Chronic pain as a manifestation of potassium channel-complex autoimmunity

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.

Figure 1. Neuropathic pain locations in 6 illustrative patients seropositive for voltage-gated potassium channel–complex-immunoglobulin G (IgG) correlated with sites of abnormal heat-induced sweat responses

Both CASPR2-IgG and LGI1-IgG were detected in 2 patients. (A–F) Yellow skin areas in thermoregulatory sweat test indicate reduced or absent sweat output (revealed by alizarin red powder; face not tested [sphygmomanometer on arm of E]). (G) Indirect immunofluorescence. IgG in serum of patients B and E bound to HEK293 cells transfected with either LGI1 or CASPR2, but not to nontransfected cells (bar, 20 μm). The remaining 4 patients were seronegative for CASPR2-IgG and LGI1-IgG.