Chronic pain caused by autoimmune attack on nerve potassium channels

Chronic pain of various types can be caused by autoimmunity through inflammation, and now an important paper just published in the journal Neurology reveals a mechanism by which autoimmunity causes chronic pain in nerves by attacking potassium channels in the nerve cell membranes. The authors state:

"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."

Voltage-gated potassium channels reside in nerve cell membranes and detect voltage changes in the cell's electrical potential. They act importantly to allow the cell to return to its resting state. Impairment in doing so can result in the nerve hyper-excitability associated with chronic pain. They investigated this by correlating chronic pain with the presence of autoantibodies attacking the VGKC complexes, including CASPR2 antibodies. Their findings were revealed a significant cause of chronic pain:

"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."

In other words, there was a strong correlation between the CASPR2 antibody that attacks the voltage-gated potassium channel in the nerve cell membrane and chronic pain. The authors conclude:

"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."

Relevant comments appear in an accompanying editorial:

"Autoantibodies to the voltage-gated potassium channel (VGKC) complex have been implicated in a number of autoimmune neurologic conditions, including limbic encephalitis, neuromyotonia, and Morvan syndrome (neuromyotonia, insomnia, and autonomic dysfunction)...Although pain, often neuropathic, has been reported previously in some VGKC-complex antibody positive patients, particularly those with CASPR2 antibodies, the report in this issue of Neurology® suggests that pain is common and often chronic in these patients."

Case management of chronic pain should never overlook the possibility of an autoimmune component.