LGI1¶
Leucine-rich glioma-inactivated protein 1¶
Description¶
Anti-LGI1 antibodies are IgG4 antibodies direct against a secreted neuronal protein linked to the voltage gated potassium channel on the neuronal cell surface. They are most often associated with seizures and limbic encephalitis but frequently have autonomic, sleep, and peripheral associations. Less than 10% are associated with malignancy.
Anti-LGI1 antibodies may coexist with anti-CASPR2 antibodies.
Mechanism of action¶
LGI1 is a secreted neuronal protein most strongly expressed in the mossy fibre CA43 layer of the hippocampus and cerebellum. It is a ligand to the the extracellular receptors ADAM22 and ADAM23 which are in turn linked to the voltage gated potassium channel on the cell surface of neurones. IgG anti-LGI1 antibodies disrupt this interaction and trigger internalisation of the VGKC complex. This results in hyperexcitability of the neurone leading to the disease state.
Associated clinical features¶
- Seizures in 80% (1) with epileptiform EEG. Seizures often begin prior to the onset of cognitive impairment as a result of limbic encephalitis.
- Cognitive impairment
- Abnormal neuropsychological examination (2)
- Paroxysmal dizziness spells
- Insomnia
- REM sleep behaviour disorder
- Abnormal polysomnogram
- Parkinsonism
- Myoclonus
- Personality change
- Depression
- Hallucinations
- Paranoia
- Anxiety
- Neuropathic pain
- Hyperhidrosis, hypohidrosis
- Hyponatraemia
- Neuromyotonia
- Morvan's syndrome
- 2:1 male to female.
- EMG hyperexcitability
- EMG neuropathy
- Cramps
- Sensory and motor symptoms
- Nerve conduction abnormalities
- Tilt test positive
- MRI abnormal
- PET abnormal
- CSF may be normal
- Predominantly complex partial 46%, simple partial 43%, and faciobrachial dystonic 34%
- Probably don't need to include this point
Associated neoplasia¶
<10% associated with malignant thymoma and neuroendocrine tumours. Paraneoplastic cases are mainly observed in patients with Morvan syndrome and both serum LGI1 and CASPR2 antibodies.
Laboratory method¶
Cell based assay
Indirect immunofluoresence on rat brain
In cases of negative above assays and strongly characteristic clinical features then live hippocampal neuronal assays could be considered if accessible (1)
- May need to have a list of labs here, or S Irani's lab if none other available
Notes of performance characteristics¶
Commercial CBA (Euroimmun) using CSF has a sensitivity of 62.5% and specificity of 100% for anti-LGI1 antibodies.
Grade¶
Next steps¶
Warning
Do not order with anti-VGKC antibodies due to low clinical yield of 'double negative anti-VGKC' results.
Faciobrachial dystonic seizures mostly resistant to antiseizure medications but respond to immunotherapy regimes within days.
-
Graus, Francesc, Alberto Vogrig, Sergio Muñiz-Castrillo, Jean-Christophe G. Antoine, Virginie Desestret, Divyanshu Dubey, Bruno Giometto, et al. “Updated Diagnostic Criteria for Paraneoplastic Neurologic Syndromes.” Neurology - Neuroimmunology Neuroinflammation 8, no. 4 (July 2021): e1014. https://doi.org/10.1212/NXI.0000000000001014. ↩
-
Michael, Sophia, Patrick Waters, and Sarosh R Irani. “Stop Testing for Autoantibodies to the VGKC-Complex: Only Request LGI1 and CASPR2.” Practical Neurology 20, no. 5 (October 2020): 377–84. https://doi.org/10.1136/practneurol-2019-002494. ↩
-
McCracken, Lindsey, Junxian Zhang, Maxwell Greene, Anne Crivaro, Joyce Gonzalez, Malek Kamoun, and Eric Lancaster. “Improving the Antibody-Based Evaluation of Autoimmune Encephalitis.” Neurology - Neuroimmunology Neuroinflammation 4, no. 6 (November 2017): e404. https://doi.org/10.1212/NXI.0000000000000404. ↩
-
Gadoth, Avi, Sean J. Pittock, Divyanshu Dubey, Andrew McKeon, Jeff W. Britton, John E. Schmeling, Aurelia Smith, et al. “Expanded Phenotypes and Outcomes among 256 LGI1/CASPR2-IgG-Positive Patients: LGI1/CASPR2-IgG + Patients.” Annals of Neurology 82, no. 1 (July 2017): 79–92. https://doi.org/10.1002/ana.24979." ↩
Created: 2021-12-17