Dear hopeforthebest -
I can't say that I understand it in all it's detail, but the small-fiber neuropathy theory championed by Anne Louise Oaklander, MD, PhD, appears to do a nice job with the burning pain question. And even though, as supposed theory on the verge of ending all theories, it doesn't attempt to explain how it is, given the sheer breath of the theory, that "secondary central nervous system changes" may still be required to "perpetuate pathology" - or if so it did it shot right by me - I commend the full text for your attention. I am happy send it to you and anyone else who PMs me with their email address, where it's not up on the RSDSA site and is too big to post here:
"Is reflex sympathetic dystrophy/complex regional pain syndrome type I a small-fiber neuropathy?" Oaklander AL, Fields HL,
Annals of Neurology, Vol 65 No 6 June 2009 pp. 629-38.
Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA.
aoaklander@partners.org
Neurologist S. Weir Mitchell first described "causalgia" following wartime nerve injury, with its persistent distal limb burning pain, swelling, and abnormal skin color, temperature, and sweating. Similar post-traumatic symptoms were later identified in patients without overt nerve injuries after trauma. This was labeled reflex sympathetic dystrophy (RSD; now complex regional pain syndrome type I [CRPS-I]). The pathophysiology of symptoms is unknown and treatment options are limited. We propose that persistent RSD/CRPS-I is a post-traumatic neuralgia associated with distal degeneration of small-diameter peripheral axons. Small-fiber lesions are easily missed on examination and are undetected by standard electrophysiological testing. Most CRPS features-spreading pain and skin hypersensitivity, vasomotor instability, osteopenia, edema, and abnormal sweating-are explicable by small-fiber dysfunction. Small fibers sense pain and temperature but also regulate tissue function through neuroeffector actions. Indeed, small-fiber-predominant polyneuropathies cause CRPS-like abnormalities, and pathological studies of nerves from chronic CRPS-I patients confirm small-fiber-predominant pathology. Small distal nerve injuries in rodents reproduce many CRPS features, further supporting this hypothesis. CRPS symptoms likely reflect combined effects of axonal degeneration and plasticity, inappropriate firing and neurosecretion by residual axons, and denervation supersensitivity. The resulting tissue edema, hypoxia, and secondary central nervous system changes can exacerbate symptoms and perpetuate pathology. Restoring the interest of neurologists in RSD/CRPS should improve patient care and broaden our knowledge of small-fiber functions.
PMID: 19557864 [PubMed - indexed for MEDLINE]
http://www.ncbi.nlm.nih.gov/pubmed/1...ubmed_RVDocSum
For a couple of earlier papers on the same topic, that are available in full text, but may be less nuanced than the most recent effort (in particular the assertion in Dr. Oaklander's editorial that all observed changes in the brains of CRPS patients are simply adaptions to pain, where Apkarian's lab at Northwestern has fairly convincingly shown that a number of different but disabling pain conditions have totally different profiles in the MRI tube) see:
1. The truly groundbreaking: "Evidence of focal small-fiber axonal degeneration in complex regional pain syndrome-I (reflex sympathetic dystrophy)," Oaklander AL, Rissmiller JG, Gelman LB, Zheng L, Chang Y, Gott R,
Pain 2006; 120: 235-243, full text at
http://www.rsds.org/2/library/articl..._pain_2006.pdf, and
2. "RSD/CRPS: the end of the beginning," [Editorial] Oaklander AL,
Pain 2008 Oct 15; 139(2): 239-40, a copy of which is attached.
Mike
ps As intitially posted, I said that the most recent article, "Is reflex sympathetic dystrophy/complex regional pain syndrome type I a small-fiber neuropathy?" did not, as far as I could see, provide "an explicit tie-in with much of what's known from a neuro-immune angle." As they say in the world of statutory interpretation, the firsst rule is "read" and the second rule is "read on." Only in my case it should have been, read again. Here's what appears in the article, along with the matching footnotes:
Small-fiber axonopathies can produce other aspects of inflammation as well. Plasma extravasation produces intraluminal hemoconcentration that promotes adhesion and diapedesis of white blood cells. Neuropeptides released from small-fibers also directly recruit and activate immunocytes including lymphocytes, macrophages, and mast cells. Their cytokines amplify local inflammation and can sensitize nearby primary afferent nociceptors in a vicious neural-immune cycle. Tryptase, a mast-cell–specific product, is increased in CRPS-I–affected skin,33 and proinflammatory cytokines are increased in tissue fluid34 and serum35 from CRPS patients and patients with painful SFPN. [p. 633]
Footnotes:
33. Huygen FJPM, Ramdhani N, van Toorenenbergen A, et al.
Mast cells are involved in inflammatory reactions during Complex
Regional Pain Syndrome type 1. Immunol Lett 2004;91:
147-154.
34. Huygen FJ, De Bruijn AG, De Bruin MT, et al. Evidence for
local inflammation in complex regional pain syndrome type 1.
Mediators Inflamm 2002;11:47–51.
35. Uceyler N, Eberle T, Rolke R, et al. Differential expression patterns
of cytokines in complex regional pain syndrome. Pain
2007;132:195–205.
36. Uceyler N, Rogausch JP, Toyka KV, et al. Differential expression
of cytokines in painful and painless neuropathies. Neurology
2007;69:42– 49.
And while I have removed my caveat, I would be more comfortable had the article provided authority for one key sentence from the saving paragraph, which may for all I am aware be generally understood by those in the know:
Neuropeptides released from small-fibers also directly recruit and activate immunocytes including lymphocytes, macrophages, and mast cells.
And what's bizzare is that when I run a PubMed search on neuropeptide "small fiber" I get 13 or 14 hits (depending on whether neuropeptide is singular or plural and none without the internal quotation marks around small fiber or if the term is hyphenated) but if I then add ANY of the words immunocytes, lymphocytes, macrophages, OR mast cells (or the singular thereof) the search result drops away to zero, not even picking up the article from which the sentence is taken.
Nor does a Google search of "small fiber [or small-fiber or "small fibre"] neuropeptides immunocyte lymphocyte macrophage mast cells" produce any results where the words small fiber are linked together, even though they appear first in the search sequence. Any thoughts?