian brain lysates (21; 30; 54). Alpha-dendrotoxin binds with high affinity to 3 specific VGKC subunits: Kv1.1, 1.2, and 1.6 (21), and these were initially thought to be the antigenic targets (29). However, cell-based assays, using direct transfection of a native full-length human antigen into a live human cell line revealed that the majority of patients in fact had antibodies that targeted 2 main proteins complexed with the VGKC; specifically, LGI1 and CASPR2 (21; 30). Hence, the term VGKC-complex antibodies was used to describe this collective group. Patients with LGI1 antibodies were more likely to have a limbic encephalitis presentation with prominent seizures, whereas those with CASPR2 antibodies more commonly showed neuromyotonia, dysautonomia, and neuropathic pain as well as typical limbic encephalitis. A direct comparison between LGI1- and CASPR2-antibody encephalitis is outlined in Table 1.

Table 1. Comparison of LGI1- and CASPR2-Antibody Autoimmune Encephalitis




64 kDa secreted protein expressed in hippocampus and neocortex

148 kDa cell adhesion molecule and a member of the neurexin intravenous superfamily, colocalizes with Kv1.1 and Kv1.2 at neural juxtaparanodes

Most commonly associated syndromes

CNS involvement: limbic encephalitis, faciobrachial dystonic seizures, other seizure types

CNS and PNS involvement: limbic encephalitis, Morvan syndrome, neuromyotonia


Adults, median age of onset 60 to 70 years of age (range, 20s to 90s)

2:1 male: female ratio

Extremely rare in children, with no support for testing in pediatric patients with encephalopathy and seizures

Adults, median age of onset 60 to 70 years of age (range 20s to 90s)

80% to 90% males

Extremely rare in children

Antibody subtype

IgG4 greater than IgG1

IgG4 greater than IgG1

Clinical features

Seizures, amnesia, confusion, hyponatremia (in 60% to 75%)

Cognitive impairment (in over 90%) (particularly verbal and visuospatial domains)

Seizures in up to 90%; faciobrachial dystonic seizures 50%; focal seizures 65% (dyscognitive/autonomic); generalized tonic-clonic seizures 60%

Sleep disturbance, insomnia in up to 50%

Less commonly, pain (15%), cerebellar ataxia, chorea, parkinsonism, dystonia, severe bradycardia, and other arrhythmias

Seizures in over half the patients, amnesia, hyponatremia more rare

Neuromyotonia, neuropathic pain (up to 40%), insomnia, dysautonomia, hyperhidrosis, and weight loss are more common

More chronic cognitive impairment (sometimes resembling dementia phenotype)

Sleep disturbance (agrypnia excitata most distinctively)

Less commonly, hyponatremia, cerebellar ataxia, chorea, orthostatic myoclonus, arrhythmias

CASPR2-antibody patients with thymomas often have AChR-antibody myasthenia gravis


Acutely, medial temporal lobe (hippocampal changes) on MRI, may have contralateral basal ganglia involvement with faciobrachial dystonic seizures

May be normal in around 50%

Long-term, hippocampal atrophy and whole brain atrophy more common; mesial temporal sclerosis present; reduction in pallidal volume with faciobrachial dystonic seizures

Often T2 hippocampal hyperintensities

Can be normal in around 70%


Often unremarkable in close to 75%

Minority have CSF pleocytosis or elevated protein

Rare to have intrathecal IgG synthesis

Normal in 60% to 70%

Paraneoplastic associations

Less common, 0% to 11%; thymoma, lung cancer, neuroendocrine pancreas tumor, abdominal mesothelioma

More common, 20% to 30%: mainly thymomas; also lung cancer, endometrial adenocarcinoma

Therapeutic response

Improvement with immunotherapy, particularly with regard to seizure cessation and control in response to corticosteroids

Improvement with immunotherapy in those without tumor associations, less of a response in those with tumor association

Management of underlying neoplasia essential in those with tumor

Outcomes and prognosis

Memory impairment and cognitive impairment present as long-term sequelae, particularly in the absence of early and appropriate immunotherapy; mortality rate reported between 6% to 19%

Over 70% have a favorable outcome with immunotherapy

10% fatality rate

Relapse rate

0% to 35%

0% to 32%

(21; 26; 30; 34; 54; 55; 51; 05; 07; 49; 56; 41)

Although the pathogenic role of LGI1 or CASPR2 antibodies is increasingly clear, the role of VGKC-complex antibodies without antibodies to either LGI1 or CASPR2 is important to consider, not least because these may account for more than 60% of the VGKC antibody-positive results (53). These “double-negative” patients do not form a uniform subgroup; rather, they are clinically heterogenous with presentations including epilepsy, neuropathic pain, sleep disorders, or Creutzfeldt-Jacob disease, and there appear to be very limited correlations between VGKC-complex antibody levels and clinical severity (van Sonderen et al 2010a; 34; 09; 31). Indeed, up to 5% of community controls may be positive for VGKC-complex antibodies (57). Furthermore, it was additionally found that antibodies to CASPR2, and less commonly LGI1, were also detected in patients with absent VGKC-complex antibodies (26; 53). A study identified that double negative VGKC-complex antibodies very rarely bind the surface of live neurons in culture, and many are definitively proven to target cytosolic epitopes of Kv1 subunits or the non-mammalian alpha-dendrotoxin (31). Therefore, the presence of VGKC-complex antibodies in the absence of antibodies to LGI1 or CASPR2 is of doubtful clinical or biological relevance; evidence for pathogenic potential is lacking; and these antibodies do not seem to correlate with a distinct immunotherapy-responsive syndrome.

For these reasons, a firm move should be made toward testing specifically for LGI1 and CASPR2 antibodies in the appropriate clinical setting in order to enhance the sensitivity and specificity of diagnosis and optimize clinical translatability.

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