Anti-LGI1 Encephalitis

Anti-LGI1 encephalitis is an autoimmune limbic encephalitis with antibodies against leucine rich glioma inactivated 1, causing subacute memory loss, confusion, seizures (including faciobrachial dystonic seizures) and hyponatraemia. It responds well to immunotherapy.

It is the second commonest autoimmune encephalitis, with an incidence of about 0.83 in every million people each year. The median age is 60 years, and men are affected about twice as often as women.

Associations. HLA-DRB1*07:01. A tumour (thymoma or small cell lung cancer) is found in under 10%, so it is mostly non-paraneoplastic.

Course. Subacute over weeks to months. Faciobrachial dystonic seizures often appear weeks to months before cognitive symptoms and respond to early immunotherapy, which may prevent encephalitis. Relapse occurs in about 20 to 35%, and cognitive deficits remain in many despite treatment.

Pathophysiology.

IgG4 antibodies against LGI1 disrupt its link with ADAM22 and ADAM23, reducing AMPA receptor function and Kv1.1 potassium channel stability, and so increasing neuronal excitability in the hippocampus and basal ganglia.

Hyponatraemia may reflect hypothalamic involvement.

• Faciobrachial dystonic seizures: brief (under 3 seconds), frequent (up to dozens a day) dystonic jerks of the face and arm.
• Memory impairment, confusion, behavioural change and temporal lobe seizures with déjà vu or fear.
• Hyponatraemia in about 60%; sleep disorder, including REM sleep behaviour disorder.
• Pilomotor seizures, autonomic features and painful neuropathy in some.
• Subacute progression to cognitive decline and, if untreated, status epilepticus or coma.

Red flags.

• Status epilepticus, severe hyponatraemia or reduced consciousness.
• Rapid cognitive decline in an older adult.
• Cancer features: cough, weight loss or a mediastinal mass.

• Clinical syndrome with LGI1 antibodies in serum (more sensitive) and cerebrospinal fluid.
• MRI of the brain: medial temporal lobe T2 or FLAIR hyperintensity in about 70%, which may be normal; FDG-PET shows hippocampal and basal ganglia hypermetabolism.
• EEG: temporal slowing or epileptiform discharges; often normal in faciobrachial dystonic seizures.
• Serum sodium, electrolytes and osmolality; cerebrospinal fluid is often normal or shows mild changes.
• CT chest, abdomen and pelvis for tumour search (thymoma, small cell lung cancer); repeat if negative.

Differential diagnosis. Herpes simplex encephalitis, Creutzfeldt-Jakob disease, Alzheimer disease, anti-CASPR2 encephalitis, paraneoplastic limbic encephalitis, epilepsy of other cause, nonconvulsive status epilepticus and primary psychiatric illness.

• First line immunotherapy, started early: methylprednisolone 1000 mg intravenously once daily for 3 to 5 days, with intravenous immunoglobulin 2 g/kg in total over 2 to 5 days (or plasma exchange, 5 exchanges over 10 days). Maximum 5 g of methylprednisolone in a course and 2 g/kg of immunoglobulin in any 4 week period. Monitor blood pressure, glucose, mood, infection, renal function, thrombosis and aseptic meningitis; check IgA before immunoglobulin. Avoid with active untreated infection and in IgA deficiency with anti-IgA antibodies; use caution in diabetes, renal impairment and heart failure.
• Continue with oral prednisolone 1 mg/kg daily (maximum 60 mg) tapered over 6 to 12 months, or weekly or monthly intravenous methylprednisolone as a steroid sparing step. Monitor blood pressure, glucose, bone density and infection; give bone and gastric protection.
• Second line therapy for poor response by 4 weeks, or relapse: rituximab 1000 mg intravenously on days 1 and 15, repeated at 6 months if indicated. Maximum 1000 mg for each dose. Screen for hepatitis B before treatment; monitor infusion reactions, infection and immunoglobulins. Avoid in active infection and pregnancy.
• Seizures: carbamazepine 100 mg orally twice daily, increased by 100 mg every 2 days to a usual 400 to 800 mg daily in 2 to 3 divided doses. Maximum 1600 mg daily. Monitor sodium (carbamazepine can worsen hyponatraemia), full blood count and liver function; check HLA-B*1502 before starting in people of at risk Asian ancestry; stop at the first rash. Avoid in atrioventricular block and porphyria; reduce dose in hepatic impairment and older adults. Antiseizure drugs are often stopped after the immunotherapy response.
• Hyponatraemia: correct slowly, with a rise of no more than 8 mmol/L in 24 hours, using fluid restriction and treating the encephalitis.
• Treat sleep disorder and depression; cognitive rehabilitation, occupational therapy and carer support.
• Tumour treatment when found.

Monitoring. Review at 2 to 4 weeks, then every 3 months for 2 years; repeat cognitive testing, sodium and MRI; watch for relapse during steroid taper.

Referral and escalation. Neurology and neuroimmunology for all patients; oncology if tumour; intensive care for status epilepticus.

Special groups. Older adults: higher infection and steroid toxicity risk. Pregnancy: specialist neuroimmunology and obstetric care.