带状疱疹性神经痛病人痛区皮下纤维的神经功能评估

LOCAL NEUROSENSORY EVAULATION OF THE AFFECTED CUTANEOUS INNERVATIONS WITH HERPETIC NEURALGIA

目的:采用电流感觉阈值(current perception threshold,CPT)和皮肤活检对带状疱疹神经痛病人痛区皮下神经功能和形态进行评估。方法:120位T6节段病人和30位志愿者进行了CPT测试。对15位不同病程病人的最痛点和参考点进行皮肤活检,分别进行蛋白基因产物9.5(Protein gene product 9.5,PGP9.5)和生长相关蛋白43(Growth associated protein 43,GAP-43)免疫组化。结果:痛区5、250和2 000 Hz三种频率CPT值的受试者工作特征曲线下面积依次为0.74,0.80和0.87。确定高于60、79和200可鉴别出异常的神经功能变化。秩和检验显示不同病程痛点与参考点CPT比差异有统计学意义(P<0.05),HN-30天较HN-15天组3个频率的CPT比有明显增高(P<0.05)。250 Hz和2 000 Hz的CPT比在不同疼痛强度间差异有统计学意义(P<0.05)。伤害性感受器兴奋型或小纤维失神经支配型组病人3个频率的CPT比值与中枢整合型或无激惹型组病人比值比较差异有统计学意义(P<0.05)。正常皮区有丰富(34.2IENF/mm)的PGP9.5阳性纤维(intraepidermal nerve fiber,IENF)和少量的GAP-43阳性纤维(4.2IENF/mm)表达。不同病程PGP9.5和GAP-43阳性纤维的变化差异有统计学意义(P<0.0001)。HN-15天组病人PGP9.5阳性轴突肿胀明显,GAP-43阳性纤维数较正常皮区显著增高(8.5IENF/mm,P<0.05);HN-30天组GAP-43阳性IENF最高(21.7IENF/mm);HN>90天组PGP-9.5和GAP-43阳性IENF均较HN-90天组明显减少(P<0.05)。通过CPT和皮肤病理结果提示发病15~30天是HN的转换期,即急性炎症性疼痛向神经病理性疼痛演变。结论:本研究属于初步报告,表明CPT可反映痛区皮下神经纤维的功能状态。CPT比值对无髓纤维的异常敏化,即激惹型和混合型疼痛有一定的协助诊断作用。而GAP-43免疫组化结合IENFD可反映皮下神经纤维的损伤状态,结合CPT和皮肤病理可确定发病15~30天是HN的关键转换期,皮下纤维的功能和可塑性改变达到高峰,提示疼痛的病理生理学机制从急性炎症性疼痛向神经损伤性疼痛演变。

Objective:To evaluate functional and structural changes of local cutaneous innervation with herpetic neuralgia(HN)by current perception threshold(CPT)and skin biopsy.Methods:One hundred and twenty subjects with unilateral T6torso HN and30age-matched healthy volunteers were tested by standardized CPT.Fifteen patients within five different periods of HN,were taken skin biopsies from the most painful point and the reference point.Immunohistochemistry with the axonal marker PGP9.5and neuroplasticity marker GAP-43were identified.Results:The area under the receiver operating characteristic curve were0.74(5Hz),0.80(250Hz)and0.87(2000Hz)and were able to distinguish neurological changes of local epidermal nerve fiber when the CPT cut-off values were greater than60(5Hz),79(250Hz)and200(2000Hz).By comparison of the ratio of the painful point to the reference point within different groups,the results indicated significant differences in CPTs at3frequencies within different pain durations groups(P<0.05).Post hoc test showed significant differences in CPTs at3frequencies compared HN-15days with HN-30days(P<0.05),and at250Hz and2000Hz within different pain intensity groups(P<0.05).There wassignificant difference in the CPT ratio between the irritable nociceptor group or the deafferentation group,with the central reorganization group or the normal nociceptor group(P<0.05),respectively.There wasenough PGP9.5positive intraepidermal nerve fiber(IENF,34.2IENF/mm)and a few GAP-43immunoreactive(4.2IENF/mm)fibers in the normal skin area.ANOVA showed that the changes of PGP9.5and GAP-43-positive fibers were statistically significant in the different duration groups(P<0.0001).The axon for PGP9.5positive were swelling significantly in the HN-15days group,GAP-43postive IENF significantly increased compared to those in normal skin area(8.5IENF/mm,P<0.05);GAP-43-positive IENF count up to21.7/mm in the HN-30days group;PGP9.5and GAP-43IENF were significantly reduced in the HN>90daysgroup compared to those in the HN-90-day groups,respectively(P<0.05).15~30days after pain onset was the key transition period,which were changing from acute inflammatory pain to neuropathic pain for HN by CPT testing and skin biopsy.Conclusions:The results of this preliminary study showed that CPT testing and skin biopsy were useful tools to present the neurological function and impaired conditions of local IENF for HN,as indicated by PGP9.5and GAP-43.CPT ratio could be used as aided diagnosis on the abnormal sensitization of myelinated fibers for the irritable nociceptive or the deafferentation pain.Combined with CPTs and skin pathology can determine from15to30days is a key transition period of HN,the function and plasticity changes of subcutaneous fibers reached the peak,which suggested that the pathophysiology of HN had changed from acute inflammatory to nerve damage.