【作者】 王敏；

【导师】 洪思琦；

【作者基本信息】 重庆医科大学 ， 儿科学， 2015， 硕士

【摘要】 目的通过对抗癫痫药物(antiepileptic drugs, AEDs)诱导皮肤不良反应的患儿的临床资料进行回顾性分析,探讨抗癫痫药物诱导皮肤不良反应的常见致敏药物、临床特点、治疗及转归,为临床儿科合理用药提供参考。方法收集重庆医科大学附属儿童医院神经内科病房收治的5218名口服AEDs的癫痫患儿资料,对其中47例确诊为AEDs诱导的皮肤不良反应的患儿资料进行回顾性分析。根据致敏药物的数量将病例分为单药致敏组和多药致敏组；根据AEDs诱导的皮肤不良反应的临床表现的严重程度将病例分为轻型药疹组及抗癫痫药物高敏综合征(antiepileptic drug hypersensitivity syndrome, AHS)组,进而对不同组别中患儿的性别、年龄、致敏药物种类、临床特点、治疗方案及转归进行比较,使用SPSS 21.0软件包统计分析。结果1.47例AEDs诱导皮肤不良反应的患儿中,男性27例,女性20例；发病年龄0.18～15.00岁,平均年龄(5.32±4.21)岁。单药致敏组和多药致敏组、轻型药疹组和AHS组间年龄、性别无显著差异。2. AEDs诱导皮肤不良反应的发生率为,拉莫三嗪(LTG)14.81%；苯妥英钠(PHT)5.00%；卡马西平(CBZ)2.84%；奥卡西平(OXC)1.72%；苯巴比妥钠(PB)1.61%；丙戊酸钠(VPA)0.68%；左乙拉西坦(LEV)0.23%。不同种类的AEDs在引起皮疹严重程度方面无显著差异；致敏药物的数量在引起皮疹严重程度方面亦无显著差异。3. AEDs诱导皮肤不良反应潜伏期为1-90天,潜伏期为1-7天的占38.30%；1-2周占29.79%；2-3周占23.40%；3周以上占8.51%。4.皮疹发生率100%,分布于颜面、躯干及四肢。39例为发疹型皮疹；1例为荨麻疹；3例轻型多型性红斑；4例重症多形性红斑,伴口腔、眼周、肛周黏膜糜烂渗出,个别病例可见靶形损害及可疑尼氏征。发疹型皮疹多见于轻型药疹组(P<0.05),重症多形性红斑仅见于AHS组。出疹期6-29天,AHS组出疹期较轻型药疹组长(P<0.05)。5.其他表现：发热32例(68.01%),黏膜损害8例(17.02%),淋巴结肿大8例(17.02%),血液系统异常25例(53.19%),其中嗜酸性粒细胞增高10例(21.28%),肝功能损害24例(51.06%),肾功能异常10例(21.28%),心肌损害14例(29.79%)。发热、淋巴结肿大、血液系统异常、肝功能损害和心肌损害多见于AHS组(P<0.05),不同AEDs诱导的皮肤不良反应在临床表现上无显著差异。6.立即停用致敏药物可缩短出疹期(P<0.05)。26例(55.32%)患儿予以肾上腺糖皮质激素治疗,16例(34.04%)患儿予以人血免疫球蛋白(Intravenous immunoglobulin, IVIG)治疗。由于样本量较小,本研究未能确认肾上腺糖皮质激素与缩短出疹期的相关性；而在IVIG治疗方面,皮疹越重,使用IVIG的机率越大。7.本组研究中,替代治疗的AEDs为：LEV 9例,LEV+NZP 2例,LEV+TPM 1例,LEV+NZP+TPM 1例,NZP 15例,NZP+TPM 1例,TPM 9例,VPA 2例。换用其他AEDs后,均未再发生皮肤不良反应。结论1.AEDs诱导的皮肤不良反应为特异质反应,与年龄、性别、AEDs的数量及剂量无关。2.芳香族类AEDs诱导皮肤不良反应的风险较非芳香族类AEDs高,特别在口服芳香族类AEDs,包括LTG、PB、CBZ、OXC、PHT时需注意观察有无皮肤不良反应,而服用VPA、LEV等非芳香族类AEDs时也需警惕皮肤不良反应的发生。3.对于服用AEDs的患儿,在治疗早期应注意随访患儿有无发热、皮疹及淋巴结肿大,出现皮疹的患儿应同时监测血常规、嗜酸性细胞计数、肝肾功、心肌酶谱等检查,以早期识别AEDs诱导皮肤不良反应,尤其是AHS的发生。4.治疗AEDs诱导的皮肤不良反应的关键是早期识别和及早停用致敏或可疑致敏AEDs,结合患儿药疹的严重程度决定是否使用肾上腺糖皮质激素、IVIG等免疫治疗。5.发生AEDs诱导的皮肤不良反应后,可考虑使用的替代AEDs以苯二氮卓类药物更为安全。更多还原

【Abstract】 ObjectiveTo retrospectively analysis the clinical data of the children suffered from cutaneous adverse reactions induced by AEDs, and to explore the culprit drugs, clinical characteristics, the therapy and the prognosis, for providing reasonable clinical protocol in treating of cutaneous adverse reactions induced by AEDs in children.MethodsCollected the data of 5218 children who suffered from epilepsy, and charged in department of neurology in children’s hospital of Chongqing medical university. Retrospectively studying the data of 47 cases who were diagnosed cutaneous adverse reactions induced by AEDs. The 47 cases were divided into two groups according to the amount of the culprit AEDs, the single culprit drug group and the multiple culprit drug group. These cases were also divided into two groups according to the severity of clinical manifestation, the mild drug eruption group and AHS group. The data of the age, gender, culprit AEDs, clinical characteristics, the therapy and the outcome of different groups were analyzed and compared. SPSS 21.0 software package were used for data analysis.Results1.There were 27 male and 20 female children, the average ages were (5.32±4.21) years old. There were no significant difference in gender and age between single culprit drug group and multiple culprit drug group, and the same result can be seen between mild drug eruption group and AHS group.2.The incidence of cutaneous adverse reactions induced by different AEDs were:LTG 14.81%, PHT5.00%, CBZ2.84%, OXC1.72%, PB 1.61%, VPA 0.68%, LEV 0.23%. There were no significant difference in the severity of skin eruption between different species of AEDs and between different amounts of AEDs.3.The incubation period of cutaneous adverse reactions induced by different AEDs were 1-90 days. The incubation period between 1-7 days accounted for 38.30%,1-2 weeks accounted for 29.79%,2-3 weeks accounted for 23.40%, and>3weeks accounted for 8.51%.4.All the cases had skin eruption, and the eruptions were be seen on face, body and limbs.39 cases had exanthematous eruptions,1 case had urticaria,3 cases had mild erythema multiforme,4 cases had severe erythema multiforme. The exanthematous eruptions mostly existed in mild drug eruption group, and the severe erythema multiforme only existed in AHS group (P<0.05). The period of skin eruption of AHS group was longer than that of mild drug eruption group (P<0.05).5.Other clinical feature:fever in 32 cases (68.01%), mucosal injury in 8 cases (17.02%), lymphadenopathy in 8cases (17.02%), blood routine abnormalities in 25 cases (53.19%), abnormal liver function in 24 cases (51.06%), abnormal kidney function in 10 cases (21.28%), myocardial injury in 14 cases (29.79%). Fever, lymphadenopathy, blood routine abnormalities, abnormal liver function and myocardial injury mostly were seen in AHS group (P<0.05). There were no significant differences of clinical manifestations between different species AEDs.6.Withdrawing the culprit AEDs in the early stage of therapy could shorten the period of skin eruption (P<0.05). Glucocorticoid therapy were used in 26 cases (55.32%), and IVIG were used in 16 cases (34.04%). In this study, we did not find the role of Glucocorticoid using for shortening the period of skin eruption, for the sample is small. But we found that the skin eruption was more serious, the greater probability of IVIG using.7.In this study, the alternative AEDs were LEV in 9cases, LEV+NZP in 2 cases, LEV+TPM in 1cases, LEV+NZP+TPM in 1cases, NZP in 15 cases, NZP+TPM in 1 cases, TPM in 9cases, VPA in 2cases. No cutaneous adverse reactions happened after using alternative AEDs.Conclusion1. The cutaneous adverse reactions induced by AEDs were idiosyncratic reactions, and were not age-specific and gender-specific reactions. The cutaneous adverse reactions had no relevance with the amount and dosage of AEDs.2. The risk of cutaneous adverse reactions induced by AEDs is much higher in aromatic AEDs, including LTQ PB, CBZ, OXC, PHT. When taking any of these AEDs, we should pay attention to the possibility of the cutaneous adverse reactions, and we should pay attention to VPA and LEV as well.3. If fever, skin eruption, and lymphadenopathy be seen in the early stage of AEDs using, we should do the lab tests, including blood routine examination, liver function test, kidney function test and myocardical enzymes test for early recognize the cutaneous adverse reactions of AEDs, especially for AHS.4. The key point of therapy of the cutaneous adverse reactions induced by AEDs is withdrawing the culprit AEDs as soon as possible, and glucocorticoid and IVIG can be used according to the severity of the cutaneous adverse reactions.5. When there is the cutaneous adverse reactions induced by AEDs, we need to choose other AEDs replacing the culprit AEDs. Benzodiazepines may be more safe than other AEDs, and we should avoid choosing the AEDs which may have cross-reactivity with the culprit AEDs.更多还原