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).
Comments
Andreas Goebel, Liverpool University
The study by Klein et al. is
The study by Klein et al. is notable because the authors conducted a detailed, retrospective evaluation of painful symptoms in a group of patients who, in the majority, had additional neurological findings, and the researchers found an association between anti-VGKC serum autoantibodies and the occurrence of pain in their patients. In addition, they found that some patients with these serum-autoantibodies had "only" pain, without additional neurological abnormalities.
In the accompanying editorial, Bennett and Vincent highlight that autoantibody-mediated, functional effects on neurons, without accompanying structural damage, may be responsible for causing chronic pain. The editorialists also caution that it is not yet clear that the causative autoimmune agents in Dr. Klein’s patients are indeed anti-VGKC autoantibodies.
Of course, autoimmunity-associated chronic pains have been well described before, such as in the cases of Sjoegren-associated neuropathies, or rheumatoid arthritis-associated fibromyalgia. But the results of Klein et al. suggest something novel: that autoimmune mechanisms may cause pain without causing accompanying disease, perhaps without even causing those minimal structural changes which characterize small-fiber neuropathies.
Finding out exactly how these autoantibodies work will be crucial to determine whether Dr. Klein’s patients have neuropathic or nociceptive pain. Should autoantibodies directly alter nerve function, and/or cause nerve fiber rarification, then these patients ought to be considered to have neuropathic pain ("pain arising as a direct consequence of a lesion or disease affecting the somatosensory system"), or if they affect predominantly immune or soft tissue cells, which, in turn, release mediators exciting sensory neurons, then these pains should be considered nociceptive—the answer to this question is also still open in the case of CRPS; see below.
The study has several limitations, including the absence of information about the causes for referral of the study patients: Is it possible that VGKC-associated pains are even more common in a general pain clinic population than in the authors' cohort? On the other hand, the appropriateness of the chosen control group in Dr. Klein’s study is not clear, because patients in this group may have been referred for different reasons than the patient group. Since pain intensity in the VGKC group was not recorded, and as some patients may have had mild pain, it is unclear just how much more common pain in people with VGKC autoantibodies is, when compared with the general population. In a large, population-based European survey, moderate or severe chronic pain was reported by as many as 18 percent of responders (1).
Independently, the patients included in the study by Klein et al. had not been systematically assessed for epidermal small-fiber loss. As suggested by the editorialists, it is likely that pain-inducing autoantibodies would affect small fibers—information about epidermal nerve fiber densities would support an understanding on whether there are structural abnormalities; minor fiber loss induced by autoantibodies might contribute to causing pain independent of any direct functional effects of the autoantibodies on nerve or immune cells.
The study supports the fascinating possibility that some "functional"/"idiopathic" pain conditions may, in fact, be caused by autoantibodies.
In tertiary pain medicine centers, patients such as those described in the case reports are seen with some regularity. How should we treat them? The authors used immune modulators: After they had identified serum VGKC, they treated patient 2, who had the "only" symptom of widespread pain by using high-dose methyl-prednisolone, and plasma exchange. In some parts of the world, including the UK, the idea of "autoimmune pain" alone does not suffice to justify use of immune modifiers, nor does the demonstration of associated autoantibodies(2). Clinical trials are required, and one would hope that Klein at al. will now be able to get such trials underway.
Our research in complex regional pain syndrome has similarly been based on the idea that autoantibodies may cause CRPS pain through a functional effect on either nerves or surrounding tissues in the absence of substantial tissue destruction (patients have a mild epidermal nerve fiber rarification; see ref. 3)—thus, that CRPS is "autoimmune pain," at least in some cases (4,5). Autoantibodies may also cause additional recognized chronic pain syndromes; the authors allude to that. For example, both we and others have earlier reported that a subgroup of patients with fibromyalgia responds to treatment with low-dose immunoglobulins; such a response is considered circumstantial evidence for an autoimmune involvement (6,7).
In clinical practice, one feels sometimes bewildered by the variety of painful presentations, and one can be at a loss to explain how they develop. Perhaps the concept of "autoimmune pain" can provide new answers. Research into the exact mechanisms of how autoantibodies cause pain could also deliver novel drug development targets, providing additional hope for the affected patients.
References
1. Breivik H, Collett B, Ventafridda V, Cohen R, Gallacher D. Survey of chronic pain in Europe: prevalence, impact on daily life, and treatment. Eur.J.Pain. 2006/5;10(4):287-333.
2. Kohr D, Singh P, Tschernatsch M, et al. Autoimmunity against the beta(2) adrenergic receptor and muscarinic-2 receptor in complex regional pain syndrome. Pain. Dec 2011;152(12):2690-2700.
3. Oaklander AL, Fields HL. Is reflex sympathetic dystrophy/complex regional pain syndrome type I a small-fiber neuropathy? Ann.Neurol. 2009/6;65(6):629-638.
4. Goebel A, Stock M, Deacon R, Sprotte G, Vincent A. Intravenous immunoglobulin response and evidence for pathogenic antibodies in a case of complex regional pain syndrome 1. Ann.Neurol. 2005/3;57(3):463-464.
5. Goebel A, Blaes F. Complex Regional Pain Syndrome, prototype of a novel kind of autoimmune disease. Autoimmunity Reviews. in press 2012.
6. Caro XJ, Winter EF, Dumas AJ. A subset of fibromyalgia patients have findings suggestive of chronic inflammatory demyelinating polyneuropathy and appear to respond to IVIg. Rheumatology (Oxford). 2008/2;47(2):208-211.
7. Goebel A, Netal S, Schedel R, Sprotte G. Human pooled immunoglobulin in the treatment of chronic pain syndromes. Pain Med. 2002/6;3(2):119-127.
Mamoru Takeda, Nippon Dental University
Several different types of
Several different types of animal models of neuropathic pain have been developed and extensively studied (1), but no common therapeutic molecular target has been identified for neurons located in the nociceptive pathway. Multiple types of voltage-gated ion channels contribute to neuronal excitability. Among these, voltage-gated potassium channels (VGKC) are important physiological regulators of neuronal excitability (e.g., membrane potential, action potential shape, threshold, and firing adaptation; ref. 2). Actually, peripheral nerve injury/inflammation markedly reduces the current densities of VGKCs, implicating them in the development of neuropathic/inflammatory pain (3). Since the opening of VGKCs, leads to hyperpolarization of the cell membrane, which results in a decrease of cell excitability, several types of voltage-gated potassium channels have been proposed as potential target candidates for therapeutic approaches to pain (4).
In this paper, Klein and colleagues report an impressive and important finding. Their studies provide evidence that VGKC-complex immunoreactivity is a cause of chronic pain: 1) pain was detected as a symptom in 50 percent of seropositive patients, five times more common than in control patients with other neural autoantibodies, and 2) 80 percent of antibody- positive patients had improvement in their pain with immunotherapies. Therefore, these results suggest that VGKC-complex autoantibodies inducing the suppression of VGKC currents in each pain relay station contribute to the neuronal hyperexcitability within pain pathways in chronic pain (autoimmune pain).
Concerning the therapeutic approaches to pain, a potassium channel opener is one of the candidates for attenuation for chronic pain, such as allodynia (5). Thus, the findings of Klein and colleagues indicate new avenues for chronic pain treatment. This study focused on only the VGKC-complex proteins LGI1 and CASPR2. Since recent studies indicated that impairment of glial cell-specific VGKCs, for example, the inwardly rectifying potassium (Kir) channels, also contribute to induction of pain (6,7), we hope that a future study will extend the analysis to the relationship between other types of VGKC complexes in neurons and glial cells, and pathophysiological pain.
References
1. Scholtz J, Wollf CJ. Can we conquer pain ? Nat Neurosci 2002; 5:1062-1067.
2. Takeda M, Tsuboi Y, Kitagawa J, Nakagawa K, Iwata K, Matsumoto S. Potassium channels as a potential therapeutic target for trigeminal neuropathic and inflammatory pain. Mol Pain 2011;7:5.
3. Evervill and Kocsis, Reduction in potassium currents in identified cutaneous afferent dorsal root ganglion neurons after axotomy. J Neurophysiol 1999; 82: 700-708.
4. Lawson, Potassium channel as targets for the management of pain. CNS agent Med Chem 2006; 6 :119-128.
5. Xu W, Wu Ym, Bi Y, Tan L, Gan Y, Wang KW, Activation of voltage gated KCNQ/Kv7 channels by anticonvulsant retigabine attenuates mechanical allodynia of inflammatory temporomandibular joint in rats. Mol Pain 2010; 6:49.
6. Vit JP, Ohara PT, Bhargava A, Kelly K, Jasmin L, Silencing the Kir 4.1 pottassium channels subunit in satellite glial cells of the rat trigeminal ganglion results in pain like behabiro in the absence of nerve injury. J Neurosci 2008;28;4161-4171.
7. Takeda M, Takahashi M, Nasu M, Matsumoto S. Peripheral inflammation suppress inward rectifying potassium currents of satellite glia cells in the trigeminal ganglia. Pain 2011;152: 2147-2156.
Ron Birch, Isaacs Syndrome/Neuromyotonia World Information Forum
My personal interest is with neuromyotonia. Sixty percent of neuromyotonia patients are diagnosed without positivity to VGKC Abs. With this is mind, perhaps this is where we could look to help understand what is discussed here by looking at the differences between these two sets of neuromyotonia patients.
Do seronegative VGKC Ab neuromyotonia patients have nerve biopsies that look any different from seropositive VGKC Ab neuromyotonia patients?
The question remaining is what are the specific immune differences between these two sets of patients (60 percent positive versus 40 percent negative) diagnosed with the same illness and with the same symptoms, given that both sets of neuromyotonia patients have pain.