Diagnosis and therapy of tuberculous meningitis in children

Children are among the subjects most frequently affected by tuberculous meningitis (TBM) due to their relative inability to contain primary Mycobacterium tuberculosis infection in the lung. TBM is a devastating disease with about 30% mortality among the most severe cases; moreover, 50% of survivors have neurological sequelae despite an apparently adequate administration of antibiotics. Early diagnosis and prompt treatment are crucial for reducing the risk of a poor outcome. However, especially in children, the best and most rapid way to confirm the diagnosis is controversial; the optimal choice, dose, and treatment duration of anti-tuberculosis drugs are not precisely defined, and the actual importance of adjunctive therapies with steroids and neurosurgery has not been adequately demonstrated. This review is an effort to discuss present knowledge of the diagnosis and treatment of pediatric TBM in order to offer the best solution to address this dramatic disease. In conclusion, we stress that new studies in children are urgently needed because data in the early years of life are more debatable than those collected in adults. In the meantime, when treating a child with suspected TBM, the most aggressive attitude to diagnosis and therapy is necessary, because TBM is a devastating disease.     

结核性脑膜炎的诊断与治疗

结核性脑膜炎(结脑)是结核分枝杆菌引起的以脑膜为主的非化脓性炎症,是常见最严重的肺外结核病.近年来,由于耐药结核病例的增加,加之人口流动及AIDS流行等因素,全球结核病发病率明显上升,结脑患者也随之增多.影响结脑预后的关键在于早期诊断和及时治疗.由于结脑临床表现较复杂,脑脊液(CSF)改变不典型,易与其他中枢神经系统感染相混淆.提高结脑早期诊断水平和及时有效的治疗是临床上十分关注的热点,现将结脑的诊断和治疗方法作一概述.     

The course and outcome of tuberculous meningitis in adults

The course and outcomes of tuberculosis of the central nervous system (CNS) in adults were studied comparatively within two 10-year periods i.e. from 1968 to 1977 and from 1978 to 1987. It was shown that within the last 10-year period the number of the adults with tuberculous meningitis had lowered while the proportion of the adults with tuberculosis of the CNS among all the patients with that form of tuberculosis had remained unchanged. There was no increase in the number of the patients of the elderly and senile ages. Acute onset of the disease as well as asymptomatic and atypical onsets and courses were recorded. It was stated that association of tuberculosis of the CNS with active pulmonary tuberculosis became more frequent. Higher levels of neutrophilic-lymphocytic pleocytosis as compared to the previous ones, marked hypoglycorrhachia and more frequent isolation of mycobacteria from the liquor were noted. No increase in the efficacy of the treatment was stated. The death rate did not change. The situation should be explained by the incidence of common forms of pulmonary tuberculosis including fibrocavernous and disseminated tuberculosis, insufficient prophylaxis, the incidence of concomitant diseases, sometimes acute onset of the disease, asymptomatic process of the disease, inattention of physicians as to possible incidence of tuberculous meningitis.     

新型隐球菌性脑膜炎与结核性脑膜炎的诊断与鉴别诊断

目的 总结分析新型隐球菌性脑膜炎(CNM)与结核性脑膜炎(TBM)的临床特点,以提高CNM与TBM诊断与鉴别诊断水平。方法 搜集2016年1月至2017年12月成都市公共卫生临床医疗中心收治的CNM患者32例(CNM组)及同期收治的TBM患者171例(TBM组),对两组患者的一般资料(年龄、性别、生活区域、是否并发免疫功能低下)、临床症状(头痛、发热、呕吐、呼吸道症状、抽搐、脑膜刺激征及病理征)、脑脊液(CSF)实验室检查指标(CSF压力、细胞数、淋巴细胞百分比、蛋白、葡萄糖)、头颅CT检查(正常、脑水肿、脑积液、脑实质结节样改变、多发软化灶)情况进行对比分析。结果 TBM组患者年龄为(39.23±12.77)岁,高于CNM组患者[(28.71±11.29)岁],差异有统计学意义(t=4.35,P=0.000);TBM组患者呼吸道症状、抽搐、头颅CT检查提示脑实质结节样改变及多发软化灶发生率分别为94.74%(162/171)、35.09%(60/171)、41.52%(71/171)、38.01%(65/171),均明显高于CNM组患者[分别为34.38%(11/32)、15.62%(5/32)、6.25%(2/32)、9.38%(3/32)],差异均有统计学意义(χ ²值分别为73.26、4.69、13.07、8.68,P值分别为0.000、0.030、0.000、0.003);CNM组患者免疫功能低下(包括并发HIV感染、尿糖病,接受器官移植,长期口服糖皮质激素或免疫抑制剂等)和头颅CT检查提示脑水肿改变发生率分别为34.38%(11/32)、46.88%(15/32),均高于TBM组患者[分别为18.13%(31/171)、25.15%(43/171)],差异均有统计学意义(χ ²值分别为4.34、6.24,P值分别为0.037、0.013);CSF实验室检查中,TBM组患者CSF细胞数[中位数(M)(四分位数;Q₁,Q₃)]、蛋白[M(Q₁,Q₃)]、葡萄糖含量分别为208.00(178.00,240.00)×10 ⁶/L、1058.00(940.00,1204.00)mg/L、(1.77±0.79)mmol/L,均明显高于CNM组患者[分别为64.50(51.00,81.00)×10 ⁶/L、764.00(608.00,894.50)mg/L、(0.25±0.17)mmol/L],差异均有统计学意义(Z=-76.77,P=0.000;Z=-6.83,P=0.000;t=10.82,P=0.000);CNM组患者CSF压力为[(273.42±71.58)mm H₂O(1mm H₂O=0.098kPa)],明显高于TBM组患者[(214.22±88.38)mm H₂O],差异有统计学意义(t=3.57,P=0.000)。结论 CNM患者并发免疫功能低下和头颅CT提示脑水肿改变的比率高于TBM患者,而在呼吸道及抽搐症状的发生、头颅CT提示脑实质结节样改变、多发软化灶等发生的比率均低于TBM患者。     

Pathophysiology and prognosis in vietnamese adults with tuberculous meningitis

The pathogenesis of tuberculous meningitis remains unclear, and there are few data describing the kinetics of the immune response during the course of its treatment. We measured concentrations of pro- and anti-inflammatory cytokines in serial blood and cerebrospinal fluid (CSF) samples from 21 adults who were being treated for tuberculous meningitis. CSF concentrations of soluble tumor necrosis factor-alpha receptors and of matrix metalloprotein-9 and its tissue inhibitor were also measured, and blood-brain barrier permeability was assessed by the albumin and IgG partition indices. CSF concentrations of lactate, interleukin-8, and interferon-gamma were high before treatment and then decreased rapidly with antituberculosis chemotherapy. However, significant immune activation and blood-brain barrier dysfunction were still apparent after 60 days of treatment. Death was associated with high initial CSF concentrations of lactate, low numbers of white blood cells, in particular neutrophils, and low CSF glucose levels.     

结核性脑膜炎评分系统对儿童结核性脑膜炎的诊断价值

目的 评价结核性脑膜炎(TBM)评分系统对儿童TBM与病毒性脑炎进行鉴别的价值。方法 回顾性分析2010年1月1日至2017年12月31日天津市儿童医院呼吸科收住院的确诊及临床诊断TBM的患儿102例(TBM组),以及同期病毒性脑炎患儿125例(病毒性脑炎组)。TBM评分系统采用包括临床表现、脑脊液检测结果、影像学表现、肺结核或肺外结核的其他表现进行综合评分来诊断TBM(分值越高,越支持TBM诊断;评分≥12分可以临床诊断TBM)。采用病例对照研究的方法,比较该评分系统诊断TBM的敏感度及特异度;同时比较该评分系统与结核菌素皮肤试验(TST)、γ干扰素释放试验(IGRA)及脑脊液病原学检测敏感度的差异。结果 TBM组患儿中,16例(15.69%,16/102)脑脊液病原学检测阳性,确诊为TBM患儿;其余86例(84.31%,86/102)TBM患儿经评分系统评估,分值为(13.25±2.22)分,明显高于病毒性脑炎组患儿的评分[(3.79±2.48)分],差异有统计学意义(t=29.97,P<0.001)。86例患儿中,76例患儿TBM评分≥12分,判断为临床诊断TBM患儿;TBM诊断的敏感度为90.20%(92/102),特异度为100.00%(102/102)。脑脊液病原学检查中,抗酸杆菌染色的敏感度为15.69%(16/102),结核分枝杆菌培养的敏感度为10.78%(11/102),DNA检测的敏感度为16.47%(14/85),均明显低于TBM评分系统(χ ²值分别为113.65、128.66、100.64,P值均<0.001)。免疫学检查方法中,TST的敏感度为50.00%(51/102),特异度为99.20%(124/125);IGRA的敏感度为72.55%(74/102),特异度为99.20%(124/125);敏感度均明显低于TBM评分系统(χ ²值分别为39.31、10.48,P值均<0.001)。 结论 TBM评分系统对TBM诊断价值较好,其敏感度明显高于脑脊液抗酸染色、脑脊液结核分枝杆菌培养、脑脊液DNA检测、TST及IGRA等检测方法。