Neurophysiological and histopathological evaluation of small fiber pathways as diagnostic characterization of neuropathic pain and autonom dysfunction syndromes

This manuscript is made up of two individual not related articles about peripheral neuropathic pain syndrome. The first article reports the effect on pain relief in patients with peripheral neuropathic pain after brachial plexus lesions or distal peripheral nerve injury using an implanted peripheral nerve stimulator applied directly on nerve branch using a peculiar surgical technique. Seven patients with post-traumatic lesion of brachial plexus or peripheral nerve complaining severe intractable pain were selected. Neuropathic pain diagnosis according with redefinition and the grading system of NEUPSIG (2008) was assessed. Conventional drugs for neuropathic pain and traditional surgical treatment were not effective. Patients underwent at baseline clinical evaluation with careful neuroalgological evaluation recording negative signs and positive phenomena, pain questionnaires, thermal-Quantitative Sensory Testing (QST). Surgical treatment consists in a new surgical technique for neurostimulator implant: quadripolar electrocatheters were placed directly on the sensory peripheral branch of nerve mainly involved into the ascellary cavity. To assess neuromodulation effect we perform clinical neuroalgological evaluation, pain scales and QST after 1 week and again after 1 month, and after each 6 months. No significant or unexpected adverse events occurred. The pain intensity dropped decrease from a NRS of 9±1.15 before surgery to 2.14±1.57 at 6-month of follow-up and to 2.57±1.13 at 12-months of follow-up (P < 0.001). We assessed after about 12 months with double-blind control with Neurostimulation turned off the restart of severe ongoing pain and paroxysms. These results expressed in details in the article show the safety and efficacy of this innovative technique in treatment of chronic and usually intractable severe pain in selected patients. The second article reported a peculiar phenotype of cold pain in patients with small fiber neuropathies. The aim of study was to characterize the distinct pattern of pain phenomena in these patients and to compare clinical, neurophysiological and histological features in order to assess the underlying pain mechanisms. 9 patients with painful small fiber neuropathy (SFN) complaining cold pain were selected and compared with patients with SFN complaining burning pain. A complete neuroalgological examination, nerve conduction studies, pain questionnary (NPSI), thermal-Quantitative Sensory Testing (QST) battery and skin biopsy at distal and proximal sites were performed. Then L-menthol and cinnamaldeyd (CA), TRPM8 and TRPA1 receptors agonists respectively, were topically applied to the calf in two different days and the effect on pain (recorded with 11-point Likart scale for 20 minutes), thermal sensation, tactile sensation and skin flare size (skin area mm2) were evaluated. We compared the results with 15 healthy subjects and 10 patients with SFN with burning pain as the main pain quality. At baseline evaluation cold-SFN showed a cold hyperalgesia or cold allodynia at lower limb in a disto-proximal fashion associated with severe cold and mild warm hypoaesthesia. L-menthol induced no sensation in 5 of 9 cold-SFN patients and burning pain sensation in 4. The L-menthol responses (vasodilatation and flare) were significantly reduced or nearly abolished in the allodynic area in cold-SFN pts. The CA effects were less significative, it produced a slight burning sensation in 3 pts, tactile allodynia and heat hyperalgesia in 2 pts affected by cold SFN. Skin biopsy showed in patients with cold painful SFN more severe denervation of dermal nerves compared with burning SFN and MBP-positive fibers were reduced compared with burning-SFN. All the other findings were detailed in the article. In conclusion, this study showed the existence of a peculiar neuropathic phenotype of cold pain that could be explained by selective or predominant dysfunction of TRPM8 receptor and A-delta thinly myelinated nerve fibers. Furthermore a selective group of patients with SFN complaining burning feet as exclusive painful syndrome shown a prevalent involvement of TRPA1 receptor afferent.