神经病学：中枢神经系统感染

1、Infections of Central Nervous System,中枢神经系统感染,概述,All kinds of pathogen,invade,cerebral parenchyma meninges and blood vessel,lead to,acute subacute or chronic,infections.,Bacteria Viruses Parasites Fungi Prion protein Spirochete Rickettsia,概述-Classification according to the pathogen,Purulent Meningit

2、is Tuberculous Meningitis,Herpes Simplex Virus Encephalitis,Cerebral Cysticercosis,Cryptococcal Meningitis,Creutzfeldt-Jakob disease,Central Nervous System Syphilis,概述-Classification according to the pathology,Parenchyma encephalitis myelitis encephalomyelitis Meninges meningitis Parenchyma Phenytoi

3、n po 血药浓度1525ug/ml Duration of anticonvulsant therapy several months following recovery,Acute Management,Antiviral chemotherapy A potential diagnosis of HSE begin intravenous acyclovir without delay (history, examination, neuroimaging, CSF profile） Outcome measure in HSE 症状出现至阿昔洛韦治疗的时间 患者年龄 就诊时患者的意识

4、障碍严重程度,Treatment：intravenous acyclovir or ganciclovir Dosage：10mg/kg q8h14-21days GFR 10-50ml/min2.5mg/kg q12h 10ml/min 2.5mg/kg q24h,Acute Management,Continued Management,Maintain a positive nitrogen balance Serum electrolytic balance Paradoxical antidiuretic hormone secretion Renal dysfunction Pro

5、phylaxis against deep venous thrombosis Prophylaxis against gastrointestinal ulceration Rehabilitating train,Herpes Zoster,Herpes zoster is characterized by pain and rash, usually restricted to two or three dermatomes. It was caused by reactivation of varicella-zoster virus latent in cranial or dors

6、al ganglia since childhood chickenpox.,Herpes Zoster,50y Analgesia Antivirals not required but may speed healing of rash,Immunocompetent,Immunocompromised Acyclovir iv 5-10mg/kg q8h 5-7 days,50y Famciclovir 500mg tid Analgesia Prednisone 60mg po 3-5 days,Herpes Zoster,Treatment of Post-herpetic Neur

7、algia Topical agents: 水杨酸三乙醇胺乳膏剂 Amitriptyline 25-75mg/d Carbamazepine 600-1200mg/d Gabapentin 900-3600mg/d Oxycodone 10-30mg/d 羟氢可待酮 Diazepam 2mg tid,谢 谢!,病毒性脑膜炎 Viral Meningitis,概念,是一组由各种病毒感染引起的软脑膜弥漫性炎症的临床综合征,病因及发病机制,85%95%由肠道病毒引起 消化道感染病毒与肠道细胞结合入血病毒血症中枢神经系统,病理,侧脑室和第四脑室的脉络丛炎症细胞浸润。 室管膜内层局灶性破坏的血管壁纤维化

8、以及纤维化的基底软脑膜炎。 室管膜下的星形细胞增多和增大。,临床表现及辅助检查,夏秋季高发，热带和亚热带发病率高。85%-95%由肠道病毒引起，该病毒属于微小核糖核酸病毒科，有60多个亚型，包括脊髓灰质炎病毒、柯萨奇病毒A和B、埃可病毒等。 儿童多见，成人也可发病。 急性发病，病程常持续1-2周。 临床表现： 全身中毒症状：如发热、畏光、肌痛、食欲 减退、腹泻和全身乏力等 脑膜刺激征：头痛、呕吐、颈强和Kernig征等,CSF压力可能增高，细胞数增多10-1000106/L，早期以多形核为主，8-48h后以淋巴细胞为主。蛋白可轻度增高，糖、氯水平正常 PCR检查病毒阳性。,临床表现及辅助检查,

9、诊断及治疗,确诊需脑脊液病毒学检查 治疗是自限性疾病，抗病毒治疗可以缩短病程，主要是对症支持治疗（止痛、抗癫痫、脱水治疗等）。,朊蛋白病 Prion Disease,概述,由具传染性的朊蛋白（Prion protein, PrP）所致的一组中枢神经系统变性疾病 动物朊蛋白病 羊瘙痒病、传染性水貂脑病、麋鹿和骡鹿慢性消耗病、牛海绵状脑病 人类朊蛋白病 CJD、Kuru病、Gerstmann-Straussler Syn (GSS)、fatal familial insomnia (FFI 致命性家族性失眠症)、朊蛋白痴呆,朊蛋白(Prion protein, PrP)-既具有传染性又缺乏核酸的非

10、病毒性致病因子,概述,概述,Creutzfeldt-Jakob 病,最常见的人类朊蛋白病，主要累及皮质、基底节和脊髓，故又称为皮质纹状体脊髓变性。 多见于老年人。 PrP可通过角膜、硬脑膜移植、经肠道外给予人生长激素制剂和埋藏未充分消毒的脑电极而传播,分型 1型和2型存在于散发性CJD。 3型Type-3为医源性(iatrogenic)。 4型是新变异型-与疯牛病(MCD)具有相似的种系特异性。 PrP基因突变形成遗传性家族型CJD。,Creutzfeldt-Jakob 病,Gross evident: cerebral atrophy Microscopic findings: neuron

11、al loss, astrocytosis, and the development of cytoplasmic vacuoles in neurons and astrocytes (status spongiosis); Amyloid plaques containing the abnormal PrP; no inflammation The cortex and basal ganglia are most affected, but all parts of the neuraxis may be involved.,病理改变,CJD临床表现,隐袭起病，缓慢进行性发展。 分三期

12、 初期：神经症表现，头痛、眩晕、共济失调 中期：进行性痴呆、脊髓前角损害出现肌萎缩、 肌阵 挛（最具特征性）、锥体束征。 晚期：尿失禁、无动性缄默、昏迷与去皮层强直 状态，可因褥疮或肺感染而死亡,CJD辅助检查,荧光免疫检测CSF中1433蛋白可呈阳性。 血清S100蛋白随病情进展而持续性增高。 脑电图可出现棘慢复合波。 晚期CT或MRI出现脑萎缩；MRI示双侧尾状核、壳核T2对称性均质高信号，很少波及苍白球，T1正常，对诊断有意义。,Creutzfeldt-Jakob disease Record of a 65-year-old man shows spikes of sharp wave

13、s at intervals of 0.7 seconds throughout the recording. Such periodicity with 0.5- to 2.0-second intervals occurs in the middle and late stages and may be absent in the early stages of the disease.,诊断,在2年内发生的进行性痴呆。 肌阵挛、视力障碍、小脑症状、无动性缄默4项中具2项。 脑电图特征性改变。 诊断：具备3项为很可能CJD，仅具1、2项为可能CJD，确诊需靠脑活检,Alzheimer病 进

14、行性核上性麻痹 橄榄脑桥小脑萎缩 脑囊虫病 肌阵挛性癫等鉴别,鉴别诊断,Tuberculous meningitis TBM,Overview,TBM differs from that caused by most other common bacteria in that the course is more prolonged the mortality rate is higher CSF changes are less severe treatment is less effective in preventing sequelae,Pathogenesis,TBM is alwa

15、ys secondary to TB elsewhere in the body The primary focus is usually in the lungs but may be in the lymph glands, bones, nasal sinuses, gastrointestinal tract, or any organ in the body.,The onset of meningeal symptoms may coincide with signs of acute miliary dissemination, or there may be clinical

16、evidence of activity in the primary focus; however, meningitis is often the only manifestation of the disease. 结核菌经血播散脑膜、软脑膜下种植结核结节结节破溃蛛网膜下腔,Pathogenesis,Potts disease (spinal tuberculosis). A: T2W sagittal magnetic resonance (MR) scan: increased signal intensity within four to five consecutive vert

17、ebral bodies of the lower thoracic spine, compression fracture of one of the thoracic vertebral bodies. B and C: T1W sagittal MR scans of thoracic spine before and after gadolinium enhancement show marked enhancement of affected thoracic vertebral bodies with mild epidural extension, especially at t

18、he level of the compression fracture.,Pathology,The meningescloudy and thickened most intense at the base of the brain. A thick collar of fibrosisaround the optic nerves, cerebral peduncles, the pons and midbrain. The ventriclesmoderately dilated The ependymal liningcovered with exudate or appears r

19、oughened (granular ependymitis 颗粒性室管膜炎) Minute tuberclesbe visible in the meninges, choroid plexus, and cerebral parenchyma.,Pathologymicroscopy,The exudatemononuclear cells, lymphocytes, plasma cells, macrophages, and fibroblasts with an occasional giant cell. The inflammatory process may extend fo

20、r a short distance into the cerebral substance where microscopic granulomas may also be found. Proliferative changes are frequently seen in the inflamed vessels of the meninges, producing a pan-arteritislead to thrombosis of the vessel and cerebral infarcts.,Epidemiology,Incidence 活动性结核 8百万年 TBM7万年

21、CNS结核瘤和脑实质肉芽肿1020,high risk population 艾滋病患者 结核病密切接触者 酒精中毒或营养不良者 流浪者 老年人 长期使用类固醇或免疫抑制剂者 偏远落后地区 其他部位结核病者,Clinical Manifestation,亚急性或急性起病，慢性过程。 结核中毒症状、脑膜刺激征。 脑积水，颅高压（交通性或梗阻性脑积水）。 治疗不及时可出现脑实质损害症状。 颅神经损害，脊髓损害。 老年患者颅高压不明显，CSF改变不典型，常发生结核性动脉内膜炎,Auxiliary Examination,CSF压力增高，外观黄色，静止后可有薄膜形成，细胞数增多，淋巴细胞为主，蛋白升高

22、，糖及氯化物降低 抗酸杆菌染色，阳性低 结核杆菌培养是确诊的金指标，但阳性率低 MRI和CT检查（脑膜强化，犹以颅底脑膜明显）,CSF change of TBM,increased pressure slightly cloudy or ground-glass appearance formation of a clot on standing moderate pleocytosis of 25 to 500 cells/mm3 lymphocytes as the predominating cell type increased protein content decreased s

23、ugar content with values in the range of 20 to 40 mg/dL a negative serologic test for syphilis or cryptococcal antigen,CSF change of TBM,Although none of these abnormalities is diagnostic, their occurrence in combination is usually pathognomonic and is sufficient evidence to warrant intensive therap

24、y until the diagnosis can be confirmed by stained smears of the sediment or pellicle or by culture of the CSF.,A and B: (A) large nonenhancing hypodense lesion in the left temporal lobe and (B) left basal ganglia Significant basal cisternal enhancement consistent with meningitis C and D: T1W axial M

25、RI after gadolinium enhancement show florid contrast enhancement within basal cisterns most consistent with exudative meningitis of tuberculosis. Enhancement of the left temporal lobe and left basal ganglia lesions suggests persistent inflammation within these infarcts.,Intracranial Multifocal Lesio

26、ns Associated with Phthisis Miliaris: Tuberculoma or Inflammatory Granuloma?,Diagnosis,Diagnosis of TBM presents a challenge The mycobacterium is difficult to culture from CSF (positive rate 50%) Acid-fast staining (positive rate 5%-10%) Because isolation of mycobacterium requires several weeks, a r

27、apid method of diagnosis is needed(TB DNA fragment PCR),Methods to improve the positive rate Culture of large volumes of CSF(10-30ml)3 30% 75% High-speed centrifugation of the CSF for a prolonged period(3000gravity for 30 minutes),诊断及鉴别诊断,诊断： 结核病史及接触史 脑膜刺激征 脑脊液特征性改变 神经影像学特征性改变 鉴别： 其它脑膜炎如隐球菌性脑膜炎 蛛网膜下

28、腔出血 血管性头痛,Management of TBM General priciple,Multiple antimicrobial drugs are required Drugs must adequately cross the blood-CSF barrier to achieve therapeutic concentration in CSF Drugs should be taken on a regular basis Drugs should be taken for a sufficient period to eradicate the CNS infection T

29、reatment should be started immediately without waiting for bacteriologic confirmation of the diagnosis in a patient with the characteristic clinical symptoms and CSF findings.,Management of TBMAntibiotics,Resistance to antibiotics INH 10% Ethambutol 7% Rifampin 3% No CSF isolate was multidrug resist

30、ance. A four first-line drug regimen of INH, rifampin, and PZA with addition of streptomycin or ethambutol is recommended. Period of antibiotic therapy 9-12 months 6 months 18-24 months,Management of TBMAntibiotics,INHbactericidal; impair DNA synthesis Rifampinbactericidal; impair RNA synthesis PZAa

31、 unique ability to kill slowly metabolizing mycobacteria Streptomycinsevere sensorineural hearing loss and usually discontinued after 2 months of treatment. Ethambutolbacteriostatic, less effective than streptomycin, usually discontinued after 2 months,Management of TBMAntibiotics,Second-line antitu

32、berculous drugs ofloxacin氧氟沙星 ciprofloxacin环丙沙星 capreomycin卷曲霉素 kanamycin卡那霉素 cycloserine环丝氨酸 amikacin丁胺卡那霉素 clofazimine氯苯吩嗪 rifabutin利福布丁,Management of TBMAntibiotics,Management of TBMIncreased ICP,Early in clinical courseacetazolamide (乙酰唑胺,醋唑磺胺)(30mg/kg/day tid po) Repeated lumbar punctures Manni

33、tol Ventriculoperitoneal shunt is required for long-term reduction of ICP, especially when obstruction of ventricular system is present.,Management of TBMSeizures,Seizures occur in up to 50% of patient and may be generalized or focal. Anticonvulsants should be administered according the type of seiz

34、ures. Phenytoin 300mg/day PO Valproic acid ,if need, should be given with care, because many antituberculous drugs affect liver metabolism.,Management of TBMCorticosteroids,Adjunctive therapy with corticosteroids is recommended for severely ill patients. Childrenprednisone4mg/kg/day dexamethasone8mg

35、/day Adultsdexamethasone12-16mg/day for first 1 to 2 months of therapy If the likelihood of the diagnosis is not high, the practitioner should consider omitting corticosteroids until the diagnosis is established because use of corticosteroids without appropriate drug therapy can worsen other infecti

36、ous causes of subacute meningitis.,隐球菌性脑膜炎 Cryptococcal meningitis,Clinical Characteristics,Symptomatic onset of nervous system involvement is subacute. Meningeal symptoms usually predominate The usual clinical picture is that of subacute meningitis or encephalitis.,Changes of CSF,The CSF findings i

37、n infections with cryptococci are similar to those of tuberculous meningitis. Increased pressure A slight or moderate pleocytosis of 10 to 500 cells/mm3 The protein content is increased The sugar content is decreased, between 15 and 35 mg/dL The diagnosis is made by finding the organisms in the coun

38、ting-chamber centrifuge sediment of the fluid,Fresh preparation of sediment from CSF stained with India ink. The capsule is three times the diameter of the cell.,Management of Cryptococcal meningitis,Amphotericin B0.7 to 10mg/kg/day iv with or without 5-flucytosine氟胞嘧啶 25 to 37.2 mg/kg/day CSF cultu

39、re per two weeks, until they are negative. Stop amphotericin B and 5-flucytosine, continued with fluconazole氟康唑(200 to 400 mg/day) for 8 to 10 weeks Predictors of poor outcomeincreased CSF pressure; positive India ink stain; low CSF lymphocyte count; CSF hypoglycorrhachia; high cryptococcal antigen titers; positive blood cultures and extraneural involvement.,脑 囊 虫 病 Brain cysticercosis,概述,脑囊虫病(brain cysticercosis)是猪绦虫幼虫(囊尾蚴)寄生脑部所致。 脑囊虫病的发病率颇高，约占人囊虫病的5070 患者以青壮年为多见。,发病机制,因食入绦虫卵或是已患肠绦虫病的患者呕吐时虫卵逆流入胃，在十二指肠内孵化，六钩蚴逸出，穿入肠壁，随血循环而至身体各处，发育成为囊尾蚴，