LGI1 (Leucine-rich glioma-inactivated 1) antibody encephalitis is an autoantibody mediated form of limbic encephalitis. It is the most common antibody-mediated encephalopathy in those over 50 years of age. It was accurately first described in 2010. However, the clinical syndrome was also observed in association with voltage gated potassium channel antibodies in 2004 – it later became apparent the actual target of these antibodies was LGI1.

LGI1 is a secreted neuronal protein which helps regulate the communication between neurons. Researchers have determined that LGI1 binds to receptor proteins on the surface of neurons, which help LGI1 signal to the neurons. Together, these, and other, proteins help control the release of certain brain chemicals called neurotransmitters which allow neighboring neurons to communicate and relay signals throughout the brain. LGI1 is found primarily in neurons in the brain, including a part of the brain called the temporal lobe. The temporal lobe of the brain is involved in memory and emotion and its disruption is especially vulnerable to causing seizures.

LGI1-antibody encephalitis is the second most common form of autoimmune encephalitis overall and the most common in those over 50 years. Men are affected more frequently than women (2:1) and it is extremely rare in children.

Faciobrachial dystonic seizures (FBDS) are the most common seizure type associated with this type of encephalitis and are seen in around 60% of cases. A person with FBDS typically appears awake during the episodes. Initially, they will experience occasional involuntary muscle jerk of their arm and their face, on that same side. FBDS may begin as only a rare episode, lasting 1 to 30 seconds, but their progressively increase to become very frequent, often hundreds of time per day. Also, patients develop other types of seizures including those which involve shivering feelings and twitching of their mouth and fingers.

FBDS, and the other seizures in patients with LGI1-antibody encephalitis, typically appear earlier than other symptoms. As early treatment is thought to improve outcomes, therefore, they are important to recognize. Other symptoms associated with LGI1-antibody encephalitis are: cognitive impairment, which often present as memory deficits, seizures (including FBDS), sleep disturbance, psychiatric and behavioral disorders.

Diagnosis of LGI1-antbody encephalitis can be difficult; patients may present to psychiatrists or movement disorder specialists prior to autoimmune neurologists. LGI1-antibodies can be detected in spinal fluid and blood although with a higher rate of detection in blood.

Around 50% of MRI scans show changes in the affected parts of the brain (especially the temporal lobe). The spinal fluid can show increased white blood cell count and protein levels but is often completely normal. Hence, both MRI and spinal fluid tests can be normal in these patients. Brainwave examination (“EEG”) often shows abnormal activity in the affected areas.
Some patients have reduced blood sodium levels as a clue to the illness, although this can be found in many conditions.

A tumor is rarely seen, when found, it is often tumor of the thymus gland in the upper chest.

Patients with LGI1 autoantibodies respond very well to immunotherapy, with improvements in >95% of patients. Treatment is classically described as first line immunotherapy (corticosteroids, intravenous immunoglobulin, or plasma exchange), with early combinatorial treatments providing better efficacy. It may sometimes be necessary to add second-line immunotherapy (cyclophosphamide or rituximab). FBDS are largely resistant to antiseizure medications but respond well to immunotherapies – and so immunotherapies should be prioritized over antiseizure medications.

The forecast is considered good. Most patients recover to recapture many of their previous functions. However, there is often persistent memory and cognitive difficulties and a range of side effects from the immunotherapies. Also, there is a risk that the disease may flare up again in approximately 25% of patients. This is usually seen within the first few months, often with treatment withdrawal. LGI1-antibody encephalitis has a very low mortality rate, in the order of <1%.

• Irani et al., Faciobrachial dystonic seizures precede Lgi1 antibody limbic encephalitis, Ann Neurol. 2011
• Kim et al., Anti-LGI1 encephalitis is associated with unique HLA subtypes, Ann Neurol, 2017
• Wang et al., Clinical features of limbic encephalitis with LGI1 antibody, Neuropsychiatr Dis Treat. 2017
• Aurangzeb et al., LGI1-antibody encephalitis is characterised by frequent, multifocal clinical and subclinical seizures, Seizure. 2017
• Binks at al., LGI1, CASPR2 and related antibodies: a molecular evolution of the phenotypes, J Neurol Neurosurg Psychiatry. 2018
• Lehmann-Horn et al., Intrathecal B-cell activation in LGI1 antibody encephalitis, Neurol Neuroimmunol Neuroinflamm. 2020
• Dubey et al., Randomized Placebo-Controlled Trial of Intravenous Immunoglobulin in Autoimmune LGI1/CASPR2 Epilepsy, Ann Neurol. 2020

Sarosh Irani, Associate Professor and Consultant Neurologist, University of Oxford and John Radcliffe Hospital, Oxford, UK