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Clinical spectrum of voltage-gated potassium channel autoimmunity

From the Departments of Neurology (K.M.T., V.A.L., C.J.K., B.F.B., S.J.P.), Laboratory Medicine and Pathology (K.M.T., V.A.L., S.J.P.), and Immunology (V.A.L.), Mayo Clinic College of Medicine, Rochester, MN.

Address correspondence and reprint requests to Dr. Sean J. Pittock, Neuroimmunology Laboratory, Hilton 3-78F, Mayo Clinic, 200 First St. SW, Rochester, MN 55905 pittock.sean{at}mayo.edu

Objective: To document neurologic, oncologic, and serologic associations of patients in whom voltage-gated potassium channel (VGKC) autoantibodies were detected in the course of serologic evaluation for neuronal, glial, and muscle autoantibodies.

Methods: Indirect immunofluorescence screening of sera from 130,000 patients performed on a service basis for markers of paraneoplastic neurologic autoimmunity identified 80 patients whose IgG bound to the synapse-rich molecular layer of mouse cerebellar cortex in a pattern consistent with VGKC immunoreactivity. Antibody specificity was confirmed in all cases by immunoprecipitation of detergent-solubilized brain synaptic proteins complexed with ¹²⁵I-alpha-dendrotoxin.

Results: Clinical information was available for 72 patients: 51% women, median age at symptom onset 65 years, and median follow-up period 14 months. Neurologic manifestations were acute to subacute in onset in 71% and multifocal in 46%; 71% had cognitive impairment, 58% seizures, 33% dysautonomia, 29% myoclonus, 26% dyssomnia, 25% peripheral nerve dysfunction, 21% extrapyramidal dysfunction, and 19% brainstem/cranial nerve dysfunction. Creutzfeldt-Jakob disease was a common misdiagnosis (14%). Neoplasms encountered (confirmed histologically in 33%) included 18 carcinomas, 5 adenomas, 1 thymoma, and 3 hematologic malignancies. Hyponatremia was documented in 36%, other organ-specific autoantibodies in 49%, and a co-existing autoimmune disorder in 33% (including thyroiditis 21%, type 1 diabetes mellitus 11%). Benefit was reported for 34 of 38 patients (89%) receiving immunotherapy and was marked in 50%.

Conclusions: The spectrum of neurologic manifestations and neoplasms associated with voltage-gated potassium channel (VGKC) autoimmunity is broader than previously recognized. Evaluation for VGKC antibodies is recommended in the comprehensive autoimmune serologic testing of subacute idiopathic neurologic disorders.

Abbreviations: AGNA-1 = anti-glial/neuronal nuclear antibody type 1; ANNA = anti-neuronal nuclear autoantibody; CJD = Creutzfeldt-Jakob disease; CRMP-5 = collapsin response-mediator protein-5; NSE = neuron-specific enolase; PCA = Purkinje-cell cytoplasmic autoantibody; PSA = prostate-specific antigen; RIA = radioimmunoprecipitation assay; VGKC = voltage-gated potassium channel.

Supplemental data at www.neurology.org

Disclosure: The authors report no conflicts of interest.

Received November 19, 2007. Accepted in final form January 24, 2008.

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