In people, autoantibodies to neuronal voltage-gated potassium channel (VGKC) complexes are associated with diverse neurologic disturbances, including seizures, encephalitis, and muscle cramps and twitching. The symptoms, many of which are attributed to antibody-induced neuronal hyperexcitability, often respond to immunotherapy. Now, researchers led by Christopher Klein at the Mayo Clinic, Rochester, Minnesota, US, have shown that the autoantibodies frequently associate with another condition: pain. In a paper published August 15 in Neurology, Klein and colleagues report pain, often chronic, in half of a group of 316 patients with VGKC-complex autoreactive antibodies. Patients with pain showed signs of hyperexcitability in sensory pathways, and, among the few who received immunotherapy, pain improved for most.
The results bolster the emerging concept that autoimmune reactions can contribute to some forms of chronic pain. In an accompanying editorial, David Bennett of King’s College London, UK, and Angela Vincent of John Radcliffe Hospital, Oxford, UK, write, “We may … be entering an exciting phase in which autoantibodies to neural antigens are recognized as having a role in the etiology of a number of hitherto poorly understood chronic pain states, opening new avenues for treatment.”
An unusual case
Klein, a neurologist, said the investigation started with one patient, a healthy 80-year-old professor who suddenly developed disabling pain in his hands and lower legs that kept him out of the classroom and home in bed. The doctors suspected neuropathy, but nerve conduction studies, and even nerve biopsy, showed no signs of damage. The physicians considered a diagnosis of psychogenic pain. But tests revealed VGKC-complex antibodies, so Klein initiated immunotherapy with an intravenous steroid. The treatment rapidly relieved the man’s pain, and the patient eventually discontinued narcotic pain relievers and returned to his normal activities.
The finding of pain with no apparent cause, coupled with the presence of VGKC antibodies and the success of immunotherapy, was unexpected, Klein said, and intriguing. VGKC autoantibodies had been linked to pain previously, but there was little information about the scope of pain symptoms in seropositive patients. To fill the gap, Klein and his colleagues embarked on a systematic review of pain symptoms in the records of 316 seropositive patients who had undergone neurologic evaluation at the Mayo Clinic. The results were surprising: 159 (50 percent) of the patients studied had pain that was not explained by other causes. In contrast, among 167 patients with one of several other neural autoantibodies, only 9 percent reported pain.
Remarkably, 45 of the patients with VGKC-complex immunoglobulin (IgG) reported pain as their only symptom. Many, like Klein’s patient, were evaluated for neuropathy or CNS disease, but no abnormalities turned up. The discovery of isolated, unexplained pain in so many “was kind of a shock to us,” Klein said.
Examination of patient records revealed that, in most cases, pain reached maximal severity within two weeks of onset, and often became chronic. The pain took a variety of forms: In half of patients, pain was isolated to extremities, while others reported total body pain, head or face pain, abdominal visceral pain, or pain in multiple locations. Patients’ descriptions suggested the pain was either neuropathic or nociceptive.
In support of an autoimmune source of pain, Klein and colleagues found that, of 16 patients in the pain group who had been treated with immunotherapy (usually for other neurologic issues), 14 showed reduced or eliminated pain symptoms. “Many of these patients were on multiple [pain] medications including narcotics, and were able to come off of them with immunotherapy,” Klein said.
Laying the blame
Were the VGKC antibodies the cause of pain? On average, titers of VGKC-complex IgG were no different in the pain group and the patients without pain. However, VGKC-complex IgG is heterogeneous: Antibodies that react with different proteins in the channel complex are thought to be associated with different clinical symptoms (Irani et al., 2010). When the Mayo group checked for antigen specificity, they detected reactivity to one accessory protein, contactin-associated protein-2 (CASPR2), more frequently in the pain group than the non-pain patients. That finding agreed with previous work by Vincent (coauthor of the accompanying editorial), who found a high incidence of pain in VGKC-complex IgG-positive patients with CASPR2 autoimmunity (Irani et al., 2010; Irani et al., 2012).
CASPR2 antibodies are not the whole answer, though. Overall, CASPR2-specific antibodies were found in just 16 percent of the seropositive patients with pain. That means that for most patients, “we still don’t know what the primary antigen is,” said Klein.
In light of the new findings, Bennett and Vincent ask in their editorial, “Should we be testing patients with chronic pain for VGKC-complex antibodies, and if so, which patients?” For patients with other telltale signs of VGKC autoimmunity, they say, the answer is yes. “The more problematic issue is those patients whose sole complaint is pain.... Larger focused studies and more detailed pain phenotyping will be required to determine the true prevalence of VGKC-complex antibodies in chronic pain cohorts.”
Klein, too, wants to know how often, and in which patients, VGKC autoantibodies might explain chronic pain. To address that question, he and his colleagues are investigating the frequency of neural autoimmunity in patients being treated at a chronic pain center.
Meanwhile, the mechanism by which the autoantibodies could cause pain remains unclear. VGKCs, also known as Kv channels, cooperate with other neuronal channels to set resting membrane potentials and regulate neuronal excitability, and some family members have already been linked to nociceptor excitability and pain (for a review, see Takeda et al., 2011). Antibodies that block VGKC function could render sensory neurons hyperexcitable, as previously seen for motor neurons. Indeed, Klein and colleagues did see evidence of abnormal sensory excitability: Excessive sweating and quantitative heat-pain hyperalgesia (C fiber allodynia) were reported only in the pain group, supporting the idea that hyperexcitability of nociceptive pathways leads to pain in patients with VGKC antibodies.
Also in support of that idea, the Mayo team recently implicated VGKC-complex autoimmunity in an unusual instance of job-related pain. They found the autoantibodies in workers at two slaughterhouses; the workers developed painful neuropathy after exposure to aerosolized brain tissue from pigs (Lachance et al., 2010; Meeusen et al., 2012). In those cases, the workers showed signs of neuronal hyperexcitability.
But Klein is cautious. “It’s an attractive theory” that the antibodies alter neuronal VGKC-complex function, “but maybe it’s more complicated than that.” In fact, the current finding “simply helps us to tell if there’s an autoimmune component,” he said. He noted that VGKCs are located on immune cells as well as neurons, so that VGKC-specific antibodies might affect neuronal excitability indirectly via cytokines, rather than targeting neurons directly. Moreover, it is possible that the VGKC-complex IgG is what Klein calls a “sentinel finding,” meaning that other—as-yet undetected—antibodies may be the real culprits.
Other labs are also providing evidence that autoantibodies play a role in pain. Recent clues point to an autoimmune basis for chronic regional pain syndrome (CRPS), where researchers have reported autoantibodies against autonomic neuron proteins in patients, including the β2 adrenergic receptor and M2 muscarinic acetylcholine receptor (Kohr et al., 2011). And, in an encouraging preliminary study, a small, randomized, placebo-controlled trial of immunotherapy with intravenous immunoglobulin reduced pain in patients with refractory CRPS (Goebel et al., 2010).