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Anne Louise Oaklander, Massachusetts General Hospital
This paper provides
This paper provides electrophysiological evidence of small-fiber neuropathy that complements and enriches the pathological evidence of small-fiber polyneuropathy (SFPN) from three independent laboratories. [Editors’ note: See PRF related news story.] The changes in brain functioning revealed by prior functional imaging studies of fibromyalgia patients may be secondary to primary peripheral nervous system abnormalities, at least in the roughly half of fibromyalgia patients with PNS abnormalities.
So the overlap between SFPN and fibromyalgia is now firmly established and needs to be translated to clinical practice. The reason that fibromyalgia patients might want to consider being evaluated for SFPN is that potentially treatable causes are identifiable in some cases of SFPN, whereas there have been no definitive treatment options for fibromyalgia. Given the prevalence of fibromyalgia, this poses considerable logistic challenges for both rheumatologists and neurologists.
Howard Fields, University of California San Francisco
For many years, there has
For many years, there has been widespread acceptance of the idea that symptomology of fibromyalgia represented sensitization of the pain sensory system; however, there was little to indicate whether the primary pathophysiology was in the periphery or central nervous system. Interestingly, many of the medications that showed efficacy for neuropathic pain were also at least somewhat effective in fibromyalgia. Over the past few years, anatomical evidence has emerged documenting that some fibromyalgia patients have a pathological process affecting their peripheral nervous system. This paper extends our understanding by presenting physiological evidence that the unmyelinated primary afferent nociceptors of fibromyalgia patients are sensitized. The challenge ahead will be to determine whether the sensitization represents pathology in the primary afferent nociceptor or is an inflammatory process secondarily affecting the primary afferent. Once the offending tissue is identified, the inquiry into the actual pathological process can begin.
John Quintner, Arthritis and Osteoporosis WA
Reflecting upon the comments
Reflecting upon the comments of Howard Fields and others makes me wonder whether we might be looking at a situation where both the central and peripheral nervous systems have become sensitized in the course of undamped activation of stress response systems.
The findings reported in the peripheral nervous system may at least explain dermagraphia, which can be an association of chronic widespread pain (aka Fibromyalgia Syndrome).
The idea that there always has to be a "driver" has overlooked the possibility that in some patients once they have been activated by a stressor or stressors, these systems may no longer be unable to switch themselves off. Epigenetic changes that have occurred involving stress response genes could be the key.
Our group has recently published an hypothesis in support of these possibilities:
Lyon P, Cohen ML, Quintner JL. An evolutionary stress-response hypothesis for chronic widespread pain (Fibromyalgia Syndrome). Pain Medicine 2011; 12: 1167-1178.
Claudia Sommer, University of Würzburg
This paper is a start to
This paper is a start to bridging the gap between the anatomical findings in the peripheral nervous system by my laboratory and by others and the symptoms that patients with fibromyalgia suffer from. It may give an answer to the often posed question of why a reduced density of nociceptors is associated with pain: They are not merely reduced in number, but also the remaining fibers are ill with pathological function or are sensitized by some not yet determined mediator. We may even speculate that the pathological function precedes the reduction of innervation density, but this would be a question to ask in longitudinal studies. There is a lot to find out, still. We would like to know if and how these findings in the peripheral nervous system relate to the central nervous system symptoms that patients suffer from, like the depression and the fatigue. Of course we would like to know what underlies the malfunction at the molecular level, so that people can start developing drugs that address this very special mechanism.
John Quintner, Arthritis and Osteoporosis WA
Claudia, have you considered
Claudia, have you considered "cytokine-induced autotoxicity" as a possible mechanism to explain the observed anatomical changes in the peripheral nervous system? As you correctly say, "there is still a lot to find out".
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Stephani Sutherland, www.stephanisutherland.com
A study from Jordi Serra et
The study from Jordi Serra and colleagues mentioned in the article above was published November 16 in the Annals of Neurology (Serra et al., 2013). Whereas Oaklander and Sommer focused on the anatomical features of peripheral nerve fibers, Serra investigated their physiology. All subjects in the study were female, including 30 fibromyalgia syndrome (FMS) patients, 17 small fiber neuropathy (SFN) patients, and 9 healthy controls. Serra and colleagues used microelectrodes to record from superficial peroneal nerve C-fiber nociceptors in the ankle. Whereas mechanically sensitive nociceptors behaved similarly in all three populations, so-called “silent” mechanically-insensitive nociceptors displayed abnormal activity in three quarters of the FMS and 65 percent of the SFN patients. About a third of these silent nociceptors exhibited spontaneous activity in FMS and SFN patients but not controls. Also similar to SFN patients, about one quarter of silent nociceptors in FMS patients were abnormally sensitive to mechanical stimuli. Despite their similarities, one feature did set FMS patients apart from SFN patients: 40 percent of nociceptors from FMS cases showed abnormally high activity-dependent slowing of conduction velocity in response to electrical stimulation.
“So not only do nerve fibers look abnormal,” as Oaklander and Sommer saw, "but here we've shown that they act hyperexcitable—they generate action potentials spontaneously, and spontaneous activity in C-fibers has been correlated with pain,” Serra told PRF. In contrast to normal nociceptors, which sit quietly in the absence of noxious stimuli, these hyperexcitable nociceptors discharge spontaneously and signal the brain, Serra explained. “This may be the basis of ongoing pain. So finding this hyperactivity in C-fibers of FMS patients gives us a good reason to believe it is the cause, or at least an initial cause, of their pain,” he said.