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.
Backgrounds
Patients with diabetic polyneuropathy commonly suffer from ongoing burning pain and dynamic mechanical allodynia. In this clinical and skin biopsy study, we aimed at assessing how ...intraepidermal regenerating nerve sprouts are associated with these two types of pain.
Methods
We consecutively enrolled 85 patients with diabetic polyneuropathy. All patients underwent skin biopsy at the distal leg. Intraepidermal nerve fibres were immunostained with the anti‐protein gene product 9.5 (PGP9.5) to quantify all intraepidermal nerve fibres, and the growth‐associated protein 43 (GAP43) to quantify regenerating nerve sprouts.
Results
We found that the GAP43‐stained intraepidermal nerve fibre density and the ratio GAP43/PGP9.5 were significantly higher in patients with ongoing burning pain than in those without. The area of receiver operating characteristic (ROC) curve for the ratio GAP43/PGP9.5 was 0.74 and yielded a sensitivity and specificity for identifying ongoing burning pain of 72% and 71%, respectively. Conversely, although the density of PGP9.5 and GAP43 intraepidermal nerve fibre was higher in patients with dynamic mechanical allodynia than in those without, this difference was statistically weak and the ROC curve analysis of skin biopsy variables for this type of pain failed to reach the statistical significance.
Conclusion
Our clinical and skin biopsy study showed that ongoing burning pain was strongly associated with regenerating sprouts, as assessed with GAP43 immunostaining. This finding improves our understanding on the mechanisms underlying neuropathic pain in patients with diabetic polyneuropathy and suggests that the GAP43/PGP 9.5 ratio might be used as an objective marker for ongoing burning pain due to regenerating sprouts.
Significance
Our skin biopsy study showing that regenerating sprouts, as assessed with GAP43‐staining, were strongly associated with ongoing burning pain, improves our knowledge on the mechanisms underlying neuropathic pain in patients with diabetes
Patients with peripheral and central nervous system diseases may suffer from different types of pain, namely nociceptive, neuropathic and mixed pain. Although in some cases, the distinction between ...these types of pain is clinically evident, yet in some patients an accurate differential diagnosis requires dedicated clinical examination, screening questionnaires and diagnostic techniques some of which are available only in specialized pain centres. This review briefly addresses the currently agreed definitions of the different types of pain and shows how clinical examination, pain questionnaires and diagnostic tests can help the clinicians in identifying neuropathic pain.
Abstract Despite concerted efforts from pharmacologic research into neuropathic pain, many patients fail to achieve sufficient pain relief with medication alone. For this reason, increasing interest ...centres on neurostimulation techniques. We assessed whether transcutaneous spinal direct current stimulation (tsDCS) modulates conduction in ascending nociceptive spinal pathways. We measured changes induced by anodal and cathodal tsDCS over the thoracic spinal cord on face- and foot-laser evoked potentials (LEPs) and foot-cold pressor test responses in 20 healthy subjects. Whereas anodal tsDCS reduced the amplitude of the N1 and N2 components of foot-LEPs ( P < 0.05) neither anodal nor cathodal tsDCS changed LEPs evoked by face stimulation. Pain tolerance to the cold pressor test was significantly higher after anodal than after cathodal tsDCS ( P < 0.05). Conversely, no difference was found in the pain threshold or pain ratings to the cold pressor test between the two polarity conditions. Our data suggest that anodal tsDCS over the thoracic spinal cord might impair conduction in the ascending nociceptive spinal pathways, thus modulating LEPs and increasing pain tolerance in healthy subjects.
We designed a new paired associative stimulation (PAS) protocol that combines experimental pain evoked by laser stimuli and transcranial magnetic stimulation (TMS) (Laser-PAS) to primary motor cortex ...(M1). We tested in healthy subjects whether Laser-PAS elicits cortical plasticity as reflected by long-term changes in motor-evoked potentials (MEPs) (after-effects). In separate experiments, we examined numerous variables including changes induced by varying the interstimulus intervals (ISIs) and Laser-PAS-induced changes in target and non-target muscle MEPs. We measured MEPs after repetitive laser or TMS (rTMS) pulses, and compared magnetic- and electric (TES)-induced MEPs. We tested MEPs after applying Laser-PAS with laser pulses ipsilaterally to M1. Finally, we studied subjects receiving an N-methyl-D-aspartate (NMDA) receptor antagonist (memantine) or placebo (α-lipoic acid). During Laser-PAS at the 50 ms ISI MEPs decreased, thereafter they increased for 60 min; other ISIs induced no after-effects. The after-effects remained restricted to the target muscle. Repetitive laser pulses and rTMS induced no after-effects. After Laser-PAS, TMS-induced MEPs increased, whereas TES-induced MEPs did not. Laser-PAS with laser pulses ipsilaterally to M1 left MEPs unchanged. Memantine, but not α-lipoic acid, abolished the after-effects. In conclusion, Laser-PAS elicits NMDA-dependent cortical plasticity and provides new insights into human pain-motor integration.
Abstract The periaqueductal gray (PAG), a brain area belonging to the descending pain modulatory system, plays a crucial role in pain perception. Little information is available on the relationship ...between PAG activation and perceived pain intensity. In this study, we acquired functional magnetic resonance imaging (fMRI) scans from the PAG during the cold pressor test, a model for tonic pain, in 12 healthy volunteers. fMRI data were acquired with a 12-channel head-coil and a 3-Tesla scanner and analyzed with Statistical Parametric Mapping (SPM8) software. During the cold pressor test, fMRI showed significant activation clusters in pain-related brain areas: bilateral middle and superior frontal gyrus, anterior cingulate cortex and thalamus, left insula, right inferior frontal gyrus, left inferior temporal gyrus and in the bilateral PAG (cluster level corrected threshold p < 0.05). PAG activation correlated directly with the pain threshold and inversely with the participant's perceived pain intensity (cluster level corrected threshold (p < 0.05). The cold pressor test consistently activated the PAG as well as other pain-related areas in the brain. Our study, showing that the greater the PAG activation the higher the pain threshold and the weaker the pain intensity perceived, highlights the key role of the PAG in inhibiting the pain afferent pathway function. Our findings might be useful for neuroimaging studies investigating PAG activation in patients with chronic idiopathic pain conditions possibly related to dysfunction in the descending pain modulatory system.
We aimed at seeking more precise diagnostic information on the sensory nervous system involvement described in patients with amyotrophic lateral sclerosis (ALS). We investigated large myelinated ...nerve fibres with nerve conduction study and small-nerve fibres with Quantitative Sensory Testing (QST) (assessing thermal-pain perceptive thresholds) and skin biopsy (assessing intraepidermal nerve fibre density) in 24 consecutive patients with ALS, 11 with bulbar-onset and 13 with spinal-onset. In 23 of the 24 patients, regardless of ALS onset, nerve conduction study invariably showed large myelinated fibre sparing. In patients with bulbar-onset ALS, QST found normal thermal-pain perceptive thresholds and skin biopsy disclosed normal intraepidermal nerve fibre density. Conversely, in patients with spinal-onset, thermal-pain thresholds were abnormal and distal intraepidermal nerve fibre density was reduced. Sensory nervous system involvement in ALS differs according to disease onset. Patients with spinal-onset but not those with bulbar-onset ALS have concomitant distal small-fibre neuropathy. Neurologists should therefore seek this ALS-related non-motor feature to improve its diagnosis and treatment.
Abstract Background In Parkinson's disease (PD), the influence of chronic pain on motor features has never been investigated. We have recently designed a technique that combines nociceptive system ...activation by laser stimuli and primary motor cortex (M1) activation through transcranial magnetic stimulation (TMS), in a laser-paired associative stimulation design (Laser-PAS). In controls, Laser-PAS induces long-term changes in motor evoked potentials reflecting M1 long-term potentiation-like plasticity, arising from pain-motor integration. Objective We here examined the possible influence of chronic pain on motor responses to Laser-PAS in patients with PD, with and without chronic pain. Methods We compared motor responses to Laser-PAS in healthy subjects and in patients with PD, with and without chronic pain. Results Unlike controls, we found reduced responses to Laser-PAS in patients with PD, with and without pain. Patients off and on dopaminergic therapy had similar responses to Laser-PAS. When comparing responses to Laser-PAS in patients with and without pain, the two patients' subgroups had similar abnormalities. When we compared patients with pain in the body region investigated with Laser-PAS, with those with pain in other body regions, we found prominent changes in patients with homotopic pain. Finally, when comparing Laser-PAS with the original PAS protocol, which combines electric peripheral nerve stimuli and TMS, in patients without pain and those with homotopic pain, we found similar responses to both techniques in patients without pain, whereas Laser-PAS induced greater abnormalities than PAS in patients with pain. Conclusions In PD, chronic pain degrades response to Laser-PAS through abnormal pain-motor integration.
Background
In the neurophysiological assessment of patients with neuropathic pain, laser evoked potentials (LEPs), contact heat evoked potentials (CHEPs) and the evoked potentials by the ...intraepidermal electrical stimulation via concentric needle electrode are widely agreed as nociceptive specific responses; conversely, the nociceptive specificity of evoked potentials by surface concentric electrode (SE‐PREPs) is still debated.
Methods
In this neurophysiological study we aimed at verifying the nociceptive specificity of SE‐PREPs. We recorded LEPs, CHEPs and SE‐PREPs in eleven healthy participants, before and after epidermal denervation produced by prolonged capsaicin application. We also used skin biopsy to verify the capsaicin‐induced nociceptive nerve fibre loss in the epidermis.
Results
We found that whereas LEPs and CHEPs were suppressed after capsaicin‐induced epidermal denervation, the surface concentric electrode stimulation of the same denervated skin area yielded unchanged SE‐PREPs.
Conclusion
The suppression of LEPs and CHEPs after nociceptive nerve fibre loss in the epidermis indicates that these techniques are selectively mediated by nociceptive system. Conversely, the lack of SE‐PREP changes suggests that SE‐PREPs do not provide selective information on nociceptive system function.
Significance
Capsaicin‐induced epidermal denervation abolishes laser evoked potentials (LEPs) and contact heat evoked potentials (CHEPs), but leaves unaffected pain‐related evoked potentials by surface concentric electrode (SE‐PREPs). These findings suggest that unlike LEPs and CHEPs, SE‐PREPs are not selectively mediated by nociceptive system.
We aimed at assessing the prevalence of peripheral neuropathy in newly diagnosed, treatment-naïve patients with multiple myeloma. We enrolled 153 patients with multiple myeloma at initial diagnosis. ...All patients underwent neurological examination and nerve conduction study. Patients with suspected pure small fiber neuropathy underwent skin biopsy. Of the 153 patients included in this study, 7.2 % had a multiple myeloma-related neuropathy. All patients suffered from a distal symmetric sensory peripheral neuropathy, associated with age (
P
= 0.04). Our study on prevalence rate of multiple myeloma-related peripheral neuropathy might provide a basis for improving the clinical management of this condition.
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