中枢神经系统感染220108142426590

null中枢神经系统感染中枢神经系统感染华山医院感染科 陈 澍中枢神经系统感染分类中枢神经系统感染分类脑膜炎和脑实质感染：相互影响，可以转换 脑膜炎可分为化脓性及非化脓性二大类 化脓性：起病急，由各种化脓性细菌引起； 非化脓性：由病毒及阿米巴原虫引起者起病多急，而由结核杆菌、新型隐球菌、及其它真菌所致者多呈亚急性或慢性过程。脑膜炎分类脑膜炎分类Infectious Bacterial Viral Fungal Non-infectious Drug-Induced Neoplastic Autoimmune流行病学资料 流行病学资料 年龄 婴儿患者（<2M）:多为大肠杆菌、B组链球菌（国内较少见）及李司特菌； 幼儿(3M～3Y)：以流感杆菌脑膜炎为多见，其中5～9个月者占70％，成人患者罕见。 流行性脑脊髓膜炎各年龄组均可发生，但6M以下的发病率极低，小儿患者多于成人； 肺炎双球菌脑膜炎（肺脑）：1岁以下及老年人发病率较高，但其它各年龄组均可发病。流行病学资料流行病学资料季节 冬春季：流脑、流感杆菌脑膜炎 夏秋季：以肠道病毒脑膜炎为多见 全年发病：肺脑、结脑、真菌 家族中发病情况 二人同时发病多为流脑及流感杆菌脑膜炎 动物接触 养鸽及接触鸽粪者与隐球菌性脑膜炎（隐脑）有关；饲养田鼠或小白鼠者可感染淋巴细胞脉络丛脑膜炎。 入侵途径入侵途径脑膜旁邻近器官的感染直接侵犯 血行感染播散 脑脊液漏所致细菌入侵 颅脑外伤：闭合性颅外伤以肺炎双球菌及革兰氏阴性菌为主，开放性颅外伤以革兰氏阴性杆菌及金葡菌为主 医源性损伤：神经外科手术后、腰椎穿刺、VP分流术后临床现临床表现全身症状： （1）化脓性脑膜炎（化脑）：起病急骤，高热伴畏寒、寒战，全身酸痛等毒血症状，部分婴儿及少数成人可有呕吐、腹泻等胃肠道症状、精神萎糜、嗜睡、烦燥等。 （2）非化脓性脑膜炎： 病毒性脑膜炎：起病急骤，全身毒血症状和恶心、呕吐及淡漠、嗜睡等。 结核性脑膜炎：起病大多缓慢，伴结核中毒症状 隐球菌性脑膜炎：起病以亚急性者为多，低热为主，起病重，呈持续性神经系统表现：神经系统表现：1、颅内压增高：头痛、喷射性呕吐，视乳头水肿，视力模糊，意识障碍及抽搐等，幼儿可见前囱饱满 2、脑膜刺激征：颈项强直，克氏征阳性 3、脑实质炎症表现： （1）皮层的病变可引起意识障碍 （2）运动通路的改变：表现为惊厥、瘫痪。 （3）神经反射的改变：腹壁、提睾等浅反射消失、膝反射亢进及踝阵挛等。 （4）严重的脑实质损害可使脑水肿加剧，引起脑疝。 表 各种脑膜炎的脑脊液变化     化脓性脑膜炎化脓性脑膜炎BACTERIAL MENINGITIS What is it? What is it? Bacterial meningitis is a serious infection of the spinal cord and the fluid that surrounds the brain.What causes it?What causes it?There are 3 main bacterial species that contribute to this disease: Haemophilus influenzae type b Neisseria meningitidis (Meningococcal) Streptococcus pneumoniae (Pneumococcal) null 病原学How is it diagnosed?How is it diagnosed?When patient presents symptoms of Meningitis, a sample of CSF is acquired from a spinal tap, which is then analyzed for bacterial presence.Bacterial Meningitis FactsBacterial Meningitis FactsThere are 1.2 million cases annually worldwide, approximately 135,000 deaths. Bacterial meningitis is 1 of the top 10 infectious causes of death worldwide, according to the CDC. Half of survivors suffer neurological damage, and/or other permanent side effects. Haemophilus influenzae type bHaemophilus influenzae type bAffects about 13/1,000,000 children (2005), 3-4% are fatal. Infection has decreased drastically: From 4-10/10,000; since routine use of the Hib vaccine (since 1990) A major cause of lower respiratory tract infections in developing countriesNeisseria meningitidisNeisseria meningitidis5-50/1,000,000 people are infected worldwide every year. Most Deadly form of Bacterial Meningitis Humans are only host of bacteria, it is present in the nasopharynx 11-19% of people who have recovered suffer from permanent hearing loss, mental retardation, or other serious health problems. 10-14% of cases are fatalStreptococcus pneumoniaeStreptococcus pneumoniaeInfection rate in the U.S. has now decreased to 13/ 100,000, due to vaccination. (2002) Kills 14% of hospitalized adults with invasive disease. In some recovery cases, the patients sustain learning disabilities, and/or other impairments typical of meningitis, but less so than with other forms of meningitis. Overuse of antibiotics contributes to emerging drug resistance in this strain. SymptomsSymptomsMost Common Fever Headache Stiff Neck Nausea & vomiting Sensitivity to light Confusion Sleepiness In Infants Inactivity Irritability Vomiting Poor feedingAdvanced Disease Bruises develop under skin & spread rapidly Advanced Disease can lead to: Brain Damage Coma DeathSymptomsSymptomsRisk FactorsRisk FactorsInfants and young children Elderly College freshmen who live in dorms Patients without spleens People exposed to active or passive tobacco smoke. African Americans, American Indians, Alaskan Natives. People with underlying medical conditions (Ex. HIV & Sickle-cell disease) Treatment & MedicationTreatment & MedicationAntibiotics: Broad-Spectrum cephalosporin Ampicillin & Broad-Spectrum cephalosporin Vancomycin plus ceftazidime All antibiotics administered intravenously H. Influenzae & N. meningitidis- 7 days S. pneumoniae- 10-14 days Medications ContinuedMedications ContinuedN. meningitidis Chloramphenicol resistance Used in resource-limited settings (Sub-Saharan Africa). Stopped using in West because of very rare, yet serious side effect: Aplastic anemia. Very cheap synthesis Derived from bacteria- disrupts translation process by preventing peptide bond formation There are no non-pharmaceutical treatments for bacterial meningitis.Vaccines: H. influenzae type bVaccines: H. influenzae type bBacteria contains polysaccharide capsule Questions have arisen on the length of time the vaccine is effective. Cost of vaccine: $7.00 (typical vaccines are $1.00) The cost of this vaccine has limited their use in developing countries, even though this bacteria is a major cause of death.Vaccine: N. MeningitidisVaccine: N. MeningitidisMeningococcal conjugate vaccine (MCV4) Price: $82; intramuscularly as single dose. Effective in all age groups Preferred over MPSV4 Meningococcal Polysaccharide Vaccine (MPSV4) Price: $86.10; subcutaneously as single dose. Re-administered every 3-5 years Age groups: Not under 2 and 11-12 years old Vaccine: S. PneumoniaeVaccine: S. PneumoniaeBacteria contains polysaccharide capsule β –lactam resistance is common, resistance to multiple classes of drugs are increasing. 23-valent polysaccharide vaccine (Prevnar)- NEW $80.00 per dose Underused Supplies are inadequate New urinary antigen test may be useful in adults to identify if S. pneumoniae is present. Research for Paper Research for Paper Mechanism that causes the side effects and symptoms of bacterial meningitis and their role in cytokine response. Mechanism of antibiotics to specific bacteria and mechanisms of resistance by bacteria to antibiotics Interview Peter Hicks, Epidemiologist at the CDC. nullnullShock: Sepsis ProtocolSummary: An Approach to the Adult Patient with Suspected Bacterial MeningitisFrom supplement to: Van de Beek D. Community-acquired bacterial meningitis in adults. N Engl J Med. 2006; 354:44-53nullShock: Sepsis ProtocolSummary: An Approach to the Adult Patient with Suspected Bacterial MeningitisFrom supplement to: Van de Beek D. Community-acquired bacterial meningitis in adults. N Engl J Med. 2006; 354:44-53nullShock: Sepsis ProtocolSummary: An Approach to the Adult Patient with Suspected Bacterial MeningitisCorticosteroids Give dexamethasone IV before or with 1st dose of antibiotics Contraindications Antibiotics w/in 48 hrs Shunt Head traumaFrom supplement to: Van de Beek D. Community-acquired bacterial meningitis in adults. N Engl J Med. 2006; 354:44-53nullShock: Sepsis ProtocolSummary: An Approach to the Adult Patient with Suspected Bacterial MeningitisFrom supplement to: Van de Beek D. Community-acquired bacterial meningitis in adults. N Engl J Med. 2006; 354:44-53Contraindications to LP Recent seizure Signs of herniation at any time GCS < 11 or rapidly declining LOC Focal neurologic deficits Papilledema * SOL or brain shift on CT CoagulopathynullShock: Sepsis ProtocolFrom supplement to: Van de Beek D. Community-acquired bacterial meningitis in adults. N Engl J Med. 2006; 354:44-53Summary: An Approach to the Adult Patient with Suspected Bacterial MeningitisEmpiric Antibiotic Therapy Cefotaxime 2g IV or Ceftriaxone 2g IV +/- Ampicillin 3g IV +/- Vancomycin 1g IVnull Antibiotic treatment of meningitis Treatment before hospitalisation* Benzylpenicillin (60 mg/kg, up to) 3 g intravenously or intramuscularly or ceftriaxone (50 mg/kg, up to) 2 g intravenously (in patients hypersensitive to penicillin or in remote areas where further parenteral therapy may be substantially delayed [over 6 h]). Empirical treatment in hospital Cefotaxime (child, 50 mg/kg up to) 2 g intravenously, 6-hourly or ceftriaxone (child, 100 mg/kg up to) 4 g intravenously, daily in 1 or 2 divided doses for 7 to 10 days plus benzylpenicillin (child, 60 mg/kg up to) 1.8 g intravenously 4-hourly for 7 to 10 days (if aged under 3 months or over 50 years). Vancomycin (15 mg/kg up to) 500 mg four times daily intravenously or rifampicin (20 mg/kg up to) 600 mg daily should be added if Streptococcus pneumoniae is suspected on Gram stain, to ensure adequate cover for penicillin- or cephalosporin-intermediate or -resistant isolates before susceptibility results are available.nullSpecific treament (organism and susceptibility known) Haemophilus influenzae type b Cefotaxime 2 g intravenously 6-hourly or ceftriaxone 4 g intravenously daily in 1 or 2 divided doses for 7 to 10 days or, if the organism is proven to be susceptible, (amoxy)ampicillin 2 g intravenously, 4-hourly for 7 to 10 days. Neisseria meningitidis Benzylpenicillin 1.8 g intravenously, 4-hourly for 5 to 7 days. For patients hypersensitive to penicillin, cefotaxime 2 g intravenously, 6-hourly or ceftriaxone 4 g intravenously daily in 1 or 2 divided doses for 5 to 7 days. Streptococcus pneumoniae For strains with minimum inhibitory concentration (MIC) > 0.125 mg/L, vancomycin or rifampicin plus either cefotaxime or ceftriaxone. For penicillin-susceptible strains (MIC < 0.125 mg/L), benzylpenicillin (child: 60 mg/kg up to) 1.8 g intravenously 4-hourly for at least 10 days. Listeria monocytogenes Penicillin and (amoxy)ampicillin appear equally efficacious. In patients hypersensitive to penicillin, trimethoprim–sulfamethoxazole may be used alone. Trimethoprim–sulfamethoxazole 160/800 mg intravenously 6-hourly plus either benzylpenicillin 1.8 g intravenously, 4-hourly or (amoxy)ampicillin 2 g intravenously 4-hourly.隐脑 cryptococcal meningitis隐脑 cryptococcal meningitis慢 免疫低下/有否HIV or Tumour/养鸽史 脑膜炎or脑膜脑炎 可累及II、III、VI、 VII 、VIII 颅内、肺内可形成肉芽肿 CSF:墨汁染色、 真菌培养、乳胶凝集试验+滴度 病原治疗：amphotericin B、 5-Fc、 Fluconazole、Itraconazole amphotericin Bamphotericin B机制 不良反应 即刻反应：寒战、发热、头/恶/吐、胸闷、心动过速、室颤、惊厥 心脏损害：长期应用者发生心动过缓 肝脏损害 肾脏损害：尿WBC/RBC/管型、BUN/Scr I型RTA 血液系统毒性：贫血、PLT 低钾血症：排钾 静脉炎 amphotericin Bamphotericin B静滴 逐渐加量：1mg-2-3-5-10-15-20-25-30 mg 日最大剂量: 国外1mg/kg；国内25-35mg/d，相当于0.5-0.7mg/kg左右 总剂量：2-4g 左右，据具体情况定 +5-Fc—协同作用，耐药， amphotericin B dosage +5% GS 500ml +DXM 避光 >6hrs 深静脉穿刺 amphotericin Bamphotericin B鞘注 逐渐加量：0.1mg-0.2-0.3-0.4------1.0mg 最大单次剂量：1mg 最大累计剂量：20mg Biw-Qod 注射用水稀释 +DXM CSF反复稀释推注20min左右 amphotericin Bamphotericin B注意事项 监测血/尿常规、肝肾功能电解质，注意尿量变化，必要时测血气 深静脉穿刺护理 鞘注的不良反应：头/恶/吐、放射性痛、尿潴留、下肢感觉丧失、轻瘫 cryptococcus neoformanscryptococcus neoformansnull结核性脑膜炎null 近年结核病发病率有上升之势，原因为: - 爱滋病传播促进了结核病在全球的回升 - 结核杆菌的多药抗药性 - 治疗延误或者不完全 概述结核性脑膜炎结核性脑膜炎- 结核杆菌引起的非化脓性脑膜炎 - 最常见的、最严重的肺外结核病之一，占肺外结核5%-15% - 细胞免疫低下者发病率高 - 成人、儿童发生率各占50% - 临床表现多样化、脑脊液不典型 - 死亡率或严重的神经系统后遗症达50% 发病机理及病理 PATHOPHYSIOLOGY发病机理及病理 PATHOPHYSIOLOGY结核性脑膜炎是结核菌全身血行播散的结果。 直接蔓延 蛛网膜下腔 脑膜 原发病灶 血 脑实质、脑膜形成隐匿病灶 破溃 外伤 疾病 （麻疹、百日咳 ） 病 理 PATHOLOGICAL病 理 PATHOLOGICAL脑膜 弥漫性充血、水肿、炎性渗出、形成结核 结节 蛛网膜下腔 大量渗出物在颅底聚集，其次在 神经交叉、桥脑、延髓、大脑外侧裂。最 容易造成颅神经损害如VII、III、IVnull 结核性脑膜炎的颅底渗出null脑实质 室管膜及脉络丛受累，出现脑室管 膜炎，脊髓膜、脊髓、脊神经根受 累出现截瘫等 脑血管 早期急性动脉炎 晚期动脉内膜炎 管腔闭塞 脑室质软化 null 脉络膜充血 脑脊液生成增加（早期） 脑膜炎症粘连 脑脊液回吸收减少 大脑导水管及第 交通性脑积水 四脑室以上阻塞   阻塞性脑积水 null 左、右侧脑室脉络丛 左、右侧脑室   血 浆 室间孔   第三脑室 第三脑室 血 脉络丛 液 循 中脑导水管 环 系 统 第四脑室脉络丛 第四脑室   脑 部 左侧孔 中央孔 右侧孔 静 脉 窦 脑蛛网膜粒 脑与脊髓蛛网膜下腔脑脊液循环图nullFigure. Axial Section of a Brain from a Patient with Tuberculous Meningitis. Ventricular dilatation is present (asterisks), as well as inflammatory exudate in the ambient cistern (black arrows)and multiple foci of vasculitis-associated subacute, ischemic necrosis (white arrows). 临床表现临床表现典型表现 非典型表现 -以精神异常为突出表现 -以急性化脓性脑膜炎为首发症状 -以头痛为首发症状 86%有头痛，20%无发热 -脑实质受损为首发症状 -脑神经受损为首发症状 -以脑血管病为首发症状 -以癫痫发作为首发症状 诊断诊断细菌学诊断 -阳性率低 涂片10%，培养20--30%，与病期、取材部位、CSF量、检查、次数等因素有关。 - 快速培养：阳性率高，时间缩短 BACTEC-TB460或960以及BacT ALERT 3D 诊 断诊 断免疫学诊断 -结核抗体测定： 结核杆菌38Kda抗原、膜蛋白抗原、PPD抗原对结脑的诊断价值，敏感性分别为51.8%、 53.6%、55.4%；特异性分别为100%, 100%和94%。 假阳性率在2-15%，假阴性率在5-45%。 -结核抗原测定： BAS放射免疫法 反相被动血凝试验 诊 断诊 断免疫复合物测定 -Gupta 等 采用ELISA测定了33例临床诊断的结脑患者和34例其它脑 膜炎患者CSF中的抗BCG-IgG免疫复合物，并与3种类型的 结核抗体测定结果比较。结果结脑组CSF特异性免疫复合物 阳性21例，阳性率64%，而其它疾病患者假阳性3例，假阳 性率9% 免疫复合物可辅助判断疗效和病人预后null生化检查方法 -腺苷脱氨酶(ADA）： 敏感度 50%-90% -结核杆菌硬脂酸(TSA)：特异性 100% 基因诊断诊 断诊 断诊 断CT、MR检查 -基底池渗出：明显强化，呈绒线样、斑片、团快、串珠、结节样或环形强化 -颅内结核瘤形成诊 断诊 断治疗治疗化学治疗 第一线抗结核药：IHN、RFP、EMB、PZA、SM等。 第二线抗结核药：PAS、丁胺卡那 第三线抗结核药：胺硫脲、环丝氨酸等 透过BBB ： INH、RFP、PZA、环丝氨酸 有条件透过BBB： SM、EMB、PAS 杀菌药： INH、RFP 条件杀菌药： PZA、SM 抑菌药： EMB、PZA、丁胺卡那治疗治疗化学治疗 遵循“早期、联合、长期、足量”原则 早期：越早越好 联合：强化治疗期（2-3M），3-4种易透过BBB的杀菌剂或 加1个抑菌剂 巩固治疗期（10-24M），至少1种杀菌剂或加1个抑菌剂 适量、规则、全程： IHN：1200mg/d 3m; 900mg/d 6m; 600mg/d 12m;300mg/d 维持治疗 治 疗治 疗糖皮质激素的辅助治疗 目前尚有争议 null