Expanded phenotypes and outcomes among 256 LGI1/CASPR2‐IgG–positive patients

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Voltage‐gated potassium channel (VGKC)‐complex autoimmunity was initially described in patients with neuromyotonia (Isaacs syndrome), and then found with Morvan syndrome, in which neuromyotonia is accompanied by limbic encephalitis, insomnia, and autonomic dysfunction.1 As more patients were identified with VGKC‐complex autoimmunity, the spectrum of neurological presentations expanded.3 It was then recognized that LGI1 (leucine‐rich glioma‐inactivated 1) and CASPR2 (contactin‐associated protein‐like 2) were the 2 main antigenic targets within the VGKC complex.7
Prominent clinical associations described for LGI1‐IgG are encephalitis and seizures, including faciobrachial–dystonic seizures (FBDS),7 and for CASPR2‐IgG, Morvan syndrome,14 epilepsy and encephalitis7 and autoimmune pain.16 These clinical presentations are consistent with the antigenic localization and current functional understanding of LGI1 and CASPR2. LGI1 has 2 isoforms, one secreted presynaptically as an integral component of the synaptic membrane Kv1‐channel complex and the other, a truncated form, retained in the neuronal cytosol.18 LGI1 within the neuronal presynaptic membrane prevents rapid Kv1‐channel inactivation.19 The function of the intracellularly retained isoform is not known. CASPR2, as an adhesion protein, promotes juxtaparanodal clustering of Kv1 channels in both the peripheral nervous system (PNS) and central nervous system (CNS).20
Here, we review patients in whose serum or cerebrospinal fluid (CSF) LGI1‐IgG and/or CASPR2‐IgG were detected in the course of comprehensive serological evaluation for suspected neurological autoimmunity. Clinical correlative findings in this patient cohort, the largest and longest followed to date, reveal novel insights relevant to seroprevalence rates, clinical presentations, neuraxis level affected, and clinical outcomes.
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