Cold intolerance and neuropathic pain after peripheral nerve injury in upper extremity

Cold intolerance and pain can be a substantial problem in patients with peripheral nerve injury. We aimed at investigating the relationships among sensory recovery, cold intolerance, and neuropathic pain in patients affected by upper limb peripheral nerve injury (Sunderland type V) treated with microsurgical repair, followed by early sensory re‐education. In a cross‐sectional clinical study, 100 patients (male/female 81/19; age 40.5 ± 14.8 years and follow‐up 17 ± 5 months, mean ± SD), with microsurgical nerve repair and reconstruction in the upper extremity and subsequent early sensory re‐education, were evaluated, using Cold Intolerance Symptoms Severity questionnaire‐Italian version (CISS‐it, cut‐off pathology >30/100 points), CISS questionnaire‐12 item version (CISS‐12, 0‐46 points‐grouping: healthy that means no cold intolerance [0‐14], mild [15‐24], moderate [25‐34], severe [35‐42], very severe [43‐46] cold intolerance), probability of neuropathic pain (DouleurNeuropathique‐4; [DN4] 4/10), deep and superficial sensibility, tactile threshold (monofilaments), and two‐point discrimination (cutoff S2; Medical Research Council scale for sensory function; [MRC‐scale]). A high CISS score is associated with possible neuropathic pain (DN4 ≥ 4). Both a low CISS‐it score (ie, < 30) and DN4 < 4 is associated with good sensory recovery (MRC ≥ 2). In conclusion patients affected by upper limb peripheral nerve injuries with higher CISS scores more often suffer from cold intolerance and neuropathic pain, and the better their sensory recovery is, the less likely they are to suffer from cold intolerance and neuropathic pain.     

Differential induction of c-Fos and phosphorylated ERK by a noxious stimulus after peripheral nerve injury

Purpose: In this study, we compared induction of c-Fos and phosphorylated extracellular signal-regulated kinase (p-ERK) in the spinal dorsal horn after peripheral nerve injury.

Materials and methods: We examined the spinal dorsal horn for noxious heat-induced c-Fos and p-ERK protein-like immunoreactive (c-Fos- and p-ERK-IR) neuron profiles after tibial nerve injury. The effect of administration of a MEK 1/2 inhibitor (PD98059) on noxious heat-induced c-Fos expression was also examined after tibial nerve injury.

Results: A large number of c-Fos- and p-ERK-IR neuron profiles were induced by noxious heat stimulation to the hindpaw in sham-operated animals. A marked reduction in the number of c-Fos- and p-ERK-IR neuron profiles was observed in the medial 1/3 (tibial territory) of the dorsal horn at 3 and 7 days after nerve injury. Although c-Fos-IR neuron profiles had reappeared by 14 days after injury, the number of p-ERK-IR neuron profiles remained decreased in the tibial territory of the superficial dorsal horn. Double immunofluorescence labeling for c-Fos and p-ERK induced by noxious heat stimulation to the hindpaw at different time points revealed that a large number of c-Fos-IR, but not p-ERK-IR, neuron profiles were distributed in the tibial territory after injury. Although administration of a MEK 1/2 inhibitor to the spinal cord suppressed noxious heat-induced c-Fos expression in the peroneal territory, this treatment did not alter c-Fos induction in the tibial territory after nerve injury.

Conclusions: ERK phosphorylation may be involved in c-Fos induction in normal nociceptive responses, but not in exaggerated c-Fos induction after nerve injury.     

Increased miR‐195 aggravates neuropathic pain by inhibiting autophagy following peripheral nerve injury

Following peripheral nerve injury (PNI) microglia proliferates and adopts inflammation that contributes to development and maintenance of neuropathic pain. miRNAs and autophagy are two important factors in the regulation of inflammation. However, little is known about whether miRNAs regulate neuroinflammation and neuropathic pain by controlling autophagy. In the study, we demonstrated that miR‐195 levels were markedly increased in rats subjected to L5 spinal nerve ligation (SNL). Upregulated miR‐195 was also found in spinal microglia of rats with SNL. The overexpression of miR‐195 contributed to lipopolysaccharide‐induced expression of proinflammatory cytokines IL‐1β, TNF‐α, and iNOS in cultured microglia. Upregulated miR‐195 also resulted in increased mechanical and cold hypersensitivity after PNI, whereas miR‐195 inhibition reduced mechanical and cold sensitivity. We further demonstrated that PNI significantly inhibited microglial autophagy activation, whereas miR‐195 inhibitor treatment increased autophagy activation and suppressed neuroinflammation in vivo and in vitro. More important, autophagy inhibition impaired miR‐195 inhibitor‐induced downregulation of neuroinflammation and neuropathic pain. Additionally, ATG14 was identified as the functional target of miR‐195. Conclusions: These data demonstrated that miR‐195/autophagy signaling represents a novel pathway regulating neuroinflammation and neuropathic pain, thus offering a new target for therapy of neuropathic pain.     

Skin biopsy and quantitative sensory testing do not predict response to lidocaine patch in painful neuropathies

Predictors of response to neuropathic pain treatment in patients with painful distal sensory neuropathies are lacking. The 5% lidocaine patch is believed to exert its effects on neuropathic pain via a local stabilizing effect on cutaneous sensory afferents. As such, it provides a model to assess whether the status of epidermal innervation as determined by skin biopsy or quantitative sensory testing (QST) of small- and large-diameter sensory afferents might serve as predictors of response to topical, locally active treatment. In this study we assessed associations between epidermal nerve fiber (ENF) densities, sensory nerve conduction studies (NCS), QST, and response to a 5% lidocaine patch in patients with painful distal sensory neuropathies. We observed no association between distal leg epidermal and subepidermal innervation and response to the lidocaine patch. Several patients with complete loss of distal leg ENF showed a response to the lidocaine patch. Similarly we observed no consistent association between treatment response and QST for vibration, cooling, warm, heat-pain, and cold-pain thresholds, or distal sensory NCS. Thus, distal-leg skin biopsy, QST, and sensory NCS cannot be used to identify patients with painful polyneuropathy likely to respond to a lidocaine patch in clinical practice. Further studies are required to clarify precisely the mechanism and site of action of the lidocaine patch in patients with peripheral neuropathic pain.     

Supraspinal nociceptive networks in neuropathic pain after spinal cord injury

Neuropathic pain following spinal cord injury involves plastic changes along the whole neuroaxis. Current neuroimaging studies have identified grey matter volume (GMV) and resting‐state functional connectivity changes of pain processing regions related to neuropathic pain intensity in spinal cord injury subjects. However, the relationship between the underlying neural processes and pain extent, a complementary characteristic of neuropathic pain, is unknown. We therefore aimed to reveal the neural markers of widespread neuropathic pain in spinal cord injury subjects and hypothesized that those with greater pain extent will show higher GMV and stronger connectivity within pain related regions. Thus, 29 chronic paraplegic subjects and 25 healthy controls underwent clinical and electrophysiological examinations combined with neuroimaging. Paraplegics were demarcated based on neuropathic pain and were thoroughly matched demographically. Our findings indicate that (a) spinal cord injury subjects with neuropathic pain display stronger connectivity between prefrontal cortices and regions involved with sensory integration and multimodal processing, (b) greater neuropathic pain extent, is associated with stronger connectivity between the posterior insular cortex and thalamic sub‐regions which partake in the lateral pain system and (c) greater intensity of neuropathic pain is related to stronger connectivity of regions involved with multimodal integration and the affective‐motivational component of pain. Overall, this study provides neuroimaging evidence that the pain phenotype of spinal cord injury subjects is related to the underlying function of their resting brain.     

定量感觉及神经传导检测在糖尿病患者中的应用比较

目的:分析定量感觉检查(QST)及神经传导检测(NCS)在糖尿病患者中的应用价值.方法:用QST对100例2型糖尿病(T2DM)组和50例正常对照组分别进行四肢的冷觉(CS)、温觉(WS)、冷痛觉(CP)、热痛觉(HP)的感觉阈值测定并进行比较分析;并对T2DM患者进行上肢的正中神经、尺神经,下肢的胫神经、腓神经运动和感觉支的NCS、复合肌肉动作电位(CMAP)、感觉神经动作电位(SNAP)以及运动末梢潜伏期(DML)进行测定并分析.T2DM患者分为有症状组和无症状组,分别对QST及NCS的异常率进行分析并比较.结果:T2DM组QST和NCS结果与正常对照组比较差异有显著意义(P＜0.01); QST与NCS异常率比较差异有显著意义(P＜0.01),QST的异常率均显著大于NCS;提示糖尿病周围神经病(DPN)患者中周围神经小纤维受损比大纤维更明显,T2DM患者有症状组和无症状组各值比较差异均有显著意义(P＜0.01).结论:QST对DPN的早期诊断提供可靠依据,QST对DPN的诊断敏感性高,但特异性低,需与NCS结合对糖尿病周围神经状况进行评价更为完善.QST和NCS不能相互替代,全面了解DPN病情需QST和NCS结合,并密切结合临床.     

Loss of sensory function in patients with idiopathic hand dystonia

Former studies suggest an additional involvement of the sensory nervous system, beside the involuntary contractions of antagonist muscles, in idiopathic hand dystonia. We studied contact heat‐evoked potentials and quantitative sensory testing (QST) in 10 patients suffering from idiopathic hand dystonia and 10 age‐matched healthy controls. Cortical potentials recorded from the vertex (Pz) after contact heat stimulation of the volar forearm and the dorsum of the hand at a temperature of 51°C showed significantly reduced A‐δ‐amplitudes. Numerical pain ratings on the affected side in comparison to the unaffected side and to healthy controls were significantly reduced. QST results showed an impairment of the thermal detection thresholds, the mechanical pain sensitivity and the mechanical pain threshold at the affected body side of the patients. Our results suggest a loss of distinct sensory functions of the affected hand in comparison with the contralateral hand and to matched healthy subjects in patients suffering from idiopathic hand dystonia. For the first time, an extended loss of sensory function could be shown in patients suffering from idiopathic hand dystonia. © 2010 Movement Disorder Society.     

Ulnar nerve impairment at the wrist does not contribute to extramedian sensory symptoms in carpal tunnel syndrome

ObjectiveExtramedian spread of sensory symptoms is frequent in carpal tunnel syndrome (CTS) but its mechanisms are unclear. We explored the possible role of subtle ulnar nerve abnormalities in the pathogenesis of extramedian symptoms.MethodsWe recruited 350 CTS patients. After selection, 143 patients (225 hands) were included. The hand symptoms distribution was graded with a diagram into median (MED) and extramedian (EXTRAMED) pattern. We tested the correlation of ulnar nerve conduction measures with the distribution and the severity of symptoms involving the ulnar territory. The clinical significance of ulnar nerve conduction findings was explored with quantitative sensory testing (QST).ResultsEXTRAMED distribution was found in 38.7% of hands. The ulnar neurographic measures were within normal values. Ulnar nerve sensory measures were significantly better in EXTRAMED vs MED hands and not significantly correlated to ulnar symptoms severity. Ulnar and median nerve sensory measures were significantly correlated. QST showed normal function of ulnar nerve Aβ-fibers.ConclusionsUlnar nerve sensory abnormalities do not contribute to the spread of sensory symptoms into the ulnar territory.SignificanceOur data favour the hypothesis that spinal and supraspinal neuroplastic changes may underlie extramedian spread of symptoms in CTS.     

Sensory perception in complete spinal cord injury

OBJECTIVES: To describe sensations evoked by painful or repetitive stimulation below injury level in patients with a clinically complete (American Spinal Injury Association, ASIA Grade A) spinal cord injury (SCI). MATERIAL AND METHODS: Twenty-four patients (11 with central neuropathic pain and 13 without pain) with a traumatic SCI above the tenth thoracic vertebra were examined using quantitative sensory testing, MR imaging, and somatosensory evoked potentials (SEP). RESULTS: Painful (pressure, pinch, heat or cold) or repetitive (pinprick) stimuli elicited vague localized sensations in 12 patients (50%). Pain, spasticity, and spasms were equally seen in SCI patients with or without localized sensations. SEP and MRI did not differentiate between these two groups. CONCLUSION: The present study suggests retained sensory communication across the injury in complete SCI, i.e. 'sensory discomplete' SCI.     

施万细胞在修复外周神经损伤中作用机制的研究进展

外周神经损伤后若不能及时准确的修复,则会导致外周神经功能的永久丧失。目前研究显示施万细胞(SC)参与外周神经损伤后碎片清除、轴突和髓鞘再生以及靶器官再支配过程中,外周神经损伤后SC被迅速激活进入修复过程,经历一系列动态的细胞重塑变化,转化为修复表型,促进神经再生、引导对靶器官再支配,从而恢复神经功能,其中有许多信号通路,转录调节因子等调控这些过程。基于此,该文系统总结了SC在外周神经再生过程中的研究进展,为深入研究外周神经修复提供新的方法和策略。     

Neuropathic pain in spinal cord injury: significance of clinical and electrophysiological measures

A large percentage of spinal cord-injured subjects suffer from neuropathic pain below the level of the lesion (bNP). The neural mechanisms underlying this condition are not clear. The aim of this study was to elucidate the general effects of spinal deafferentiation and of bNP on electroencephalographic (EEG) activity. In addition, the relationship between the presence of bNP and impaired function of the spinothalamic tract was studied. Measurements were performed in complete and incomplete spinal cord-injured subjects with and without bNP as well as in a healthy control group. Spinothalamic tract function, assessed by contact heat evoked potentials, did not differ between subjects with and without bNP; nevertheless, it was impaired in 94% of subjects suffering from bNP. In the EEG recordings, the degree of deafferentiation was reflected in a slowing of EEG peak frequency in the 6–12-Hz band. Taking into account this unspecific effect, spinal cord-injured subjects with bNP showed significantly slower EEG activity than subjects without bNP. A discrimination analysis in the subjects with spinothalamic tract dysfunction correctly classified 84% of subjects as belonging to either the group with bNP or the group without bNP, according to their EEG peak frequency. These findings could be helpful for both the development of an objective diagnosis of bNP and for testing the effectiveness of new therapeutic agents.     

Neuronal changes resulting in up-regulation of alpha-1 adrenoceptors after peripheral nerve injury

Under normal conditions, the sympathetic neurotransmitter noradrenaline inhibits the production and release of pro-inflammatory cytokines. However, after peripheral nerve and tissue injury, pro-inflammatory cytokines appear to induce the expression of the alphalA-adreno- ceptor subtype on immune cells and perhaps also on other cells in the injured tissue. In turn, noradrenaline may act on up-regulated alphal-adrenoceptors to increase the production of the pro-inflammatory cytokine interleukin-6. In addition, the release of inflammatory mediators and nerve growth factor from keratinocytes and other cells may augment the expression of alphal-adrenoceptors on peripheral nerve fibers. Consequently, nociceptive afferents acquire an abnormal excitability to adrenergic agents, and inflammatory processes build. These mechanisms could contribute to the development of sympathetically maintained pain in conditions such as post-herpetic neuralgia, cutaneous neuromas, amputation stump pain and complex regional pain syndrome.     

Somatosensory evoked potentials induced by stimulating a variable number of nerve fibers in rat

Somatosensory evoked potentials (SEPs) were recorded from rat spinal cord (sSEPs) and cerebral cortex (cSEPs). Stimulus sites included either one or both sural nerve branches having different fiber populations (group A), or distal to a lesion of controlled size of the sural nerve made 1 week earlier (group B). In the two groups of animals, amplitudes of SEPs correlated with the quantity of large myelinated nerve fibers. Peak latencies of sSEPs in group A related to the ratio of sizes of transmitting fibers. sSEPs and cSEPs in both groups A and B could be recorded in a reproducible fashion by stimulating sural nerve branches or lesioned nerve trunks containing only 100 or less nerve fibers greater than 4 m?m in size. Thus, presence of sSEPs or cSEPs after stimulation distal to a lesion site does not insure that many nerve fibers have continuity with the central nervous system (CNS). © 1993 John Wiley & Sons, Inc.     

定量感觉检查对糖尿病周围神经病的早期诊断价值

目的　探讨定量感觉检查(QST)对糖尿病周围神经病的早期诊断价值。方法　对46例糖尿病 患者神经传导速度(NCV)和QST进行检测,并将其结果进行对比研究。结果　46例糖尿病患者中NCV异常 率为72.8%(35/46),NCV诊断糖尿病周围神经病32例(69.6%);QST异常率为91.3%(42/46),QST诊断 糖尿病周围神经病40例(86.9%),两者差异有显著性(P<0.05)。结论　QST较NCV对糖尿病周围神经病 变的诊断敏感性高;糖尿病患者温度觉异常率显著高于振动觉和NCV;提示其小神经纤维受损比大神经纤维 受损更常见。     

Aspects of peripheral nerve involvement in patients with treated hypothyroidism

Background:  We studied involvement of large and small nerve fibres in patients with hypothyroidism and symptoms and signs of polyneuropathy.
Methods:  Sixteen patients with established diagnosis of hypothyroidism were extracted from a patient population participating in a 'polyneuropathy study'. In addition, seven patients with other additional potential causes of polyneuropathy than hypothyroidism were investigated. The patients underwent neurological examination, routine blood tests, nerve conduction studies (NCS), quantitative sensory testing (QST) and skin biopsies with assessment of intraepidermal nerve fibre (IENF) density.
Results:  Sixty-three per cent of the patients with 'pure' hypothyroidism had abnormalities on NCS, 25% had reduced IENF density and 31% had abnormalities on QST. Four patients (25%) met criteria for small fibre polyneuropathy, the other (75%) were classified as having mixed fibre polyneuropathy. There were no differences in the amount of abnormalities on NCS, QST and skin biopsy between patients with hypothyroidism and those with hypothyroidism and other potential causes of polyneuropathy.
Conclusions:  The majority of patients with hypothyroidism had involvement of both large and small nerve fibres. However, some patients had isolated small fibre polyneuropathy. Patients with 'pure' hypothyroidism had essentially the same degree of peripheral nerve fibre involvement as those with other additional causes of polyneuropathy.     

The effect of peripheral nerve injury on dorsal root potentials and on transmission of afferent signals into the spinal cord

The sciatic nerve adults rats was either cut and ligated or was crushed on one side. The response of the spinal cord to stimulation of the proximal part of the injured nerve was examined at various times after the lesion and compared to the effects of stimulating the intact nerve on the other side. During the first 10 days after nerve section the following measures were not affected: (i) the size of the input volley (compound action potential, CAP, measured on a dorsal root that carried sciatic nerve afferents (L5); (ii) the volley running in the dorsal columns; (iii) the dorsal root potential (DRP) evoked on neighbouring dorsal roots which do not contain sciatic afferents (L2 and L3); (iv) the post-synaptic volleys ascending in the spinal cord. However, by the fourth day after nerve section, there was a decrease of the DRP evoked on the ipsilateral L5 dorsal root by stimulation of the cut nerve. By 10 days this DRP had decreased by 50%. There was also a decrease in the DRP on the L5 root evoked by stimulation of the contralateral intact nerve. Crush lesions of the sciatic nerve did not produce DRP charge. Beginning 10–20 days after nerve cut, there was a decrease in the amplitude of the afferent CAP and of all the measures of central response to the afferent volley. We discuss the possibility that the loss of the DRP may be associated with a disinhibition which results in novel receptive fields which we observe in cord cells deafferented by the peripheral nerve section. The decrease of DRP and the appearance of novel receptive fields do not occur if the peripheral nerve is crushed rather than cut.     

Effects of continuous peripheral nerve block by tetrodotoxin on growth associated protein-43 expression during neuropathic pain development

BACKGROUND: Peripheral nerve injury may lead to neuropathic pain and cause a markedly increase expression of growth associated protein-43 (GAP-43) in the spinal cord and dorsal root ganglion, local anesthetics blocking electrical impulse propagation of nerve fibers may also affect the expression of GAP-43 in the spinal cord and dorsal root ganglion. OBJECTIVE: To determine the effects of continuous peripheral nerve block by tetrodotoxin before and after nerve injury on GAP-43 expression in the dorsal root ganglion during the development of neuropathic pain. DESIGN: A randomized controlled animal experiment. SETTINGS: Department of Anesthesiology, the Second Hospital of Xiamen City; Department of Anesthesiology, the Second Affiliated Hospital of Shantou University Medical College. MATERIALS: Thirty-five Sprague Dawley (SD) rats, weighing 200–250 g, were randomly divided into four groups: control group (n =5), simple sciatic nerve transection group (n =10), peripheral nerve block before and after sciatic nerve transection groups (n =10). All the sciatic nerve transection groups were divided into two subgroups according to the different postoperative survival periods: 3 and 7 days (n =5) respectively. Mouse anti-GAP-43 monoclonal antibody (Sigma Co., Ltd.), supervision TM anti-mouse reagent (HRP, Changdao antibody diagnosis reagent Co., Ltd., Shanghai), and HMIAS-100 image analysis system (Qianping Image Engineering Company, Tongji Medical University) were employed in this study. METHODS: This experiment was carried out in the Department of Surgery and Pathological Laboratory, the Second Affiliated Hospital of Shantou University Medical College from April 2005 to April 2006. ①The animals were anesthetized and the right sciatic nerve was exposed and transected at 1 cm distal to sciatic notch. ② Tetrodotoxin 10 μg/kg was injected percutaneously between the greater trochanter and the posterior superior iliac spine of right hind limb to block the sciatic nerve proximally at 1 hour before or 4 hours after nerve injury respectively, the injection was repeated in all the rats every 12 hours. ③ At 3 or 7 days after nerve injury, immunohistochemistry and image analysis were used to evaluate the expression of GAP-43 in the dorsal root ganglions of L5 to the transected sciatic nerve, and quantitative analysis was also performed. ④ Statistical analysis was performed using one way analysis of variance followed by t test. MAIN OUTCOME MEASURE: Expression of GAP-43 in the right dorsal root ganglions of L5. RESULTS: All the 35 SD rats were involved in the final analysis of results. In normal rats, there were very low expressions of GAP-43 in the dorsal root ganglions. In simple sciatic nerve transection rats 3 and 7 days after sciatic nerve transection, the average absorbance value of GAP-43 immunopositive neurons were significantly different from that in normal rats (t =8.806, 6.771, P < 0.01). Whereas 3 and 7 days after sciatic nerve transection in rats with peripheral nerve block before and after nerve injury, the average absorbance value of GAP-43 immunopositive neurons were not significantly different from that in normal rats (P > 0.05). CONCLUSION: Local anesthetic continuous peripheral nerve block before or after nerve injury can suppress nerve injury induced high expression of GAP-43 during the development of neuropathic pain.