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August 15, 2012

Chronic pain as a manifestation of potassium channel-complex autoimmunity

September 11, 2012 issue
79 (11) 1136-1144

Abstract

Objective:

Autoantibodies targeting voltage-gated potassium channel (VGKC) complexes cause a spectrum of neuronal hyperexcitability disorders. We investigated pain as a manifestation of VGKC-complex autoimmunity.

Methods:

We reviewed the prevalence and characteristics of pain in VGKC-complex-immunoglobulin G (IgG)–seropositive patients in 25 months of comprehensive service testing for neural autoantibodies, subtyped positive sera for LGI1-IgG and CASPR2-IgG specificities, and reviewed pain prevalence in autoimmune control patients.

Results:

VGKC-complex-IgG was identified in 1,992 patients of 54,853 tested (4%). Of 316 evaluated neurologically at Mayo Clinic, 159 (50%) had pain, in isolation (28%) or with accompanying neurologic manifestations (72%), and not attributable to alternative cause. Pain was subacute in onset, chronic in course, neuropathic, nociceptive, regional, or diffuse and sometimes attributed to fibromyalgia (6%) or psychogenic cause (13%). Most patients had normal peripheral nervous system function, measured by neuropathy impairment scores and nerve conduction. Evidence of neuronal hyperexcitability (hyperhidrosis, quantitative heat-pain hyperalgesia, or electromyographic excitability) was 25-fold more common in pain patients. Pain management required multiple medications in 70% (narcotics, 30%); 13 of 16 patients reported pain relief with immunotherapy. Pain was significantly associated with CASPR2-IgG-positivity (16% positive with pain, 7% without pain; p = 0.014) but not with LGI1-IgG. Less than 10% of 167 patients with neural autoantibodies other than VGKC-complex-IgG reported pain.

Conclusions:

Chronic idiopathic pain is a syndromic manifestation of VGKC-complex autoimmunity. Hyperexcitability of nociceptive pathways is implicated. CASPR2-IgG significantly associates with pain, but in most patients the antigenic VGKC-complex molecule remains to be determined. VGKC-complex autoimmunity represents an important new direction for pain research and therapy.

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Supplementary Material

File (chronic_pain_final.pdf)
File (figure_e-1.pdf)
File (klein.pdf)
File (table_e-1.doc)
File (znl03512001080.pdf)

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Information & Authors

Information

Published In

Neurology®
Volume 79Number 11September 11, 2012
Pages: 1136-1144
PubMed: 22895588

Publication History

Received: November 28, 2011
Accepted: March 8, 2012
Published online: August 15, 2012
Published in print: September 11, 2012

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Disclosure

C.J. Klein has received funds from Pfizer for helping in a study design for a drug trial in neuropathy. Serologic testing for VGKC-complex autoantibodies is offered on a service basis by Mayo Collaborative Service, Inc., an agency of Mayo Foundation, but no author benefits financially from this testing. V.A. Lennon, P.A. Aston, and A. McKeon report no disclosures. Go to Neurology.org for full disclosures.

Authors

Affiliations & Disclosures

Christopher J. Klein, MD
From the Departments of Neurology (C.J.K., V.A.L., P.A.A., A.M., S.J.P.), Laboratory Medicine and Pathology (V.A.L., A.M., S.J.P.), and Immunology (V.A.L.), Mayo Clinic, Rochester, MN.
Disclosure
Scientific Advisory Boards:
1.
NONE
Gifts:
1.
NONE
Funding for Travel or Speaker Honoraria:
1.
NONE
Editorial Boards:
1.
Editorial Board Journal of Peripheral Nerve Society.
Patents:
1.
NONE
Publishing Royalties:
1.
NONE
Employment, Commercial Entity:
1.
NONE
Consultancies:
1.
Pfizer,Inc
Speakers’ Bureaus:
1.
NONE
Other Activities:
1.
NONE
Clinical Procedures or Imaging Studies:
1.
NONE
Research Support, Commercial Entities:
1.
NONE
Research Support, Government Entities:
1.
K08NS065007 funded by NINDS principal instigator IDENTIFICATION OF GENETIC CAUSES OF HEREDITARY SENSORY AND AUTONOMIC NEUROPATHIES Project Start Date: 1-SEP-2009 Project End Date: 30-AUG- 2014
Research Support, Academic Entities:
1.
NONE
Research Support, Foundations and Societies:
1.
NONE
Stock/stock Options/board of Directors Compensation:
1.
NONE
License Fee Payments, Technology or Inventions:
1.
NONE
Royalty Payments, Technology or Inventions:
1.
NONE
Stock/stock Options, Research Sponsor:
1.
NONE
Stock/stock Options, Medical Equipment & Materials:
1.
NONE
Legal Proceedings:
1.
NONE
Vanda A. Lennon, MD, PhD
From the Departments of Neurology (C.J.K., V.A.L., P.A.A., A.M., S.J.P.), Laboratory Medicine and Pathology (V.A.L., A.M., S.J.P.), and Immunology (V.A.L.), Mayo Clinic, Rochester, MN.
Disclosure
Scientific Advisory Boards:
1.
NONE
Gifts:
1.
NONE
Funding for Travel or Speaker Honoraria:
1.
NONE
Editorial Boards:
1.
NONE
Patents:
1.
Dr. Lennon and Mayo Clinic have a financial interest in the following intellectual property: "Marker for Neuromyelitis Optica." A patent has been issued for this technology, and it has been licensed to commercial entities. They have received cumulative royalties of greater than the federal threshold for significant financial interest from the licensing of these technologies. The author receives no royalties from the sale of these tests by Mayo Medical Laboratories; however, Mayo Collaborative Services, Inc. does receive revenue for conducting these tests.
Publishing Royalties:
1.
NONE
Employment, Commercial Entity:
1.
NONE
Consultancies:
1.
NONE
Speakers’ Bureaus:
1.
NONE
Other Activities:
1.
NONE
Clinical Procedures or Imaging Studies:
1.
NONE
Research Support, Commercial Entities:
1.
NONE
Research Support, Government Entities:
1.
NONE
Research Support, Academic Entities:
1.
NONE
Research Support, Foundations and Societies:
1.
Guthy-Jackson Charitable Foundation
Stock/stock Options/board of Directors Compensation:
1.
NONE
License Fee Payments, Technology or Inventions:
1.
"Marker for Neuromyelitis Optica". A patent has been issued to Mayo Foundation for this technology, and it has been licensed to RSR/Kronus. Dr. Lennon has received cumulative royalties of greater than the federal threshold for significant financial interest from the licensing of these technologies.
Royalty Payments, Technology or Inventions:
1.
Dr. Lennon has a potential financial interest in the technologies listed below: "Marker for Neuromyelitis Optica".
Stock/stock Options, Research Sponsor:
1.
NONE
Stock/stock Options, Medical Equipment & Materials:
1.
NONE
Legal Proceedings:
1.
NONE
Paula A. Aston, MD
From the Departments of Neurology (C.J.K., V.A.L., P.A.A., A.M., S.J.P.), Laboratory Medicine and Pathology (V.A.L., A.M., S.J.P.), and Immunology (V.A.L.), Mayo Clinic, Rochester, MN.
Disclosure
Scientific Advisory Boards:
1.
NONE
Gifts:
1.
NONE
Funding for Travel or Speaker Honoraria:
1.
NONE
Editorial Boards:
1.
NONE
Patents:
1.
NONE
Publishing Royalties:
1.
NONE
Employment, Commercial Entity:
1.
NONE
Consultancies:
1.
NONE
Speakers’ Bureaus:
1.
NONE
Other Activities:
1.
NONE
Clinical Procedures or Imaging Studies:
1.
NONE
Research Support, Commercial Entities:
1.
NONE
Research Support, Government Entities:
1.
NONE
Research Support, Academic Entities:
1.
NONE
Research Support, Foundations and Societies:
1.
NONE
Stock/stock Options/board of Directors Compensation:
1.
NONE
License Fee Payments, Technology or Inventions:
1.
NONE
Royalty Payments, Technology or Inventions:
1.
NONE
Stock/stock Options, Research Sponsor:
1.
NONE
Stock/stock Options, Medical Equipment & Materials:
1.
NONE
Legal Proceedings:
1.
NONE
Andrew McKeon, MD
From the Departments of Neurology (C.J.K., V.A.L., P.A.A., A.M., S.J.P.), Laboratory Medicine and Pathology (V.A.L., A.M., S.J.P.), and Immunology (V.A.L.), Mayo Clinic, Rochester, MN.
Disclosure
Scientific Advisory Boards:
1.
NONE
Gifts:
1.
NONE
Funding for Travel or Speaker Honoraria:
1.
NONE
Editorial Boards:
1.
NONE
Patents:
1.
NONE
Publishing Royalties:
1.
NONE
Employment, Commercial Entity:
1.
NONE
Consultancies:
1.
NONE
Speakers’ Bureaus:
1.
NONE
Other Activities:
1.
NONE
Clinical Procedures or Imaging Studies:
1.
NONE
Research Support, Commercial Entities:
1.
NONE
Research Support, Government Entities:
1.
NONE
Research Support, Academic Entities:
1.
NONE
Research Support, Foundations and Societies:
1.
Guthy Jackson Charitable Foundation
Stock/stock Options/board of Directors Compensation:
1.
NONE
License Fee Payments, Technology or Inventions:
1.
NONE
Royalty Payments, Technology or Inventions:
1.
NONE
Stock/stock Options, Research Sponsor:
1.
NONE
Stock/stock Options, Medical Equipment & Materials:
1.
NONE
Legal Proceedings:
1.
NONE
Sean J. Pittock, MD
From the Departments of Neurology (C.J.K., V.A.L., P.A.A., A.M., S.J.P.), Laboratory Medicine and Pathology (V.A.L., A.M., S.J.P.), and Immunology (V.A.L.), Mayo Clinic, Rochester, MN.
Disclosure
Scientific Advisory Boards:
1.
NONE
Gifts:
1.
NONE
Funding for Travel or Speaker Honoraria:
1.
NONE
Editorial Boards:
1.
NONE
Patents:
1.
Dr. Pittock and Mayo Clinic have a financial interest in the technology entitled "Aquaporin-4 Autoantibody as a Cancer Marker." This technology has been licensed to a commercial entity but no royalties have been received. In addition, Dr. Pittock is an inventor of technology entitled "Aquaporin-4 Binding Autoantibodies in Patients with Neuromyelitis Optic Impair Glutamate Transport by Down-Regulating EAAT2." Mayo Clinic has filed a non- provisional patent application for this technology.
Publishing Royalties:
1.
NONE
Employment, Commercial Entity:
1.
NONE
Consultancies:
1.
NONE
Speakers’ Bureaus:
1.
NONE
Other Activities:
1.
NONE
Clinical Procedures or Imaging Studies:
1.
NONE
Research Support, Commercial Entities:
1.
Dr. Pittock has received a research grant from Alexion pharmaceuticals for his investigator-initiated study entitled "An Open Label Study of Eculizumab in NMO"
Research Support, Government Entities:
1.
RO1 NS065829-01 entitled “CNS Demyelinating Autoimmunity Targeting Water Channel Complexes”
Research Support, Academic Entities:
1.
NONE
Research Support, Foundations and Societies:
1.
Guthy Jackson Charitable Foundation grant for NMO research
Stock/stock Options/board of Directors Compensation:
1.
NONE
License Fee Payments, Technology or Inventions:
1.
NONE
Royalty Payments, Technology or Inventions:
1.
NONE
Stock/stock Options, Research Sponsor:
1.
NONE
Stock/stock Options, Medical Equipment & Materials:
1.
NONE
Legal Proceedings:
1.
NONE

Notes

Correspondence & reprint requests to Dr. Klein: [email protected]
Study funding: Mayo Foundation and a NIH grant (NS065007, C.J.K.) and Mayo Clinic CTSA through grant number UL1 RR024150 from the National Center for Research Resources (NCRR), a component of the NIH.

Author Contributions

C.J.K.: study concept or design, drafting and revising the manuscript, interpretation of data, statistical analysis, obtaining funding. P.A.A.: interpretation of data, acquisition of data. V.A.L.: study concept or design, revising the manuscript. S.J.P.: study concept or design, study supervision or coordination, drafting and revising the manuscript. A.M.: analysis or interpretation of data, revising the manuscript.

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