这是用户在 2024-6-11 14:10 为 https://app.immersivetranslate.com/pdf-pro/5a16c269-cfc0-4f1a-b55e-948d105a87d1 保存的双语快照页面，由 沉浸式翻译 提供双语支持。了解如何保存？
2024_06_11_399db9d584f02353865ag

Community-acquired Bacterial Meningitis in Adults With Cerebrospinal Fluid Leakage
成人脑脊液渗漏的社区获得性细菌性脑膜炎

Liora ter Horst, Matthijs C. Brouwer, Arie van der Ende, and Diederik van de Beek
Liora ter Horst、 Matthijs C. Brouwer、 Arie van der Ende 和 Diederik van de Beek 'Department of Neurology, Amsterdam Neuroscience, Department of Medical Microbiology, Amsterdam Infection and Immunity, and Netherlands Reference Laboratory for Bacterial Meningitis,
'阿姆斯特丹神经科学神经病学系、 阿姆斯特丹感染与免疫医学微生物学系和 荷兰细菌性脑膜炎参考实验室，Amsterdam University Medical Centers, University of Amsterdam, The Netherlands
荷兰阿姆斯特丹大学阿姆斯特丹大学医学中心

Background. Cerebrospinal fluid (CSF) leakage is a risk factor for developing bacterial meningitis.
背景。脑脊液 （CSF） 渗漏是发生细菌性脑膜炎的危险因素。
Methods. We analyzed episodes of community-acquired bacterial meningitis associated with CSF leakage from a prospective nationwide cohort study.
方法。我们分析了与脑脊液渗漏相关的社区获得性细菌性脑膜炎发作，这些事件来自一项前瞻性全国性队列研究。
Results. CSF leakage was identified in 65 episodes of 2022 episodes ( ) in 53 patients. The cause of CSF leakage was identified in 49 of 65 episodes ( ), which most commonly consisted of ear-nose-throat surgery ( 19 of 49 episodes [29%]) and remote head trauma ( 15 of 49 episodes [23%]). The episode was a recurrent meningitis episode in 38 patients ( ). Of the recurrent episodes, 27 had known CSF leakage ( ) of whom had previous surgery aiming to close the leak Nine patients ( ) with known CSF leakage had been vaccinated ( 23 -valent pneumococcal vaccine in 9 patients, meningococcal serogroup vaccine in 2 , meningococcal serogroup A and Haemophilus influenzae type b vaccine each in 1 patient). Streptococcus pneumoniae was cultured in 33 episodes ( ) and H. influenzae in 11 episodes ( ). The most common pneumococcal serotypes were 3 ( 4 episodes), 35B, , 38, and 15C (each 2 episodes). Haemophilus influenzae was unencapsulated in all 10 episodes with known capsule type. The outcome was unfavorable in 8 episodes ( ) and no patient died.
结果。在 53 例患者的 2022 年发作的 65 次发作中发现了脑脊液渗漏 （ ）。脑脊液渗漏的原因在 65 例发作中的 49 例中被确定 （ ），最常见的包括耳鼻喉手术（49 例中的 19 例 [29%]）和远程头部外伤（49 例中的 15 例 [23%]）。该事件是 38 例患者的复发性脑膜炎发作 （ ）。在复发发作中，27 例已知脑脊液渗漏 （ ） 其中 9 例已知脑脊液渗漏的患者 （ ） 已接种疫苗（9 例患者接种了 23 价肺炎球菌疫苗，2 例接种了脑膜炎球菌血清型 疫苗，1 例患者接种了 A 型脑膜炎球菌血清型和 B 型流感嗜血杆菌疫苗）。肺炎链球菌培养33次（ ），流感嗜血杆菌培养11次 （ ）。最常见的肺炎球菌血清型为3型（4例）、35B型、 38型和15C型（各2例）。流感嗜血杆菌在所有 10 次发作中均未包膜，具有已知的胶囊类型。结果在8次发作中呈不良状态（ ），无患者死亡。
Conclusions. Bacterial meningitis in patients with CSF leakage has a high recurrence rate, despite surgical repair or vaccination, and outcome is generally favorable. CSF leakage should be suspected in patients with bacterial meningitis presenting with liquorrhea, recurrent meningitis, or with disease caused by . influenzae.
结论。脑脊液渗漏患者的细菌性脑膜炎复发率很高，尽管进行了手术修复或接种疫苗，但结果总体上是有利的。对于表现为胃泻、复发性脑膜炎或由 引起的 疾病的细菌性脑膜炎患者，应怀疑脑脊液渗漏。流行性感冒。
Keywords. cerebrospinal fluid leakage; risk factor; bacterial meningitis.
关键字。脑脊液渗漏;危险因素;细菌性脑膜炎。
Risk factors for community-acquired bacterial meningitis include immunocompromise, distant foci of infection, and anatomic deficits in the natural barriers of the brain [1-4]. Anatomic defects can be caused by congenital abnormalities of the skull, through contiguous spread of infection during ear and sinus infections, or after neurosurgery, ear-nose-throat (ENT) surgery, or neurotrauma, which can all lead to cerebrospinal fluid (CSF) leakage [5, 6]. Bacterial meningitis in patients with CSF leakage can be classified as community acquired, in case of anatomic defects or contiguous spread of infection, or nosocomial or healthcare-associated meningitis after surgery for trauma . Symptoms suggestive of CSF leakage include rhinorrhea and otorrhea, but CSF leakage may also go
社区获得性细菌性脑膜炎的危险因素包括免疫功能低下、远处感染灶和脑天然屏障的解剖缺陷[1-4]。解剖缺陷可由颅骨先天性异常、耳部和鼻窦感染期间、神经外科手术、耳鼻喉手术或神经创伤后感染的连续扩散引起，这些都可能导致脑脊液（cerebrospinal fluid， CSF）渗漏[5,6]。脑脊液渗漏患者的细菌性脑膜炎可分为社区获得性脑膜炎，如果解剖学缺陷或感染连续扩散，或创伤手术后院内或医疗相关的脑膜炎 。提示脑脊液渗漏的症状包括流涕和耳漏，但脑脊液渗漏也可能消失
Received 24 April 2019; editorial decision 1 July 2019; accepted 11 July 2019; published online July 12, 2019.
收稿日期： 2019-04-24;编辑决定 2019年7月1日;2019年7月11日接受;2019年7月12日在线发布。
Correspondence: D. van de Beek, Department of Neurology, Amsterdam Neuroscience, Amsterdam University Medical Centers, University of Amsterdam, PO Box 22660. 11000D Amsterdam. The Netherlands (d.vandebeek@amc..vva.ni).
通信：D. van de Beek，阿姆斯特丹神经科学系，阿姆斯特丹大学医学中心，阿姆斯特丹大学医学中心，邮政信箱22660。11000D阿姆斯特丹。荷兰 （d.vandebeek@amc..vva.ni）。

Clinical Infectious Diseases 2020;70(11)2256-61
临床传染病 2020; 70(11)2256-61

(c) The Author(s) 2019. Published by Oxford University Press for the Infectious Diseases Society of America. This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs licence (http://creativecommons.org/licenses) by-nc-nd/4.0/. which permits non-commercial reproduction and distribution of the work, in any medium, provided the original work is not altered or transformed in any way, and that the work is properly cited. For commercial re-use, please contact journals.permissions@oup.com DOI: 10.1093/cid/ciz649 unnoticed [9]. In patients with skull-base fracture due to head trauma, CSF leakage resolves spontaneously within 24 hours after onset , but once persistent, meningitis occurs in of patients . Cerebrospinal fluid leakage has previously been reported in of patients with communityacquired bacterial meningitis and in of patients with recurrent meningitis [13-16]. We evaluated patients with bacterial meningitis associated with identified CSF leakage from a prospective nationwide cohort study in adults with communityacquired bacterial meningitis.
（c） 作者 2019.由牛津大学出版社为美国传染病学会出版。这是一篇开放获取文章，根据知识共享署名-非商业性使用-禁止演绎许可 （ http://creativecommons.org/licenses） by-nc-nd/4.0/ 的条款分发。允许以任何媒介对作品进行非商业性复制和发行，前提是原始作品不得以任何方式更改或转换，并且该作品被正确引用。如需商业再利用，请联系 journals.permissions@oup.com DOI： 10.1093/cid/ciz649 unnotice [9]。在颅底骨折因头部外伤的患者中，脑脊液渗漏在发病 后 24 小时内自行消退，但一旦持续存在，患者 就会发生 脑膜炎。既往有社区获得性细菌性脑膜炎患者和 复发性脑膜炎患者脑脊液渗漏的报道 [13-16]。我们评估了与已确定的脑脊液渗漏相关的细菌性脑膜炎患者，该研究来自一项针对社区获得性细菌性脑膜炎成人的前瞻性全国性队列研究。

METHODS 方法

In the MeninGene study, a nationwide observational cohort study in the Netherlands, we prospectively included 2022 episodes of community-acquired bacterial meningitis. Methods of the cohort have been described in detail previously [13]. In summary, patients over 16 years old with CSF cultureconfirmed community-acquired bacterial meningitis were included between January 2006 and December 2017. The patients were listed in the database of the Netherlands Reference Laboratory for Bacterial Meningitis; this database receives CSF and blood samples from over of all patients with bacterial meningitis in the Netherlands and provides daily updates to the researchers after which the treating physicians were contacted.
在荷兰的一项全国性观察性队列研究 MeninGene 研究中，我们前瞻性地纳入了 2022 例社区获得性细菌性脑膜炎发作。该队列的方法先前已详细描述[13]。总之，2006 年 1 月至 2017 年 12 月期间纳入了 16 岁以上经脑脊液培养确诊的社区获得性细菌性脑膜炎患者。这些患者被列入荷兰细菌性脑膜炎参考实验室的数据库;该数据库接收来自荷兰所有细菌性脑膜炎患者 的脑脊液和血液样本，并向研究人员提供每日更新，然后联系治疗医生。
Written informed consent was obtained from all participating patients or their legal representatives. We excluded patients with hospital-acquired meningitis, patients with recent (within 1 month) head injury or neurosurgery, and patients with neurosurgical devices.
获得所有参与患者或其法定代表人的书面知情同意书。我们排除了医院获得性脑膜炎患者、近期（1个月内）头部损伤或神经外科手术的患者以及使用神经外科器械的患者。
Data on patients' characteristics, symptoms and signs on admission, laboratory results, radiological examination, treatment, and outcome were prospectively collected with an online case record form (CRF). In this CRF we defined predisposing factors for developing bacterial meningitis such as otitis media, sinusitis, pneumonia, endocarditis, remote neurosurgical procedure or head trauma, and an immunocompromised state (eg, caused by use of immunosuppressive drugs, splenectomy, diabetes mellitus, cancer, alcoholism, or human immunodeficiency virus). The CRF also included a standard question on the presence or absence of CSF leakage, of which the judgment was left to the discretion of the treating physician. If CSF leakage was reported, additional information was retrospectively collected and all discharge letters were screened for causes of leakage, duration of leakage, the presence of liquorrhea, number of recurrent episodes, vaccination policy, and treatment of CSF leakage. At discharge, neurological examination was performed and this outcome was graded according to the Glasgow Outcome Scale (GOS), with outcome scores varying from 1 (death) to 5 (good recovery). A favorable outcome was scored as 5 and an unfavourable outcome was scored as 1-4.
通过在线病例记录表 （CRF） 前瞻性收集有关患者入院时的特征、症状和体征、实验室结果、放射学检查、治疗和结果的数据。在本CRF中，我们定义了发生细菌性脑膜炎的诱发因素，如中耳炎、鼻窦炎、肺炎、心内膜炎、远程神经外科手术或头部外伤，以及免疫功能低下状态（例如，由使用免疫抑制药物、脾切除术、糖尿病、癌症、酗酒或人类免疫缺陷病毒引起）。CRF还包括一个关于是否存在脑脊液渗漏的标准问题，其判断由主治医师自行决定。如果报告了脑脊液渗漏，则回顾性收集其他信息，并筛查所有出院信的渗漏原因、渗漏持续时间、是否存在腹泻、复发次数、疫苗接种政策和脑脊液渗漏的治疗。出院时，进行神经系统检查，并根据格拉斯哥结果量表 （GOS） 对结果进行分级，结果评分从 1（死亡）到 5（恢复良好）不等。有利的结果得分为5分，不利的结果得分为1-4。
Statistical analyses were conducted with the use of SPSS statistical software, version 24 (SPSS, Inc). We used descriptive statistics for baseline characteristics. To identify differences between episodes in patients with and without CSF leak-associated bacterial meningitis we used Mann-Whitney test for continuous data. For categorical data the chi-square test and Fisher's exact test were used. All tests were 2 -tailed, and was considered significant.
使用SPSS统计软件第24版（SPSS，Inc）进行统计分析。我们对基线特征使用描述性统计。为了确定有和没有脑脊液渗漏相关细菌性脑膜炎患者发作之间的差异，我们使用 Mann-Whitney 检验获得连续数据。对于分类数据，使用卡方检验和 Fisher 精确检验。所有测试均为 2 尾，并 被认为具有显著性。

RESULTS 结果

Over the 12-year period, CSF leakage was reported in 65 of 2022 episodes (3%) of community-acquired bacterial meningitis (Table 1) in 53 patients. The median age was 51 years (interquartile range [IQR], 40-61 years) and 33 were male ( ). Upon admission, CSF leakage was reported in 40 of 65 episodes ( ), most commonly rhinoliquorrhea ( 31 of 40 episodes [76%]). On presentation, the triad of fever, neck stiffness, and altered mental status was present in 20 of 63 episodes ( ); and in 43 of 64 episodes ( ) the duration of symptoms was shorter than 24 hours. In 31 of 65 episodes ( ), the patients presented with a Glasgow Coma Scale (GCS) score of less than 14, indicating an altered mental state. The duration of symptoms at the moment of presentation was shorter in episodes with CSF leak-associated meningitis compared with other meningitis episodes included in the cohort ( hours in 43 of 64 [67%] vs 869 of 1877 [46%]; ) (Supplementary Table 1). Fewer patients presented with an altered mental state, defined as a score on the GCS of less than 14, in episodes associated with a CSF leak ( 31 of 65 [48%] vs 1364 of 1945 [70%]; ). The cause of CSF leakage was identified in 49 episodes ( ): ENT surgery in 19 episodes ( ), remote head trauma in 15 ( ), previous neurosurgery in 4 ( ), malignancy in , a congenital defect in , and were diagnosed with idiopathic intracranial hypertension (Table 1).
在 12 年期间，2022 年社区获得性细菌性脑膜炎发作中有 65 例 （3%） 报告了 53 例患者的脑脊液渗漏（表 1）。中位年龄为 51 岁（四分位距 [IQR]，40-61 岁），33 岁为男性 （ ）。入院时，65 次发作中有 40 次报告脑脊液渗漏 （ ），最常见的是鼻漏（40 次发作中有 31 次 [76%]）。就诊时，63 次发作中有 20 次出现发热、颈部僵硬和精神状态改变三联征 （ ）;在64次发作 中，有43次症状持续时间短于24小时。在 65 次发作中的 31 次 （ ），患者的格拉斯哥昏迷量表 （GCS） 评分低于 14，表明精神状态改变。与队列中包括的其他脑膜炎发作相比，脑脊液渗漏相关脑膜炎发作时症状的持续时间更短（64 例中有 43 例 [67%] vs 1877 例中有 869 例 [46%]; ）（补充表1）。在与脑脊液渗漏相关的发作中，出现精神状态改变（定义为 GCS 评分低于 14）的患者较少（65 例中有 31 例 [48%] vs 1945 年有 1364 例 [70%]; ）。脑脊液渗漏的病因49例 （ ）：耳鼻喉科手术19例 （ ），远端颅脑外伤15例 （ ），既往神经外科手术4例（ ），恶性肿瘤， 先天性缺陷， 诊断为特发性颅内压增高（表1）。
Thirty-eight of 65 episodes (59%) had a history of meningitis prior to the current episode. In 20 of 38 episodes (53%), the recurrence occurred despite previous surgery aimed at closing the leak. Of the patients with a first episode of CSF leak-associated meningitis, 10 of 27 episodes (37%) were due to a previously identified CSF leak. Other predisposing factors for bacterial meningitis than CSF leakage were present in 23 of 65 episodes ( ), most commonly ear or sinus infections ( 16 of ) and pneumonia ( 4 of 23 [17%]). An immunocompromised state was present in 7 of 65 episodes ( ), which was due to the use of immunosuppressive drugs , diabetes , or alcoholism .
65 例中有 38 例 （59%） 在本次发作前有脑膜炎病史。在 38 次发作中的 20 次 （53%） 中，尽管先前进行了旨在闭合渗漏的手术，但复发还是发生了。在首次发作脑脊液漏相关性脑膜炎的患者中，27 次发作中有 10 次 （37%） 是由于先前发现的脑脊液漏所致。除脑脊液渗漏外，细菌性脑膜炎的其他诱发因素见于 65 例发作中的 23 例 （ ），最常见的是耳部或鼻窦感染 （ 16 例 ） 和肺炎 （ 4 例 / 23 例 [17%]）。在65次发作中，有7次出现免疫功能低下状态（ ），这是由于使用免疫抑制药物 、糖尿病 或酗酒 所致。
Brain imaging was performed in 53 of 65 episodes ( ) (Figure 1) and consisted of cranial computed tomography (CT) in all 53 episodes and cranial magnetic resonance imaging (MRI) with 3-dimensional (3D) constructive interference in steady state (CISS) in 11 of 53 episodes (21%). Cerebrospinal fluid markers ( -2 transferrin test and -trace) were used in 17 episodes and confirmed CSF leakage in 14 episodes. Cranial imaging could localize the anatomic location of CSF leakage in 60 of 65 episodes (92%). In 4 additional episodes (6%) the CSF leakage was revealed by a -2 transferrin test, and in 1 episode (2%) the CSF leak was found using myelography with intrathecal contrast. For 27 of 65 episodes ( ), endoscopic surgical repair of the defect was scheduled after recovery. Surgical outcome in these episodes could be retrieved in 17 episodes (63%). For 11 of 17 episodes it was the first attempt of surgical repair and had a success rate of ( 10 of 11 episodes) after a follow-up between 3 months and 6 years.
在 65 次发作中的 53 次进行了脑成像 （ ） （图 1），包括所有 53 次发作的颅脑计算机断层扫描 （CT） 和 53 次发作中的 11 次 （21%） 的颅脑磁共振成像 （MRI） 和 3 维 （3D） 建设性干扰稳态 （CISS）。脑脊液标志物（ -2转铁蛋白试验和 -trace）在17次发作中使用，在14次发作中确认脑脊液渗漏。颅脑影像学检查可在 65 例发作中的 60 例 （92%） 中定位脑脊液渗漏的解剖位置。在另外 4 次发作 （6%） 中， 通过 -2 转铁蛋白试验显示脑脊液渗漏，在 1 次发作 （2%） 中，使用脊髓造影和鞘内造影剂发现脑脊液渗漏。对于 65 次发作中的 27 次 （ ），计划在恢复后对缺损进行内窥镜手术修复。这些发作的手术结果可以在 17 次发作 （63%） 中恢复。对于 17 集中的 11 集，这是第一次手术修复尝试，在 3 个月至 6 年的随访后，成功率为 （11 集中的 10 集）。
Lumbar puncture was performed in all episodes and showed a median opening pressure of ). The median CSF leukocyte count in episodes with CSF leak-associated meningitis was 4870 (IQR, 1840-7927), and an elevated white blood cell count (WBC) in CSF of over 1000 cells was present in 54 of 61 episodes ( ). In 57 of 65 episodes ( ) at least 1 independent predictor of bacterial meningitis (glucose concentration, ; ratio of glucose concentration to blood glucose concentration, ; protein concentration, ; WBC count, cells ; or CSF neutrophil count, cells ) was present in the .
所有发作均进行腰椎穿刺，中位开口压为）。 脑脊液渗漏相关性脑膜炎发作的中位脑脊液白细胞计数为 4870 （IQR， 1840-7927），61 次发作中有 54 次脑脊液白细胞计数 （WBC） 升高超过 1000 个细胞 （ ）。在 65 次发作中的 57 次 （ ） 中，至少有 1 个细菌性脑膜炎的独立预测因子（葡萄糖浓度、 葡萄糖浓度与血糖浓度之比 、 蛋白质浓度、 ;白细胞计数， 细胞 ;或脑脊液中性粒细胞计数， 细胞 ）存在于 .
The CSF culture in episodes with CSF leak-associated meningitis identified the causative organism in 53 of 65 episodes
脑脊液渗漏相关脑膜炎发作的脑脊液培养在 65 次发作中的 53 次中确定了致病微生物
Table 1. Characteristics of 53 Patients With a Cerebrospinal Fluid Leakage With 65 Bacterial Meningitis Episodes
表 1.53例脑脊液渗漏伴65例细菌性脑膜炎发作患者的特征
Characteristics 特性 Values 值 Characteristics 特性 Values 值
Median (UQR) age,
中位年龄 （UQR），		 Index of CSF-Inflammation
脑脊液炎症指数
Male sex 男性 (62)  （62） Leukocyte count (cells )
白细胞计数（细胞 ）
Eause of CSF leak
脑脊液渗漏		 cells
细胞
Remote head trauma 远程头部外伤 cells
细胞 		(12)  （12）
Neurosurgery 神经外科 Mëdian (IOR) protein,
Mëdian（IOR）蛋白，
ENT surgery 耳鼻喉科手术 19/66 (29) Median (IOR) CSF to blood glucose ratio
中位 （IOR） 脑脊液与血糖比值
Congenital 先天 6/85 (9) Median (1OR) blood chemical test result
中位 （1OR） 血液化学检测结果
Tumor 瘤 ESR,  ESR， 7 (3-29)
Other" 其他” C-reacinie protein, wgg C-reacinie 蛋白 （wgg）
Unknown 未知 Thrombocytes,  血小板， 225 (191-266)
Presumed onset time of CSF leak
脑脊液漏的推定发作时间		 Causative organism 致病微生物
s1 year S1 年 Streptococcus pneumoniae
肺炎链球菌
year  年 Haemophitus influenzao 流感血孢
210 years 210 岁 Neisseria meningitidis 脑膜炎奈瑟菌
Unrevesled leak at:fust episode
未解泄的泄漏时间：fust episode		 (26)  （26） Other organismo 其他生物体 जin  ज在
CSF leak identified on CTMRI
CTMRI 发现脑脊液渗漏		 (92)  （92） Negative culture 消极文化
Equorrhea 国漏 Fransfer to lCU department
Fransfer 到 lCU 部门		 20/64 (31) 当
Rhinoliquorrhea 犀牛病 Impaired consciousness during admission
入院期间意识障碍		 19/62 (31)
Otoliquorrhea 耳漏 Systemic complications 全身并发症
Both 双 Respiratory failure 呼吸衰竭 (8)  （8）
Erevious vaccination Erevious 疫苗接种 Circulatory shock 循环休克
Previous surgery for CSF leakage
既往脑脊液渗漏手术史		 23/65 (35) Neurologic complications
神经系统并发症
Surgery during or after admission
入院期间或入院后进行手术		 27/65 (42) Seizures 发作 (16) Iㅏ읙ㄴ  （16） Iᅡ읙ᄂ
Recurrence 复发 (59)  （59） Cerebrovascular accident
脑血管意外
1 ime 1 个 IME Score on GOS  在GOS 上得分
times  次 (23)  （23） 1 (Death) 1 （死亡）
times  次 2 Negetative state): 2 否定状态）：
Predisposing factors 诱发因素 23/65 (35) 3 (Severely disabled) 3 （严重残疾）
timmunocompromised state
免疫功能低下状态		 4. Moderately disabledr 4.中度残疾者
Pneumonia 肺炎 (6)  （6） 5 (No or minor disability)
5 （无残疾或轻微残疾）
Ofitis media Ofitis 媒体 8885 (12) Sequelae at discharge 出院时的后遗症
Sinusitis 窦炎 Cognitive impairment 认知障碍 (9)  （9）
Symptoms on presentation
就诊时的症状		 Monofhemiparesis 单偏瘫
Headache 头痛 (92)  （92） Cranial nerve palsy 颅神经麻痹
ENausea
Neck stiffness 颈部僵硬
Temperature  温度 47164 (23)
Focal neurological deficits
局灶性神经功能缺损
Triad of symptoms
三联征症状 		20/83 (32)
Score on GCS GCS评分
Mecian (IOR) 梅西亚 （IOR） 14. (II)-15) 14.（二）-15）
58
Data are presented as unless othervise noted.
除非另有说明，否则数据均以 其他方式呈现。
Abbreviaions: CSF, cerebrospinal fluid; CT, computed tomography; ENT, ear-nose-throat; ESR, erychrocye sedimentation rate; GCS, Glasgow Coma Scale; GOS, Glasgow outcome scale: ICU. intensive care unit: IQR. interquartile range; MRI. magnetic resonance imaging.
缩写：CSF，脑脊液;CT，计算机断层扫描;耳鼻喉科，耳鼻喉;ESR， 红细胞沉降速率;GCS，格拉斯哥昏迷量表;GOS，格拉斯哥结果量表：ICU。重症监护病房：IQR。四分位距;核磁共振成像。磁共振成像。
'Other etiology: idiopathic intracranial hypenension, enlarged Meckel's cave.
其他病因：特发性颅内催眠，梅克尔洞扩大。
Focal neurological deficits defined as aphasia or hemiparesis or cranial nerve palsies and hearing loss.
局灶性神经功能缺损定义为失语症或偏瘫或颅神经麻痹和听力损失。
'Triad of symptoms a fover. neck stiffness, and change in mental status.
“症状的三联征是福佛。颈部僵硬和精神状态改变。
  1. ii!
indicates a change in mental status, s8 indicates come.
表示精神状态发生变化，S8表示来。
'Other organısms: Streptococous salivarius, Streptococcus agalactiae, Escrerichia coli, Streptococcus mitis.
其他器官：唾液链球菌、无乳链球菌、大肠杆菌、螨虫链球菌。
'Neurological complications defined as impaired consciousness or seizures or focal neurological deficits or cerebrovascular accidents or sinus thrombosis.
“神经系统并发症定义为意识障碍或癫痫发作或局灶性神经功能缺损或脑血管意外或鼻窦血栓形成。
(82%); in an additional 2 episodes the pathogen could be identified through blood culture, and in 1 episode the pathogen was identified by polymerase chain reaction. Streptococcus pneumoniae was identified in 33 of 65 episodes ( ) and
(82%);在另外 2 次发作中，病原体可以通过血培养进行鉴定，在 1 次发作中，病原体通过聚合酶链反应进行鉴定。肺炎链球菌在 65 次发作中的 33 次被发现 （ ） 和
Haemophilus influenzae in 11 episodes (17%). Other causative agents, as identified by CSF or blood culture, were Streptococcus agalactiae in 4 episodes (6%), Streptococcus salivarius in 3 episodes (5%), Streptococcus mitis in 3 episodes (4%), Neisseria
流感嗜血杆菌 11 次发作 （17%）。通过脑脊液或血培养鉴定的其他病原体是 4 次 （6%） 的无乳链球菌、3 次 （5%） 的唾液链球菌、3 次 （4%） 的螨丝链球菌、奈瑟菌
Figure 1. A-D, Examples of cranial imaging in patients with CSF leak-associated bacterial meningitis. Coronal cranial CT (A) and sagittal 30 CISS-weighted cranial MRI showing a defect of the lamina cribrosa (arrow in ) and CSF collection in the nasopharynx (arrow in B). C. Three-dimensional CISS-weighted sagittal MRI showing defect of the skull base below the crista Galli (arrow in 9. D. Threedimensional CISS-weighted sagittal MRI showing CSF leak into the sphenoid sinus (arrow in D). Abbreviations: CISS, constructive interference in steady state; CSF. cerebrospinal fluid; CT, computed tomography: MRI, magnetic resonance imaging: 3-D, 3-dimensional.
图 1.A-D，脑脊液渗漏相关细菌性脑膜炎患者的颅脑成像示例。冠状颅 CT （A） 和矢状面 30 CISS 加权颅脑 MRI 显示筛板缺陷（箭头） 和鼻咽脑脊液收集（B 箭头）。C. 三维 CISS 加权矢状 MRI 显示 Crista Galli 下方颅底缺损（9 中的箭头。 D. 三维 CISS 加权的矢状 MRI 显示 CSF 泄漏到蝶骨窦中（D 中的箭头）。缩写：CISS，稳态建设性干涉;脑脊液。脑脊液;CT、计算机断层扫描：MRI、磁共振成像：3D、3D。
meningitidis in 1 episode (2%) and Escherichia coli in 1 episode (2%). The causative pathogen was not identified in 9 of 65 episodes ( ). The distribution of serotypes of . pneumoniae was type 3 in 4 episodes ( ); types , or 15C in 2 episodes each ( ); and types 4, 8, 31, 34, 22F, 35F, 16F, 23A, , or in 1 episode each (3%). The serotypes of . influenzae were unencapsulated in all 10 episodes in which capsule type was assessed. The seroptype of N. meningitides was type B. Antibiotic treatment consisted of amoxicillin and ceftriaxone according to protocol in 27 patients , whereas 16 patients ( ) received monotherapy third-generation cephalosporins, 10 patients (15%) received penicillin or amoxicillin monotherapy, and 12 (18%) received a different regimen. Differences in initial antibiotic treatment were not associated with outcome.
脑膜炎 1 例 （2%） 和大肠杆菌 1 例 （2%）。在 65 次发作中有 9 次未发现致病病原体 （ ）。血清型的 分布。肺炎在 4 次发作中为 3 型 （ ）;类型 ，或 15C，每集 2 集 （ ）;和 4、8、31、34、22F、35F、16F、23A 型或 各 1 集 （3%）。的 血清型。流感在评估胶囊类型的所有 10 次发作中均未封装。脑膜炎奈瑟菌血清型为B型，27例患者 按方案使用阿莫西林和头孢曲松进行抗生素治疗，16例（ ）接受第三代头孢菌素单药治疗，10例（15%）接受青霉素或阿莫西林单药治疗，12例（18%）接受不同治疗方案。初始抗生素治疗的差异与结局无关。
Among the patients with known CSF leakage, vaccination status could be retrieved in 24 of 65 episodes ( ). Of these, 9 patients ( ) were vaccinated ( 23 -valent pneumococcal polysaccharide vaccine [PPV-23] in 9 patients, 1 patient with
在已知脑脊液渗漏的患者中，可以在 65 次发作中的 24 次中检索疫苗接种状态 （ ）。其中，9 例患者 （ ） 接种了 23 价肺炎球菌多糖疫苗 [PPV-23]，9 例患者，1 例患者
H. influenzae type b [Hib] conjugate vaccine, meningococcal serogroup conjugate vaccine in 2 patients, and meningococcal serogroup A conjugate vaccine in 1 patient) (Table 2). Among 9 episodes in 9 vaccinated patients, 2 (22%) were documented as vaccination failures in 2 patients. Both were infected by serotype 7F pneumococci despite vaccination with PPV-23.
乙型流感嗜血杆菌 [Hib] 结合疫苗、2 例脑膜炎球菌血清群 结合疫苗和 1 例患者脑膜炎球菌血清群 A 结合疫苗）（表 2）。在 9 名接种疫苗的患者的 9 次发作中，2 例 （22%） 被记录为 2 例患者的疫苗接种失败。尽管接种了PPV-23疫苗，但两人都感染了血清型7F肺炎球菌。
Neurological complications in episodes with CSF leak-associated meningitis occurred in 25 of 60 episodes ( ) and systemic complications in 11 of 64 episodes ( ). In 8 of 65 episodes ( ) an unfavorable outcome occurred and no patients died. The outcome did not significantly differ between patients with a first episode or a recurrence (Supplementary Table 2). The rate of favorable outcome (GOS 5) was higher in patients with CSF leak-associated meningitis compared with other episodes ( 57 of 65 [88%] vs 1231 of 1957 [63%]; ) (Supplementary Table 1).
脑脊液渗漏相关脑膜炎发作的神经系统并发症发生在 60 次发作中的 25 次 （ ），全身并发症发生在 64 次发作中的 11 次 （ ）。在65次发作中的8次（ ）中发生了不良结局，没有患者死亡。首次发作或复发的患者结局无显著差异（补充表2）。与其他发作相比，脑脊液渗漏相关性脑膜炎患者的良好结局率 （GOS 5） 更高（65 例中有 57 例 [88%] vs 1957 年有 1231 例 [63%]; ）（补充表1）。

DISCUSSION 讨论

Our study shows that CSF leakage was identified in a small minority of patients with community-acquired bacterial meningitis (3%). The most common causes of leakage were ENT surgery and remote head trauma, which is consistent with previous studies . The most common causative pathogens are S. pneumoniae and H. influenzae, and the outcome of these episodes is generally favorable.
我们的研究表明，在少数社区获得性细菌性脑膜炎患者 （3%） 中发现了脑脊液渗漏。渗漏最常见的原因是耳鼻喉科手术和远程头部外伤，这与以前的研究 一致。最常见的致病病原体是肺炎链球菌和流感嗜血杆菌，这些发作的结果通常是有利的。
Prior studies in patients with CSF leak-associated bacterial meningitis are scarce. The relatively favorable outcome has been described previously in patients with recurrent bacterial meningitis episodes [14]. This study hypothesized that due to the awareness of bacterial meningitis, either because of a previous episode or counseling by their physician, patients may recognize bacterial meningitis symptoms early and present themselves to the hospital [14]. Our findings are in line with this hypothesis and showed that patients with CSF leak-associated meningitis
既往对脑脊液渗漏相关细菌性脑膜炎患者的研究很少。先前在细菌性脑膜炎复发患者中报道了相对有利的结局[14]。该研究假设，由于对细菌性脑膜炎的认识，无论是由于既往发作还是医生的咨询，患者可能及早发现细菌性脑膜炎症状并到医院就诊[14]。我们的研究结果与这一假设一致，并表明脑脊液渗漏相关性脑膜炎患者
Table 2. Vaccination Status
表 2.疫苗接种情况
Causative Agent 病原体 Pathogen Serotype 病原体血清型 Vaccine 疫苗
Streptococcus mitis. 螨虫链球菌。 u PPV-23
Streptococcus mitis 螨虫链球菌 PPV-23
Streptococcus pneumoniae
肺炎链球菌		 PPV-23 + Men-A + Men-C
PPV-23 + 男士 A + 男士 C
Haemophilus influenzae 流感嗜血杆菌 Unencapsulated 未封装 PPV-23 + Hib + Men-C
PPV-23 + Hib + 男士-C
Streptococcus pneumoniae
肺炎链球菌		 7F. PPV-23
Streptococcus pneumoniae
肺炎链球菌		 PPV-23
Unknown causative agent 未知病原体 ... PPV-23
Unknown causative agent
未知病原体 		PPV-23
Unknown causative agent 未知病原体 a...+2 一个。。。+2 PPV-23
Abbreviations: Hib, H-influenzae type b conjugate vaccine: Men-A group A conjugate meningococcal vaccine: Men-C, group C conjugate meningococcal vaccine, PPV-23. 23 -va'ent pneumococcal polysaccharide vaccine.
缩写：Hib，H-流感 b 型结合疫苗：Men-A A 组结合脑膜炎球菌疫苗：Men-C，C 组结合脑膜炎球菌疫苗，PPV-23。23 -va'ent肺炎球菌多糖疫苗。
No bacteria cultured
无细菌培养
presented more frequently less than 24 hours of symptom onset compared with those without CSF leak.
与无脑脊液渗漏的患者相比，症状发作不到 24 小时的就诊频率更高。
In our cohort nearly all CSF leaks were identified with cranial imaging. Modern cranial imaging techniques such as scan and MRI 3D-CISS can effectively be used to localize the anatomic location of the CSF leakage [20,21]. Identification of the CSF leak is essential for surgical repair. Our study shows that endoscopic surgical repair is successful in the majority of patients, especially when this is a first attempt ( ). This success rate is in line with previous reviews that reported rates of successful repair ranging from to , with an average of [22-24]. In all patients with recurrent or persisting leakage, consultation with a neurosurgeon or otolaryngologist is warranted to evaluate the necessity of reconstruction of the defect to prevent further episodes .
在我们的队列中，几乎所有的脑脊液渗漏都是通过颅脑影像学确定的。扫描和MRI 3D-CISS等现代颅脑成像技术 可有效定位脑脊液渗漏的解剖位置[20,21]。识别脑脊液渗漏对于手术修复至关重要。我们的研究表明，内窥镜手术修复在大多数患者中是成功的，尤其是当这是第一次尝试时（ ）。这一成功率与既往的评价一致，后者报告的修复成功率从 到 ，平均为 [22-24]。在所有复发性或持续性渗漏的患者中，有必要咨询神经外科医生或耳鼻喉科医生，以评估重建缺损的必要性，以防止进一步发作 。
Nevertheless, we identified a subgroup of patients with persistent CSF leakage despite various attempts at surgical repair. Previous retrospective studies suggested that this might be due to various factors that can impact the effectiveness of endoscopic repair, such as duration of the leak, leak etiology, size of the leak, CSF leak location, body mass index, type of identification that was used, and patient's comorbidity [23, 24]. Surgical repair of defects that have existed for several years is probably more prone to fail when compared with leaks that are identified and repaired shortly after onset. This might be explained by the mucosal lining, instead of simple dural tearing in the acute phase [24]. In these patients, the risk of recurrent meningitis episodes increases with the duration of leakage and therefores early identification and adequate treatment with surgical repair or vaccination.
尽管如此，我们还是确定了一组尽管进行了各种手术修复尝试，但仍存在持续性脑脊液渗漏的患者。既往回顾性研究表明，这可能是由于影响内镜修复效果的各种因素所致，如渗漏持续时间、渗漏病因、渗漏大小、脑脊液渗漏位置、体重指数、使用的识别类型和患者的合并症[23,24]。与在发病后不久发现并修复的泄漏相比，对已经存在数年的缺陷进行手术修复可能更容易失败。这可能是由于黏膜内膜，而不是急性期的单纯硬脑膜撕裂[24]。在这些患者中，复发性脑膜炎发作的风险随着渗漏的持续时间而增加 ，因此需要早期识别和通过手术修复或疫苗接种进行充分治疗。
The episodes of CSF leakage-associated meningitis were predominantly caused by . pneumoniae and . influenzae. Previous studies have suggested to consider a disruption of the blood-brain barrier when S. pneumoniae is cultured [4, 14]. However, given the higher proportion of pneumococcal meningitis in other patients with meningitis, this pathogen seems to be less distinctive for a leakage. On the contrary, our results show that . influenzae meningitis is significantly more common in patients with a CSF leak and, in addition, of all . influenzae meningitis episodes were due to a CSF leak. Therefore, the search for a CSF leak should be considered when H. influenzae is cultured.
脑脊液渗漏相关性脑膜炎的发作主要由 .肺炎和 .流行性感冒。既往研究建议在培养肺炎链球菌时考虑血脑屏障的破坏[4,14]。然而，鉴于其他脑膜炎患者肺炎球菌性脑膜炎的比例较高，这种病原体似乎不太明显。相反，我们的结果表明 .流感脑膜炎在脑脊液漏患者中更为常见，此外， 所有 .流感脑膜炎发作是由于脑脊液渗漏所致。因此，在培养流感嗜血杆菌时，应考虑寻找脑脊液渗漏。
There is no evidence for vaccination in patients with CSF leakage. Previous studies reported an effect of vaccination in the reduction of all-age incidence of pneumococcal meningitis, Hib meningitis, and meningococcal meningitis [3, 27]. Vaccination is minimally invasive, with a low risk of adverse reaction [3,27] The expert opinion is that vaccination is indicated in this small subgroup of adults with community-acquired bacterial meningitis with high risk on recurrence. Although not supported by evidence, we recommend the use of Hib, PPV-23, meningococcal serogroup ACYW, and meningococcal serogroup B vaccines in patients presenting with community-acquired bacterial meningitis and CSF leak.
没有证据表明脑脊液渗漏患者接种疫苗。既往研究报道了疫苗接种对降低肺炎球菌性脑膜炎、Hib脑膜炎和脑膜炎球菌性脑膜炎所有年龄段发病率的影响[3,27]。疫苗接种是微创的，不良反应风险低[3,27] 专家意见认为，这一小亚组的社区获得性细菌性脑膜炎患者需要接种疫苗，复发风险高。虽然没有证据支持，但我们建议在社区获得性细菌性脑膜炎和脑脊液渗漏的患者中使用Hib、PPV-23、脑膜炎球菌血清群ACYW和脑膜炎球菌血清群B疫苗。
The relatively mild disease course resulted in a better outcome in patients with CSF leak-associated bacterial meningitis compared with patients with meningitis not associated with a CSF leak. There are several explanations for this relatively favorable outcome. First, we identified fewer indicators of sepsis in episodes with CSF leakage, such as low CSF leukocyte counts, which have been associated with a high bacterial load, systemic complicationsk and unfavorable outcome [28, 29]. Second, there is a relatively high rate of . influenzae in CSF leak-associated meningitis episodes, and this pathogen has been associated with a less severe clinical course and favorable outcome [30]. Finally, patients with episodes of CSF leak-associated meningitis were significantly younger and had less comorbidity, which also have been identified as predictors of poor outcome [2,13].
与脑脊液漏无关的脑膜炎患者相比，相对温和的病程导致脑脊液渗漏相关细菌性脑膜炎患者的预后更好。对于这个相对有利的结果，有几种解释。首先，我们发现脑脊液渗漏发作的脓毒症指标较少，例如脑脊液白细胞计数低，这与高细菌负荷、全身并发症和不良结局有关[28,29]。其次，有相对较高的比率 。脑脊液渗漏相关性脑膜炎发作中的流感，这种病原体的临床病程较轻，结局良好[30]。最后，脑脊液渗漏相关脑膜炎发作的患者明显更年轻，合并症更少，这也被认为是不良结局的预测因素[2,13]。
There are several limitations to this study. First, the presence of CSF leakage was initially recorded by the treating physician, which could have led to both over- and underestimation of the rate of leak. However, as all reported cases were confirmed by cranial imaging or a CSF protein marker, overestimation could be ruled out. Underestimation of the frequency of CSF leaks could have occurred because small, occult CSF leaks may have been missed. Furthermore, in patients who presented with acute bacterial meningitis who died within the first days, CSF leaks may have gone unnoticed. Additionally, because all patients who do not survive the first episode cannot develop a second episode, the outcome data are possibly skewed toward a better prognosis resulting in biased results. Therefore, the proportion we found should be considered the minimal frequency. Second, this is a prospective observational study with clinical data collected through an online CRF, which was retrospectively supplemented with additional information from discharge letters, such as cause of leak, duration of leak, previous surgery, vaccination status, and serotypes. For some patients, this specific information was not described in discharge letters and thus registered as unknown, which might have led to a less accurate description of patients' characteristics. Finally, only culture-proven bacterial meningitis episodes were included in the study while negative CSF cultures occur in 11-30% of episodes with bacterial meningitis, and this may be more common in CSF leak-associated meningitis episodes [7, 14]. Because we performed a nationwide study we were able to describe a representative group of patients with CSF leak-associated community-acquired bacterial meningitis. Furthermore, our prospective approach ensured the collection of comprehensive data on predisposing factors and causes of CSF leakage, clinical characteristics, spectrum of causative pathogens, and outcome.
这项研究有几个局限性。首先，脑脊液渗漏的存在最初是由主治医生记录的，这可能导致对 渗漏率的高估和低估。然而，由于所有报告的病例均通过颅脑影像学检查或脑脊液蛋白标志物确诊，因此可以排除高估。脑脊液漏的频率可能被低估了，因为可能遗漏了小的、隐匿的脑脊液漏。此外，在最初几天内死亡的急性细菌性脑膜炎患者中，脑脊液渗漏可能被忽视。此外，由于所有在第一次发作后无法存活的患者都不能发生第二次发作，因此结果数据可能偏向于更好的预后，从而导致结果偏倚。因此，我们发现的比例应被视为最小频率。其次，这是一项前瞻性观察性研究，通过在线 CRF 收集临床数据，回顾性补充了出院信中的其他信息，例如泄漏原因、泄漏持续时间、既往手术、疫苗接种状态和血清型。对于一些患者来说，出院信中没有描述这些特定信息，因此被登记为未知，这可能导致对患者特征的描述不太准确。最后，该研究仅纳入经培养证实的细菌性脑膜炎发作，而11%-30%的细菌性脑膜炎发作发生脑脊液培养阴性，这在脑脊液渗漏相关脑膜炎发作中可能更常见[7,14]。由于我们进行了一项全国性研究，因此我们能够描述一组具有代表性的脑脊液渗漏相关社区获得性细菌性脑膜炎患者。 此外，我们的前瞻性方法确保收集了有关脑脊液渗漏的诱发因素和原因、临床特征、致病病原体谱和结局的综合数据。
In conclusion, this study shows that patients with CSF leakassociated bacterial meningitis have a relatively high recurrence rate, despite attempts to repair the leak or vaccination.
总之，这项研究表明，尽管尝试修复渗漏或接种疫苗，但脑脊液渗漏相关细菌性脑膜炎患者的复发率相对较高。
The majority of patients have a relatively mild disease course with a generally favorable outcome. Cerebrospinal fluid leakage should be suspected in those patients with bacterial meningitis presenting with liquorrhea, recurrent meningitis, or with disease caused by . influenzae. In these patients, cranial imaging and otolaryngology consultation are recommended.
大多数患者的病程相对较轻，结局普遍良好。对于表现为酒溢、复发性脑膜炎或由 . 流行性感冒。对于这些患者，建议进行颅脑影像学检查和耳鼻喉科会诊。

Supplementary Data 补充数据

Supplementary materials are available at Clinical Infectious Diseases online. Consisting of data provided by the authors to benefit the reader, the posted materials are not copyedited and are the sole responsibility of the authors, so questions or comments should be addressed to the corresponding author.
补充材料可在临床传染病在线获得。由作者提供的数据组成，以造福读者，发布的材料未经复制编辑，由作者全权负责，因此问题或意见应向通讯作者提出。

Notes 笔记

Acknowledgments. The authors are indebted to all the Dutch physicians and patients who participated in the MeninGene study.
确认。作者感谢所有参与MeninGene研究的荷兰医生和患者。
Financial support. This work was supported by the Netherlands Organization for Health Research and Development (ZonMw; NWO-Vidi grant [grant number 917.17 .308 to M. C. B.], NWO-Vidi-Grant [grant number 016.116.358 to D. v. d. B.]), the Academic Medical Center (AMC Fellowship to D. v. d. B.), and the European Research Council (ERC starting grant to D. v. d. B.).
财政支持。这项工作得到了荷兰卫生研究与发展组织（ZonMw;NWO-Vidi 赠款 [授予 MCB 的赠款编号 917.17 .308]、NWO-Vidi-Grant [授予编号 016.116.358 至 D. V. D. B.]）、学术医疗中心（AMC 奖学金授予 D. V. D. B.）和欧洲研究委员会（ERC 开始授予 D. V. D. B.）。
Potential conflicts of interest. A. v. d. E reports grants from Pfizer, consultancy fees from GlaxoSmithKline, and participation in scientific boards for Pfizer. He reports a grant to the institution from ZonMw, the Academic Medical Center, and the European Research Council. M. C. B. reports a grant to the institution from ZonMw. All authors report no potential conflicts of interest. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed.
潜在的利益冲突。A. v. d. E 报告了辉瑞公司的赠款、葛兰素史克公司的咨询费以及辉瑞公司科学委员会的参与情况。他报告了 ZonMw、学术医学中心和欧洲研究委员会对该机构的资助。M. C. B. 报告了 ZonMw 向该机构提供的赠款。所有作者均未报告存在潜在的利益冲突。所有作者均已提交ICMJE潜在利益冲突披露表。编辑认为与稿件内容相关的冲突已被披露。

References 引用

  1. Brouwer MC, de Gans J, Heckenberg SG, Zwinderman AH, van der Poll T van de Beek D. Host genetic susceptibility to pneumococcal and meningococcal disease: a systematic review and meta-analysis. Lancet Infect Dis 2009 .
    Brouwer MC， de Gans J， Heckenberg SG， Zwinderman AH， van der Poll T van de Beek D. 宿主对肺炎球菌和脑膜炎球菌病的遗传易感性：系统评价和荟萃分析。柳叶刀感染 Dis 2009 .
  2. van de Beek D, Brouwer M, Hasbun R, Koedel U, Whitney CG, Wijdicks E Community-acquired bacterial meningitis. Nat Rev Dis Primers 2016; 2:16074.
    van de Beek D、Brouwer M、Hasbun R、Koedel U、Whitney CG、Wijdicks E 社区获得性细菌性脑膜炎。Nat Rev Dis Primers 2016年;2:16074.
  3. Brouwer MC, Tunkel AR, van de Beek D. Epidemiology, diagnosis, and antimicrobial treatment of acute bacterial meningitis. Clin Microbiol Rev 2010; 23:467-92.
    Brouwer MC， Tunkel AR， van de Beek D. 急性细菌性脑膜炎的流行病学、诊断和抗菌治疗。临床微生物学修订版 2010;23:467-92.
  4. Adriani KS, Brouwer MC, van de Beek D. Risk factors for community-acquired bacterial meningitis in adults. Neth J Med 2015; 73:53-60.
    Adriani KS， Brouwer MC， van de Beek D. 成人社区获得性细菌性脑膜炎的危险因素。Neth J Med 2015 年;73:53-60.
  5. van de Beek D, de Gans J, Tunkel AR, Wijdicks EF. Community-acquired bacterial meningitis in adults. N Engl J Med 2006; 354:44-53.
    范德贝克 D、德甘斯 J、通克尔 AR、维迪克斯 EF。成人社区获得性细菌性脑膜炎。N Engl J Med 2006;354:44-53.
  6. Weisfelt M, van de Beek D, Spanjaard L, de Gans J. Nosocomial bacterial meningitis in adults: a prospective series of 50 cases. J Hosp Infect 2007; 66:71-8.
    Weisfelt M， van de Beek D， Spanjaard L， de Gans J. 成人院内细菌性脑膜炎：50 例的前瞻性系列。J Hosp 感染 2007;66:71-8.
  7. van de Beek D, Drake JM, Tunkel AR. Nosocomial bacterial meningitis. N Engl J Med 2010; 362:146-54
    van de Beek D， Drake JM， Tunkel AR. 院内细菌性脑膜炎。N Engl J Med 2010 年;362:146-54
  8. Tunkel AR, Hartman BJ, Kaplan SL, et al. Practice guidelines for the management of bacterial meningitis. Clin Infect Dis 2004; 39:1267-84.
    Tunkel AR、Hartman BJ、Kaplan SL 等。细菌性脑膜炎管理实践指南。临床感染病 2004;39:1267-84.
  9. Choi D, Spann R. Traumatic cerebrospinal fluid leakage: risk factors and the use of prophylactic antibiotics. Br J Neurosurg 1996; 10:571-5.
    Choi D， Spann R. 创伤性脑脊液渗漏：危险因素和预防性抗生素的使用。Br J 神经外科 1996;10:571-5.
  10. Tebruegge M, Curtis N. Epidemiology, etiology, pathogenesis, and diagnosis of recurrent bacterial meningitis. Clin Microbiol Rev 2008; 21:519-37.
    Tebruegge M， Curtis N. 复发性细菌性脑膜炎的流行病学、病因、发病机制和诊断。临床微生物学修订版 2008;21:519-37.
  11. Friedman JA, Ebersold M, Quast LM. Persistent posttraumatic cerebrospinal fluid leakage. Neurosurg Focus 2000; 9:e1.
    弗里德曼 JA、埃伯塞尔德 M、夸斯特 LM。持续性创伤后脑脊液渗漏。神经外科焦点 2000;9：E1。
  12. Koso-Thomas AK, Harley EH. Traumatic cerebrospinal fluid fistula presenting as recurrent meningitis. Otolaryngol Head Neck Surg 1995; 112:469-72.
    科索-托马斯 AK，哈雷 EH。创伤性脑脊液瘘表现为复发性脑膜炎。耳鼻喉头颈外科 1995;112:469-72.
  13. Bijlsma MW, Brouwer MC, Kasanmoentalib ES, et al. Community-acquired bacterial meningitis in adults in the Netherlands, 2006-14: a prospective cohort study. Lancet Infect Dis 2016; 16:339-47.
    Bijlsma MW、Brouwer MC、Kasanmoentalib ES 等。2006-14 年荷兰成人社区获得性细菌性脑膜炎：一项前瞻性队列研究。柳叶刀感染 Dis 2016;16:339-47.
  14. Adriani KS, van de Beek D, Brouwer MC, Spanjaard L, de Gans J. Communityacquired recurrent bacterial meningitis in adults. Clin Infect Dis 2007; 45:e46-51.
    Adriani KS， van de Beek D， Brouwer MC， Spanjaard L， de Gans J. 社区获得性成人复发性细菌性脑膜炎。临床感染 Dis 2007;45：E46-51。
  15. Dzupova O, Rozsypal H, Prochazka B, Benes J. Acute bacterial meningitis in adults: predictors of outcome. Scand J Infect Dis 2009; 41:348-54.
    Dzupova O， Rozsypal H， Prochazka B， Benes J. 成人急性细菌性脑膜炎：结果预测因素。Scand J 感染 Dis 2009;41:348-54.
  16. Durand ML, Calderwood SB, Weber DJ, et al. Acute bacterial meningitis in adults. A review of 493 episodes. N Engl J Med 1993; 328:21-8.
    Durand ML、Calderwood SB、Weber DJ 等。成人急性细菌性脑膜炎。493集回顾。N Engl J Med 1993;328:21-8.
  17. Spanos A, Harrell FE Jr, Durack DT. Differential diagnosis of acule meningitis: an analysis of the predictive value of initial observations. JAMA 1989; 262:2700-7.
    斯帕诺斯 A、小哈雷尔 FE、杜拉克 DT。尖头脑膜炎的鉴别诊断：初步观察的预测价值分析。美国医学会 1989;262:2700-7.
  18. Asad S, Peters-Willke J, Brennan W, Asad S. Clival defect with primary CSF Rhinorrhea: a very rare presentation with challenging management. World Neurosurg 2017; 106: 1052 el-e4.
    Asad S， Peters-Willke J， Brennan W， Asad S. 原发性脑脊液根留血的 Clival 缺损：一种非常罕见的表现，具有挑战性的管理。2017年世界神经外科;106：1052 EL-E4。
  19. Ivan ME, Iorgulescu JB, El-Sayed I, et al. Risk factors for postoperative cerebrospinal fluid leak and meningitis after expanded endoscopic endonasal surgery. J Clin Neurosci 2015; 22:48-54.
    Ivan ME、Iorgulescu JB、El-Sayed I 等人。扩大内窥镜鼻内手术术后脑脊液渗漏和脑膜炎的危险因素。临床神经科学杂志 2015;22:48-54.
  20. Oakley GM, Alt JA, Schlosser RJ, Harvey RJ, Orlandi RR. Diagnosis of cerebrospinal fluid rhinorrhea: an evidence-based review with recommendations. Int Forum Allergy Rhinol 2016; 6:8-16.
    奥克利 GM、Alt JA、Schlosser RJ、Harvey RJ、Orlandi RR。脑脊液流鼻漏的诊断：一项循证综述和建议。2016年国际论坛过敏鼻醇;6:8-16.
  21. Algin O, Hakyemez B, Gokalp G, Ozcan T, Korfali E, Parlak M. The contribution of 3D-CISS and contrast-enhanced MR cisternography in detecting cerebrospinal fluid leak in patients with minorrhoea. Radiol 2010; 83:225-32.
    阿尔金 O、哈基梅兹 B、戈卡尔普 G、奥兹坎 T、科法利 E、帕拉克 M。3D-CISS 和对比增强 MR 脑池造影在检测轻度漏患者脑脊液渗漏方面的贡献。 Radiol 2010 年;83:225-32.
  22. Martín-Martín C, Martínez-Capoccioni G. Serramito-Garcia R, EspinosaRestrepo F. Surgical challenge: endoscopic repair of cerebrospinal fluid leak. BMC Res Notes 2012; 5:459.
    Martín-Martín C， Martínez-Capoccioni G. Serramito-Garcia R， EspinosaRestrepo F. 手术挑战：脑脊液渗漏的内窥镜修复。BMC Res Notes 2012 年;5:459.
  23. Psaltis AJ, Schlosser RJ, Banks CA, Yawn J, Soler ZM. A systematic review of the endoscopic repair of cerebrospinal fluid leaks. Otolaryngol Head Neck Surg 2012; .
    Psaltis AJ、Schlosser RJ、Banks CA、Yawn J、Soler ZM。脑脊液渗漏内镜修复的系统评价。耳喉头颈外科 2012; 。
  24. Lee DH, Lim SC, Joo YE. Treatment outcomes of endoscopic repairs of sinonasal cerebrospinal fluid leaks. J Craniofac Surg 2011; 22:1266-70.
    Lee DH， Lim SC， Joo YE.鼻窦脑脊液渗漏内镜修复的治疗结果。J 颅面外科 2011;22:1266-70.
  25. Carrol ED, Latif AH, Misbah SA, et aL. Lesson of the week-Recurrent bacterial meningitis: the need for sensitive imaging. Bmj 2001; 323:501-3.
    卡罗尔 ED、拉蒂夫 AH、Misbah SA 等。本周的教训 - 复发性细菌性脑膜炎：需要灵敏的成像。BMJ 2001年;323:501-3.
  26. Ansari S, Carron DB, Smith MJ. Recurrent late onset post-traumatic meningitis. J Pak Med Assoc 1994; 44:193-4.
    安萨里 S、卡伦 DB、史密斯 MJ。复发性迟发性创伤后脑膜炎。J Pak Med Assoc 1994 年;44:193-4.
  27. McIntyre PB, O'Brien KI, Greenwood B, van de Beek D. Effect of vaccines on bacterial meningitis worldwide. Lancet 2012; 380:1703-11.
    McIntyre PB， O'Brien KI， Greenwood B， van de Beek D. 疫苗对全球细菌性脑膜炎的影响。柳叶刀 2012;380:1703-11.
  28. van de Beek D, de Gans J, Spanjaard L, Weisfelt M, Reitsma JB, Vermeulen M. Clinical features and prognostic factors in adults with bacterial meningitis. Engl J Med 2004; 351(18): 1849-59.
    van de Beek D， de Gans J， Spanjaard L， Weisfelt M， Reitsma JB， Vermeulen M. 成人细菌性脑膜炎的临床特征和预后因素。 工程医学杂志 2004;351(18): 1849-59.
  29. Weisfelt M, van de Beek D, Spanjaard L, Reitsma JB, de Gans J. Attenuated cerebrospinal fluid leukocyte count and sepsis in adults with pneumococcal meningitis: a prospective cohort study. BMC Infect Dis 2006; 6:149.
    Weisfelt M， van de Beek D， Spanjaard L， Reitsma JB， de Gans J. 肺炎球菌性脑膜炎成人脑脊液白细胞计数和败血症减弱：一项前瞻性队列研究。BMC 感染 Dis 2006;6:149.
  30. Brouwer MC, van de Beek D, Heckenberg SG, Spanjaard L, de Gans J. Communityacquired Haemophilus influenzae meningitis in adults. Clin Microbiol Infect
    Brouwer MC， van de Beek D， Heckenberg SG， Spanjaard L， de Gans J. 成人社区获得性流感嗜血杆菌脑膜炎。临床微生物感染