The diagnostic challenge of atypical tuberculous meningitis in children from rural area

Abstract

Tuberculous meningitis (TBM) is a severe form of Mycobacterium tuberculosis infection, while its diagnosis is still a challenge in children. Here, six children with atypical TBM were retrospectively reviewed and the main findings were displayed as follows. The enrolled cases exhibited non-specific symptoms on admission, mainly including fever (n = 5), headache (n = 3), vomiting (n = 5), and drowsiness (n = 3), but no typical symptoms of TB infection. Two of them exhibited progressive symptoms under routine treatment. Cerebrospinal fluid (CSF) examinations revealed increased white blood cells and proteins, as well as decreased glucose and chloride in all cases. Chest imaging identified the possibly of pulmonary tuberculous in 2 cases. Cranial CT and MRI revealed neuroimaging abnormality in 1 and 3 cases, respectively. In addition, next-generation sequencing directly supported the diagnosis of TBM in case 5. To sum up, TBM should be highly suspected in children with central nervous system infection, when there are no improvements under routine treatment and/or the presence of progressive symptoms. Timely rechecking of CSF combined with cranial imaging is feasible and valuable for the diagnosis of TBM.

Keywords

tuberculous meningitis children diagnosis cerebrospinal fluid next-generation sequencing

Introduction

Tuberculous meningitis (TBM) is a sub-acute to chronic meningitis in the central nervous system that induced by Mycobacterium tuberculosis (TB), a prototypic intracellular pathogen in macrophages.^1,2 Tuberculous meningitis shows a peak incidence in children of less than 5 years old.³ Although TBM has a low morbidity in children, it is associated with a high mortality.⁴ At present, pediatric TBM is still easy to be misdiagnosed because of nonspecific symptoms, leading to a diagnosis in late-stage.⁵ Therefore, early diagnosis of TBM remains a challenge in children. This study retrospectively analyzed six children with atypical TBM, aiming to provide guidance for the diagnosis of TBM in clinical practice.

Methods

This is a retrospective study. Total six TBM children with atypical symptoms of TB infection were collected form the Affiliated Children’s Hospital, Capital Institute of Pediatrics between June 2015 and December 2020. The clinical characteristics, diagnosis and treatment processes, and outcomes of these cases were assessed retrospectively. Ethical approval for this study was obtained from The Affiliated Children’s Hospital, Capital Institute of Pediatrics in accordance with the Declaration of Helsinki (SHERLLM-2016022). Written informed consent was obtained from legally authorized representatives before the study.

Results

Case 1

A pre-school boy, aged 3 years and 4 months was admitted into a local hospital due to fever. CSF examinations showed increased WBC (635 × 10⁶/L), monocytes (88%), and Pro (1580 mg/L), and decreased Glu (0.69 mmol/L). After 15 days of routine antibiotic treatment, ceftriaxone and vancomycin were administrated in this case for another 10 days. However, the fever was not alleviated, and the symptoms of vomiting and drowsiness emerged during treatments. After transferred to our hospital, CSF rechecking further determined increased CSF pressure (150 mmH₂O), WBC (155 × 10⁶/L), monocytes (40%), and Pro (1270.7 mg/L), as well as decreased CL (115 mmol/L) and Glu (0.66 mmol/L). In addition, cranial MRI revealed central nervous system infection, evidenced by deepened sulcus, decrescent gyrus, slightly expanded bilateral ventricles, as well as abnormal signals in basal ganglia, left hippocampus, and corpus callosum knee. On the second day of admission in our hospital, this case exhibited progressive symptoms of consciousness disorder and suspicious convulsion. Combined with the above characteristics, this case was diagnosed as TBM, and was then transferred to specialized hospital for treatment. Unfortunately, the fever and consciousness disorder were still not alleviated after 1 month of anti-tuberculosis treatment. This case finally discontinued treatment and died (Tables 1–4).

Table 1.

The demographic and clinical characteristics of enrolled cases.

Case	Gender	Age	Course, d	History of TB exposure (scar)	Onset symptoms					Progressive symptoms
Case	Gender	Age	Course, d	History of TB exposure (scar)	Fever/heat spike	Headache	Vomiting	Mental/consciousness	Other
1	Male	3 years and 4 months old	25	Denied (+)	(+)/39.7°C	(−)	(+)	Drowsiness	—	Consciousness disorder; suspicious convulsion
2	Male	14 years and 7 months old	7	Denied (+)	(+)/39°C	(+)	(+)	—	—	Consciousness disorder
3	Female	10 years and 7 months old	17	Denied (−)	(+)/38°C	(+)	(+)	Drowsiness	—	—
4	Male	8 years and 7 months old	60	Denied (+)	(−)	(−)	(+)	Drowsiness	Blurred vision (20d)	—
5	Female	10 years and 11 months old	12	Denied (−)	(+)/38.5°C	(+)	(−)	Personality change	—	—
6	Male	1 year and 3 months old	10	Denied (−)	(+)/39°C	(−)	(+)	Restlessness	Convulsions	—

Table 2.

Auxiliary examinations of blood and cerebrospinal fluid.

Case	Detection time^a	Blood			Cerebrospinal fluid								PPD
		Blood			Appearance	Pressure (mmH₂O)	Routine		Biochemistry
		WBC (× 10⁹/L)	Lymphocyte ratio	CRP (mg/L)	Appearance	Pressure (mmH₂O)	WBC (× 10⁶/L)	Monocyte (%)	Glu (mmol/L)	CL (mmol/L)	Pro (mg/L)	Etiology
1	Local hospital (day 15)	—	—	—	Colorless and transparent	—	635↑	88↑	0.69↓	119	1580↑	(−)	—
1	Our hospital (day 25)	7.16	25.3	5	Colorless and transparent	150↑	155↑	40↑	0.66↓	115↓	1270.7↑	(−)	(−)
2	Our hospital (day 7)	5.16	22.8↓	19↑	Colorless and transparent	80	224↑	10↑	1.97↓	121	618.9↑	(−)	—
2	Our hospital (day 11)	—	—	—	Light yellow and slightly turbid	180↑	300↑	65↑	1.59↓	102↓	1267.5↑	(−)	(−)
3	Local hospital (day 8)	9.70	19.4↓	<1	—	—	214↑	—	0.90↓	113↓	852.1↑	—	(++++)
3	Our hospital (day 17)	—	—	—	—	—	—	—	—	—	—	—	—
4	Local hospital (day 7–45)	—	—	—	—	—	17–26↑	—	2.33↓	—	1000–2480↑	—	—
4	Our hospital (day 60)	7.16	28.6	1.7	Light yellow and transparent	90	8	—	0.47↓	109↓	3773.5↑	(−)	(−)
5	Our hospital (day 12)	12.67↑	4.5↓	6	Light yellow and transparent	80	172↑	76↑	1.39↓	100↓	5401↑	Mycobacterium tuberculosis + (NGS)	(−)
6	Local hospital (day 3)	—	—	—	Colorless and transparent	—	58↑	95↑	1.45↓	110↓	1115.7↑	—	—
6	Our hospital (day 10)	11.87↑	19↓	9↑	Colorless and transparent	200↑	86↑	40↑	0.58↓	104↓	998↑	(−)	(++)

Note: Normal reference range: WBC (Blood), 4–10 × 10/L; Lymphocyte ratio, 23–53%; CRP < 8 mg/L; Pressure, 50–100 mmHO; WBC (CSF), 0–10 × 10/L; Glu (glucose), 2.8–3.5 mmol/L; CL (chloride), 117–127 mmol/L; Pro (protein), 200–400 mg/L.

^a course of disease.

Table 3.

Chest and cranial imaging.

Case	Chest imaging	Cranial imaging
1	Chest X-ray: (−)	Cranial MRI: Deepened sulcus, decrescent gyrus, slightly expanded bilateral ventricles, and abnormal signals in basal ganglia, left hippocampus, and corpus callosum knee (diagnosis: Central nervous system infection with the possibility of TBM)
2	Chest enhanced CT: Multiple dense patches in the upper lobe of lungs, thickened right interlobar fissure, multiple enlarged lymph nodes in the mediastinum, thickened bilateral pleura, and bilateral pleural effusion	Cranial CT: (−)
3	Chest X-ray: (−)	Cranial CT: the left part of basal ganglia and the center of semideovale had a slightly lower density than the contralateral section, and the lateral ventricle was in plump form
4	Chest enhanced CT: (−)	Cranial MRI: Abnormal signal shadows in the right hippocampus, corpus callosum and right cerebrumContrast-enhanced MRI: Patchy long T1 and T2 signals in white matter of the right hippocampus, subcingulate cortex and pontine, and around bilateral ventricles, as well as thickened bilateral optic chiasma (diagnosis: Central nervous system infection with the possibility of TBM
5	—	Cranial CT: (−)
6	Chest enhanced CT: right lung exudate, and calcification nodules in the lung, mediastinum, and right hilum (diagnosis: Possibly of pulmonary tuberculosis)	Contrast-enhanced MRI: Punctate diffusion limitations, and meningeal enhancement

Table 4.

Therapeutic drugs and outcomes.

Case	Local hospital			Our hospital			Outcomes
Case	Antibiotic	γ-globulin	Others	Antibiotic	γ-globulin	Others
1	Azithromycin + Amoxicillin (15d) Ceftriaxone + vancomycin (10d)	5d	Dexamethasone + mannitol (5d)	Azithronmycin + cephalosporin (5d)	5d	Mannitol (9d)	Death
2	Antibiotic drugs (unknown details, 5d)	—	—	—	3d	Mannitol (9d) Dexamethasone (3d)	Recovered
3	Azithronmycin + cephalosporin (9d)	—	—	—	—	Mannitol (1d)	Recovered with memory decline
4	Unclear	3d	Mannitol (7d) Methylprednisolone (4d) Prednisone (10d)	—	—	Mannitol (7d)	Loss follow-up
5	—	—	—	—	—	Mannitol (3d)	Recovered
6	Cephalosporin (6d)	—	Mannitol (6d)	—	5d	Mannitol (6d)	Recovered

Case 2

A boy, aged 14 years and 6 months was admitted to our hospital due to fever, headache, and vomiting for 7 days (acute onset). Upon admission, blood examinations showed increased CRP (19 mg/L) and decreased lymphocyte ratio (22.8%). Cerebrospinal fluid examinations determined increased WBC (224 × 10⁶/L), monocytes (10%), and Pro (618.9 mg/L), and decreased Glu (1.97 mmol/L). These results indicated the possibility of viral encephalitis. After 4 days of regular treatment, fever and headache still existed, and consciousness disorder progressively emerged. Cerebrospinal fluid rechecking showed some characteristics of TBM, evidenced by the appearance of light yellow and slightly turbid, increased CSF pressure (180 mmH₂O), WBC (300 × 10⁶/L), monocytes (65%), and Pro (1267.5 mg/L), as well as decreased Glu (1.59 mmol/L) and CL (102 mmol/L). In addition, enhanced CT in chest revealed multiple dense patches in the upper lobe of the lungs, thickened right interlobar fissure, multiple enlarged lymph nodes in the mediastinum, thickened bilateral pleura, and bilateral pleural effusion. This case was then diagnosed as TBM and transferred to specialized hospital for treatment. After 3 months of anti-tuberculosis treatment, this case was recovered, exhibiting normal temperature, clear consciousness, and no sequelae. Cerebrospinal fluid examination and chest CT also revealed normal results. At present, this case can attend school normally (Tables 1–4).

Case 3

A girl, aged 10 years and 7 months, in Inner Mongolia was manifested by acute fever, headache, vomiting, and drowsiness for 17 days. She had not vaccinated with BCG vaccine (negative scar). In the local hospital, CSF examinations indicated increased WBC (214 × 10⁶/L) and Pro (852.1 mg/L), and decreased Glu (0.90 mmol/L) and CL (113 mmol/L). PPD test identified strong positive (++++). In addition, cranial CT revealed slightly lower density in the left basal ganglia and the center of semideovale than the contralateral section, and plump form of the lateral ventricle. Viral encephalitis and mycoplasma encephalitis were then considered in this case, which were treated with azithromycin and cephalosporin for anti-infection and mannitol for reducing intracranial pressure. She was subsequently transferred to our hospital due to poor curative effects, and TBM was immediately considered. After 1 day of mannitol treatment, she was further transferred to specialized hospital. Followed by 3 months of anti-tuberculosis treatments, she was recovered with normal CSF and cranial CT findings. Despite the decline in memory, she can attend school normally and communicate freely in daily life (Tables 1–4).

Case 4

A boy, aged 8 years and 7 months old with the characteristics of vomiting and drowsiness lasting for 2 months was admitted to the local hospital. Multiple detection of CSF showed increased WBC (17–26 × 10⁶/L), Pro (1000–2480 mg/L), and decreased Glu (2.33 mmol/L). The onset symptoms were relieved by the treatment as “viral encephalitis” for 10 days. However, blurred vision appeared in this case, which was further treated with γ-globulin, mannitol, methylprednisolone, and prednisone (total 20 days). Upon admission in our hospital, CSF re-examinations determined the appearance of light yellow and transparent, increased Pro (3773.5 mg/L), and decreased Glu (0.47 mmol/L) and CL (109 mmol/L). Cranial MRI showed abnormal signal shadows in the right hippocampus, corpus callosum and right cerebrum. Contrast-enhanced MRI further determined patchy long T1 and T2 signals in white matter of the right hippocampus, subcingulate cortex and pontine, and around bilateral ventricles, as well as thickened bilateral optic chiasma. Combined with the above findings, this case was diagnosed as TBM involving optic chiasm. This case was then transferred to the local specialized hospital, however, the vomiting and drowsiness were not alleviated after 1 month of anti-tuberculosis treatment. This case finally discontinued treatment and loss follow-up (Tables 1–4).

Case 5

A girl, aged 10 years and 11 months old was characterized by acute fever and headache, followed by personality changes (fidgety, talking to oneself, unable to answer completely correctly) within 12 days. She had an unknown history of vaccination with negative scar. Upon admission in our hospital, the use of mannitol improved her consciousness by reducing intracranial pressure (80 mmH₂O). Blood examinations determined increased WBC (12.67 × 10⁹/L) and decreased lymphocyte ratio (4.5%). Cerebrospinal fluid examinations determined the appearance of light yellow and transparent, increased WBC (172 × 10⁶/L), monocytes (76%), and Pro (5401 mg/L), as well as decreased Glu (1.39 mmol/L) and CL (100 mmol/L). Notably, M. tuberculosis was identified by next-generation sequencing (NGS), directly contributing to the diagnosis of TBM. This case was then was transferred to a specialized hospital for treatment. She was recovered after 2 months of anti-tuberculosis treatment, exhibiting disappeared fever, headache, and personality changes, as well as normal CSF findings. At present, this case can go to school normally (Tables 1–4).

Case 6

A boy (1 year and 3 months old) with negative scar for vaccination was admitted to local hospital due to acute onset of fever, vomiting, restlessness, and convulsions (3 days). Cerebrospinal fluid examinations showed increased WBC (58 × 10⁶/L), monocytes (95%), and Pro (1115.7 mg/L), as well as decreased Glu (1.45 mmol/L) and CL (110 mmol/L). Despite active treatment (cephalosporin and mannitol) was applied for 7 days, the fever and convulsions were not alleviated. This case was subsequently transferred to our hospital. Cerebrospinal fluid rechecking (WBC, 86 × 10⁶/L; monocytes, 40%; Pro, 998 mg/L; Glu, 0.58 mmol/L; CL, 104 mmol/L) showed consistent abnormal trends with the first detection. PPD test identified a positive result (++). In addition, chest enhanced CT showed right lung exudate, and calcification nodules in the lung, mediastinum, and right hilum (pulmonary tuberculosis possibility). Contrast-enhanced MRI determined punctate diffusion limitation and meningeal enhancement. Combined with the above findings, this case was diagnosed as TBM. After transferred to a specialized hospital, this case was recovered following 2 weeks of anti-tuberculosis treatments, evidenced by normal temperature and spirit, no convulsion, and normal CSF findings. Because of convulsive state with epileptiform discharges, anti-tuberculosis drugs were administrated for another 3 months. At present, this case has no convulsion and mental/motor retardation (Tables 1–4).

Discussion

Tuberculous meningitis is the most severe form of tuberculosis that accompanied with high mortality and disability.⁶ Although progresses have been made in the diagnosis of TBM, TBM is still easily misdiagnosed due to vague clinical symptoms.^7–9 Since delay in diagnosis directly contributes to poor prognosis, such as death, neurological sequelae, and neurocognitive disorders, early diagnosis of TBM is urgently needed. In this study, six children with TBM were retrospectively reviewed and the findings were discussed as follows.

TBM exhibits atypical clinical symptoms in children

Tuberculous meningitis clinically presents non-specific and fluctuating prodrome at the early stage.¹⁰ A retrospective study in Romania has revealed that fever (73%), headache (60%), vomiting (51%), and confusion (27%) are frequent symptoms in TBM children.¹¹ Another retrospective cohort study in South Africa has shown that TBM children mainly exhibit non-specific symptoms of consciousness loss (70%), fever (67%), vomiting (53%), malaise (52%), and convulsion (47%), as well as the manifestations of poor weight gain/weight loss (91%) and motor deficit (63%).¹² In this study, no weight change and motor deficit were observed in all cases. Fever (n = 5), headache (n = 3), vomiting (n = 5), and drowsiness (n = 3) were revealed as the principal symptoms of enrolled cases on admission, which were all non-specific. These non-specific symptoms may contribute to the misdiagnosis of 4 cases in the local hospital, since they are not distinguished from some other diseases, like pulmonary TB and flu-like illness.⁵ Until there are no improvements under routine treatment and/or the presence of progressive symptoms, TBM was suspected in our hospital. With the progress of TBM, deepening neurological symptoms appear, such as meningeal irritation, cranial nerve palsies, neurological deficits, and sensorium and movement disorders.¹³ Here, progressive consciousness disorder was observed in 2 cases. Although this progressive symptom involving nervous system indicates disease aggravation, it is still not specific for TBM. In addition to neurological symptoms, toxic symptoms of TB infection, including low fever, night sweat, weight loss, etc. should also be noted.^14,15 However, there no toxic symptoms were observed in all six enrolled cases without TB exposure history in this study. This phenomenon may be attributed to a good constitution, TB strain variation, or late diagnosis.

CSF and imaging findings are the basis for TBM diagnosis

Cerebrospinal fluid analysis and imaging are conventional diagnostic methods for TBM.⁴ CSF in TBM is characterized by leucocytosis, protein elevation, and glucose decreasing.¹⁶ Uniform research case definition criteria for TBM involving CSF indicate clear appearance, 50–100/μl cells, > 50% lymphocytes, > 1 g/L protein, and <2.2 mmol/L glucose.^17,18 A prospective study in South Africa has determined that glucose <2.2 mmol/l (96% specificity and 68% sensitivity) and protein >1 g/L in CSF (94% specificity and 78% sensitivity) have a certain diagnostic value in TBM.¹⁹ In this study, all the enrolled 6 cases showed increased WBC and Pro, as well as decreased Glu and CL. Among them, four out of 6 cases met the above criteria set for CSF protein and glucose. Our findings illustrate that CSF findings are of great significance in the diagnosis of TBM. However, it is noteworthy that purulent meningitis with similar CSF findings should be excluded.²⁰ Here, four enrolled children were not at the age of a high incidence of purulent meningitis, and all children had no near infection (such as purulent otitis media) and high-risk of dermal sinus. Therefore, more attention should be paid to TBM in patients without the risk of purulent meningitis when abnormal CSF emerges. In addition, cryptococcal meningitis, despite with relatively low incidence rate should also be excluded through pathogen detection.

The lung is the first affected organ by TB before TBM development. A retrospective analysis in Romania has determined that there 30% TBM children have a contact history with individuals with pulmonary tuberculosis.¹¹ Therefore, chest abnormality is considered to be helpful in guiding the diagnosis of TBM.²¹ Evidence has determined that 50% children with TBM are accompanied with chest imaging changes, such as primary pulmonary syndrome, miliary change, and mediastinal lymphotuberculosis.²² In this study, there is no contact history of pulmonary tuberculosis in all cases. Chest enhanced CT determined mediastinal lymphotuberculosis in case 2 and case 6, indicating the possibly of pulmonary TB. However, chest CT findings in TBM are not differ from pulmonary TB in isolation, and normal CT findings still exist in half of the children diagnosed with TBM.²³ Cranial imaging is also crucial for TBM diagnosis. Hydrocephalus, meningeal enhancement, and infarctions are common neuroradiologic manifestations of TBM.²⁴ Cranial CT and MRI are the dominant imaging strategies to assess the possibility of TBM.²⁵ For CT, hydrocephalus and meningeal enhancement are the main observations in TBM, accounting for about 80 and 75% pediatric patients, respectively.^17,26 Compared with CT, MRI is more effective in detecting meningeal enhancement, infarcts, and granulomas.²⁴ In this study, contrast-enhanced MRI showed meningeal enhancement in case 4 and 6, which support the diagnosis of TBM. This finding indicates that cranial imaging is valuable to assess the possibility of TBM in suspected cases with central nervous system infection. Although neuroimaging abnormality develops in most patients with TBM, the cranial imaging of TBM is still not typical and it may also be normal at an early stage.²⁷ Therefore, cranial imaging is recommended to be combined with CSF in clinical diagnosis of TBM, because either of them cannot accurately diagnose TBM alone.

The differences on the diagnosis of TBM between children and adults

As a severe form of extra-pulmonary tuberculosis, TBM can also be seen in adults. Some common symptoms of TBM in adults are similar with those in children. For example, headache (86%), fever (69%), vomiting (64%), and blurred consciousness (59%) are frequent symptoms in 160 adults with TBM in Turkey.²⁸ The clinical manifestations of 80 TBM adults in Qatar mainly include fever (79%), headache (71%), meningism (56%), and vomiting (48%).²⁹ Most of the above symptoms were also dominant in the enrolled children in our cohort. Indeed, there are also differences on the diagnosis of TBM between children and adults. A comparative retrospective analysis in Romania has determined that TBM adults are more likely to have consciousness abnormalities of dizziness, confusion, and personality change (72% vs. 27%), CSF Pro >5000 mg/L (18% vs. 4%), and fibrocavitary in chest X-ray (13% vs. 3%) compared with children.¹¹ Here, only case 5 presented personality change and CSF Pro >5000 mg/L. There no dizziness and confusion symptoms and chest fibrocavitary were observed in any cases in our cohort. These findings indicate that some diagnostic bases in adults are different from children.

Advantaged diagnostic strategy for TBM

In addition to conventional diagnostic methods, molecular-based technologies have been developed in the diagnosis of TBM, such as PCR, Xpert, and NGS. PCR is a kind of nucleic acid-based amplification, which exhibits a good sensitivity to detect TB from trace samples.³⁰ A meta-analysis has indicated that commercial in-house PCR has a high specificity but low sensitivity in the diagnosis of TBM, along with the limitations on heterogeneity and diagnostic accuracy.³¹ Xpert, recently superseded by Xpert Ultra is an automated system based on real-time PCR, which can simultaneously detect TB and rifampicin resistance.^32,33 Xpert has been endorsed by the World Health Organization for diagnosis of TB, while it lacks sensitivity for TBM and cannot be used in diagnosis of exclusion.³⁴ In this study, PCR and Xpert were both not applied due to the laboratory conditions in our hospital, which makes it impossible to assess the diagnostic value of these methods. In addition, NGS is a rapid method that can identify pathogens in plasma, CSF, and bronchoalveolar lavage fluid.³⁵ Through detecting TB in CSF, NGS has been considered as an effective strategy for early diagnosis of TBM with high sensitivity and specificity.^36–38 In this study, TB was detected in the CSF of case 5 by NGS, directly proving pathogenic support for TBM. Our findings in case 5 illustrate a great value of NGS in the diagnosis of TBM. However, NGS alone may be not entirely credible, and it needs to combine with clinical symptoms and CSF findings for accurate diagnosis. Moreover, NGS may be still expensive in the epidemic area of TB, despite the cost of NGS has been reduced since its advantage in 2004.³⁵

Early diagnosis improves the prognosis of TBM

Tuberculous meningitis is frequently associated with mortality and sequel despite receiving adequate treatments. A series of retrospective studies on pediatric TBM have determined a mortality of 5–23% and a neurological sequel incidence of 14–52%.⁴ In this study, case 2, 5, and six recovered without neurological sequelae, and case 3 recovered with memory decline. Unfortunately, case 1 died and case 4 discontinued treatment and loss follow-up. Combined with the basic characteristics of case 1 (3 years and 4 months old, 25 d course) and 4 (8 years and 7 months old, 60 d course), we suspect that the poor prognosis of TBM is related with the small age and long disease course. Therefore, early diagnosis is particularly important to prevent the poor prognosis of TBM, especially for young children.

The importance of vaccination and medical conditions

Bacillus Calmette-Guerin (BCG) is the only TB vaccine licensed for protecting human beings against miliary TB and TBM. Considerable evidence has determined the effective and long-lasting protective role of BCG against TBM in children.³⁹ In this study, three out of 6 cases exhibited negative scar of BCG, indicating a relatively high risk of TBM in children without BCG vaccination. Since all enrolled children suffered with TBM were living in rural areas, the limitation on the cognition of local people may be one of the important reasons for the lack of vaccination in these 3 cases. In addition, the limitation in local medical condition may also contribute to misdiagnosis. For example, case 3 came from grassland of Inner Mongolia exhibited typical pathological changes in CSF, but TBM was not considered in the local hospital probably due to lack of diagnostic experience. Because medical conditions are diverse in different areas of China, hospitals with limited condition need to strengthen learning and communication. At the same time, in places with relatively good medical condition, TBM should also be noticed in view of TB infection reduction and atypical symptoms.

Conclusion

This study revealed that the enrolled children with TBM present non-specific symptoms on admission, but no typical symptoms of TB infection. For children with central nervous system infection, TBM should be highly suspected when there are no improvements under routine treatment and/or the presence of progressive symptoms. Timely rechecking of CSF combined with cranial imaging is a clinically feasible strategy to provide significant guidance for the diagnosis of TBM. Besides, NGS shows great potential in TBM diagnosis, but its popularization is still challenge, particularly in endemic area.

Footnotes

Author contributions

J. D. was involved in the conception and design of the study; J. D. and X. P. were involved in the data collection; J. D. and X. P. were involved in the analysis and the interpretation of data; J. D. was involved in writing the drafts of the manuscript. All authors critically revised the manuscript and gave final approval of the submitted manuscript.

Declaration of conflicting interests

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Ethics approval

Ethical approval for this study was obtained from The Affiliated Children’s Hospital, Capital Institute of Pediatrics in accordance with the Declaration of Helsinki (SHERLLM-2016022).

Funding

The author(s) received no financial support for the research, authorship, and/or publication of this article.

Informed consent

Written informed consent was obtained from legally authorized representatives before the study.

ORCID iD

Jingjing Dong

References

Singh

Agarwal

Baiswar

. Isolated oculomotor nerve palsy - a rare initial manifestation of tuberculous meningitis. J Assoc Physicians India 2020; 68: 73–74.

Guirado

Schlesinger

Kaplan

. Macrophages in tuberculosis: friend or foe. Semin Immunopathol 2013; 35: 563–583.

Dodd

Gardiner

Coghlan

, et al. Burden of childhood tuberculosis in 22 high-burden countries: a mathematical modelling study. Lancet Glob Health 2014; 2: e453–e459.

Daniel

Grace

Natrajan

. Tuberculous meningitis in children: clinical management & outcome. Indian J Med Res 2019; 150: 117–130.

van Toorn

Solomons

. Update on the diagnosis and management of tuberculous meningitis in children. Semin Pediatr Neurol 2014; 21: 12–18.

Donovan

Figaji

Imran

, et al. The neurocritical care of tuberculous meningitis. Lancet Neurol 2019; 18: 771–783.

Wang

Sheng

. Progress in diagnosis of tuberculous meningitis in children. Int J Lab Med 2010; 31: 979–981.

Thwaites

van Toorn

Schoeman

. Tuberculous meningitis: more questions, still too few answers. Lancet Neurol 2013; 12: 999–1010.

Mai

Thwaites

. Recent advances in the diagnosis and management of tuberculous meningitis. Curr Opin Infect Dis 2017; 30: 123–128.

10.

Kent

Crowe

Yung

, et al. Tuberculous meningitis: a 30-year review. Clin Infect Dis 1993; 17: 987–994.

11.

Miftode

Dorneanu

Leca

, et al. Tuberculous meningitis in children and adults: a 10-year retrospective comparative analysis. PLoS One 2015; 10: e0133477.

12.

van Well

Paes

Terwee

, et al. Twenty years of pediatric tuberculous meningitis: a retrospective cohort study in the western cape of South Africa. Pediatrics 2009; 123: e1–e8.

13.

Chatterjee

. Brain tuberculomas, tubercular meningitis, and post-tubercular hydrocephalus in children. J Pediatr Neurosci 2011; 6: S96–S100.

14.

Getahun

Sculier

Sismanidis

, et al. Prevention, Diagnosis, and treatment of tuberculosis in children and mothers: evidence for action for maternal, neonatal, and child health services. J Infect Dis 2012; 205(Suppl 2): S216–S227.

15.

Mert

Arslan

Kuyucu

, et al. Miliary tuberculosis: epidemiologicaland clinical analysis of large-case series from moderate to low tuberculosis endemic Country. Medicine 2017; 96: e5875.

16.

Principi

Esposito

. Diagnosis and therapy of tuberculous meningitis in children. Tuberculosis 2012; 92: 377–383.

17.

Marais

Thwaites

Schoeman

, et al. Tuberculous meningitis: a uniform case definition for use in clinical research. Lancet Infect Dis 2010; 10: 803–812.

18.

Solomons

Wessels

Visser

, et al. Uniform research case definition criteria differentiate tuberculous and bacterial meningitis in children. Clin Infect Dis 2014; 59: 1574–1578.

19.

Solomons

Visser

Donald

, et al. The diagnostic value of cerebrospinal fluid chemistry results in childhood tuberculous meningitis. Childs Nerv Syst 2015; 31: 1335–1340.

20.

Chen

Zhai

Ooi

, et al. Risk factors for hydrocephalus in neonatal purulent meningitis: a single-center retrospective analysis. J Child Neurol 2021; 36: 491–497.

21.

Uniyal

Garg

Malhotra

, et al. Computed tomography thorax abnormalities in immunocompetent patients with tuberculous meningitis: an observational study. J Neurol Sci 2019; 397: 11–15.

22.

Wan

Fan

. Diagnosis and treatment of tuberculous meningitis in children. J Appl Clin Pediatr 2008; 23: 723–726.

23.

Solomons

Goussard

Visser

, et al. Chest radiograph findings in children with tuberculous meningitis. Int J Tuberc Lung Dis 2015; 19: 200–204.

24.

Pienaar

Andronikou

van Toorn

. MRI to demonstrate diagnostic features and complications of TBM not seen with CT. Childs Nerv Syst 2009; 25: 941–947.

25.

Bomanji

Gupta

Gulati

, et al. Imaging in tuberculosis. Cold Spring Harb Perspect Med 2015; 5: a017814.

26.

Ozates

Kemaloglu

Gurkan

, et al. CT of the brain in tuberculous meningitis. a review of 289 patients. Acta Radiol 2000; 41: 13–17.

27.

Garg

Malhotra

Jain

. Neuroimaging in tuberculous meningitis. Neurol India 2016; 64: 219–227.

28.

Pehlivanoglu

Yasar

Sengoz

. Tuberculous meningitis in adults: a review of 160 cases. ScientificWorldJournal 2012; 2012: 169028–169036.

29.

Imam

Ahmedullah

Akhtar

, et al. Adult tuberculous meningitis in Qatar: a descriptive retrospective study from its referral center. Eur Neurol 2015; 73: 90–97.

30.

Philip

Wilkes

Yeo

, et al. Potential use of multiplex PCR in diagnosis of tuberculous meningitis. Trop Biomed 2017; 34: 870–876.

31.

Pai

Flores

Pai

, et al. Diagnostic accuracy of nucleic acid amplification tests for tuberculous meningitis: a systematic review and meta-analysis. Lancet Infect Dis 2003; 3: 633–643.

32.

Denkinger

Schumacher

Boehme

, et al. Xpert MTB/RIF assay for the diagnosis of extrapulmonary tuberculosis: a systematic review and meta-analysis. Eur Respir J 2014; 44: 435–446.

33.

Bahr

Nuwagira

Evans

, et al. Diagnostic accuracy of Xpert MTB/RIF Ultra for tuberculous meningitis in HIV-infected adults: a prospective cohort study. Lancet Infect Dis 2018; 18: 68–75.

34.

Mechai

Bouchaud

. Tuberculous meningitis: challenges in diagnosis and management. Rev Neurol 2019; 175: 451–457.

35.

Miller

Chiu

. Clinical metagenomic next-generation sequencing for pathogen detection. Annu Rev Pathol 2019; 14: 319–338.

36.

Yan

Sun

, et al. Metagenomic Next-Generation Sequencing (mNGS) in cerebrospinal fluid for rapid diagnosis of Tuberculosis meningitis in HIV-negative population. Int J Infect Dis 2020; 96: 270–275.

37.

Zhao

Shen

, et al. Metagenomic next generation sequencing for the diagnosis of tuberculosis meningitis: a systematic review and meta-analysis. PLoS One 2020; 15: e0243161.

38.

Lin

Cheng

Han

, et al. Value of next-generation sequencing in early diagnosis of patients with tuberculous meningitis. J Neurol Sci 2021; 422: 117310.

39.

Lange

Aaby

Behr

, et al. 100 years of Mycobacterium bovis bacille Calmette-Guerin. Lancet Infect Dis 2022; 22: e2–e12.