Mechanisms of pain in distal symmetric polyneuropathy: A combined clinical and neurophysiological study

Abstract

In patients with distal symmetric polyneuropathy we assessed non-nociceptive Abeta- and nociceptive Adelta-afferents to investigate their role in the development of neuropathic pain. We screened 2240 consecutive patients with sensory disturbances and collected 150 patients with distal symmetric polyneuropathy (68 with pain and 82 without). All patients underwent the Neuropathic Pain Symptom Inventory to rate ongoing, paroxysmal and provoked pains, a standard nerve conduction study (NCS) to assess Abeta-fibre function, and laser-evoked potentials (LEPs) to assess Adelta-fibre function. Patients with pain had the same age (P>0.50), but a longer delay since symptom onset than those without (P<0.01). Whereas the LEP amplitude was significantly lower in patients with pain than in those without (P<0.0001), NCS data did not differ between groups (P>0.50). LEPs were more severely affected in patients with ongoing pain than in those with provoked pain (P<0.0001). Our findings indicate that the impairment of Abeta-fibres has no role in the development of ongoing or provoked pain. In patients with ongoing pain the severe LEP suppression and the correlation between pain intensity and LEP attenuation may indicate that this type of pain reflects damage to nociceptive axons. The partially preserved LEPs in patients with provoked pain suggest that this type of pain is related to the abnormal activity arising from partially spared and sensitised nociceptive terminals. Because clinical and neurophysiological abnormalities followed similar patterns regardless of aetiology, pain should be classified and treated on mechanism-based grounds.

Reappraising neuropathic pain in humans—how symptoms help disclose mechanisms

“…17 Clinical and experimental studies collectively show that neuropathic pain arises mainly from nociceptive pathway damage. 18,19 As such, standard neurophysiological techniques that are designed to assess nonnociceptive afferent fibres seem to be unhelpful in diagnosing neuropathic pain. Despite their limitations, these standard techniques are still useful to demonstrate, locate and quantify damage along peripheral and central somato-sensory pathways.…”

“…Indeed, skin biopsy examination shows reduced IENF density not only in all patients with painful neuropathy, but also in some patients with nonpainful neuropathy, presumably because loss of IENF is necessary, but not sufficient, for development of painful neuropathy. 19 A further possible limitation of skin biopsy is that the PGP9.5 marker might not indicate regenerating axons, which could participate in the development of pain. 32…”

How to diagnose neuropathic pain? The contribution from clinical examination, pain questionnaires and diagnostic tests

“…Laser-generated radiant heat pulses selectively excite free nerve endings in the superficial skin layers, activate Ad and C nociceptors and evoke scalp potentials [41]. In peripheral and central neuropathic pain, LEPs are more sensitive than any other neurophysiological test and LEP suppression is a finding that helps to diagnose neuropathic pain [42]. Although the clinical usefulness of LEPs is widely agreed, their sensitivity and specificity for detecting neuropathic pain is still poorly reported [15].…”

“…Skin biopsy enables quantification of the number of IENFs, which provides a measure of small-fibre loss. IENF intraepidermal nerve fibre, SNAP sensory nerve action potential (modified from [2]) Neurol Sci diseases suggest a highly significant difference with controls, with high specificity but low sensitivity [31,32,42].…”

Laboratory tools for assessing neuropathic pain

“…LEPs have proved reliable for assessing damage to the peripheral and central nociceptive system in peripheral neuropathies, syringomyelia, multiple sclerosis, Wallenberg syndrome and brain infarction [10,11]. In peripheral and central neuropathic pains, LEPs are more sensitive than any other neurophysiological test and the finding of LEP suppression helps to diagnose neuropathic pain [5].…”