神经阻滞剂恶性综合征

神经阻滞剂恶性综合征王学敏江伟（上海市第六人民医院麻醉科，上海200233）神经阻滞剂恶性综合征（neurolepticmalignantsyndrome,NMS）是一种服用神经阻滞剂后产生的少见却可能致命的并发症。1960年Delay等[ADDINEN.CITE<EndNote><Cite><Author>Delay</Author><Year>1960</Year><RecNum>56</RecNum><MDL><REFERENCE_TYPE>0</REFERENCE_TYPE><REFNUM>56</REFNUM><AUTHORS><styles><stylefont='12124'start='5'></style><stylestart='6'></style><stylefont='12124'start='15'></style><stylestart='16'></style><stylefont='12124'start='29'></style><stylestart='30'></style><stylefont='12124'start='41'></style><stylestart='42'></style><stylefont='12124'start='51'></style><stylestart='52'></style></styles><AUTHOR>Delay,J</AUTHOR><AUTHOR>Pichot,P</AUTHOR><AUTHOR>Lemperiere,T</AUTHOR><AUTHOR>Elissade,B</AUTHOR><AUTHOR>Peigne,F</AUTHOR></AUTHORS><YEAR><styles><stylefont='12123'start='2'></style></styles>1960</YEAR><TITLE>Unneuroleptiquemajeurnon-phenothiazineetnonreserpinique,l'haloperidol,dansletraitementdespsychoses</TITLE><SECONDARY_TITLE>AnnalesMedico-Psychologique</SECONDARY_TITLE><VOLUME><styles><stylefont='12123'></style></styles>118</VOLUME><NUMBER>10</NUMBER><PAGES><styles><stylefont='12123'start='1'></style><stylestart='3'></style><stylefont='12123'start='4'></style></styles>145-52</PAGES><DATE>Oct</DATE><ACCESSION_NUMBER>2863986</ACCESSION_NUMBER><KEYWORDS><KEYWORD>Adolescent</KEYWORD><KEYWORD>Adult</KEYWORD><KEYWORD>Aged</KEYWORD><KEYWORD>AntipsychoticAgents/adverseeffects/pharmacology</KEYWORD><KEYWORD>BasalGangliaDiseases/*diagnosis</KEYWORD><KEYWORD>Bromocriptine/therapeuticuse</KEYWORD><KEYWORD>Child</KEYWORD><KEYWORD>Dantrolene/therapeuticuse</KEYWORD><KEYWORD>Diagnosis,Differential</KEYWORD><KEYWORD>Dopamine/physiology</KEYWORD><KEYWORD>DopamineAntagonists</KEYWORD><KEYWORD>Female</KEYWORD><KEYWORD>Humans</KEYWORD><KEYWORD>Male</KEYWORD><KEYWORD>MalignantHyperthermia/diagnosis</KEYWORD><KEYWORD>MiddleAged</KEYWORD><KEYWORD>NeurolepticMalignantSyndrome/*diagnosis/drugtherapy/physiopathology</KEYWORD><KEYWORD>PsychoticDisorders/drugtherapy</KEYWORD><KEYWORD>Receptors,Dopamine/drugeffects/physiology</KEYWORD><KEYWORD>Rhabdomyolysis/diagnosis</KEYWORD><KEYWORD>Schizophrenia/drugtherapy</KEYWORD></KEYWORDS><URL>/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=2863986</URL></MDL></Cite></EndNote>1]进行氟哌啶醇的实验时发现并首先报道。1980年后随着对NMS认识加深，大量临床案例被报道。发病机制NMS发病机制多认为与神经阻滞剂导致中枢神经调节机制改变有关；也有认为与骨骼肌不正常反应有关。中枢多巴胺受体阻滞中枢黑质纹状体途径多巴胺受体阻滞是NMS发病机制中最为广泛接受的观点。该理论是Henderson和Wooten首先提出[ADDINEN.CITE<EndNote><Cite><Author>Henderson</Author><Year>1981</Year><RecNum>60</RecNum><MDL><REFERENCE_TYPE>0</REFERENCE_TYPE><REFNUM>60</REFNUM><ACCESSION_NUMBER>6110195</ACCESSION_NUMBER><VOLUME>31</VOLUME><NUMBER>2</NUMBER><YEAR>1981</YEAR><DATE>Feb</DATE><TITLE>Neurolepticmalignantsyndrome:apathogeneticrolefordopaminereceptorblockade?</TITLE><PAGES>132-7</PAGES><AUTHORS><AUTHOR>Henderson,V.W.</AUTHOR><AUTHOR>Wooten,G.F.</AUTHOR></AUTHORS><SECONDARY_TITLE>Neurology</SECONDARY_TITLE><KEYWORDS><KEYWORD>AntipsychoticAgents/*adverseeffects/pharmacology</KEYWORD><KEYWORD>BasalGangliaDiseases/etiology/*metabolism</KEYWORD><KEYWORD>BodyTemperatureRegulation</KEYWORD><KEYWORD>CreatineKinase/blood</KEYWORD><KEYWORD>Fever/etiology/*metabolism</KEYWORD><KEYWORD>Haloperidol/adverseeffects</KEYWORD><KEYWORD>Humans</KEYWORD><KEYWORD>Hypothalamus/physiology</KEYWORD><KEYWORD>Lithium/adverseeffects</KEYWORD><KEYWORD>Male</KEYWORD><KEYWORD>MiddleAged</KEYWORD><KEYWORD>Receptors,Dopamine/*drugeffects/physiology</KEYWORD><KEYWORD>ResearchSupport,Non-U.S.Gov't</KEYWORD><KEYWORD>Syndrome</KEYWORD></KEYWORDS><URL>/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=6110195</URL></MDL></Cite></EndNote>2]。神经阻滞剂阻滞视丘下部多巴胺受体可影响体温调节，阻滞纹状体多巴胺受体可引起锥体外系反应。但其作用可能不仅限于此，神经阻滞剂对下丘脑和纹状体多巴胺受体阻滞不能解释NMS所有症状。有人提出5羟色胺和多巴胺的平衡是影响NMS发病重要因素[ADDINEN.CITE<EndNote><Cite><Author>Ames</Author><Year>1993</Year><RecNum>62</RecNum><MDL><REFERENCE_TYPE>0</REFERENCE_TYPE><REFNUM>62</REFNUM><ACCESSION_NUMBER>8426445</ACCESSION_NUMBER><VOLUME>269</VOLUME><NUMBER>7</NUMBER><YEAR>1993</YEAR><DATE>Feb17</DATE><TITLE>Ecstasy,theserotoninsyndrome,andneurolepticmalignantsyndrome--apossiblelink?</TITLE><PAGES>869-70</PAGES><AUTHORS><AUTHOR>Ames,D.</AUTHOR><AUTHOR>Wirshing,W.C.</AUTHOR></AUTHORS><SECONDARY_TITLE>Jama</SECONDARY_TITLE><KEYWORDS><KEYWORD>3,4-Methylenedioxyamphetamine/*adverseeffects</KEYWORD><KEYWORD>CentralNervousSystem/*drugeffects</KEYWORD><KEYWORD>Humans</KEYWORD><KEYWORD>*NeurolepticMalignantSyndrome</KEYWORD><KEYWORD>Receptors,Serotonin/*physiology</KEYWORD></KEYWORDS><URL>/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=8426445</URL></MDL></Cite></EndNote>3]。在黑质纹状体途径，多巴胺受体阻滞或5羟色胺过度释放可造成相似的临床表现，给患者服用5羟色胺再摄取抑制剂可促进NMS的发生[ADDINEN.CITE<EndNote><Cite><Author>Kontaxakis</Author><Year>2003</Year><RecNum>63</RecNum><MDL><REFERENCE_TYPE>0</REFERENCE_TYPE><REFNUM>63</REFNUM><AUTHORS><AUTHOR>Kontaxakis,V.P.</AUTHOR><AUTHOR>Havaki-Kontaxaki,B.J.</AUTHOR><AUTHOR>Pappa,D.A.</AUTHOR><AUTHOR>Katritsis,D.E.</AUTHOR><AUTHOR>Christodoulou,G.N.</AUTHOR></AUTHORS><YEAR>2003</YEAR><TITLE>Neurolepticmalignantsyndromeafteradditionofparoxetinetoolanzapine</TITLE><SECONDARY_TITLE>JClinPsychopharmacol</SECONDARY_TITLE><VOLUME>23</VOLUME><NUMBER>6</NUMBER><PAGES>671-2</PAGES><DATE>Dec</DATE><ACCESSION_NUMBER>14624202</ACCESSION_NUMBER><KEYWORDS><KEYWORD>Benzodiazepines/administration&dosage/*adverseeffects</KEYWORD><KEYWORD>DrugTherapy,Combination</KEYWORD><KEYWORD>Female</KEYWORD><KEYWORD>Humans</KEYWORD><KEYWORD>MiddleAged</KEYWORD><KEYWORD>NeurolepticMalignantSyndrome/*etiology</KEYWORD><KEYWORD>Paroxetine/administration&dosage/*adverseeffects</KEYWORD><KEYWORD>SerotoninUptakeInhibitors/administration&dosage/*adverseeffects</KEYWORD></KEYWORDS><URL>/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=14624202</URL><IMAGE>200312000-00022.pdf</IMAGE></MDL></Cite></EndNote>4]。原发性骨骼肌缺陷NMS和恶性高热临床表现类似，如高热、肌强直、肌酸激酶升高、死亡率10-30％等；两种疾病应用丹曲林钠治疗都有效；两类患者肌肉都有异常收缩反应。提示两者可能有相似的病理生理学机制[ADDINEN.CITE<EndNote><Cite><Author>Adnet</Author><Year>2000</Year><RecNum>2</RecNum><MDL><REFERENCE_TYPE>0</REFERENCE_TYPE><REFNUM>2</REFNUM><AUTHORS><AUTHOR>Adnet,P.</AUTHOR><AUTHOR>Lestavel,P.</AUTHOR><AUTHOR>Krivosic-Horber,R.</AUTHOR></AUTHORS><YEAR>2000</YEAR><TITLE>Neurolepticmalignantsyndrome</TITLE><SECONDARY_TITLE>BrJAnaesth</SECONDARY_TITLE><VOLUME>85</VOLUME><NUMBER>1</NUMBER><PAGES>129-35</PAGES><DATE>Jul</DATE><ACCESSION_NUMBER>10928001</ACCESSION_NUMBER><KEYWORDS><KEYWORD>Diagnosis,Differential</KEYWORD><KEYWORD>Humans</KEYWORD><KEYWORD>NeurolepticMalignantSyndrome/diagnosis/*etiology/therapy</KEYWORD><KEYWORD>RiskFactors</KEYWORD></KEYWORDS><URL>/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=10928001</URL><AUTHOR_ADDRESS>DepartmentofAnesthesiologyandEmergencyMedicine,UniversityHospital,Lille,France.</AUTHOR_ADDRESS><IMAGE>2782063415129.pdf</IMAGE><CAPTION>+*NMS</CAPTION></MDL></Cite></EndNote>5]。神经阻滞剂可能影响NMS患者肌细胞钙转运，造成肌强直、横纹肌溶解和高热等反应。氟烷-咖啡因实验是测试患者是否易感恶性高热最可靠的实验。一些研究者检测了NMS患者肌纤维对氟烷和咖啡因的敏感性，但结果并不一致。还有人提出神经阻滞剂可能直接对肌肉产生毒性作用。有实验提示NMS可能与基因改变有关[ADDINEN.CITE<EndNote><Cite><Author>Kawanishi</Author><Year>2003</Year><RecNum>38</RecNum><MDL><REFERENCE_TYPE>0</REFERENCE_TYPE><REFNUM>38</REFNUM><AUTHORS><AUTHOR>Kawanishi,C.</AUTHOR></AUTHORS><YEAR>2003</YEAR><TITLE>Geneticpredispositiontoneurolepticmalignantsyndrome:implicationsforantipsychotictherapy</TITLE><SECONDARY_TITLE>AmJPharmacogenomics</SECONDARY_TITLE><VOLUME>3</VOLUME><NUMBER>2</NUMBER><PAGES>89-95</PAGES><ACCESSION_NUMBER>12749726</ACCESSION_NUMBER><KEYWORDS><KEYWORD>Animals</KEYWORD><KEYWORD>AntipsychoticAgents/adverseeffects/metabolism/*therapeuticuse</KEYWORD><KEYWORD>GeneticPredispositiontoDisease/*genetics</KEYWORD><KEYWORD>Humans</KEYWORD><KEYWORD>NeurolepticMalignantSyndrome/*genetics/metabolism</KEYWORD></KEYWORDS><URL>/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=12749726</URL><AUTHOR_ADDRESS>DepartmentofPsychiatry,YokohamaCityUniversitySchoolofMedicine,Yokohama,Japan.chiaki@med.yokohama-cu.ac.jp</AUTHOR_ADDRESS><IMAGE>2430091576idSearchResults.mht</IMAGE></MDL></Cite></EndNote>6]。危险因素由于研究对象、研究方法以及诊断标准的不同，NMS发病率报道不一。综合现有资料看，其发病率约为0.2％[ADDINEN.CITE<EndNote><Cite><Author>Caroff</Author><Year>1993</Year><RecNum>64</RecNum><MDL><REFERENCE_TYPE>0</REFERENCE_TYPE><REFNUM>64</REFNUM><ACCESSION_NUMBER>8093494</ACCESSION_NUMBER><VOLUME>77</VOLUME><NUMBER>1</NUMBER><YEAR>1993</YEAR><DATE>Jan</DATE><TITLE>Neurolepticmalignantsyndrome</TITLE><PAGES>185-202</PAGES><AUTHOR_ADDRESS>DepartmentofPsychiatry,UniversityofPennsylvania,Philadelphia.</AUTHOR_ADDRESS><AUTHORS><AUTHOR>Caroff,S.N.</AUTHOR><AUTHOR>Mann,S.C.</AUTHOR></AUTHORS><SECONDARY_TITLE>MedClinNorthAm</SECONDARY_TITLE><KEYWORDS><KEYWORD>AgeFactors</KEYWORD><KEYWORD>AntipsychoticAgents/*adverseeffects</KEYWORD><KEYWORD>Dantrolene/therapeuticuse</KEYWORD><KEYWORD>Diagnosis,Differential</KEYWORD><KEYWORD>DopamineAgents/therapeuticuse</KEYWORD><KEYWORD>ElectricStimulationTherapy</KEYWORD><KEYWORD>Humans</KEYWORD><KEYWORD>*NeurolepticMalignantSyndrome/diagnosis/etiology/physiopathology</KEYWORD><KEYWORD>Prognosis</KEYWORD><KEYWORD>Recurrence</KEYWORD><KEYWORD>RiskFactors</KEYWORD><KEYWORD>SexFactors</KEYWORD></KEYWORDS><URL>/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=8093494</URL></MDL></Cite></EndNote>7]。NMS在不同性别和年龄人群都可能发生，以年轻男性患者居多。其并不局限于某些精神疾患，在多发性创伤，甚至应用神经阻滞剂作为止吐、镇静、术前用药的患者也可发生NMS。酗酒者由于酒精毒性作用和营养不良，可能导致肌肉代谢异常，更易诱发NMS[ADDINEN.CITE<EndNote><Cite><Author>Adnet</Author><Year>2000</Year><RecNum>2</RecNum><MDL><REFERENCE_TYPE>0</REFERENCE_TYPE><REFNUM>2</REFNUM><AUTHORS><AUTHOR>Adnet,P.</AUTHOR><AUTHOR>Lestavel,P.</AUTHOR><AUTHOR>Krivosic-Horber,R.</AUTHOR></AUTHORS><YEAR>2000</YEAR><TITLE>Neurolepticmalignantsyndrome</TITLE><SECONDARY_TITLE>BrJAnaesth</SECONDARY_TITLE><VOLUME>85</VOLUME><NUMBER>1</NUMBER><PAGES>129-35</PAGES><DATE>Jul</DATE><ACCESSION_NUMBER>10928001</ACCESSION_NUMBER><KEYWORDS><KEYWORD>Diagnosis,Differential</KEYWORD><KEYWORD>Humans</KEYWORD><KEYWORD>NeurolepticMalignantSyndrome/diagnosis/*etiology/therapy</KEYWORD><KEYWORD>RiskFactors</KEYWORD></KEYWORDS><URL>/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=10928001</URL><AUTHOR_ADDRESS>DepartmentofAnesthesiologyandEmergencyMedicine,UniversityHospital,Lille,France.</AUTHOR_ADDRESS><IMAGE>2782063415129.pdf</IMAGE><CAPTION>+*NMS</CAPTION></MDL></Cite></EndNote>5]。一般认为NMS发生与周围环境、温度无关。某些精神疾患、紧张症、脱水、狂躁、血清铁降低都是诱发NMS危险因素，先天性中枢多巴胺系统疾患、感染、并发脑部疾病患者都易于发生NMS。所有可阻滞多巴胺-2受体的药物都可能诱发NMS。氟哌啶醇是目前控制躁动和精神错乱最常用药物，也是文献报道中诱发NMS最多的药物。除抗精神病药物外，其它一些具有神经阻滞剂特性的药物也可诱发NMS，如胃复安、氟哌利多、异丙嗪等。NMS的发生与用药时间长短和药物是否过量无关[ADDINEN.CITE<EndNote><Cite><Author>Caroff</Author><Year>2001</Year><RecNum>58</RecNum><MDL><REFERENCE_TYPE>0</REFERENCE_TYPE><REFNUM>58</REFNUM><AUTHORS><styles><stylefont='12124'start='18'></style><stylestart='20'></style><stylefont='12124'start='40'></style><stylestart='42'></style></styles><AUTHOR>Caroff,S.N.</AUTHOR><AUTHOR>Mann,SC.</AUTHOR><AUTHOR>CabrinaCampbell,E</AUTHOR></AUTHORS><YEAR><styles><stylefont='12123'start='3'></style></styles>2001</YEAR><TITLE>Neurolepticmalignantsyndrome</TITLE><SECONDARY_TITLE>AdverseDrugReactionBulletin</SECONDARY_TITLE><VOLUME><styles><stylefont='12123'></style></styles>209</VOLUME><NUMBER><styles><stylefont='12123'></style></styles>8</NUMBER><PAGES><styles><stylefont='12123'></style><stylestart='3'></style><stylefont='12123'start='4'></style></styles>799-802</PAGES><DATE>Jul</DATE><ACCESSION_NUMBER>10928001</ACCESSION_NUMBER><KEYWORDS><KEYWORD>Diagnosis,Differential</KEYWORD><KEYWORD>Humans</KEYWORD><KEYWORD>NeurolepticMalignantSyndrome/diagnosis/*etiology/therapy</KEYWORD><KEYWORD>RiskFactors</KEYWORD></KEYWORDS><URL>/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=10928001</URL><AUTHOR_ADDRESS>DepartmentofAnesthesiologyandEmergencyMedicine,UniversityHospital,Lille,France.</AUTHOR_ADDRESS><IMAGE>0966059520WhatisNMS.pdf</IMAGE><CAPTION>+*NMS</CAPTION></MDL></Cite></EndNote>8]。研究显示较大剂量、快速、非肠道用药易于诱发NMS。临床表现典型NMS多在服药后24-72小时发生。16％患者在应用神经阻滞剂后24小时发生NMS，66％患者在一周内发生，几乎所有病例都在服药后30天内发病。NMS本身是自限性疾病，停药后恢复时间一般为7-10天。63％患者在一周内恢复，几乎所有患者都在30天内恢复[ADDINEN.CITE<EndNote><Cite><Author>Caroff</Author><Year>2000</Year><RecNum>66</RecNum><MDL><REFERENCE_TYPE>0</REFERENCE_TYPE><REFNUM>66</REFNUM><ACCESSION_NUMBER>10770467</ACCESSION_NUMBER><VOLUME>20</VOLUME><NUMBER>2</NUMBER><YEAR>2000</YEAR><DATE>Apr</DATE><TITLE>Residualcatatonicstatefollowingneurolepticmalignantsyndrome</TITLE><PAGES>257-9</PAGES><AUTHOR_ADDRESS>DepartmentofPsychiatry,UniversityofPennsylvaniaSchoolofMedicine,andtheDepartmentofVeteransAffairsMedicalCenter,Philadelphia,PA19104,USA.caroff@</AUTHOR_ADDRESS><AUTHORS><AUTHOR>Caroff,S.N.</AUTHOR><AUTHOR>Mann,S.C.</AUTHOR><AUTHOR>Keck,P.E.,Jr.</AUTHOR><AUTHOR>Francis,A.</AUTHOR></AUTHORS><SECONDARY_TITLE>JClinPsychopharmacol</SECONDARY_TITLE><KEYWORDS><KEYWORD>Adult</KEYWORD><KEYWORD>Aged</KEYWORD><KEYWORD>AntipsychoticAgents/*adverseeffects/therapeuticuse</KEYWORD><KEYWORD>Catatonia/*chemicallyinduced/diagnosis/mortality/therapy</KEYWORD><KEYWORD>ElectroconvulsiveTherapy</KEYWORD><KEYWORD>Female</KEYWORD><KEYWORD>Humans</KEYWORD><KEYWORD>Male</KEYWORD><KEYWORD>MiddleAged</KEYWORD><KEYWORD>NeurolepticMalignantSyndrome/*diagnosis/mortality/therapy</KEYWORD><KEYWORD>NeurologicExamination/drugeffects</KEYWORD><KEYWORD>ResearchSupport,Non-U.S.Gov't</KEYWORD><KEYWORD>SubstanceWithdrawalSyndrome/*diagnosis/mortality/therapy</KEYWORD><KEYWORD>SurvivalRate</KEYWORD><KEYWORD>TreatmentOutcome</KEYWORD></KEYWORDS><URL>/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=10770467</URL></MDL></Cite></EndNote>9]。NMS早期临床表现包括意外的精神状态改变，难以控制的锥体外束和延髓损害症状，如强直、吞咽困难、发音困难。NMS早期症状还包括反应迟钝、体温升高，心动过速，呼吸急促，血压不稳定、出汗、流口水、麻痹性失禁、肌阵挛、阵颤、血中肌酸激酶升高等[ADDINEN.CITE<EndNote><Cite><Author>Velamoor</Author><Year>1994</Year><RecNum>67</RecNum><MDL><REFERENCE_TYPE>0</REFERENCE_TYPE><REFNUM>67</REFNUM><ACCESSION_NUMBER>7906709</ACCESSION_NUMBER><VOLUME>182</VOLUME><NUMBER>3</NUMBER><YEAR>1994</YEAR><DATE>Mar</DATE><TITLE>Progressionofsymptomsinneurolepticmalignantsyndrome</TITLE><PAGES>168-73</PAGES><AUTHOR_ADDRESS>DepartmentofPsychiatry,VictoriaHospital,London,Ontario,Canada.</AUTHOR_ADDRESS><AUTHORS><AUTHOR>Velamoor,V.R.</AUTHOR><AUTHOR>Norman,R.M.</AUTHOR><AUTHOR>Caroff,S.N.</AUTHOR><AUTHOR>Mann,S.C.</AUTHOR><AUTHOR>Sullivan,K.A.</AUTHOR><AUTHOR>Antelo,R.E.</AUTHOR></AUTHORS><SECONDARY_TITLE>JNervMentDis</SECONDARY_TITLE><KEYWORDS><KEYWORD>Adolescent</KEYWORD><KEYWORD>Adult</KEYWORD><KEYWORD>Aged</KEYWORD><KEYWORD>AntipsychoticAgents/adverseeffects</KEYWORD><KEYWORD>AutonomicNervousSystemDiseases/diagnosis</KEYWORD><KEYWORD>Child</KEYWORD><KEYWORD>Child,Preschool</KEYWORD><KEYWORD>Female</KEYWORD><KEYWORD>Fever/diagnosis</KEYWORD><KEYWORD>Follow-UpStudies</KEYWORD><KEYWORD>Humans</KEYWORD><KEYWORD>Infant</KEYWORD><KEYWORD>Male</KEYWORD><KEYWORD>MentalDisorders/diagnosis</KEYWORD><KEYWORD>MiddleAged</KEYWORD><KEYWORD>MuscleRigidity/diagnosis</KEYWORD><KEYWORD>NeurolepticMalignantSyndrome/*diagnosis/etiology</KEYWORD><KEYWORD>RetrospectiveStudies</KEYWORD><KEYWORD>TimeFactors</KEYWORD></KEYWORDS><URL>/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=7906709</URL></MDL></Cite></EndNote>10]。这些症状缺乏特异性，且不一定都出现，任何服用神经阻滞剂的患者出现上述症状都要考虑NMS可能性。体温升高，是NMS主要症状之一，且往往伴有大量出汗。但亦有报道NMS患者无发热的[ADDINEN.CITE<EndNote><Cite><Author>Anand</Author><Year>2004</Year><RecNum>26</RecNum><MDL><REFERENCE_TYPE>0</REFERENCE_TYPE><REFNUM>26</REFNUM><AUTHORS><AUTHOR>Anand,H.</AUTHOR><AUTHOR>Spaner,D.</AUTHOR></AUTHORS><YEAR>2004</YEAR><TITLE>Acuriouscaseofneurolepticmalignantsyndrome</TITLE><SECONDARY_TITLE>CanJPsychiatry</SECONDARY_TITLE><VOLUME>49</VOLUME><NUMBER>9</NUMBER><PAGES>645-6</PAGES><DATE>Sep</DATE><ACCESSION_NUMBER>15503743</ACCESSION_NUMBER><KEYWORDS><KEYWORD>AntipsychoticAgents/*adverseeffects</KEYWORD><KEYWORD>Humans</KEYWORD><KEYWORD>Male</KEYWORD><KEYWORD>MiddleAged</KEYWORD><KEYWORD>NeurolepticMalignantSyndrome/*diagnosis</KEYWORD><KEYWORD>Schizophrenia/*drugtherapy</KEYWORD></KEYWORDS><URL>/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=15503743</URL><IMAGE>0021421112out.pdf</IMAGE><CAPTION>+NMSwithoutfever</CAPTION></MDL></Cite></EndNote>11]，并且30％NMS患者没有出汗[ADDINEN.CITE<EndNote><Cite><Author>Adnet</Author><Year>2000</Year><RecNum>2</RecNum><MDL><REFERENCE_TYPE>0</REFERENCE_TYPE><REFNUM>2</REFNUM><AUTHORS><AUTHOR>Adnet,P.</AUTHOR><AUTHOR>Lestavel,P.</AUTHOR><AUTHOR>Krivosic-Horber,R.</AUTHOR></AUTHORS><YEAR>2000</YEAR><TITLE>Neurolepticmalignantsyndrome</TITLE><SECONDARY_TITLE>BrJAnaesth</SECONDARY_TITLE><VOLUME>85</VOLUME><NUMBER>1</NUMBER><PAGES>129-35</PAGES><DATE>Jul</DATE><ACCESSION_NUMBER>10928001</ACCESSION_NUMBER><KEYWORDS><KEYWORD>Diagnosis,Differential</KEYWORD><KEYWORD>Humans</KEYWORD><KEYWORD>NeurolepticMalignantSyndrome/diagnosis/*etiology/therapy</KEYWORD><KEYWORD>RiskFactors</KEYWORD></KEYWORDS><URL>/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=10928001</URL><AUTHOR_ADDRESS>DepartmentofAnesthesiologyandEmergencyMedicine,UniversityHospital,Lille,France.</AUTHOR_ADDRESS><IMAGE>2782063415129.pdf</IMAGE><CAPTION>+*NMS</CAPTION></MDL></Cite></EndNote>5]。极度高温可造成危象和多种并发症，如不可逆的脑损害等。肌强直是NMS核心症状，常伴肌坏死；肌张力增高可致肺顺应性降低，通气功能不足，肺部感染；肌张力升高多同时伴有运动障碍，发音困难，震颤麻痹等锥体外系损害症状；神智改变可有烦躁、木僵、昏迷、精神错乱、紧张症；自主神经系统改变包括心动过速、血压波动、呼吸急促。其它少见症状还有角弓反张、癜痫、巴彬斯基征、舞蹈病、牙关紧闭等。NMS患者实验室检查可有多种变化，但往往是非特异的，不具诊断意义。血白细胞升高是常见症状，可以从轻度升高到30x109/L。患者血中肌酸激酶的浓度往往升高，有时达非常高的水平（>1000IU/L），提示横纹肌溶解。血中肌酸激酶水平虽不具特异性，但却是估计横纹肌溶解严重程度和肾衰风险性的重要指标。其它实验室异常还包括酸中毒、低氧血症、血清铁降低、血中儿茶酚胺浓度升高、血电解质异常、凝血功能障碍、肝酶升高等。超过半数患者脑电图显示非局灶性、弥漫性慢波，呈非特异性脑病改变。但是脑部影像学检查、脑脊液检查、以及脓毒血症的相关检查往往为阴性。随着对该病了解及早期治疗，其死亡率呈下降趋势。70年代以前NMS死亡率为76％，1970-1980年间为22％，1980年以后为15％。约50％患者死于肾功能衰竭，其它死因包括突发呼吸循环骤停、心功能衰竭、吸入性肺炎、肺栓塞、肝功能衰竭、DIC等。尸检往往无特异性改变。NMS患者康复后很少留有并发症，但亦有报道留有记忆缺失、锥体外系和小脑损害、外周神经损害、肌挛缩等[ADDINEN.CITE<EndNote><Cite><Author>Caroff</Author><Year>2001</Year><RecNum>58</RecNum><MDL><REFERENCE_TYPE>0</REFERENCE_TYPE><REFNUM>58</REFNUM><AUTHORS><styles><stylefont='12124'start='18'></style><stylestart='20'></style><stylefont='12124'start='40'></style><stylestart='42'></style></styles><AUTHOR>Caroff,S.N.</AUTHOR><AUTHOR>Mann,SC.</AUTHOR><AUTHOR>CabrinaCampbell,E</AUTHOR></AUTHORS><YEAR><styles><stylefont='12123'start='3'></style></styles>2001</YEAR><TITLE>Neurolepticmalignantsyndrome</TITLE><SECONDARY_TITLE>AdverseDrugReactionBulletin</SECONDARY_TITLE><VOLUME><styles><stylefont='12123'></style></styles>209</VOLUME><NUMBER><styles><stylefont='12123'></style></styles>8</NUMBER><PAGES><styles><stylefont='12123'></style><stylestart='3'></style><stylefont='12123'start='4'></style></styles>799-802</PAGES><DATE>Jul</DATE><ACCESSION_NUMBER>10928001</ACCESSION_NUMBER><KEYWORDS><KEYWORD>Diagnosis,Differential</KEYWORD><KEYWORD>Humans</KEYWORD><KEYWORD>NeurolepticMalignantSyndrome/diagnosis/*etiology/therapy</KEYWORD><KEYWORD>RiskFactors</KEYWORD></KEYWORDS><URL>/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=10928001</URL><AUTHOR_ADDRESS>DepartmentofAnesthesiologyandEmergencyMedicine,UniversityHospital,Lille,France.</AUTHOR_ADDRESS><IMAGE>0966059520WhatisNMS.pdf</IMAGE><CAPTION>+*NMS</CAPTION></MDL></Cite></EndNote>8]。鉴别诊断患者服用神经阻滞剂后出现发热、肌强直、自主神经系统改变须立即停止所有抗精神病治疗，直到得出确切诊断为止。可能与NMS混淆的疾病包括由其它疾病引起的横纹肌溶解、中枢系统感染、脑部肿瘤、破伤风等。鉴别诊断还要考虑神经阻滞剂引起的中暑、紧张症、药物和单胺氧化酶抑制剂相互作用、中枢抗胆碱综合症、恶性高热等。神经阻滞剂外周抗胆碱作用可抑制出汗和散热，其中枢抗多巴胺作用可干扰体温调节，从而诱发神经阻滞剂所致中暑。其危险因素包括闷热、潮湿的环境，过度激动，过度活动后未及时补充水分。其与NMS不同之处是起病急，无锥体外束损害症状，没有出汗，有大量运动或暴露于高温环境的病史。急性致命性紧张症是一种少见的精神疾患，其和NMS有一些共同点，如高热、运动障碍、肌肉强直，CT、脑电图和其它的实验室检查难以将其与NMS区分开。其鉴别需要观察患者后几周变化。事实上NMS本身就被定义为一种药物引起的医源性、致命性紧张症。抗帕金森氏病和抗胆碱药物可导致中枢抗胆碱综合症，其症状包括皮肤干燥、口干、瞳孔散大、尿潴留。病人往往有困惑、失去方向感、体温升高，但没有强直，毒扁豆碱治疗有效。此外挥发性麻醉剂和琥珀酰胆碱可诱发恶性高热，若患者用过神经阻滞剂易于与NMS混淆，但NMS很少出现在术中。一些迷幻剂也可能导致高热，癫痫发作，强直，横纹肌溶解和死亡。治疗NMS基本治疗措施是早期诊断、停止用药、加强监护和护理、积极降温、补充水分。此外还要积极治疗并发症。NMS本身是自限性疾病，充分支持治疗是最重要的。特异性药物治疗和电休克疗法（electroconvulsivetherapy,ECT）效果还不确定，甚至有学者认为药物治疗反而会延缓NMS恢复[ADDINEN.CITE<EndNote><Cite><Author>Rosebush</Author><Year>2004</Year><RecNum>7</RecNum><MDL><REFERENCE_TYPE>0</REFERENCE_TYPE><REFNUM>7</REFNUM><AUTHORS><AUTHOR>Rosebush,P.I.</AUTHOR><AUTHOR>Garside,S.</AUTHOR><AUTHOR>Mazurek,M.F.</AUTHOR></AUTHORS><YEAR>2004</YEAR><TITLE>Recognizingneurolepticmalignantsyndrome</TITLE><SECONDARY_TITLE>Cmaj</SECONDARY_TITLE><VOLUME>170</VOLUME><NUMBER>11</NUMBER><PAGES>1645</PAGES><DATE>May25</DATE><ACCESSION_NUMBER>15159345</ACCESSION_NUMBER><KEYWORDS><KEYWORD>Aged</KEYWORD><KEYWORD>Aged,80andover</KEYWORD><KEYWORD>CreatineKinase/metabolism</KEYWORD><KEYWORD>DopamineAntagonists/*adverseeffects/pharmacology</KEYWORD><KEYWORD>Haloperidol/*analogs&derivatives</KEYWORD><KEYWORD>Humans</KEYWORD><KEYWORD>Male</KEYWORD><KEYWORD>NeurolepticMalignantSyndrome/*etiology</KEYWORD><KEYWORD>Receptors,DopamineD2/antagonists&inhibitors</KEYWORD></KEYWORDS><URL>/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=15159345</URL><IMAGE>19783844391645.pdf</IMAGE><CAPTION>+*dantroleneandbromocriptineareunnecessary</CAPTION></MDL></Cite></EndNote>12]。应根据患者症状和医生经验来选择治疗方案。苯二氮卓类药物可以有效缓解紧张症，可以首先试用。氯羟安定1-2mg注射，并根据症状调整剂量，起效后口服维持效果。溴隐亭、金刚烷等多巴胺激动剂可在症状较重的患者身上应用。溴隐亭常用剂量是2.5-10mg，每日四次。主要副作用是低血压，呕吐，精神症状加重。患者往往在用药后数小时体温下降，肌强直缓解，血压平稳。对于伴有显著肌强直和高热患者可考虑使用丹曲林钠，其常用于恶性高热，可抑制肌浆网释放钙，松弛肌肉。NMS患者应用丹曲林钠可抑制肌肉收缩，降低体温，减慢心率和呼吸频率。首剂量2mg/kg静脉注射，必要时每10分钟重复一次，每日剂量可达10mg/kg。口服剂量为每日50-200mg。剂量大于10mg/kg时可出现肝损害。以上治疗措施在NMS发病开始几天应用有效，而ECT在疾病后期依然有效，其在NMS治疗中的作用越来越受到重视。ECT可改善NMS症状，适用下列情况：1）特发性致命性紧张症不能排除者；2）经其它治疗NMS症状无改善者；3）患者伴有显著的紧张症；4）NMS缓解后患者仍然伴有残余紧张状态以及精神症状者[ADDINEN.CITE<EndNote><Cite><Author>Caroff</Author><Year>1998</Year><RecNum>69</RecNum><MDL><REFERENCE_TYPE>0</REFERENCE_TYPE><REFNUM>69</REFNUM><ACCESSION_NUMBER>9777166</ACCESSION_NUMBER><VOLUME>44</VOLUME><NUMBER>6</NUMBER><YEAR>1998</YEAR><DATE>Sep15</DATE><TITLE>Specifictreatmentoftheneurolepticmalignantsyndrome</TITLE><PAGES>378-81</PAGES><AUTHORS><AUTHOR>Caroff,S.N.</AUTHOR><AUTHOR>Mann,S.C.</AUTHOR><AUTHOR>Keck,P.E.,Jr.</AUTHOR></AUTHORS><SECONDARY_TITLE>BiolPsychiatry</SECONDARY_TITLE><KEYWORDS><KEYWORD>Humans</KEYWORD><KEYWORD>NeurolepticMalignantSyndrome/physiopathology/*therapy</KEYWORD></KEYWORDS><URL>/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=9777166</URL></MDL></Cite><Cite><Author>Caroff</Author><Year>2000</Year><RecNum>66</RecNum><MDL><REFERENCE_TYPE>0</REFERENCE_TYPE><REFNUM>66</REFNUM><ACCESSION_NUMBER>10770467</ACCESSION_NUMBER><VOLUME>20</VOLUME><NUMBER>2</NUMBER><YEAR>2000</YEAR><DATE>Apr</DATE><TITLE>Residualcatatonicstatefollowingneurolepticmalignantsyndrome</TITLE><PAGES>257-9</PAGES><AUTHOR_ADDRESS>DepartmentofPsychiatry,UniversityofPennsylvaniaSchoolofMedicine,andtheDepartmentofVeteransAffairsMedicalCenter,Philadelphia,PA19104,USA.caroff@</AUTHOR_ADDRESS><AUTHORS><AUTHOR>Caroff,S.N.</AUTHOR><AUTHOR>Mann,S.C.</AUTHOR><AUTHOR>Keck,P.E.,Jr.</AUTHOR><AUTHOR>Francis,A.</AUTHOR></AUTHORS><SECONDARY_TITLE>JClinPsychopharmacol</SECONDARY_TITLE><KEYWORDS><KEYWORD>Adult</KEYWORD><KEYWORD>Aged</KEYWORD><KEYWORD>AntipsychoticAgents/*adverseeffects/therapeuticuse</KEYWORD><KEYWORD>Catatonia/*c