Insights From LGI1 and CASPR2 Potassium Channel Complex Autoantibody Subtyping
• Herein we report clinical correlations and other autoantibody accompaniments of VGKC complex IgG detected in
nonselected patients undergoing comprehensive autoimmune serologic evaluation for unexplained neurologic symptoms as well as the frequency of LGI1 IgG and CASPR2 IgG in these patients.
• The
study was approved by the Mayo Clinic institutional review board. Subjects were Mayo Clinic patients who were identified as VGKC complex autoantibody positive in serologic evaluation
• Because our
study's design did not restrict antibody testing to patients prejudged to have a pertinent syndromic presentation, it permitted broader determination of the neurologic spectrum of VGKC autoimmunity.
Study patients were identified through comprehensive neural autoantibody testing of thousands of patients undergoing service evaluation for any suspected autoimmune neurologic disorder, generally of subacute onset, with or without historic or familial stigmata of autoimmunity and
not readily explained by alternative diagnoses.
• During the 25-month study,
54853 patients had a comprehensive neural autoantibody evaluation in the Mayo Clinic Neuroimmunology Laboratory.
Voltage-gated potassium channel complex IgG was detected in 1992 patients (4%)
•
This large clinicoserologic study of VGKC complex autoimmunity makes several important observations.
•
First, both LGI1 IgG and CASPR2 IgG are associated with diverse neurologic manifestations that commonly overlap.
•
Second, only a minority of seropositive patients have antibodies that recognize LGI1 and/or CASPR2.
• Voltage-gated potassium channel (VGKC) complex autoimmunity was
initially described with acquired neuromyotonia and hyperhidrosis (Isaacs syndrome) and subsequently with limbic encephalitis, neuromyotonia, insomnia, and autonomic dysfunction (Morvan syndrome).
•
The restriction of autoantibody testing to patients with defined neurologic syndromes precludes appreciation of the full phenotypic spectrum of VGKC complex autoimmunity.
• Identification of VGKC complex antibody–positive patients through comprehensive serologic evaluation for any suspected autoimmune neurologic disorder (thus avoiding prejudgment of the clinical spectrum of VGKC complex autoimmunity)
has extended the clinical spectrum to include miscellaneous sleep disorders, neuropsychiatric presentations, seizures, mimics of Creutzfeldt-Jakob disease, and frontotemporal dementia.
•
Importantly, in these reports, robust improvement often followed immunotherapy.
• It was recently reported that VGKC complex autoantibodies detected by radioimmunoprecipitation assays generally do not bind to VGKC channel proteins per se, but they bind instead to synaptic and axonal neuronal proteins that coprecipitate with detergent-solubilized VGKCs.
• the
findings support the clinical significance of relatively low VGKC complex IgG values.
• Several earlier studies have suggested that values less than 100 pM or 400 pM (ie, 0.10 nmol/L or 0.40 nmol/L) are negligible.12,16 Had we used 0.40 nmol/L as the cutoff value in this study, we would have missed detecting 61% of the patients (50 of 82) whom reflexive cell-binding assay identified as seropositive for LGI1 IgG, CASPR2 IgG, or both
• It is noteworthy that none of the 10 CASPR2 IgG–positive patients whose VGKC complex IgG values exceeded 0.40 nmol/L had Morvan syndrome
•
The high proportion of VGKC complex IgG–seropositive patients whose serum samples lack LGI1 IgG and CASPR2 IgG specificities suggests that other VGKC complex molecular targets remain to be discovered.
Klein CJ, Lennon VA, Aston PA, McKeon A, O'Toole O, Quek A, Pittock SJ. Insights from LGI1 and CASPR2 potassium channel complex autoantibody subtyping. JAMA Neurol. 2013 Feb;70(2):229-34. doi: 10.1001/jamaneurol.2013.592. PMID: 23407760; PMCID: PMC3895328.
https://jamanetwork.com/journals/jamaneurology/fullarticle/1397614
