浙江大学医学院附属邵逸夫医院 神经内科 邵宇权 中枢神经系统感染性疾病 浙江大学医学院附属邵逸夫医院 神经内科 邵宇权

病例 现病史 A 38-year-old woman was admitted to the hospital because of fever and confusion The patient had been well until four days earlier, when a headache gradually developed and increased in intensity, accompanied by mild photophobia and stiffness of the neck. Two days before admission, she believed that she was mildly febrile. The day before admission, she was examined at another facility, where she was told she had a “viral illness.” She was given fluids intravenously and was discharged. On the morning of admission, she awoke with shaking chills and a temperature of 40°C. During the day she was aware of a rapid heartbeat, lightheadedness, and lethargy. Her husband observed that she was confused, and she was brought to this hospital and admitted.

病例 体检 T 36.4, HR 99bpm, RR 20, BP90/60 mmHg. SaO2 99% 病例 体检 T 36.4, HR 99bpm, RR 20, BP90/60 mmHg. SaO2 99% The neck was rigid, and Kernig’s sign (+) She was alert and oriented but spoke in phrases of two to four words, rather than complete sentences. The neurologic examination otherwise revealed no abnormalities.

病例 辅助检查--CSF 第五天 第一天

病例 辅助检查--器械 MRI showed a subtle hyperintensity on T2 images in both hippocampal regions and possible slight meningeal enhancement. EEG revealed generalized low-amplitude slowing and continuous focal slowing over the entire left hemisphere; no epileptiform activity

病例 病情演变 Shortly after the patient’s arrival at the hospital, T rose to 39.8, and the fever was accompanied by somnolence On the 2nd hospital day, T rose to 39.5. When questioned, she knew the month but not the date or year or the ages of her children Later on the 2nd day, she became more lethargic and responded to questions only with “yes.” During the night, the patient’s mental status improved and she was able to follow simple commands On the 3rd hospital day, the maximal T 39.2. The patient was more responsive to commands than she had been on the previous day, although she could not distinguish the right hand from the left.

定位诊断 定性诊断 诊断依据 如何求证

定义、解剖和病原学 病毒 细菌 真菌 寄生虫 螺旋体 立克次体 朊蛋白

细菌性脑膜炎 化脓性脑膜炎 非化脓性脑膜炎 细菌：结核性脑膜炎 非细菌：病毒性脑膜炎，隐球菌脑膜炎，螺旋体（神经莱姆病）等

化脓性脑膜炎 病因和发病机制 病理 临床表现 实验室检查 诊断和鉴别诊断 治疗 预后

化脓性脑膜炎--病因和发病机制 发病率：1.5人/10万/年 病原菌： 感染途径 成年人：肺炎链球菌（50%），脑膜炎双球菌（25%） 儿童：流感嗜血杆菌（50%），脑膜炎双球菌（30%） 新生儿：B组链球菌(50%)，大肠杆菌（20%） 腰穿、脑室引流和颅脑手术：金葡、绿脓 感染途径 血行播散 直接扩散 经脑脊液

病原菌国内资料 脑膜炎双球菌、肺炎球菌、流感嗜血杆菌占80% 儿童：脑膜炎双球菌（流行性脑膜炎） 老年：肺炎球菌 婴幼儿：流感嗜血杆菌 新生儿：E.coli，B组链球菌 神经外科术后、腰穿后：金葡菌、绿脓杆菌

化脓性脑膜炎--病理 大体：大量脓性渗出物，血管扩张 镜下： 脑膜：炎细胞浸润 蛛网膜下腔：中性粒细胞，纤维蛋白渗出物 室管膜和脉络膜：炎细胞浸润，充血 脑实质：偶见小脓肿

化脓性脑膜炎--临床表现 成人（包括大儿童） 婴幼儿 头痛87% 发热77% 颈强83% 低温或发热 疲软思睡 易激惹 高音调哭叫 感染症状：寒战，发热 脑膜刺激征：颈强，克氏征，布氏征阳性 颅内高压：头痛，呕吐，意识障碍 局灶症状：偏瘫，失语 其他症状：出血性皮疹 成人（包括大儿童） 婴幼儿 头痛87% 发热77% 颈强83% 低温或发热 疲软思睡 易激惹 高音调哭叫 拒食、吸吮无力 呕吐、腹泻 囟门隆起（1/3) 惊厥(40%) 意识改变69% 呕吐35% 惊厥5%

化脓性脑膜炎 实验室检查 脑脊液检查 血象 头颅MR或CT 脑电图 其他：血培养、皮肤瘀点培养 化脓性脑膜炎 实验室检查 脑脊液检查 血象 头颅MR或CT 脑电图 其他：血培养、皮肤瘀点培养 The CSF is under increased pressure, usually between 200 mm H2O and 500 mm H2O. The CSF is cloudy (purulent) because it contains a large number of cells, predominantly polymorphonuclear leukocytes. The cell count in the fluid is usually between 2,000/mm3 and 10,000/mm3. Occasionally, it may be less than 100/mm3 and infrequently more than 20,000/mm3. The protein content is increased. The sugar content is decreased, usually to levels below 20 mg/dL. Gram-negative diplococci may be seen intra- and extracellularly in stained smears of the fluid, and meningococci may be cultured in more than 90% of untreated patients.

化脓性脑膜炎 诊断和鉴别诊断 诊断：急性发病+三联征+脑脊液检查 鉴别诊断： 病毒性脑膜炎 结核性脑膜炎 隐球菌性脑膜炎

历史与现状 1805年之前 1805-1913 1913-1930 当前 病死率25% 后遗症发生率21-28% From its original recognition in 1805 until the early 1900s, bacterial meningitis was virtually 100 percent fatal. In 1913, Simon Flexner's introduction of intrathecal meningococcal antiserum prevented some deaths, but the clinical outcome did not improve dramatically until the advent of systemic antimicrobial therapy in the 1930s.

化脓性脑膜炎 治疗：抗生素 基本原则 抗生素治疗刻不容缓 全程静脉 “适当”抗生素 足量足疗程 化脓性脑膜炎 治疗：抗生素 基本原则 抗生素治疗刻不容缓 全程静脉 “适当”抗生素 足量足疗程 对于常见病原菌如肺炎球菌、流感嗜血杆菌和奈瑟氏脑膜炎球菌，经静脉给予足量抗生素，疗程至少10天，且在体温正常后至少使用7天；对于耐药菌株（肠道阴性菌、单核细胞增多性李司忒菌和B族链球菌）、或手术外伤后脑膜炎，抗生素治疗应延长至2~3周或更长。

延迟治疗的后果 269例，延迟4h，15%患者预后不良的指标增加 156例，肺链，延迟3h，是死亡率强独立指标（OR14.1） Auburtin M, Wolff M, Charpentier J, et al. Detrimental role of delayed antibiotic administration and penicillin-nonsusceptible strains in adult intensive care unit patients with pneumococcal meningitis: the PNEUMOREA prospective multicenter study. Crit Care Med 2006; 34:2758.

延迟治疗的原因 症状不典型：是患者死亡最重要的临床预测指标，OR39.4 做头颅CT

LP前是否需要CT 前瞻性研究301例拟诊细菌性脑膜炎患者 235例（78%）LP前做了CT 56例（24%）有异常表现，11例（5%）有占位效应 平均延迟治疗1小时 Hasbun R, Abrahams J, Jekel J, Quagliarello VJ. Computed tomography of the head before lumbar puncture in adults with suspected meningitis. N Engl J Med 2001; 345:1727.

什么病人需要先做CT Altered mentation Focal neurologic signs Papilledema Seizure within the previous week Impaired cellular immunity The risk of having an abnormal CT scan was predicted by a suspicious history (eg, presence of impaired cellular immunity, history of previous central nervous system disease, or a seizure within the previous week) as well as certain findings on neurologic examination (eg, reduced level of consciousness, and focal motor or cranial abnormalities). Among 96 patients with none of these abnormalities, only three had an abnormal CT scan; one of these three patients had a mild mass effect but all three underwent LP without evidence of brain herniation.

需要CT检查，如何不延误治疗 先抽血培养 经验性使用抗生素±激素 头颅CT 腰穿 50-90%阳性 抗生素对CSF细胞学和生化检查影响很小 除脑膜炎球菌外，其他致病菌在数小时内仍有高检出率 Kanegaye JT, Soliemanzadeh P, Bradley JS. Lumbar puncture in pediatric bacterial meningitis: defining the time interval for recovery of cerebrospinal fluid pathogens after parenteral antibiotic pretreatment. Pediatrics 2001; 108:1169.

“适当”的抗生素 针对病原菌的杀菌药 能透过血脑屏障 合适的药代动力学

“适当”的抗生素 肺炎球菌：头孢曲松+（万古霉素） 脑膜炎双球菌：头孢曲松 杆菌：绿脓（复达欣），其他（头孢曲松） 李斯特菌（氨苄青）；金葡（万古霉素） 未确定病原菌：头孢曲松

何为足疗程 肺链：10-14d 脑膜炎球菌：7d 流感嗜血杆菌：至少7d 李斯特菌：至少21d，影响脑实质，则6w G-杆菌（克雷白、E.coli）：21d 金葡菌：14d

化脓性脑膜炎—治疗：其他 激素：地塞米松10-20mg/d×3-5天 补液和脱水 发热 惊厥 脑积水 隔离 补液量不能过多，如果患者血压不低，成年患者一天补充生理盐水1200~1500ml，不要用糖水 脑膜炎球菌性或者是病原菌不明的脑膜炎患者，在应用抗生素的第一个24小时内应置于呼吸道隔离病房

化脓性脑膜炎 预后 病死率15% 后遗症： 智力减退 癫痫 脑积水

结核性脑膜炎 病因和发病机制 病理 临床表现 实验室检查 诊断和鉴别诊断 治疗 预后

结核性脑膜炎发病率—0.35-0.7/10万/年

结核性脑膜炎 病因和发病机制 病原菌 人型结核分枝杆菌 牛型结核分枝杆菌 感染途径 血行播散 淋巴系统播散 局部播散

结核性脑膜炎 病理 脑底部渗出物 血管炎 脑积水

结核性脑膜炎 临床表现 慢性、亚急性、急性 脑膜炎共有症状 结核菌相对有特点的症状 颅高压 脑膜刺激征 结核性脑膜炎 临床表现 慢性、亚急性、急性 脑膜炎共有症状 颅高压 脑膜刺激征 结核菌相对有特点的症状 毒血症状：低热、盗汗、纳差、乏力、精神软 脑神经损害 脑实质损害

结核性脑膜炎 辅助检查 金标准：抗酸染色，结核菌培养 新方法：PCR、ADA、免疫组化、酶联免疫 脑脊液：常规、生化 结核性脑膜炎 辅助检查 金标准：抗酸染色，结核菌培养 新方法：PCR、ADA、免疫组化、酶联免疫 脑脊液：常规、生化 影像学：胸片/CT，脑CT/MRI 其他：PPD皮试，血沉，血常规

结核性脑膜炎 Ahuja诊断标准 A临床：发热头痛>14天（必须）；呕吐/局灶缺失症状（不是必须） B脑脊液：1细胞数>20（淋巴〉60%），2蛋白>100mg/dl，糖<60%血糖，3墨汁染色（-），肿瘤细胞（-） C影像学：有下列2项或以上：1基底池和外侧裂渗出物；2脑积水；3脑梗塞；4脑回强化 D颅外结核 阳性预测值（PPV） 确诊TBM：A+找到结核杆菌或尸解 100% 高度可能TBM：A+B+C+D 91.7% 很可能TBM：A+(B+C+D)中的2个 66.7% 可能TBM：A+（B+C+D）中的1个 38.5%

结核性脑膜炎 诊断新方法 Sensitivity and specificity of immunocytochemical staining of mycobacterial antigens in the cytoplasm of cerebrospinal fluid macrophages for diagnosing tuberculous meningitis. Shao Y, Xia P, Zhu T, Hu X.J Clin Microbiol. 2011 Sep;49(9):3388-91.

结核性脑膜炎 鉴别诊断 化脓性脑膜炎 病毒性脑膜炎 隐球菌性脑膜炎 脑膜癌病

结核性脑膜炎 治疗 抗痨治疗 激素：指征 对症：脱水降颅压、抗癫痫、脑积水引流术 结核性脑膜炎 治疗 抗痨治疗 药物种类：异烟肼(H)、利福平(R)、吡嗪酰胺(Z)、乙胺丁醇(E)、链霉素(S) 合用方案和疗程：常用（HRZ），耐药加E/S 副作用和监测：肝酶、末梢神经炎 激素：指征 对症：脱水降颅压、抗癫痫、脑积水引流术 异烟肼：细胞内外、生长期、静止期均能杀菌，通过BBB，达90%血浓度。末梢神经炎（VB6对抗），肝损 利福平：干扰mRNA，对细胞内外能杀菌，通过炎症BBB，副作用小 吡嗪酰胺：杀胞内菌，自由通过BBB，肝损，关节炎 链霉素：杀胞外菌，通过炎症BBB，耳毒性和肾毒性 乙胺丁醇：抑制RNA，抑菌，只对生长期有效，防止耐药菌产生，视神经损害、末梢神经炎

结核性脑膜炎 预后 自然病程6-8周死亡 合理治疗90%恢复，但25%有后遗症 婴幼儿和老年人预后差 结核性脑膜炎 预后 自然病程6-8周死亡 合理治疗90%恢复，但25%有后遗症 婴幼儿和老年人预后差 入院时意识障碍、颅神经损害、脑脊液蛋白浓度高预后差 其他脏器结核或粟粒性结核不影响预后 后遗症轻重不一 The natural course of the disease is death in 6 weeks to 8 weeks. With early diagnosis and appropriate treatment, the recovery rate approaches 90%. Delay in diagnosis is associated with rapid progression of neurologic deficits and a poorer prognosis. Prognosis is worst at the extremes of life, particularly in the elderly person. The presence of cranial-nerve abnormalities on admission, confusion, lethargy, and elevated CSF-protein concentration are associated with a poor prognosis. The presence of active tuberculosis in other organs, or of miliary tuberculosis, does not significantly affect the prognosis if antitubercular therapy is given. Relapses occasionally occur after months or even years in apparently cured patients. Minor or major sequelae occur in about 25% of the patients who recover. These vary from minimal degree of facial weakness to severe intellectual and physical disorganization. Physical defects include deafness, convulsive seizures, blindness, hemiplegia, paraplegia, and quadriplegia. Intracranial calcifications may appear 2 years to 3 years after the onset of the disease.

单纯疱疹病毒性脑炎 病因和发病机制 病理 临床表现 实验室检查 诊断和鉴别诊断 治疗 预后 Arbovirus infections occur more frequently in the summer in the northern hemisphere, mumps in winter, and HSV encephalitis occurs year-round. 日本脑炎（乙型脑炎）789月

单疱脑炎 病因和发病机制 发病率4-8/10万 单纯疱疹病毒（HSV）I型（90%），II型（10%） 途径： 病机： 单疱脑炎 病因和发病机制 发病率4-8/10万 单纯疱疹病毒（HSV）I型（90%），II型（10%） 途径： HSV-1：密切接触、飞沫 （三叉神经节） HSV-2：性接触、母婴 （骶神经节） 病机： 病毒直接损害：HSV-1致细胞凋亡，HSV-2无 免疫介导损害 In adults, HSV-2 is spread by venereal transmission and causes aseptic meningitis. The ability of HSV-1 to induce apoptosis (programmed cell death, or “cellular suicide”) in neuronal cells, a property not shared by HSV-2 RNA viruses usually replicate within the cytoplasm of infected cells, whereas DNA viruses replicate in the nucleus. most arboviruses are more likely to produce encephalitis than meningitis, whereas most enteroviruses produce far more cases of meningitis than encephalitis

单疱脑炎 病理 部位 出血坏死 炎性 包涵体

单疱脑炎 临床表现 脑实质症状 精神行为异常、认知障碍 癫痫发作 意识障碍 局灶症状 感染症状 前驱症状：上感、疱疹

单疱脑炎 实验室检查 脑电图 影像学 脑脊液 病原学 病理 单疱脑炎 实验室检查 脑电图 影像学 脑脊液 病原学 病理 Electroencephalography (EEG), though lacking in specificity (32%), has 84% sensitivity to abnormal patterns in HSE.

单疱脑炎 诊断 临床拟诊 确诊 临床表现：前驱、感染症状、脑实质症状 脑脊液 脑电图 影像学 PCR 双份CSF发现HSV特异性抗体变化 单疱脑炎 诊断 临床拟诊 临床表现：前驱、感染症状、脑实质症状 脑脊液 脑电图 影像学 确诊 PCR 双份CSF发现HSV特异性抗体变化 脑活检 About 50% of the population has antibody to HSV-1 by age 15 years, whereas 50% to 90% of adults have antibody, depending on socioeconomic status. HSV-1 encephalitis may occur at any age, but more than 50% of cases occur in patients older than 20 years of age. PCR is highly sensitive (94-98%) and specific (98-100%). Results become positive within 24 hours of the onset of symptoms and remain positive for at least 5-7 days after the start of antiviral therapy.

单疱脑炎 鉴别诊断 其他病毒性脑炎 带状疱疹病毒 巨细胞病毒性 乙型病毒 腮腺炎病毒 麻疹病毒 急性播散性脑脊髓炎（ADEM）

单疱脑炎 治疗 抗病毒治疗 早期、按时、足疗程 阿昔洛韦，更昔洛韦 激素 对症治疗 抗癫痫 降温 治疗精神症状 降颅压

单疱脑炎 预后 不治疗死亡率70-80%，阿昔洛韦治疗后降至28% 预后取决于 后遗症10% 意识状况 患者年龄 治疗是否及时 单疱脑炎 预后 不治疗死亡率70-80%，阿昔洛韦治疗后降至28% 预后取决于 意识状况 患者年龄 治疗是否及时 后遗症10% Without treatment, the disease is fatal in about 70% to 80% of patients, and patients who survive the acute disease are usually left with severe neurologic residuals acyclovir reduced mortality to 28% Outcome depends on patient age, level of consciousness, and the rapidity with which treatment is instituted. Untreated HSE is progressive and often fatal in 7-14 days. Patients who are comatose at diagnosis have a poor prognosis regardless of their age. In noncomatose patients, the prognosis is age related, with better outcomes occurring in patients younger than 30 years. 4天内治疗死亡率7%，4天以上25%死亡率。30岁以下预后佳。

回到原来的病例

定位 根据头痛、颈强、克氏征阳性、脑膜强化定位于软脑膜 根据意识改变、失语、左右手失认、双侧海马区MRT2相高信号、脑电图异常定位于脑实质

定性 Midnight 根据急性起病、发热、寒战、脑脊液细胞数增高考虑感染 根据脑脊液不浑浊，白细胞数32-107，分类迅速从中性粒转化为淋巴细胞为主，首先考虑为非化脓性炎症，病毒性可能大 M-metabolic代谢、I-Infection传染、D-Degenerative退化、N-Neoplasm肿瘤、I-Inflammation炎症、G-gland、H-Hereditary、T-Trauma&toxin

临床印象和Work-up 脑膜脑炎：病毒性？结核性？ 疫源地接触史，昆虫叮咬史，病原检测

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