Progress in the Diagnosis and Treatment of Tuberculous Meningitis

Olga Adriana Caliman-Sturdza

doi:10.5772/intechopen.1014269

Abstract

Tuberculous meningitis (TBM) is the most severe form of tuberculosis, with high mortality and neurological disability in survivors. Recent advances include improved nucleic-acid diagnostics for cerebrospinal fluid (CSF), refined pediatric regimens, and emerging intensified/adjunctive treatments. Narrative synthesis of current guidelines and peer-reviewed articles (priority on 2019–2025), with an emphasis on pathophysiology, diagnostics, treatment (drug-susceptible and drug-resistant TBM), and age-specific issues. Xpert MTB/RIF or Xpert Ultra should be the first-line CSF tests in adults and children with suspected TBM; the latter has greater sensitivity in paucibacillary syndrome. The use of adjunctive corticosteroids (mortality benefit) remains supported, and trials of high-dose rifampicin and fluoroquinolone add-on have shown mixed clinical outcome improvements, even with improved pharmacokinetics. A 6-month intensive regimen of HRZE-ethionamide has been added as an alternative to the usual 12-month course of treatment for carefully selected, drug-susceptible TBM. With MDR–TB, linezolid and fluoroquinolones have desirable CNS penetration; bedaquiline demonstrates a quantifiable CSF exposure and is being increasingly used as part of MDR–TBM regimens. Early empiric therapy and steroids remain the cornerstone. Quick molecular diagnosis, individualized therapy with CNS-penetrant agents, and adjuncts (e.g., aspirin to decrease infarcts) are transforming care, and large trials are being conducted to clarify the best intensified therapy, particularly in children and in HIV co-infection.

Keywords

tuberculous meningitis
Xpert Ultra
pediatrics
high-dose rifampicin
linezolid
bedaquiline
corticosteroids
aspirin
hydrocephalus

Author Information

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Olga Adriana Caliman-Sturdza *
- Faculty of Medicine and Biological Sciences, Stefan cel Mare University of Suceava, Suceava, Romania

*Address all correspondence to: sturdza_olga@yahoo.com

1. Introduction

Tuberculous meningitis (TBM) is the most pernicious type of tuberculosis, with high death and neurologic disability rates [1]. It is a consequence of the hematogenous diffusion of Mycobacterium tuberculosis (M. tuberculosis) to the meninges and subarachnoid space, resulting in a subacute meningitis that is usually hard to detect and difficult to treat. Tuberculous meningitis constitutes a smaller percentage of tuberculosis (TB), with an estimated global prevalence of 1−5% (around 129,000–199,000 cases per year), although its prevalence is much higher in regions with a significant burden of TB [2]. Modeling studies show that there is a worldwide TBM mortality rate of approximately 27%, and approximately 50% of survivors experience permanent neurologic sequelae [3, 4]. Young children (less than 5 years old, in particular) and immunocompromised adults are especially susceptible: TBM manifests in children under 5 years old at a rate of about 4% of TB cases, and one out of every three to five adults who have TBM also has HIV co-infection [5]. In fact, TBM patients with HIV have a significantly increased mortality rate (~57% versus 16% when HIV-negative) [6]. Additional risk groups include infancy (poor immunity), old age, diabetes, and close contact with untreated TB patients [7]. Despite being curable with prompt therapy, TBM frequently causes delayed diagnosis and poor outcomes, underscoring the need for improved diagnostic tools and therapeutic strategies [8, 9].

2. Diagnostic approaches

Timely diagnosis of TBM is challenging due to its nonspecific early symptoms and the paucibacillary nature of CSF infection [10]. A high index of suspicion is required, particularly in endemic regions or at-risk populations (young children, HIV-positive patients). The diagnosis rests on a combination of clinical assessment, characteristic neuroimaging, and laboratory confirmation (via CSF analysis, microbiology, or molecular tests) [11].

2.1 Clinical presentation and staging

Tuberculous meningitis is generally a subacute meningitic disease that develops progressively over days to weeks, in contrast to pyogenic bacterial meningitis [12]. There is a tendency for nonspecific early symptoms: low-grade fever, malaise, night sweats, and anorexia, with headache being a typical prodromal symptom [13]. During the prodrome, patients may also complain of unspecified gastrointestinal symptoms (e.g., vomiting or constipation) [8]. The more pronounced the inflammation in the CNS, the more certain symptoms of meningitis are revealed: stiffening of the neck, photophobia, intense headache, vomiting, and changes in mental status [14]. Neurological symptoms (cranial nerve palsies, seizures, or focal weakness) are likely indicators of advanced disease complications, such as hydrocephalus or infarcts [8]. Tuberculous meningitis severity is frequently determined by the British Medical Research Council (BMRC) staging at presentation: Stage I (alert, minimal deficits), Stage II (confusion or mild focal deficits), and Stage III (coma or severe neurologic deficit) [15]. The majority of patients are in Stage II or III because their cases were not identified in a timely manner [16]. It is important to note that children also present at higher stages than adults. In a comparative series, at admission, 73% of children were in Stage III (coma) compared to approximately 41% of adults [17]. There are also more intense symptoms of elevated intracranial pressure (such as bulging fontanel in newborns and projectile vomiting) and seizures in children, with less clear symptoms of confusion or stroke-like local impairment in adults [18–20]. Important diagnostic clues may include a history of chronic cough, known TB exposure, or concomitant pulmonary TB on the chest X-ray (present in approximately 16–90% of cases in children and 22–83% of cases in adults) [21, 22]. In any chronic meningitic disease, particularly when there are risk factors or a lymphocytic CSF profile, TBM should be considered, and urgent investigations should be sought [21].

2.2 Neuroimaging findings

Neuroimaging forms part of TBM diagnosis and usually reveals typical abnormalities. The modality of choice is magnetic resonance imaging (MRI) using gadolinium contrast, as it has better sensitivity to meningeal inflammation and parenchymal lesions [23, 24]. Computed tomography (CT) may help identify gross alterations (hydrocephalus, infarcts) and is indicated in the absence of or contraindication to MRI [25]. Tuberculous meningitis has classic neuroimaging characteristics that include the following (see Table 1):

Basal cistern leptomeningeal enhancement: Contrast MRI typically shows thick enhancement of the meninges at the skull base (interpeduncular, prepontine, suprasellar cisterns) due to the gelatinous exudate [26]. This observation is highly indicative of TBM (though not a pathogen) and is observed in as many as about 90% of cases. Leptomeningeal enhancement can spread across the cerebral convexities and along cranial nerves [27]. Basal hyperintensities may also signify exudates on FLAIR sequences [28].
Hydrocephalus: Obstructed CSF pathways caused by basal exudates result in ventricular enlargement, which is apparent on imaging in most pediatric TBM patients and a significant proportion of adults [29]. The most common communication is that of hydrocephalus (dilation of the 3rd and lateral ventricles) [30]. Hydrocephalus on initial CT/MRI is reported in approximately 40–88% of children and ~ 4–62% of adults in series [24]. This complication requires emergency neurosurgical examination, as an extraventricular drain or shunt may be necessary.
Infarcts: Cerebral TB vasculitis infarctions appear on MRI as regions of limited diffusion or on CT as hypodense foci, commonly in the basal ganglia, thalamus, or frontal lobes [31]. Ischemic strokes are seen in up to 20–40% of TBM patients on imaging (range reported as 4–65%) [32]. These are normally caused by obliterative arteritis of small perforating arteries and are associated with local neurologic impairments (e.g., hemiplegia).
Tuberculomas: Coexisting tuberculous granulomas are ring-enhanced or nodular lesions, solitary or multiple. MRI is more sensitive than CT when it comes to detecting tuberculomas and related edema [33]. In adults with TBM, tuberculomas are detected in an estimated range of 10–30% (3–89% in other series) and slightly higher in children (12–50%) [34]. They can be found at baseline or may develop in the course of therapy (paradoxical reaction). Tuberculomas may cause mass effect or seizures due to the edema around them.
Other findings: MRI can reveal ependymitis (a linear problem of the lining of the ventricles) in serious cases of inflammatory dissemination into the ventricular system [35]. In cases of spinal subarachnoid involvement (particularly chronic cases), spinal imaging in TBM may disclose the presence of spinal arachnoiditis or tuberculous radiculomyelitis [36]. More modern MR imaging, including MR angiography, can show the presence of vessel narrowing or occlusion due to vasculitis, and further suggestive evidence may be obtained using perfusion MRI or MR spectroscopy, which are not standard practice [31, 34].

Finding	Description and significance	Frequency in TBM (Approx.)
Basal meningeal enhancement	Contrast uptake in basal cisterns due to tuberculous exudates; a hallmark of TBM.	Seen in the majority of cases (up to ~90%).
Hydrocephalus	Enlargement of ventricles (usually communicating type) due to CSF blockage at the base, leading to raised intracranial pressure.	Very common in children (~50–80%); ~20–50% in adults.
Infarcts (stroke)	Ischemic lesions (often in the basal ganglia or cortex) due to TB vasculitis may cause focal deficits or stroke syndrome.	Occur in approximately 20–40% of cases (range: 4–60%).
Tuberculomas	Intracranial tuberculous granulomas: ring-enhancing mass lesions that may accompany meningitis. They can cause seizures or focal signs if sizable.	Present in a subset (10–30% overall; up to ~50% in pediatrics).
Cranial nerve enhancement	Enhancement or thickening of cranial nerves (III, VI, VII, VIII commonly) due to basal arachnoiditis manifests as cranial neuropathies (e.g., diplopia, deafness, facial palsy).	Common; specific cranial nerve palsies in ~20–30% (III nerve palsy is the most frequent).

Table 1.

Common neuroimaging features in tuberculous meningitis.

Neuroimaging is useful not only in assisting with diagnosis but also in aiding management (e.g., the presence of hydrocephalus or tuberculomas may require brain surgery or steroids). It should be noted that normal imaging does not rule out TBM, particularly in its early stages. However, basal meningeal enhancement and hydrocephalus on MRI in a patient with subacute meningitic disease are excellent indications of TBM rather than other etiologies [37].

2.3 Laboratory and CSF diagnostic biomarkers

CSF analysis: Tuberculous meningitis is associated with a classic lymphocytic pleocytosis in the cerebrospinal fluid, raised protein, and low glucose. A typical CSF is: white cell count 100 to 500 cells/microliter (usually more than 80% lymphocytes), protein 100 to 500 mg/dL, and glucose less than 45 mg/dL (usually less than half the glucose in parallel blood circulation) [38]. Nonetheless, none of these findings is unique to TBM and may be shared with fungal or neoplastic meningitis. The CSF can be abnormal in very young patients with TBM or in HIV co-infected patients (e.g., neutrophil-predominant, normal glucose) [39]. Therefore, despite the support of the diagnosis by CSF chemistry and cytology, the ultimate determination of M. tuberculosis or its elements is necessary. The main diagnostic tests and their performance are highlighted in Table 2.

Test/method	Typical sensitivity	Specificity	Notes and utility
CSF AFB smear	<20% (often ~10%) [43]	~99% (high)	Rapid (minutes), but very low yield in TBM due to paucibacillary CSF. Multiple large-volume taps modestly increase yield.
Mycobacterial culture (CSF)	~30% (range 4–60%) [43]	~100%	Gold standard for confirmation and drug-susceptibility testing: slow (2–6 weeks) and low sensitivity, even with centrifugation.
Xpert MTB/RIF (PCR)	~60–70% vs. culture (up to 80% with large volume) [44]	>95%	Rapid (≈2 hours). Detects Mycobacterium tuberculosis DNA and rifampin resistance. WHO-recommended first-line test for TBM (especially in HIV).
Xpert MTB/RIF Ultra	~70–90% [45]	>90%	Improved sensitivity due to a lower detection threshold. Particularly useful in paucibacillary cases (children, early TBM).
TB-LAMP (Loop AMP)	~76–88% [49]	~99%	Isothermal NAAT, featuring faster and simpler equipment than PCR, could be deployed in resource-limited laboratories.
CSF adenosine deaminase (ADA)	~89% [52]	~91%	An ADA level > ~10 U/L in CSF is suggestive of TBM. It is a useful adjunct in smear-negative cases, but beware of overlap with other meningitides.
CSF Xpert Ultra LFA (LAM)	~50–70% (in HIV⁺) [48]	~95% (in HIV⁺)	Lateral flow assay for mycobacterial LAM antigen (usually performed on urine; CSF use is off-label) is helpful in HIV co-infected patients with disseminated TB.
CSF T-SPOT.TB (IGRA)	~70–80% [53]	~85–90%	Measures T-cell IFN-γ release in response to TB antigens in CSF. Requires a large sample volume; not routinely available.
mNGS (metagenomic sequencing)	~60–70% [57]	~98%	Unbiased sequencing that detects M. tuberculosis DNA (and others) is valuable in culture-negative cases; however, it requires high cost and technical expertise.

Table 2.

Diagnostic tests for tuberculous meningitis – performance characteristics.

AFB – acid-fast bacilli; NAAT – nucleic acid amplification test; LAM – lipoarabinomannan; IGRA – interferon-gamma release assay; mNGS – metagenomic next-generation sequencing.

Microscopy and culture: In TBM, microscopy and culture have a low yield because of the low bacillary load. A positive CSF acid-fast bacilli (AFB) smear occurs in less than 20% of cases (usually less than 10% in most series) [40]. Smear sensitivity (large-volume lumbar puncture with centrifugation) can be modestly improved by concentration techniques, achieving a sensitivity for detecting TBM of about 30–40%, although a negative smear is still expected in TBM. Mycobacterial culture (on Löwenstein-Jensen or liquid media) is the gold standard for diagnosis and drug susceptibility testing, but it is agonizingly slow (up to 4–6 weeks) and insensitive in TBM. Even with culture in liquid media (e.g., BACTEC MGIT 960), CSF cultures become positive in only 30–60% of TBM cases [41]. Therefore, a negative culture does not exclude the disease, and clinicians are frequently forced to initiate treatment on an empirical basis.

Nucleic acid amplification tests: Within the last few years, rapid molecular tests have revolutionized the diagnosis of TBM. The Xpert MTB/RIF assay (GeneXpert) is a cartridge-form PCR capable of identifying M. tuberculosis and rifampicin resistance in 2 hours [42]. In TBM, Xpert has moderate sensitivity (~63% compared to culture) but much higher sensitivity if larger CSF volumes (≥6 mL) are used or if centrifuged deposits are tested (up to ~80% sensitivity) [43]. Its specificity exceeds 95% [44]. The newer Xpert MTB/RIF Ultra has a lower detection limit (identifies bacilli some 10-fold less frequently) and is more sensitive, in the 70–90% range, in TBM [45, 46]. A multicenter study reported Ultra detecting ~90% of culture-positive TBM cases [47]. In line with its velocity and sensitivity, WHO currently suggests Xpert Ultra as the initial diagnostic test in suspected TB meningitis [48]. A moderately accurate (approximately 76–88% sensitivity) alternative PCR technique is loop-mediated isothermal amplification (TB-LAMP), which can be of value in low-resource environments [49]. Finally, NAATs can significantly assist in early diagnosis, but a negative result does not rule out TBM (empirical treatment should be continued when the clinical suspicion is high) [50]. Rifampin resistance can be identified quickly by molecular tests, which is extremely important to manage therapy at the initial stage of the course [51].

CSF biochemical markers: When microbiologic tests are not positive, several CSF biomarkers may be used to help make a diagnosis of TBM. TBM is associated with an increase in the levels of adenosine deaminase (ADA) in CSF, which is a result of T-lymphocyte activation; ADA above 10 U/L is a suggestive level of TBM, with a reported sensitivity of about 89% and specificity of about 91% [52]. ADA, however, may also be slightly raised in bacterial or fungal meningitis; hence, it is an adjunct marker. Interferon-γ release assays (IGRAs) on CSF (e.g., TB Gold in-tube or T-SPOT.TB applied to CSF cells) have shown ~70–80% sensitivity for TBM, but they require large CSF volumes and are not widely available [53, 54]. Lipoarabinomannan (LAM) is an immunoassay-detectable mycobacterial cell wall antigen; LAM CSF in TBM has moderate sensitivity (50–70%) but may prove more valuable in HIV-infected patients [55]. The lateral-flow urine LAM test is WHO-approved to diagnose TB in HIV-infected patients but has low sensitivity to detect disseminated TB by urine in the absence of co-infection with HIV [56].

New high-throughput technologies should enhance TBM diagnosis. Next-Generation Sequencing (mNGS) of CSF is capable of unbiasedly identifying M. tuberculosis DNA and other pathogens. Research indicates that mNGS is able to detect TB where other tests have failed to detect it; the sensitivity of mNGS is in the range of 60–70%, and the specificity is very high [57]. Currently, mNGS is restricted to research environments because of cost and the necessary knowledge, but it has the potential to resolve indeterminate cases [58]. Biomarkers in CSF (which include particular mRNA or protein signatures of TBM) are being studied using transcriptomic and proteomic techniques [59]. Some proposed markers include elevated CSF cytokine profiles (IL-6, IFN-γ, etc.) and unique protein panels (e.g., fragments of neural proteins reflecting injury) [60–62]. Although none of them are currently in everyday use, these markers may become useful as an additive to the diagnostic arsenal in the future to differentiate between TBM and other meningitides. To determine proteins or mRNAs unique to TBM patients versus those with other forms of meningitis, researchers are examining the total protein and gene expression profile in the CSF. Research has found patterns of various differentially expressed CSF-based proteins that are linked to TBM, such as anti-thrombin III, haptoglobin, APOAI, APOB, APOE, S100A8, and transthyretin [59, 63]. Interest also exists in applying the tools of transcriptomics and proteomics to comprehend the role of mycobacterial genes and proteins in the pathogenesis of TBM. It is possible that these biomarkers would result in a more precise and expedited identification of TBM, particularly distinguishing between the disease and other types of meningitis. Through host response analysis and bacterial factors, researchers are able to gain more insight into the disease by understanding the development of TBM. The discovery of particular molecular signatures can contribute to the development of new vaccines, new antibiotics, and host-directed treatments. Initial mass spectrometric analyses have been able to detect possible TBM-specific protein signatures in the CSF [64]. The next critical step is to confirm the existence of these biomarkers in separate groups of patients to ascertain the reproducibility and accuracy of the findings before clinical application. These forms of comprehensive analyses have become feasible with advances in proteomics and transcriptomics, overcoming technological barriers from the past to detect low-concentration biomarkers.

Integration of diagnostic methods enhances output. Practically, an urgent contrast-enhanced neuroimaging examination and lumbar puncture (barring any contraindication indicated by increased intracranial pressure) should be performed on any suspected patient of TBM. Preferably, a minimum of 5–10 mL of CSF is collected to carry out a series of tests: cell count/chemistry, AFB smear, cultures, and an Xpert Ultra PCR [65]. When initial tests are negative but there is a high level of suspicion, repeat lumbar puncture to culture or refer to send CSF for more advanced tests [66] (where available), such as mNGS. Early diagnosis is also essential because the delay in treatment is one of the major contributors to the high morbidity of TBM.

3. Treatment and management

Tuberculous meningitis requires an aggressive, multi-pronged treatment approach to eradicate the infection and manage CNS complications. The cornerstone is the prompt initiation of anti-tuberculosis therapy, combined with adjunctive corticosteroids and supportive care. Treatment is prolonged and often needs to be tailored to drug susceptibility results, especially in regions with drug-resistant TB.

3.1 Antituberculous therapy: Standard regimen

Tuberculous meningitis standard chemotherapy is similar to that of pulmonary TB but with a longer duration. Existing guidelines (e.g., WHO) suggest a minimum duration of therapy for drug-susceptible TBM of 9–12 months [67]. The standard regimen is defined by 2 months of intensive therapy with four first-line drugs, that is, isoniazid (INH), rifampicin (RIF), pyrazinamide (PZA), and ethambutol (EMB), followed by a prolonged period of INH and RIF [68]. Streptomycin may be used instead of ethambutol in the intensive phase of some programs (particularly in young children or in cases of suspected drug resistance), although EMB is likely to be preferred because it is easier to administer and equally effective [68]. This longer duration (compared to 6 months for pulmonary TB) is necessary to guarantee sterilization of the CNS, as this is not easily accomplished with large drug levels in the CSF and because relapse in the brain is a significant concern [69]. Of all first-line medications, INH and RIF play the most important roles in TBM because of their superior CSF penetration and bactericidal action [70]. INH crosses the blood–brain barrier quite well, even without inflammation. Rifampin also achieves therapeutic CSF concentrations, though inflammation increases its absorption; in particular, experimental results reveal that the prognosis in TBM is closely correlated to rifampin susceptibility – rifampin-resistant TBM has a very poor prognosis [71]. Pyrazinamide is active in the acidic environment of the CSF and is moderately penetrative. Ethambutol is not predictably penetrative of the CSF and is mainly used to prevent the emergence of resistance; instead, some authorities replace ethambutol with moxifloxacin in TBM because moxifloxacin achieves better CNS levels [72, 73]. In fact, some experts recommend moxifloxacin as an adjunct to the first-line TBM treatment, and some studies have shown its efficacy in the treatment of TBM [74]. The optimum dosage of drugs used in TBM is an active area of research. To address the problem of penetration, high-dose rifampicin (up to 30 mg/kg IV or oral, compared with the standard of around 10 mg/kg) has been studied, with some reports of improved survival in advanced TBM [75]. Intensified regimens (e.g., the INTENSE-TBM study) are undergoing trials, which involve high-dose RIF and other agents such as linezolid in the intensive stage [76]. Until results are definitive, standard dosing with careful adherence remains the practice, but clinicians should be aware of these emerging data. During therapy, drug interactions and comorbidities should be addressed. The timing of antiretroviral therapy (ART) initiation in co-infected patients is challenging: while prompt ART may cause immune reconstitution inflammatory syndrome (IRIS) in the brain, delayed ART may result in uncontrolled HIV [77]. Recent recommendations do not rule out the possibility of initiating ART during 2–8 weeks of TBM treatment, and close observation is advised [78]. TBM-IRIS will develop in approximately 10% of HIV-positive patients and may lead to paradoxical clinical deterioration (new or progressive tuberculomas, hydrocephalus) [79]. It is treated with corticosteroids and, in more severe cases, with anti-TNF therapy [80].

3.2 Adjunctive corticosteroids

The use of adjunctive corticosteroid treatment is a proven, highly supported practice in TBM management [81]. The rationale is that dexamethasone or prednisone would partly suppress the acute inflammatory process in the subarachnoid space, which would help minimize cerebral edema, intracranial pressure, and inflammatory tissue damage [82]. In a landmark randomized trial and follow-up meta-analyses, the addition of corticosteroids decreased mortality by approximately 30% in HIV-negative TBM patients [83]. Based on this, the WHO and others advise initiating corticosteroids with anti-TB medications in all TBM patients (except in cases of contraindications) [84]. The common course of action is a course of several weeks of dexamethasone IV with tapering over 6–8 weeks [85]. A sample dosing regimen in adults is 0.4 mg/kg/day IV dexamethasone during the first week, followed by gradual tapering of the drug to oral intake over a period of 6 weeks. A similar regimen of prednisone (e.g., 2 mg/kg/day) is frequently used in children [86, 87].

Steroids are demonstrated to have a significant beneficial effect on acute complications, such as infarcts and hydrocephalus, and on short-term neurological outcomes [85, 88]. However, their impact on long-term disability is less clear, and in HIV-positive patients, a large trial (Donovan et al.) found no clear survival benefit of dexamethasone [86]. Nonetheless, the majority of specialists continue to recommend steroid use despite HIV co-infection (with close supervision) due to possible advantages in the context of CNS inflammation subsidence [88]. The steroid immunosuppression effect should be weighed against the risk of infection, and therefore, opportunistic infection prevention and close attention to other infections (fungal and so on) is justified in the face of steroid therapy.

3.3 Other adjunct and supportive therapies

Management of Raised Intracranial Pressure: A significant number of patients with TBM develop raised intracranial pressure (ICP) due to either the presence of hydrocephalus or cerebral edema. Vigilant treatment is essential to avoid herniation and additional ischemia. Treatment of persistent or high-grade hydrocephalus includes repeated therapeutic lumbar punctures (to relieve the pressure), osmotic therapy (mannitol), and permanent CSF drainage by an external ventricular drain or ventriculoperitoneal (VP) shunt [89]. Neurosurgical consultation is suggested in the early stages when imaging reveals the presence of hydrocephalus; a VP shunt may be life-saving and may significantly reduce headaches and sensorium in affected patients.

Anticonvulsants: Seizures are a major cause of TBM, occurring either because of cortical tuberculomas, infarcts, or acute inflammation. Anti-epileptic drugs to prevent recurrent seizures should be initiated in patients with seizures or severe encephalopathy [90]. The importance of seizure control lies in both patient safety and the fact that seizures may cause an increase in ICP and secondary brain injury.

Aspirin: There is now some evidence on the application of antiplatelet therapy to vascular complications of TBM. A randomized trial in Vietnam established that aspirin (at 1,000 mg/day) in combination with standard therapy was not associated with a decrease in overall mortality, though it significantly decreased the incidence of stroke and new infarcts on MRI [91, 92]. It is believed that the effect of aspirin is due to the inhibition of thrombosis in inflamed arteries in the brain. There is ongoing investigation into the role of aspirin (in various doses) in TBM, and some specialists already use low-dose aspirin (300–500 mg daily) in TBM patients without contraindications, particularly when vasculitic infarcts are suspected [93].

Immunomodulators: Since steroids alone are only partially effective in modulating the immune response, other immunotherapies are under investigation in severe TBM, including steroid-refractory situations [94]. One target is TNF-α, a cytokine heavily involved in TB inflammation [93]. Thalidomide, a TNF-alpha inhibitor, has been demonstrated to decrease brain inflammation in pediatric TBM in a small series; however, due to its toxicity (peripheral neuropathy), it is not widely used [95, 96]. Tuberculous meningitis, in desperate cases of severe paradoxical reaction or vasculitis, has also been treated with infliximab and adalimumab (anti-TNF monoclonal antibodies); case reports show some success in lowering inflammation with steroids combined with one of these agents [97, 98]. Anti-TNF therapy does, however, involve a risk of uncontrolled infection and is not routine. Immunosuppressants are another option: small case series have experimented with cyclophosphamide or azathioprine in TBM IRIS or refractory inflammation [99, 100]. There is extremely little evidence, and this treatment should be used only in a specialized facility. Finally, neuroprotective activity has been demonstrated in statins (with their anti-inflammatory and adjunctive host-directed effects) and melatonin (a free-radical scavenger) in experimental models and initial clinical trials, but additional information is required before they can be used routinely [101, 102].

Nutritional and supportive care: Tuberculous meningitis requires proper nutrition and rehabilitation. A significant portion of TBM patients, particularly children, are malnourished at baseline, which is related to poor outcomes [103]. Inpatient care and follow-up should include nutritional support. Long-term function is highly enhanced by neurological rehabilitation (physiotherapy to address motor deficits, and occupational and speech therapy to address mental and speech deficits, respectively) in patients as they regain normal functioning [104]. Involved cranial neuropathies (e.g., optic nerve) may need special treatment (special visual aids or hearing rehabilitation in cases of VIII nerve damage). Patients and families may also require psychological support, as the outcome of TBM can result in life-changing neurological impairments.

3.4 Treatment of drug-resistant TBM

The development of drug-resistant tuberculosis (DR-TB) is a serious problem in the management of TBM [105]. Multidrug-resistant TBM (resistant to at least INH and RIF) is, fortunately, rare, but when it does occur, it is associated with very high mortality, with reported fatality rates of 50–100% in some series [106]. Monoresistance to rifampicin or isoniazid can also have a negative impact [107]. Thus, culture and drug susceptibility outcomes should be obtained by any available means, and in cases where drug resistance is found (or there is high epidemiological suspicion thereof), the regimen should be changed immediately. No standard regimen exists for MDR-TBM; however, treatment typically includes at least 5–6 drugs, including second-line agents, administered over 12–18 months or longer [108]. A standard MDR-TBM treatment regimen may include: a fluoroquinolone (high-dose levofloxacin or moxifloxacin), an aminoglycoside (e.g., amikacin, which has some penetration into the CSF, or streptomycin, which can be used as an alternative), ethionamide or prothionamide, cycloserine, and linezolid, along with other first-line agents that may still be effective [109–111]. Anti-TB drugs have also proven effective in TBM: bedaquiline, an anti-MDR-TB bactericidal agent, crosses the blood–brain barrier and has been used in MDR-TBM [112]. Linezolid achieves high CSF levels and has good sterilizing activity; it is often included in MDR-TBM regimens despite long-term toxicity concerns (e.g., peripheral neuropathy, bone marrow suppression) [113, 114]. A recent Phase 2 trial (LASER-TBM) examined adding linezolid to high-dose RIF regimens. While it did not show a mortality benefit and highlighted linezolid’s side effects, linezolid remains a key drug for resistant TBM when the benefits outweigh the risks [115]. Meropenem with clavulanate has activity against TB and has been used in XDR-TB cases. Meropenem penetrates the meninges when inflamed. Although there is limited experience, it is an option for fluoroquinolone-resistant TBM when combined with other drugs [115]. Treatment of drug-resistant TBM should involve expert advice (e.g., TB specialists) and customized treatment based on susceptibility outcomes. Even more critical in DR-TBM is the use of adjunctive therapies (e.g., steroids, surgery) to allow time for second-line drugs to take effect. Sadly, XDR-TBM (extensively drug-resistant TBM) is frequently fatal despite the best efforts. Newer agents such as pretomanid or delamanid do not have much data in TBM but could be used on a compassionate basis in XDR cases. Directly observed therapy and intensive supportive care should be applied to all cases of DR-TBM [116, 117]. Reducing delays in diagnosis and applying molecular tests (such as Xpert to investigate rifampin resistance) may aid in initiating the correct therapy as early as possible, which is the single hope for a cure in MDR-TBM [118].

There have been several landmark clinical trials undertaken in the last two years (2022–2025):

ZeNiX (2022): BPaL regimen (bedaquiline, pretomanid, linezolid) optimized by modulating linezolid exposure. A 600-mg course of linezolid after 6 months had 84–91% cure rates, with lower neuropathy and myelosuppression [119].
TB-PRACTECAL (2022–2024): Demonstrated that a 6-month BPaLM regimen (BPaL plus moxifloxacin) achieved ~89% favorable outcomes, far superior to the ~52% success rate of the standard 9–20 month therapy [120]. This led the WHO (2022) to recommend BPaL/BPaLM as the preferred regimen for most MDR/RR–TB patients [121, 122].
endTB (2025): Assessed five combinations of all-oral medications (9 months) combining bedaquiline, delamanid, linezolid, and clofazimine. Three regimens showed 85–90% treatment success, noninferior to standard care. These offer alternative short-course treatment, enhancing flexibility for tailored treatment [123].
endTB-Q (2025): Focused on pre-XDR-TB (MDR-TB with fluoroquinolone resistance). A 69 month regimen of bedaquiline, delamanid, linezolid, and clofazimine (BDLC) was 87% successful, almost the same as the 24-month standard, with reduced adverse events [124].

Taken together, these trials determined that MDR-TB is now essentially treatable in 6–9 months with oral regimens, without injectables, and with a significant increase in adherence, tolerability, and cure rates [125].

3.5 Emerging and adjunctive therapies

In addition to antibiotic courses, a number of host-directed therapies (HDTs) and immunomodulatory approaches are under investigation to induce better bacterial clearance and reduce lung destruction.

Metformin and statins have demonstrated potential to promote better immune responses and decrease inflammatory processes related to TB [101, 102].
Immune enhancers are under investigation, using vitamin D supplementation and interferon-gamma therapy [126].
There is some preliminary evidence of therapeutic vaccines in the form of Mycobacterium vaccae (Vaccae™), RUTI, and MIP (Mycobacterium indicus pranii), which have been shown to provide benefits as adjuncts, such as greater sputum conversion and reduced relapse rates, in some MDR-TB cohorts [127].

3.5.1 Innovations in drug delivery and diagnostics

Long-acting injectables (e.g., bedaquiline nanoformulations) and inhaled nanoparticle systems are being preclinically tested to ensure sustained drug exposure and lung targeting [105].

New diagnostic technologies, such as Xpert MTB/XDR and whole-genome sequencing (WGS), can now be used to rapidly profile resistance and select individualized regimens.
Such tools facilitate the early introduction of optimized regimens, such as BPaL/BPaLM, and minimize delays and treatment failures.

MDR-TB treatment has taken a new turn with shorter, effective, and easier treatment regimens. Regimens like BPaL and BPaLM now achieve cure rates in the 90% range and are safer and easier to tolerate. The combination of host-directed treatment, novel drug delivery, and new diagnostics will further improve treatment outcomes [128]. To ensure the consolidation of these gains and the success of global TB elimination activities, sustained drug-resistance surveillance, equitable access to new drugs, and further clinical research are critical.

4. Pediatric versus adult differences in TBM

Although the pathophysiology of TB meningitis in children and adults is similar, the epidemiology, presentation, and outcomes vary significantly between children and adults [129]. In the past, however, children and adults have been approached with equal methods, and studies tend to use all ages together, which may not be able to capture age-related differences [130].

Epidemiology and risk: Young children (especially below the age of 5 years) have the greatest risk of TBM in relation to primary TB infection due to an incomplete immune response [131]. TBM among children is usually secondary to an acute primary infection that spreads (typically within 3–6 months of the incident pulmonary TB). By contrast, adult TBM is more commonly an example of reactivation of latent TB or progression of untreated pulmonary TB; it occurs more frequently in adults with some susceptibility factors, especially HIV/AIDS, which significantly increases the risk of TBM, but also diabetes, alcoholism, or old age (immunosenescence) [132]. The highest incidence of TBM occurs in the early childhood stage, followed by older adults (e.g., >60 years) [132].

Clinical presentation: A prodrome of fever and headache is common in both children and adults, although the former may have a more nonspecific initial presentation (irritability, poor feeding, vomiting) that can be confused with other common viral infections [18, 21, 133]. Young children are unable to complain of headache or stiffness in the neck, and these symptoms usually become noticeable later in the disease process. Accordingly, children are more often found at an advanced stage with lethargy or coma (Stage III) [134]. Among children, vomiting and seizures are especially frequent early symptoms [135]. However, adults can also present with classic signs of meningitis (severe headache, photophobia, neck stiffness) and are more likely to have confusion or focal motor activity at presentation [136]. Palsies of the cranial nerves (e.g., sixth nerve leading to diplopia) are present in both but are commonly observed in older children and in adults who can cooperate during cranial nerve examination. Another distinction: a history of known TB contact or TB (e.g., pulmonary TB symptoms, abnormal chest X-ray) is often elicited in children, as in pediatric TBM the disease often occurs after recent household exposure [137]. Adults may have a history of TB more often or have other comorbidities.

Diagnostic issues: TBM is hard to diagnose in young children. Smear and even Xpert tests are less sensitive in children with lower bacillary load in CSF (paucibacillary disease) [138–140]. In addition, it may be hard to obtain sufficient volumes of CSF in infants and toddlers, which may limit diagnostic tests. In infants, clinical evidence of irritation of the meninges (stiffness of the neck, Kernig sign) is less reliable. Consequently, clinicians are frequently forced to use indirect evidence (e.g., positive TB skin test or IGRA, suggestive chest X-ray, history of exposure) along with CSF results in order to diagnose TBM in pediatrics [141]. In adults, diagnostic lumbar puncture is usually easier, and larger volumes can be tested, with Xpert Ultra showing high yield. However, in adults, the differential diagnosis is broader (e.g., chronic meningitis due to fungi, carcinomatous meningitis, etc.), and it may be difficult to rule out other etiologies [142]. Particularly, HIV-infected adults can become infected with multiple pathogens (TBM can be detected alongside or mimicked by cryptococcal meningitis, etc.). Therefore, diagnostic algorithms should prioritize identifying co-infections in adults, while in children the primary consideration should be initiating TB treatment without microbiologic evidence, provided the clinical picture fits.

Neuroimaging: The typical MRI findings (basal enhancement, hydrocephalus, infarcts) are present in both groups, but hydrocephalus is particularly noticeable in children (70–80% of TBM patients in children develop hydrocephalus, frequently necessitating shunting) [145, 146]. In adults, the incidence of significant hydrocephalus is less (~20–50%) [143]. The distribution of tuberculomas on radiography also may vary: in children, miliary brain tubercles may occur in response to miliary TB, and in adults (particularly immunocompetent), fewer tuberculomas may be evident at presentation but may develop as a paradoxical response to treatment [144, 145].

Therapeutic differences: There are no differences in the necessary drugs; only the doses vary. Children more actively break down TB drugs and often have to take in more mg/kg. As an illustration, WHO recommends pediatric doses of rifampicin at approximately 20–30 mg/kg (as opposed to 10 mg/kg in adults) and isoniazid at approximately 10–20 mg/kg (as opposed to 5 mg/kg in adults) [146]. These weight-adjusted higher doses take into account that many drugs vary in their pharmacokinetics (children have a greater volume of distribution and quicker clearance) [147, 148]. TBM cases in children also consistently undergo steroid therapy, as in adults, but the exact tapering may be modified according to weight [149]. Managing raised ICP is a greater focus in children (with earlier use of shunts), whereas in adults, careful monitoring for drug hepatotoxicity or interactions (e.g., with antiretrovirals) is a bigger issue [150]. Early physical therapy will help both children and adults, although children will also require developmental tests and support because of the effects on the developing brain [151].

Outcomes: Children, paradoxically, are equally or even more likely to survive TBM, but with more neurological disability. Meta-analyses show that the all-cause mortality of pediatric TBM is approximately 19% (range 12–58%), comparable to adults at approximately 23% (range 2–36%) [152]. Nevertheless, children have higher rates of serious neurologic sequelae among survivors (more than half of child survivors have long-term neurological impairments, such as cognitive impairment, motor deficits, and vision/hearing loss, etc.) [153]. This may be due to the fact that the infection and inflammation destroy the developing brain at key stages, resulting in permanent developmental problems [154]. Adults are also capable of having sequelae (around a third of adult survivors have cognitive or functional impairments); however, adults may have subtle deficits (e.g., memory or executive function) that do not get reported [155, 156]. Extremes in age do not fare as well in both categories: children under the age of 2 years and adults older than 60 have the highest percentage of poor outcomes [157].

In summary, pediatric TBM tends to be an acute, fulminant disease occurring soon after infection, with a high risk of hydrocephalus and long-term developmental consequences. Adult TBM often involves reactivation, intersects with other health issues like HIV, and can present more heterogeneously. These differences highlight the need for age-tailored approaches – for instance, aggressive neurosurgical management of hydrocephalus in children versus vigilant management of comorbid conditions in adults. Importantly, both groups require early therapy and supportive care; delays in diagnosis are devastating regardless of age.

5. Evolving guidelines and best practices

Guidelines and best practices on TBM have undergone immense changes in recent years, in line with new research findings. Some international professional organizations have tried to develop standard care for TBM in adults and children, and organizations such as the WHO has revised TB treatment guidelines to include TBM-specific guidelines. The evolution of TBM management can be pointed out as follows:

Diagnostic strategies: Rapid molecular diagnostics are now at the center stage. WHO guidance (2017/2019) endorsed GeneXpert as the initial test for suspected TBM, and with the improved Xpert Ultra, this is reinforced in current practice [139]. Clinicians are advised to obtain large-volume CSF and use NAATs early, rather than relying on culture, which is too slow for initial decision-making [158]. There is also an increasing focus on the importance of early neuroimaging; any patient with unexplained subacute meningitis should now receive an MRI (or CT where MRI is not available) to seek clues of TBM or other diagnoses [158, 159]. Emerging imaging methods (such as MRI perfusion or vessel wall imaging) are under investigation in order to further identify vascular alterations due to TB but are not included in current guidelines [32, 160]. It is suggested that the incorporation of clinical scoring systems (e.g., Marais diagnostic score of TBM) with contemporary tests would enhance diagnostic confidence in resource-limited settings [161].
Therapeutic regimens: Current recommendations (e.g., the 2022 WHO consolidated TB guidelines) still support a long course of TBM, usually 12 months of treatment for drug-sensitive cases [66]. Nevertheless, shorter regimens are actively being studied. Trials such as SHINE (in children with minimal TB) and TBM-specific trials (such as studies of the INSTRuCT consortium) are investigating whether 6- or 9-month regimens may be adequate in some groups of TBM [162, 163]. Until then, the advice remains conservative on TBM duration due to the stakes involved in relapse in the CNS. Motion on the intensive phase side: some authorities recommend the regular use of a fluoroquinolone (moxifloxacin) during the original TBM regimen to improve bactericidal effectiveness in the brain [164]. The current trial INTENSE-TBM is comparing conventional therapy with more intensive therapy using high-dose rifampicin, moxifloxacin, and linezolid (with adjunctive aspirin) [74]. Findings from such research might guide future practices; for instance, if high-dose rifampicin proves to have a substantial positive effect, guidelines could change their suggested dose for TBM. Likewise, in severe cases, linezolid or other new drugs that are shown to be useful may be employed [165]. Guidelines on drug-resistant TBM are also evolving: a recent consensus emphasized the use of at least five effective drugs in MDR-TBM, including newer drugs and longer durations (12–18 months), although the quality of evidence was low [166]. Individualized MDR-TBM regimens are encouraged, and clinicians are advised to consult experts or WHO DR-TB guidelines.
Adjunctive therapy: There is consensus on corticosteroids in the management of TBM. In TBM specifically, the 2018 WHO TB guidelines state that an initial adjunctive corticosteroid (dexamethasone or prednisolone), tapered over 6–8 weeks, should be used [167]. This has become the standard of care all over the world. In the case of aspirin, this is not formally recommended by WHO guidelines, although some national guidelines (such as that of Vietnam) have introduced low-dose aspirin as an adjunct in TBM in light of the evidence of stroke reduction [91]. It is only natural that once the current trials prove beneficial, aspirin can be included in the standard recommendations on TBM (at least in adults). Close, supportive care and monitoring are now regarded as a priority in best practice: guidelines stress the importance of serial clinical and radiologic evaluations during treatment, addressing complications such as hyponatremia (frequent in TBM because of SIADH or cerebral salt wasting) and the importance of rehabilitation services early [168].
HIV co-management: Any section in best practice guidelines (e.g., ATS/CDC/IDSA TB guidelines) covering the management of TBM in the context of HIV. It is agreed that TB treatment should be initiated, and after a period of 2–8 weeks, ART should be initiated with close observation of IRIS [169]. In the case of TBM-IRIS, temporary steroid doses can be increased. These guidelines also advise that co-trimoxazole prophylaxis be regularly administered to HIV/TBM patients to prevent other infections during immune reconstitution.
Surgery and critical care: The team involved in modern TBM management usually includes a neurosurgeon and an intensivist. Any patient with TBM who has hydrocephalus or a reduced level of consciousness is recommended to undergo early neurosurgical evaluation. In the case of a VP shunt, it is better to place it before the damage becomes irreversible [170]. External ventricular drains are increasingly used to control elevated ICP in ICU settings, and ICP is monitored (although this is resource-dependent) in severe cases, similar to cases of traumatic brain injury. These measures are included in the overall care guidelines of specialized centers [171].
Follow-up and outcome measurement: Understanding the long-term effect, today the guidelines emphasize post-treatment follow-up, such as neurodevelopmental assessment in children and neurocognitive testing in adults, for as long as possible [172]. The standardization of outcome definitions in TBM trials (death, disability scales, cognitive scores) is being pursued to improve comparisons between interventions [173]. This result-oriented focus ensures that, in addition to survival, the quality of survival is also considered during the course of therapy.

Lastly, one of the most important elements of best practice is early suspicion and treatment, so most national TB programs are educating health workers to consider TBM whenever meningitis is not responding promptly to standard antibiotics, particularly in regions with TB or in children. Even before a confirmed diagnosis can be made, rapid referral and empiric treatment can save lives. The consequence of late diagnosis and treatment of TB meningitis, as one review briefly stated, is immediate death or significant permanent neurological disability [174]. This is why changing practice is not only about strengthening the healthcare system (e.g., ensuring access to GeneXpert and MRI, enhanced referral pathways) but also about new drugs. As research continues, with many clinical trials ongoing, there is hope that the next generation of evidence will be used to guide shorter and more effective regimens and adjuncts that can make a significant contribution to the prognosis of TBM in adults and children [175].

6. Conclusions and future directions

For both adults and children, rapid CSF molecular testing (Xpert Ultra), immediate empiric HRZE-based therapy, and adjunctive corticosteroids remain the pillars of care. Pediatric options now include a 6-month intensive HRZE-ethionamide regimen in selected drug-susceptible cases. Research priorities include definitive trials of intensified bactericidal regimens (high-dose rifampicin, linezolid/fluoroquinolones), optimal use of bedaquiline in MDR-TBM, and host-directed strategies (e.g., aspirin) to reduce vasculitic strokes and long-term disability.

References

1. WHO. Global Tuberculosis Report 2024. Geneva: World Health Organization; 2024. Available from: https://www.who.int/teams/global-programme-on-tuberculosis-and-lung-health/tb-reports/global-tuberculosis-report-2024 [Accessed: 2025-September-01]
2. Chen Z, Wang T, du J, et al. Decoding the WHO global tuberculosis report 2024: A critical analysis of global and chinese key data. Zoonoses. 2025;5(1). DOI: 10.15212/ZOONOSES-2024-0061
3. Dodd PJ, Osman M, Cresswell FV, Stadelman AM, Lan NH, Thuong NTT, et al. The global burden of tuberculous meningitis in adults: A modelling study. PLOS Global Public Health. 2021;1(12):e0000069. DOI: 10.1371/journal.pgph.0000069
4. Wen L, Li M, Xu T, Yu X, Wang L, Li K. Clinical features, outcomes and prognostic factors of tuberculous meningitis in adults worldwide: Systematic review and meta-analysis. Journal of Neurology. 2019;266:3009–3021. DOI: 10.1007/s00415-019-09523-6
5. Huang M, Ma Y, Ji X, Jiang H, Liu F, Chu N, Li Q, et al. A study of risk factors for tuberculous meningitis among patients with tuberculosis in China: An analysis of data between 2012 and 2019. Frontiers in Public Health. 2023;10:1040071
6. Urmenyi Lucas G, Vinhaes Caian L, Klauss V-S, Mariana A-P, Andrade Bruno B. Influence of HIV co-infection on clinical presentation and disease outcome in hospitalized adults with tuberculous meningitis in Brazil: A nationwide observational study. Frontiers in Public Health. 2025;13. DOI: 10.3389/fpubh.2025.1600104
7. Gutiérrez-González LH, Juárez E, Carranza C, Carreto-Binaghi LE, Alejandre A, Cabello-Gutiérrrez C, Gonzalez Y. Immunological aspects of diagnosis and management of childhood tuberculosis. Infection and Drug Resistance. 2021;14:929–946. DOI: 10.2147/IDR.S295798
8. Malik MA, Kamran A, Ahsan D, Amjad A, Moatter S, Noor A, Sohaib A, Shaukat M, Masood W, Hasanain M, Eljack MF. 2025. Advances in management and treatment of tubercular meningitis – A narrative review. Annals of Medicine and Surgery. 87(6):3673–3681. doi:10.1097/MS9.0000000000003348
9. Wilkinson R, Rohlwink U, Misra U, et al. Tuberculous meningitis. Nature Reviews Neurology. 2017;13:581–598
10. Cresswell F, Davis A, Sharma K, Basu Roy R, Ganiem A, Kagimu E, et al. Recent developments in tuberculous meningitis pathogenesis and diagnostics. Wellcome Open Research. 2021;4:164
11. Patrascu RE, Cucu AI, Costea CF, Cosman M, Blaj LA, Hristea A. Brain tuberculosis: An Odyssey through time to understand this pathology. Pathogens. 2023;12(8):1026. DOI: 10.3390/pathogens12081026
12. Manyelo CM, Solomons RS, Walzl G, Chegou NN, Kraft CS. Tuberculous meningitis: Pathogenesis, immune responses, diagnostic challenges, and the potential of biomarker-based approaches. Journal of Clinical Microbiology. 2021;59:10.1128/jcm.01771–20. DOI: 10.1128/jcm.01771-20
13. Xuelian LI, et al. Clinical characteristics of tuberculous meningitis combined with cranial nerve palsy. Clinical Neurology and Neurosurgery. 2019;184:105443
14. Barnacle JR, Davis AG, Wilkinson RJ. Recent advances in understanding the human host immune response in tuberculous meningitis. Frontiers in Immunology. 2024;14:1326651. DOI: 10.3389/fimmu.2023.1326651
15. Thwaites G, Fisher M, Hemingway C, Scott G, Solomon T, Innes J. British infection society. British Infection Society guidelines for the diagnosis and treatment of tuberculosis of the central nervous system in adults and children. Journal of Infection. 2009;59(3):167–187. DOI: 10.1016/j.jinf.2009.06.011
16. Sher K, Firdaus F, Abbasi A, Bullo N, Kumar S.Stages of tuberculous meningitis: A clinicoradiologic analysis. Journal of the College of Physicians and Surgeons--Pakistan: JCPSP. 2013;23(6):405–408
17. Tristram D, Tobin EH Tuberculosis in Children. In: StatPearls. Treasure Island (FL): StatPearls Publishing; 2025. Available from: https://www.ncbi.nlm.nih.gov/books/NBK610681/ [Accessed: 2024-November-22]
18. van Toorn R, Solomons R. Update on the diagnosis and management of tuberculous meningitis in children. Seminars in Pediatric Neurology. 2014;21:12–18. DOI: 10.1016/j.spen.2014.01.006
19. Slane VH, Unakal CG Tuberculous Meningitis. In: StatPearls. Treasure Island (FL): StatPearls Publishing; 2025. Available from: https://www.ncbi.nlm.nih.gov/books/NBK541015/ [Available from: 2024-September-02]
20. Saal C-L, Springer P, Seddon JA, van Toorn R, Esterhuizen TM, Solomons RS. Risk factors of poor developmental outcome in children with tuberculous meningitis. Child’s Nervous System. 2023;39(4):1029–1039. DOI: 10.1007/s00381-022-05791-2
21. Daniel BD, Selladurai E, Balaji S, Venkatesan A, Venkatesan M, Giridharan P, Shanmugam S, Natrajan S, Karunaianantham R, Kandasamy D, Subramani R, Muthuramalingam K, Pramila SK, Hissar S, Dooley KE, Thakur KT. Clinical and diagnostic features of central nervous system tuberculosis in Indian children - a descriptive study. Therapeutic Advances in Infectious Disease. 2024;11:20499361241274251. DOI: 10.1007/s00381-022-05791-2
22. Galimi R.Extrapulmonary tuberculosis: Tuberculous meningitis new developments. European Review for Medical and Pharmacological Sciences. 2011;15(4):365–386
23. Chen X, Chen F, Liang C, He G, Chen H, Wu Y, Chen Y, Shuai J, Yang Y, Dai C, Cao L, Wang X, Cai E, Wang J, Wu M, Zeng L, Zhu J, Hai D, Pan W, Pan S, Zhang C, Quan S, Su F. MRI advances in the imaging diagnosis of tuberculous meningitis: Opportunities and innovations. Frontiers in Microbiology. 2023;14:1308149. DOI: 10.3389/fmicb.2023.1308149
24. Adriana Caliman-Sturdza O, Cucu A. Hydrocephalus in Tuberculous Meningitis [Internet]. Frontiers in Hydrocephalus. IntechOpen. 2023. DOI: 10.5772/intechopen.110251
25. Schaller MA, Wicke F, Foerch C, Weidauer S.Central nervous system tuberculosis: Etiology, clinical manifestations and neuroradiological features. Clinical Neuroradiology. 2019;29(1):3–18
26. Dahal P, Parajuli S. Magnetic resonance imaging findings in central nervous system tuberculosis: A pictorial review. Heliyon. 2024; 10(8):e29779. DOI: 10.1016/j.heliyon.2024.e29779
27. Ma Q, Yi Y, Liu T, et al. MRI-based radiomics signature for identification of invisible basal cisterns changes in tuberculous meningitis: A preliminary multicenter study. European Radiology. 2022;32:8659–8669
28. Mushtaq R, Arooj S, Kalsoom U, Raja R.Role of contrast enhanced FLAIR MRI as a new tool in diagnosing tuberculous meningitis. PAFMJ [Internet]. 2020;70(5):1310–1314
29. Bernaerts A, Vanhoenacker FM, Parizel PM, J.w.m. VG, Van Altena R, Laridon A, et al. Tuberculosis of the central nervous system: Overview of neuroradiological findings. European Radiology. 2003;13(8):1876–1890. DOI: 10.1007/s00330-002-1608-7
30. Khatri GD, Krishnan V, Antil N, Saigal G. Magnetic resonance imaging spectrum of intracranial tubercular lesions: One disease, many faces. Polish Journal of Radiology. 2018;83:e524–e535. DOI: 10.5114/pjr.2018.81408
31. Soni N, Kumar S, Shimle A, Ora M, Bathla G, Mishra P. Cerebrovascular complications in tuberculous meningitis—A magnetic resonance imaging study in 90 patients from a tertiary care hospital. The Neuroradiology Journal. 2020;33(1):3–16. DOI: 10.1177/1971400919881188
32. Trivedi R, Saksena S, Gupta RK. Magnetic resonance imaging in central nervous system tuberculosis. Indian Journal of Radiology and Imaging. 2009;19(4):256–265. DOI: 10.4103/0971-3026.57205
33. Ibrahim IG, Osman AA, Shikhow MG, Celik C, Mutlu E, Hassan Qalaf MS, Tahtabaşı M, Garad Mohamed Y. Magnetic resonance imaging findings of intracranial tuberculoma patients in a tertiary hospital in Mogadishu, Somalia: A retrospective study. Annals of Medicine and Surgery (2012). 2022;78:103812. DOI: 10.1016/j.amsu.2022.103812
34. Baloji A, Ghasi RG. MRI in intracranial tuberculosis: Have we seen it all? Clin. Imag. 2020;68:263–277. DOI: 10.1016/j.clinimag.2020.08.028
35. Dian S, Hermawan R, van Laarhoven A, Immaculata S, Achmad TH, Ruslami R, Anwary F, Soetikno RD, Ganiem AR, van Crevel R. Brain MRI findings in relation to clinical characteristics and outcome of tuberculous meningitis. PLoS One. 2020; 15(11):e0241974. DOI: 10.1371/journal.pone.0241974
36. Saxena D, Pinto DS, Tandon AS, Hoisala R. MRI findings in tubercular radiculomyelitis. eNeurologicalSci. 2021;22:100316. DOI: 10.1016/j.ensci.2021.100316
37. Rodriguez-Takeuchi SY, Renjifo ME, José Medina FJ. Extrapulmonary Tuberculosis: Pathophysiology and Imaging Findings. RadioGraphics. 2019;39(7):2023–2037. DOI: 10.1148/rg.2019190109
38. Imron A, Hermanto Y, Rizal A, Yunivita V, Ruslami R. Cerebrospinal fluid analysis in tuberculous meningitis: A literature review. Surgical Neurology International. 2025;16:246. DOI: 10.25259/SNI_1131_2024
39. Thomas J, Mishra U, Tavisetty C, Mandloi D. The spectrum of cerebrospinal fluid findings in tuberculous meningitis and their relation to severity, radiological features, and outcome. Journal of Neurosciences in Rural Practice. 2023;14:717–722
40. Ssebambulidde K, Gakuru J, Ellis J, Cresswell FV, Bahr NC. Improving Technology to Diagnose Tuberculous Meningitis: Are We There Yet? Frontiers in Neurology. 2022;13:892224. DOI: 10.3389/fneur.2022.892224
41. Jain SK, Tobin DM, Tucker EW, et al. Tuberculous meningitis: A roadmap for advancing basic and translational research. Nature Immunology. 2018;19:521–525
42. Ramachandra V, Brammacharry U, Muralidhar A, Muthukumar A, Mani R, Muthaiah M, Soundappan G, Frederick A. Assess the diagnostic accuracy of genexpert to detect mycobacterium tuberculosis and rifampicin-resistant tuberculosis among presumptive tuberculosis and presumptive drug resistant tuberculosis patients. Microbiology Research. 2023;15:91–108. DOI: 10.3390/microbiolres15010006
43. Lin F. Tuberculous meningitis diagnosis and treatment: Classic approaches and high-throughput pathways. Frontiers in Immunology. 2025;15:1543009
44. Cao W-F, Leng E-L, Liu S-M, Zhou Y-L, Luo C-Q, Xiang Z-B, Cai W, Rao W, Hu F, Zhang P, et al. Recent advances in microbiological and molecular biological detection techniques of tuberculous meningitis. Frontiers in Microbiology. 2023;14:1202752
45. Bahr NC, Nuwagira E, Evans EE, Cresswell FV, Bystrom PV, Byamukama A, Bridge SC, Bangdiwala AS, Meya DB, Denkinger CM, Muzoora C, Boulware DR. ASTRO-CM trial team. Diagnostic accuracy of xpert MTB/RIF ultra for tuberculous meningitis in HIV-infected adults: A prospective cohort study. The Lancet Infectious Diseases. 2018;18(1):68–75. DOI: 10.1016/S1473-3099(17)30474-7
46. Donovan J, et al. Xpert MTB/RIF ultra versus Xpert MTB/RIF for the diagnosis of tuberculous meningitis: A prospective, randomised, diagnostic accuracy study. The Lancet Infectious Diseases. 2020;20(3):299–307. DOI: 10.1016/s1473-3099(19)30649-8
47. Dorman SE, et al. Xpert MTB/RIF ultra for detection of Mycobacterium tuberculosis and rifampicin resistance: A prospective multicentre diagnostic accuracy study. The Lancet Infectious Diseases. 2018;18(1):76–84. DOI: 10.1016/s1473-3099(17)30691-6
48. World Health Organization. WHO Consolidated Guidelines on Tuberculosis. Module 3: Diagnosis - Rapid Diagnostics for Tuberculosis Detection, 2021 Update. Licence: CC BY-NC-SA 3.0 IGO, World Health Organization, Geneva, 2021. Available from: https://www.who.int/publications/i/item/9789240029415 [Accessed: 2025-September]
49. Yu G, Shen Y, Zhong F, Ye B, Yang J, Chen G. Diagnostic accuracy of the loop-mediated isothermal amplification assay for extrapulmonary tuberculosis: A meta-analysis. PLoS One. 2018; 13(6):e0199290. DOI: 10.1371/journal.pone.0199290
50. Ashkin A, Lindner D. The Challenges of Diagnosing Tuberculous Meningitis and Importance of Early Intervention. Journal of Community Hospital Internal Medicine Perspectives. 2023;13(4):84–87. DOI: 10.55729/2000-9666.1196
51. Garg RK. Tuberculous meningitis. Acta Neurologica Scandinavica. 2010;122:75–90. DOI: 10.1111/j.1600-0404.2009.01316.x
52. Song J, Kim SH, Jung YR, Choe J, Kang CI, Min JH. 10-year retrospective review of the etiologies for meningitis with elevated adenosine deaminase in cerebrospinal fluid: Etiologies other than TB. Frontiers in Cellular and Infection Microbiology. 2022;12:858724. DOI: 10.3389/fcimb.2022.858724
53. Lan Y, Chen W, Yan Q, Liu W. Interferon-γ release assays for tuberculous meningitis diagnosis: A meta-analysis. Archives of Medical Science. 2021;17(5):1241–1250. DOI: 10.5114/aoms.2019.86994
54. Caliman-Sturdza OA, Mihalache D, Luca CM. Performance of an interferon-gamma release assay in the diagnosis of tuberculous meningitis in children. Revista Romana De Medicina De Labor. 2015;23:199–212. DOI: 10.1515/rrlm-2015-0016
55. Yin X, Ye -Q-Q, Wu K-F, Zeng J-Y, Li N-X, Mo -J-J, Huang P-Y, Xie L-M, Xie L-Y, Guo X-G. Diagnostic value of Lipoarabinomannan antigen for detecting Mycobacterium tuberculosis in adults and children with or without HIV infection. Journal of Clinical Laboratory Analysis. 2022; 36(2):e24238. DOI: 10.1002/jcla.24238
56. Songkhla MN, Tantipong H, Tongsai S, Angkasekwinai N. Lateral flow urine lipoarabinomannan assay for diagnosis of active tuberculosis in adults with human immunodeficiency virus infection: A prospective cohort study. Open Forum Infectious Diseases. 2019; 6(4):ofz132. DOI: 10.1093/ofid/ofz132
57. Yan L, Sun W, Lu Z, Fan L. Metagenomic Next-Generation Sequencing (mNGS) in cerebrospinal fluid for rapid diagnosis of Tuberculosis meningitis in HIV-negative population. International Journal of Infectious Diseases. 2020;96:270–275. DOI: 10.1016/j.ijid.2020.04.048
58. Chen Y, Tang H, Zheng J, Yang Q, Han DO. Transforming tuberculosis diagnosis with clinical metagenomics: Progress and roadblocks. Journal of Clinical Microbiology. 2025;19:e00537–25. DOI: 10.1128/jcm.00537-25
59. Huang M, Ding Z, Li W, Chen W, Du Y, Jia H, Sun Q, Du B, Wei R, Xing A, Li Q, Chu N, Pan L. Identification of protein biomarkers in host cerebrospinal fluid for differential diagnosis of tuberculous meningitis and other meningitis. Frontiers in Neurology. 2022;13:886040. DOI: 10.3389/fneur.2022.886040
60. Gigase FAJ, Smith E, Collins B, Moore K, Snijders GJLJ, Katz D, Bergink V, Perez-Rodriquez MM, De Witte LD. The association between inflammatory markers in blood and cerebrospinal fluid: A systematic review and meta-analysis. Molecular Psychiatry. 2023;28(4):1502–1515. DOI: 10.1038/s41380-023-01976-6
61. Yao X-P, Hong J-C, Jiang Z-J, Pan -Y-Y, Liu X-F, Wang J-M, Fan R-J, Yang B-H, Zhang W-Q, Fan Q-C, L-x L, B-w L, Zhao M. Systemic and cerebrospinal fluid biomarkers for tuberculous meningitis identification and treatment monitoring. Microbiology Spectrum. 2024; 12(1):e0224623. DOI: 10.1128/spectrum.02246-23
62. Tomalka J, Sharma A, Smith AGC, Avaliani T, Gujabidze M, Bakuradze T, Sabanadze S, Jones DP, Avaliani Z, Kipiani M, Kempker RR, Collins JM. Combined cerebrospinal fluid metabolomic and cytokine profiling in tuberculosis meningitis reveals robust and prolonged changes in immunometabolic networks. Tuberculosis (Edinburgh). 2024;144:102462. DOI: 10.1016/j.tube.2023.102462
63. Lu W, Li Y, Deng J, Su Y, Fan H, Huang K. Advancements in the identification and utilization of cerebrospinal fluid immunological biomarkers for the diagnosis of tuberculous meningitis. Microbial Pathogenesis. 2025;206:107826. DOI: 10.1016/j.micpath.2025.107826
64. Bharucha T, Gangadharan B, Kumar A, de Lamballerie X, Newton PN, Winterberg M, Dubot-Pérès A, Zitzmann N. Mass spectrometry-based proteomic techniques to identify cerebrospinal fluid biomarkers for diagnosing suspected central nervous system infections. A systematic review. Journal of Infection. 2019;79(5):407–418. DOI: 10.1016/j.jinf.2019.08.005
65. Ahlawat S, Chaudhary R, Dangi M, Bala K, Singh M, Chhillar AK. Advances in tuberculous meningitis diagnosis. Expert Review of Molecular Diagnostics. 2020;20:1229–1241. DOI: 10.1080/14737159.2020.1858805
66. Foppiano Palacios C, Saleeb PG. Challenges in the diagnosis of tuberculous meningitis. Journal of Clinical Tuberculosis and Other Mycobacterial Diseases. 2020;20:100164. DOI: 10.1016/j.jctube.2020.100164
67. Janssen S, Murphy M, Upton C, Allwood B, Diacon AH. Tuberculosis: An Update for the Clinician. Respirology. 2025;30:196–205. DOI: 10.1111/resp.14887
68. Thwaites GE, Lan NTN, Dung NH, et al. Effect of antituberculosis drug resistance on response to treatment and outcome in adults with tuberculous meningitis. The Journal of Infectious Diseases. 2005;192(1):79–88. DOI: 10.1086/430616
69. World Health Organization. Key Updates to the Treatment of Drug-Resistant Tuberculosis: Rapid Communication. Geneva: World Health Organization; 2024. https://iris.who.int/handle/10665/378472 [Accessed: 2025-September-01]
70. Cresswell FV, Te Brake L, Atherton R, Ruslami R, Dooley KE, Aarnoutse R, Van Crevel R. Intensified antibiotic treatment of tuberculosis meningitis. Expert Review of Clinical Pharmacology. 2019;12(3):267–288. DOI: 10.1080/17512433.2019.1552831
71. Heemskerk AD, Nguyen MTH, Dang HTM, et al. Clinical outcomes of patients with drug-resistant tuberculous meningitis treated with an intensified antituberculosis regimen. Clinical Infectious Diseases. 2017;65(1):20–28. DOI: 10.1093/cid/cix230
72. Lienhardt C, Dooley K, Nahid P, et al. Target regimen profiles for tuberculosis treatment. Bulletin of the World Health Organization 2024;102:600–607
73. Dartois VA, Rubin EJ. Anti-tuberculosis treatment strategies and drug development: Challenges and priorities. Nature Reviews Microbiology. 2022;20(11):685–701
74. Gillespie SH, Crook AM, McHugh TD, et al. Four-month moxifloxacin-based regimens for drug-sensitive tuberculosis. New England Journal of Medicine. 2014;371(17):1577–1587. DOI: 10.1056/NEJMoa1407426
75. Wasserman S, Davis A, Wilkinson RJ, Meintjes G. Key considerations in the pharmacotherapy of tuberculous meningitis. Expert Opinion on Pharmacotherapy. 2019;20(15):1791–1795. DOI: 10.1080/14656566.2019.1638912
76. Maitre T, Bonnet M, Calmy A, Raberahona M, Rakotoarivelo RA, Rakotosamimanana N, Ambrosioni J, Miró JM, Debeaudrap P, Muzoora C, Davis A, Meintjes G, Wasserman S, Wilkinson R, Eholié S, Nogbou FE, Calvo-Cortes M-C, Chazallon C, Machault V, Anglaret X, Bonnet F. Intensified tuberculosis treatment to reduce the mortality of HIV-infected and uninfected patients with tuberculosis meningitis (INTENSE-TBM): Study protocol for a phase III randomized controlled trial. Trials. 2022;23(1):928. DOI: 10.1186/s13063-022-06772-1
77. Navaneethapandian P, Chandrasekaran P. Treatment of tuberculosis and the drug interactions associated with HIV-TB co-infection treatment. Frontiers in Tropical Diseases. 2022;3:2022. DOI: 10.3389/fitd.2022.834013
78. Le X, Shen Y. Advances in antiretroviral therapy for patients with human immunodeficiency virus-associated tuberculosis. Viruses. 2024;16(4):494. DOI: 10.3390/v16040494
79. Quinn CM, Poplin V, Kasibante J, Yuquimpo K, Gakuru J, Cresswell FV, NC B. Tuberculosis IRIS: Pathogenesis, presentation, and management across the spectrum of disease. Life (Basel). 2020;10(11):262. DOI: 10.3390/life10110262
80. Davis AG, Donovan J, Bremer M, Van Toorn R, Schoeman J, Dadabhoy A, Lai RPJ, Cresswell FV, Boulware DR, Wilkinson RJ, Thuong NTT, Thwaites GE, Bahr NC. Tuberculous meningitis international research consortium. Host directed therapies for tuberculous meningitis. Wellcome Open Research. 2021;5:292. DOI: 10.12688/wellcomeopenres.16474.2
81. Schutz C, Davis AG, Sossen B, Lai RP-J, Ntsekhe M, Harley YX, Wilkinson RJ. Corticosteroids as an adjunct to tuberculosis therapy. Expert Review of Respiratory Medicine. 2018;12(10):881–891. DOI: 10.1080/17476348.2018.1515628
82. Li R, Yin R, Li Y, Wei Y, Zhao B, Ge C. Advances in the treatment and clinical management strategies of tuberculous meningitis. International Journal of General Medicine. 2025;18:3267–3276. DOI: 10.2147/IJGM.S516998
83. Diallo A, BD D, OH D, Carlos-Bolumbu M, Camara M, Sidikiba S. Corticosteroids for reducing tuberculosis mortality in persons living with HIV: A systematic review and meta-analysis using reconstructed individual patient data. BMJ Global Health. 2025; 10(8):e017923. DOI: 10.1136/bmjgh-2024-017923
84. World Health Organization. WHO Consolidated Guidelines on Tuberculosis. Module 4: Treatment-drug-resistant Tuberculosis Treatment, 2022 Update. Geneva, Switzerland: World Health Organization; 2022
85. Prasad K, Singh MB, Ryan H. Corticosteroids for managing tuberculous meningitis. The Cochrane Database of Systematic Reviews. 2016; 4(4):CD002244. DOI: 10.1002/14651858.CD002244.pub4
86. Donovan J, Bang ND, Imran D, et al. Adjunctive dexamethasone for tuberculous meningitis in HIV-positive adults. New England Journal of Medicine. 2023;389:1357–1367
87. Thwaites GE, DB N, HD N, et al. Dexamethasone for the treatment of tuberculous meningitis in adolescents and adults. New England Journal of Medicine. 2004;351:1741–1751
88. Amin A, Vartanian A, Yegiazaryan A, Al-Kassir AL, Venketaraman V. Review of the effectiveness of various adjuvant therapies in treating Mycobacterium tuberculosis. Infectious Disease Reports. 2021;13(3):821–834. DOI: 10.3390/idr13030074
89. Murthy J. Management of intracranial pressure in tuberculous meningitis. Neurocritical Care. 2005;2(306-12. 10.1385/NCC:2:3):306. DOI: 10.1385/NCC:2:3:
90. Dharmana SN, Singla N, Sharma K, Modi M, Goyal M. Prevalence of seizures in patients with tuberculous meningitis (TBM) and their clinical outcomes. Cureus. 2025; 17(1):e77210. DOI: 10.7759/cureus.77210
91. Bhatia R, Shree R, Modi M, Anand A, Garg A, Haldar P, Padma Srivastava MV, Singla N, Goyal M, Supriya S, Sharma K, Wig N, Singh MB, Fatima S, Longkumer I, Bindal T, Srivastava A, Vishnu VY, Biswas A, Sinha S, Vikram NK, Vishnubhatla S, Sharma N, Singh P, Medhi B, Ahuja C. A randomised trial to assess the efficacy of add on therapy with aspirin or clopidogrel to the standard medical therapy alone in patients with tubercular meningitis: ACT TBM. The Lancet Regional Health - Southeast Asia. 2025;37:100604. DOI: 10.1016/j.lansea.2025.100604
92. Davis AG, Wilkinson RJ. Aspirin in tuberculous meningitis. Eclinicalmedicine. 2021;35:100871. DOI: 10.1016/j.eclinm.2021.100871
93. Rohilla R, Shafiq N, Malhotra S. Efficacy and safety of aspirin as an adjunctive therapy in tubercular meningitis: A systematic review and meta-analysis. EClinicalMedicine. 2021;34:100819. DOI: 10.1016/j.eclinm.2021.100819
94. Blackmore T, Manning L, Taylor W, Wallis R. Therapeutic use of infliximab in tuberculosis to control severe paradoxical reaction of the brain and lymph nodes. Clinical Infectious Diseases. 2008;47:e83–5. DOI: 10.1086/592695
95. Yuk J-M, Kim JK, Kim IS, Jo E-K. TNF in human tuberculosis: A double-edged sword. Immune Network. 2024;24(1):e4. DOI: 10.4110/in.2024.24.e4
96. van Toorn R, Zaharie S-D, Seddon JA, van der Kuip M, Marceline van Furth A, Schoeman JF, Solomons RS. The use of thalidomide to treat children with tuberculosis meningitis: A review. Tuberculosis (Edinburgh). 2021;130:102125. DOI: 10.1016/j.tube.2021.102125
97. Marais BJ, Cheong E, Fernando S, Daniel S, Watts MR, Berglund LJ, Barry SE, Kotsiou G, Headley AP, Stapledon RA. Use of infliximab to treat paradoxical tuberculous meningitis reactions. Open Forum Infectious Diseases. 2021; 8(1):ofaa604. DOI: 10.1093/ofid/ofaa604
98. Santin M, Escrich C, Majós C, et al. Tumor necrosis factor antagonists for paradoxical inflammatory reactions in the central nervous system tuberculosis Case report and review. Medicine. 2020;99. DOI: 10.1097/MD.0000000000022626
99. Ledingham D, El-wahsh S, Sebire D, Cappelen-Smith C, Hodgkinson SJ, McDougall AJ, Maley M, Cordato DJ. Adjuvant immunosuppression for paradoxical deterioration in tuberculous meningitis including one case responsive to cyclosporine. A tertiary referral hospital experience. Journal of the Neurological Sciences. 2019;404:58–62. DOI: 10.1016/j.jns.2019.07.002
100. Domínguez-Moreno R, García-Grimshaw M, Medina-Julio D, Cantú-Brito C, González-Duarte A. Paradoxical manifestations during tuberculous meningitis treatment among HIV-negative patients: A retrospective descriptive study and literature review. Neurological Sciences. 2022;43(4):2699–2708. DOI: 10.1007/s10072-021-05693-2
101. Dutta NK, Bruiners N, Zimmerman MD, Tan S, Dartois V, Gennaro ML, Karakousis PC. Adjunctive host-directed therapy with statins improves tuberculosis-related outcomes in mice. The Journal of Infectious Diseases. 2020;221(7):1079–1087. DOI: 10.1093/infdis/jiz517
102. Solima S, Bongani M, Mumin O, Mafu Trevor S, Wilkinson Robert J, Friedrich T, Reto G. Immunomodulatory effects of atorvastatin on peripheral blood mononuclear cells infected with Mycobacterium tuberculosis. Frontiers in Immunology. 2025;16:2025. DOI: 10.3389/fimmu.2025.1597534
103. Jaganath D, Mupere E. Childhood tuberculosis and malnutrition. The Journal of Infectious Diseases. 2012;206(12):1809–1815. DOI: 10.1093/infdis/jis608
104. Guo C, Liu K-W, Tong J, Gao M-Q. Prevalence and prognostic significance of malnutrition risk in patients with tuberculous meningitis. Frontiers in Public Health. 2025;12:1391821. DOI: 10.3389/fpubh.2024.1391821
105. Omoteso OA, Fadaka AO, Walker RB, Khamanga SM. Innovative strategies for combating multidrug-resistant tuberculosis: Advances in drug delivery systems and treatment. Microorganisms. 2025;13:722. DOI: 10.3390/microorganisms13040722
106. Song H-W, Tian J-H, Song H-P, Guo S-J, Lin Y-H, Pan J-S. Tracking multidrug resistant tuberculosis: A 30-year analysis of global, regional, and national trends. Frontiers in Public Health. 2024;12:1408316
107. Gygli SM, Borrell S, Trauner A, Gagneux S. Antimicrobial Resistance in Mycobacterium tuberculosis: Mechanistic and Evolutionary Perspectives. FEMS Microbiology Reviews. 2017;41:354–373
108. Brode SK, Dwilow R, Kunimoto D, Menzies D, Khan FA. Chapter 8: Drug-resistant tuberculosis. Canadian Journal of Respiratory, Critical Care, and Sleep Medicine. 2022;6(sup1):109–128. DOI: 10.1080/24745332.2022.2039499
109. Espinosa-Pereiro J, Sánchez-Montalvá A, Aznar ML, Espiau M. MDR Tuberculosis Treatment. Medicina (Kaunas). 2022;58(2):188. DOI: 10.3390/medicina58020188
110. Jang JG, Chung JH. Diagnosis and treatment of multidrug-resistant tuberculosis. Yeungnam University Journal of Medicine. 2020;37(4):277–285. DOI: 10.12701/yujm.2020.00626
111. Maranchick Nicole F, Alshaer Mohammad H, Smith Alison GC, Avaliani T, Gujabidze M, Bakuradze T, Sabanadze S, Avaliani Z, Kipiani M, Peloquin Charles A, Kempker Russell R. Cerebrospinal fluid concentrations of fluoroquinolones and carbapenems in tuberculosis meningitis. Frontiers in Pharmacology. 2022;13. DOI: 10.3389/fphar.2022.1048653
112. Ignatius EH, Dooley KE. New drugs for the treatment of tuberculosis. Clinics in Chest Medicine. 2019;40(4):811–827. DOI: 10.1016/j.ccm.2019.08.001
113. Fei ZT, Huang W, Zhou DP, et al. Clinical efficacy of linezolid in the treatment of tuberculous meningitis: A retrospective analysis and literature review. BMC Infectious Diseases. 2025;25:467
114. Liu X, Tang D, Qi M, He J. Efficacy of linezolid in the treatment of tuberculous meningitis: A meta-analysis. Archives of Medical Science. 2024;20(3):1038–1042. DOI: 10.5114/aoms/189905
115. Davis AG, Wasserman S, Stek C, Maxebengula M, Jason Liang C, Stegmann S, Koekemoer S, Jackson A, Kadernani Y, Bremer M, Daroowala R, Aziz S, Goliath R, Lai Sai L, Sihoyiya T, Denti P, Lai RPJ, Crede T, Naude J, Szymanski P, Vallie Y, Banderker IA, Moosa MS, Raubenheimer P, Candy S, Offiah C, Wahl G, Vorster I, Maartens G, Black J, Meintjes G, Wilkinson RJ. A phase 2A trial of the safety and tolerability of increased dose rifampicin and adjunctive linezolid, with or without aspirin, for human immunodeficiency virus–associated tuberculous meningitis: The LASER-TBM trial. Clinical Infectious Diseases. 2023;76(8):1412–1422. DOI: 10.1093/cid/ciac932
116. Mudde SE, Upton AM, Lenaerts A, Bax HI, De Steenwinkel JEM. Delamanid or pretomanid? A Solomonic judgement! Journal of Antimicrobial Chemotherapy. 2022;77(4):880–902. DOI: 10.1093/jac/dkab505
117. Tucker EW, Pieterse L, Zimmerman MD, Udwadia ZF, Peloquin CA, Gler MT, Ganatra S, Tornheim JA, Chawla P, Caoili JC, Ritchie B, Jain SK, Dartois V, Dooley KE. Delamanid central nervous system pharmacokinetics in tuberculous meningitis in rabbits and humans. Antimicrobial Agents and Chemotherapy. 2019;63. DOI: 10.1128/AAC.00913-19
118. Alao MA, Ibrahim OR, Ogunbosi BO. Trends of Xpert MTB/RIF in the diagnosis of Mycobacterium tuberculosis and rifampicin resistance in Southwest Nigeria: A 4-year retrospective study. Journal of the Pan African Thoracic Society. 2023;4(1):31–41. DOI: 10.25259/JPATS_25_2022
119. Conradie F, Bagdasaryan TR, Borisov S, Howell P, Mikiashvili L, Ngubane N, Samoilova A, Skornykova S, Tudor E, Variava E, Yablonskiy P, Everitt D, Wills GH, Sun E, Olugbosi M, Egizi E, Li M, Holsta A, Timm J, Bateson A, Crook AM, Fabiane SM, Hunt R, McHugh TD, Tweed CD, Foraida S, Mendel CM, Spigelman M. ZeNix trial team. Bedaquiline-pretomanid-linezolid regimens for drug-resistant tuberculosis. New England Journal of Medicine. 2022;387(9);810–823. DOI: 10.1056/NEJMoa2119430
120. Nyang’wa BT, Kloprogge F, Moore DAJ, et al. Population pharmacokinetics and pharmacodynamics of investigational regimens’ drugs in the TB-PRACTECAL clinical trial (the PRACTECAL-PKPD study): A prospective nested study protocol in a randomized controlled trial. BMJ Open. 2021;11:e047185
121. WHO. WHO consolidated guidelines on tuberculosis: Module 4: Treatment - drug-resistant tuberculosis treatment, 2022 update [Internet]. Geneva: World Health Organization; 2022. Recommendations. Available from: https://www.ncbi.nlm.nih.gov/books/NBK588557/ [Accessed: 2025-September-01]
122. Vanino E, Granozzi B, Akkerman OW, et al. Update of drug-resistant tuberculosis treatment guidelines: A turning point. International Journal of Infectious Diseases. 2023;130(1):S12–S15. DOI: 10.1016/j.ijid.2023.03.013
123. Korotych O, Achar J, Gurbanova E, et al. Effectiveness and safety of modified fully oral 9-month treatment regimens for rifampicin-resistant tuberculosis: A prospective cohort study. The Lancet Infectious Diseases. 2024;24(10):1151–1161. DOI: 10.1016/S1473-3099(24)00228-7
124. Guglielmetti L, Khan U, Velásquez GE, et al. endTB-Q Clinical Trial Team. Bedaquiline, delamanid, linezolid, and clofazimine for rifampicin-resistant and fluoroquinolone-resistant tuberculosis (endTB-Q): An open-label, multicentre, stratified, non-inferiority, randomised, controlled, phase 3 trial. The Lancet Respiratory Medicine. 2025;13(9):809–820. DOI: 10.1016/S2213-2600(25)00194-8
125. Ravikoti S, Bhatia V, Mohanasundari SK. Recent advancements in tuberculosis (TB) treatment regimens. Journal of Family Medicine and Primary Care. 2025;14(2):521–525. DOI: 10.4103/jfmpc.jfmpc_1237_24
126. Bishop EL, Ismailova A, Dimeloe S, Hewison M, JH W. Vitamin D and immune regulation: Antibacterial, antiviral, anti-inflammatory. JBMR Plus. 2020; 5(1):e10405. DOI: 10.1002/jbm4.10405
127. Bouzeyen R, Javid B. Therapeutic vaccines for tuberculosis: An overview. Frontiers in Immunology. 2022;13:878471. DOI: 10.4103/jfmpc.jfmpc_1237_24
128. Nasiri MJ, Lutfy K, Venketaraman V. Challenges of multidrug-resistant tuberculosis meningitis: Current treatments and the role of glutathione as an adjunct therapy. Vaccines (Basel). 2024;12(12):1397. DOI: 10.3390/vaccines12121397
129. Lourens R, Singh G, Arendse T, Thwaites G, Rohlwink U. Tuberculous meningitis across the lifespan. The Journal of Infectious Diseases. 2025;231(5):1101–1111. DOI: 10.1093/infdis/jiaf181
130. Miftode EG, Dorneanu OS, Leca DA, et al. Tuberculous meningitis in children and adults: A 10-year retrospective comparative analysis. PLoS One. 2015;10:e0133477
131. Chiang SS, Khan FA, Milstein MB, et al. Treatment outcomes of childhood tuberculous meningitis: A systematic review and meta-analysis. The Lancet Infectious Diseases. 2014;14:947–957
132. Tobin EH, Tristram D Tuberculosis Overview. In: StatPearls. Treasure Island (FL): StatPearls Publishing; 2025. Available from: https://www.ncbi.nlm.nih.gov/books/NBK441916/ [Accessed: 2024-December-22]
133. Daniel BD, Grace GA, Natrajan M. Tuberculous meningitis in children: Clinical management & outcome. Indian Journal of Medical Research. 2019;150(2):117–130. DOI: 10.4103/ijmr.IJMR_786_17
134. Mezochow A, Thakur K, Vinnard C.Tuberculous meningitis in children and adults: New insights for an ancient foe. Current Neurology and Neuroscience Reports. 2017;17(11):85
135. Aulakh R, Chopra S. Pediatric tubercular meningitis: A review. Journal of Pediatric Neurosciences. 2018;13(4):373–382. DOI: 10.4103/JPN.JPN_78_18
136. Katwal S, Thapa A, Adhikari A, Baral P, Alam Ansari M. Tuberculous meningitis with stroke: A case report of diagnostic dilemma and therapeutic triumph. Radiology Case Reports. 2024;19(5):1847–1850. DOI: 10.1016/j.radcr.2024.01.073
137. Huynh J, Donovan J, Phu NH, Nghia HDT, Thuong NTT, Thwaites GE. Tuberculous meningitis: Progress and remaining questions. The Lancet Neurology. 2022;21:450–464. DOI: 10.1016/S1474-4422(21)00435-X
138. Palacios CF, Saleeb PG. Challenges in the diagnosis of tuberculous meningitis. Journal of Clinical Tuberculosis and Other Mycobacterial Diseases. 2020;20:100164. DOI: 10.1016/j.jctube.2020.100164
139. Rahman SMM, Nasrin R, Kabir S, et al. Performance of Xpert MTB/RIF ultra for the diagnosis of tuberculous meningitis in children using cerebrospinal fluid. Scientific Reports. 2025;15:13060
140. Pradhan NN, et al. Performance of Xpert ® MTB/RIF and Xpert ® Ultra for the diagnosis of tuberculous meningitis in children. The International Journal of Tuberculosis and Lung Disease. 2022;26(4):317–325. DOI: 10.5588/ijtld.21.0388
141. Fatema K, Rahman MM, Akhter S, Akter N, Paul B, Begum S, Begum F. Clinicoradiologic profile and outcome of children with tubercular meningitis in a Tertiary Care Hospital in Bangladesh. Journal of Child Neurology. 2019;35:088307381988416. DOI: 10.1177/0883073819884169
142. Munakomi S, Grasso G, Chapagain R. Multi-spectral pattern of clinical presentation and the resultant outcome in central nervous system tuberculosis: A single center study on the ubiquitous pathogen. Advances in Experimental Medicine and Biology. 2020;1271:29–35
143. Chaudhary V, Bano S, Garga UC.Central Nervous System Tuberculosis: An Imaging Perspective. Canadian Association of Radiologists Journal. 2017;68(2):161–170
144. Garg RK, Malhotra HS, Jain A.Neuroimaging in tuberculous meningitis. Neurology India. 2016;64(2):219–227
145. El Aggari H, Ahsayen FZ, Aichouni N, Nasri S, Kamaoui I, Skiker I. Miliary brain tuberculomas and tuberculous meningitis presenting with stroke. Radiology Case Reports. 2024;19(2):798–801. DOI: 10.1016/j.radcr.2023.10.004
146. Radtke KK, Dooley KE, Dodd PJ, Garcia-Prats AJ, McKenna L, Hesseling AC, Savic RM. Alternative dosing guidelines to improve outcomes in childhood tuberculosis: A mathematical modelling study. The Lancet Child & Adolescent Health. 2019;3(9):636–645. DOI: 10.1016/S2352-4642(19)30196-8
147. Ramachandran G, Kumar H, Swaminathan S. Pharmacokinetics of Anti-tuberculosis Drugs in Children. The Indian Journal of Pediatrics. 2011;78:435–442. DOI: 10.1007/s12098-010-0304-x
148. Solans BP, Béranger A, Radtke K, Mohamed A, Mirzayev F, Gegia M, Linh NN, Schumacher SG, Nahid P, Savic RM. Effectiveness and pharmacokinetic exposures of first-line drugs used to treat drug-susceptible tuberculosis in children: A systematic review and meta-analysis. Clinical Infectious Diseases. 2023;76(9):s1658–1670fc. DOI: 10.1093/cid/ciac973
149. Schaaf HS, Seddon JA.Management of tuberculous meningitis in children. Paediatrics and International Child Health. 2021;41(4):231–236
150. Hill J, Marais B.Improved treatment for children with tuberculous meningitis: Acting on what we know. Archives of Disease in Childhood. 2022;107(1):68–69
151. Kumar K, Mathew JL.World Health Organization guideline on the management of tuberculosis in children: Critical appraisal, concerns, and caution. Indian Journal of Pediatrics. 2023;90(8):811–816
152. Nataprawira HM, Gafar F, Risan NA, Wulandari DA, Sudarwati S, Marais BJ, Stevens J, Alffenaar JC, Ruslami R. Treatment outcomes of childhood tuberculous meningitis in a real-world retrospective cohort, Bandung, Indonesia. Emerging Infectious Diseases. 2022;28(3):660–671. DOI: 10.3201/eid2803.212230
153. Maphalle LNF, Michniak-Kohn BB, Ogunrombi MO, Adeleke OA. Pediatric tuberculosis management: A global challenge or breakthrough? Children. 2022;9:1120. DOI: 10.3390/children9081120
154. Abdella A, Deginet E, Weldegebreal F, Ketema I, Eshetu B, Desalew A. Tuberculous meningitis in children: Treatment outcomes at discharge and its associated factors in eastern Ethiopia: A five years retrospective study. Infection and Drug Resistance. 2022;15:2743–2751
155. Wang M-G, Luo L, Zhang Y, Liu X, Liu L, He J-Q. Treatment outcomes of tuberculous meningitis in adults: A systematic review and meta-analysis. BMC Pulmonary Medicine. 2019;19:200
156. Wen L, Li M, Xu T, Yu X, Wang L, Li K. Clinical features, outcomes and prognostic factors of tuberculous meningitis in adults worldwide: Systematic review and meta-analysis. Journal of Neurology. 2019;266:3009–3021
157. van Toorn R, Solomons R. Update on the diagnosis and management of tuberculous meningitis in children. Seminars in Pediatric Neurology. 2014;21(1):12–18. DOI: 10.1016/j.spen.2014.01.006
158. Wilkhoo HS, Gundaniya P, Visvanathan H, Chatterjee S, Dzagnidze A. A case report of acute ischaemic stroke associated with tuberculous meningitis. Annals of Neurosciences. 2025;32(4):295–301. DOI: 10.1177/09727531251322546
159. Schoeman JF, Janse van Rensburg A, Laubscher JA, Springer P. The role of aspirin in childhood tuberculous meningitis. Journal of Child Neurology. 2011;26:405–408. DOI: 10.1177/0883073811398132
160. Yang H, Liu Q, Wu Y, et al. Paradoxical tuberculosis-associated immune reconstitution inflammatory syndrome in initiating ART among HIV-Infected patients in China-risk factors and management. BMC Infectious Diseases. 2024;24(5). DOI: 10.1186/s12879-023-08897-3
161. Chiang S, Faiz AK, Milstein M, Tolman A, Benedetti A, Starke J, Becerra M. Treatment outcomes of childhood tuberculous meningitis: A systematic review and meta-analysis. The Lancet Infectious Diseases. 2014;14. DOI: 10.1016/S1473-3099(14)70852-7
162. du Preez K, Jenkins HE, Donald PR, Solomons RS, Graham SM, Schaaf HS, Starke JR, Hesseling AC, Seddon JA. Tuberculous meningitis in children: A forgotten public health emergency. Frontiers in Neurology. 2022;13:751133. DOI: 10.3389/fneur.2022.751133
163. Kegne TW, Anteneh ZA, Bayeh TL, Shiferaw BM, Tamiru DH. Survival rate and predictors of mortality among TB-HIV co-infected patients during tuberculosis treatment at public health facilities in Bahir Dar city, northwest Ethiopia. Infection and Drug Resistance. 2024;17:1385–1395. DOI: 10.2147/IDR.S446020
164. Maleki Rad M, Haddad M, Sheybani F, Shirazinia M, Dadgarmoghaddam M. Mortality predictors and diagnostic challenges in adult tuberculous meningitis: A retrospective cohort of 100 patients. Tropical Medicine and Health. 2025;53(1):58. DOI: 10.1186/s41182-025-00738-0
165. Nacarapa E, Munyangaju I, Osório D, Ramos-Rincon J-M. Predictors of tuberculous meningitis mortality among persons with HIV in Mozambique. Tropical Medicine and Infectious Disease. 2025;10:276. DOI: 10.3390/tropicalmed10100276
166. Pontali E, Raviglione M. Updated treatment guidelines for drug-resistant TB: How safe are clofazimine-based regimens? IJTLD Open. 2024;1(11):486–489. DOI: 10.5588/ijtldopen.24.0490
167. Sotgiu G, Nahid P, Loddenkemper R, et al. The ERS-endorsed official ATS/CDC/IDSA clinical practice guidelines on treatment of drug-susceptible tuberculosis. European Respiratory Journal. 2016;48:963–971
168. Rashid S, van TR, Seddon James A, Solomons Regan S. The impact of hyponatremia on the severity of childhood tuberculous meningitis. Frontiers in Neurology. 2022;12:2021. DOI: 10.3389/fneur.2021.703352
169. Burke RM, Rickman HM, Singh V, Corbett EL, Ayles H, Jahn A, Hosseinipour MC, Wilkinson RJ, MacPherson P. What is the optimum time to start antiretroviral therapy in people with HIV and tuberculosis coinfection? A systematic review and meta-analysis. Journal of the International AIDS Society. 2021; 24(7):e25772. DOI: 10.1002/jia2.25772
170. Zhang X, Li P, Wen J, et al. Ventriculoperitoneal shunt for tuberculous meningitis-associated hydrocephalus: Long-term outcomes and complications. BMC Infectious Diseases. 2023;23:742
171. Costa M, Caria J, Caiano J, et al. Tuberculous meningitis: An endemic cause of intracranial hypertension. Cureus. 2024;16(1):e51532. DOI:10.7759/cureus.51532
172. Oo N, DK D. Epidemiology, pathogenesis, clinical manifestations, and management strategies of tuberculous meningitis. Archives of Internal Medicine Research. 2025;8(1):48–58. DOI: 10.26502/aimr.0195
173. Donovan J, Cresswell FV, Tucker EW, Davis AG, Rohlwink UK, Huynh J, Solomons R, Seddon JA, Bahr NC, van Laarhoven A, Anderson ST, Jain SK, Chow FC, Pattison S, Scriven JE, Singh G, Aarnoutse RE, Alffenaar JC, Dian S, Manesh A, Basu Roy R, Singh V, van Toorn R, Upton CM, van Crevel R, Dooley KE, Gibb D, Meya D, Wilkinson RJ, Rogozińska E, Misra UK, Figaji A, Thwaites GE. A clinical practice guideline for tuberculous meningitis. The Lancet Infectious Diseases. 2025;1473–3099. DOI: 10.1016/S1473-3099(25)00364-0
174. Selvakumar S, Vishwanath V. Editorial: Advances in the management of tuberculosis meningitis. Frontiers in Immunology. 2024;15:2024. DOI: 10.3389/fimmu.2024.1433345
175. World Health Organization. WHO Consolidated Guidelines on Tuberculosis Module 4: Treatment: Drug-Susceptible Tuberculosis Treatment. Geneva, Switzerland: World Health Organization; 2022. https://www.who.int/publications/i/item/9789240048126 [Accessed: 2025-September-10]

[1] 1. WHO. Global Tuberculosis Report 2024. Geneva: World Health Organization; 2024. Available from: https://www.who.int/teams/global-programme-on-tuberculosis-and-lung-health/tb-reports/global-tuberculosis-report-2024 [Accessed: 2025-September-01]

[2] 2. Chen Z, Wang T, du J, et al. Decoding the WHO global tuberculosis report 2024: A critical analysis of global and chinese key data. Zoonoses. 2025;5(1). DOI: 10.15212/ZOONOSES-2024-0061

[3] 3. Dodd PJ, Osman M, Cresswell FV, Stadelman AM, Lan NH, Thuong NTT, et al. The global burden of tuberculous meningitis in adults: A modelling study. PLOS Global Public Health. 2021;1(12):e0000069. DOI: 10.1371/journal.pgph.0000069

[4] 4. Wen L, Li M, Xu T, Yu X, Wang L, Li K. Clinical features, outcomes and prognostic factors of tuberculous meningitis in adults worldwide: Systematic review and meta-analysis. Journal of Neurology. 2019;266:3009–3021. DOI: 10.1007/s00415-019-09523-6

[5] 5. Huang M, Ma Y, Ji X, Jiang H, Liu F, Chu N, Li Q, et al. A study of risk factors for tuberculous meningitis among patients with tuberculosis in China: An analysis of data between 2012 and 2019. Frontiers in Public Health. 2023;10:1040071

[6] 6. Urmenyi Lucas G, Vinhaes Caian L, Klauss V-S, Mariana A-P, Andrade Bruno B. Influence of HIV co-infection on clinical presentation and disease outcome in hospitalized adults with tuberculous meningitis in Brazil: A nationwide observational study. Frontiers in Public Health. 2025;13. DOI: 10.3389/fpubh.2025.1600104

[7] 7. Gutiérrez-González LH, Juárez E, Carranza C, Carreto-Binaghi LE, Alejandre A, Cabello-Gutiérrrez C, Gonzalez Y. Immunological aspects of diagnosis and management of childhood tuberculosis. Infection and Drug Resistance. 2021;14:929–946. DOI: 10.2147/IDR.S295798

[8] 8. Malik MA, Kamran A, Ahsan D, Amjad A, Moatter S, Noor A, Sohaib A, Shaukat M, Masood W, Hasanain M, Eljack MF. 2025. Advances in management and treatment of tubercular meningitis – A narrative review. Annals of Medicine and Surgery. 87(6):3673–3681. doi:10.1097/MS9.0000000000003348

[9] 9. Wilkinson R, Rohlwink U, Misra U, et al. Tuberculous meningitis. Nature Reviews Neurology. 2017;13:581–598

[10] 10. Cresswell F, Davis A, Sharma K, Basu Roy R, Ganiem A, Kagimu E, et al. Recent developments in tuberculous meningitis pathogenesis and diagnostics. Wellcome Open Research. 2021;4:164

[11] 11. Patrascu RE, Cucu AI, Costea CF, Cosman M, Blaj LA, Hristea A. Brain tuberculosis: An Odyssey through time to understand this pathology. Pathogens. 2023;12(8):1026. DOI: 10.3390/pathogens12081026

[12] 12. Manyelo CM, Solomons RS, Walzl G, Chegou NN, Kraft CS. Tuberculous meningitis: Pathogenesis, immune responses, diagnostic challenges, and the potential of biomarker-based approaches. Journal of Clinical Microbiology. 2021;59:10.1128/jcm.01771–20. DOI: 10.1128/jcm.01771-20

[13] 13. Xuelian LI, et al. Clinical characteristics of tuberculous meningitis combined with cranial nerve palsy. Clinical Neurology and Neurosurgery. 2019;184:105443

[14] 14. Barnacle JR, Davis AG, Wilkinson RJ. Recent advances in understanding the human host immune response in tuberculous meningitis. Frontiers in Immunology. 2024;14:1326651. DOI: 10.3389/fimmu.2023.1326651

[15] 15. Thwaites G, Fisher M, Hemingway C, Scott G, Solomon T, Innes J. British infection society. British Infection Society guidelines for the diagnosis and treatment of tuberculosis of the central nervous system in adults and children. Journal of Infection. 2009;59(3):167–187. DOI: 10.1016/j.jinf.2009.06.011

[16] 16. Sher K, Firdaus F, Abbasi A, Bullo N, Kumar S.Stages of tuberculous meningitis: A clinicoradiologic analysis. Journal of the College of Physicians and Surgeons--Pakistan: JCPSP. 2013;23(6):405–408

[17] 17. Tristram D, Tobin EH Tuberculosis in Children. In: StatPearls. Treasure Island (FL): StatPearls Publishing; 2025. Available from: https://www.ncbi.nlm.nih.gov/books/NBK610681/ [Accessed: 2024-November-22]

[18] 18. van Toorn R, Solomons R. Update on the diagnosis and management of tuberculous meningitis in children. Seminars in Pediatric Neurology. 2014;21:12–18. DOI: 10.1016/j.spen.2014.01.006

[19] 19. Slane VH, Unakal CG Tuberculous Meningitis. In: StatPearls. Treasure Island (FL): StatPearls Publishing; 2025. Available from: https://www.ncbi.nlm.nih.gov/books/NBK541015/ [Available from: 2024-September-02]

[20] 20. Saal C-L, Springer P, Seddon JA, van Toorn R, Esterhuizen TM, Solomons RS. Risk factors of poor developmental outcome in children with tuberculous meningitis. Child’s Nervous System. 2023;39(4):1029–1039. DOI: 10.1007/s00381-022-05791-2

[21] 21. Daniel BD, Selladurai E, Balaji S, Venkatesan A, Venkatesan M, Giridharan P, Shanmugam S, Natrajan S, Karunaianantham R, Kandasamy D, Subramani R, Muthuramalingam K, Pramila SK, Hissar S, Dooley KE, Thakur KT. Clinical and diagnostic features of central nervous system tuberculosis in Indian children - a descriptive study. Therapeutic Advances in Infectious Disease. 2024;11:20499361241274251. DOI: 10.1007/s00381-022-05791-2

[22] 22. Galimi R.Extrapulmonary tuberculosis: Tuberculous meningitis new developments. European Review for Medical and Pharmacological Sciences. 2011;15(4):365–386

[23] 23. Chen X, Chen F, Liang C, He G, Chen H, Wu Y, Chen Y, Shuai J, Yang Y, Dai C, Cao L, Wang X, Cai E, Wang J, Wu M, Zeng L, Zhu J, Hai D, Pan W, Pan S, Zhang C, Quan S, Su F. MRI advances in the imaging diagnosis of tuberculous meningitis: Opportunities and innovations. Frontiers in Microbiology. 2023;14:1308149. DOI: 10.3389/fmicb.2023.1308149

[24] 24. Adriana Caliman-Sturdza O, Cucu A. Hydrocephalus in Tuberculous Meningitis [Internet]. Frontiers in Hydrocephalus. IntechOpen. 2023. DOI: 10.5772/intechopen.110251

[25] 25. Schaller MA, Wicke F, Foerch C, Weidauer S.Central nervous system tuberculosis: Etiology, clinical manifestations and neuroradiological features. Clinical Neuroradiology. 2019;29(1):3–18

[26] 26. Dahal P, Parajuli S. Magnetic resonance imaging findings in central nervous system tuberculosis: A pictorial review. Heliyon. 2024; 10(8):e29779. DOI: 10.1016/j.heliyon.2024.e29779

[27] 27. Ma Q, Yi Y, Liu T, et al. MRI-based radiomics signature for identification of invisible basal cisterns changes in tuberculous meningitis: A preliminary multicenter study. European Radiology. 2022;32:8659–8669

[28] 28. Mushtaq R, Arooj S, Kalsoom U, Raja R.Role of contrast enhanced FLAIR MRI as a new tool in diagnosing tuberculous meningitis. PAFMJ [Internet]. 2020;70(5):1310–1314

[29] 29. Bernaerts A, Vanhoenacker FM, Parizel PM, J.w.m. VG, Van Altena R, Laridon A, et al. Tuberculosis of the central nervous system: Overview of neuroradiological findings. European Radiology. 2003;13(8):1876–1890. DOI: 10.1007/s00330-002-1608-7

[30] 30. Khatri GD, Krishnan V, Antil N, Saigal G. Magnetic resonance imaging spectrum of intracranial tubercular lesions: One disease, many faces. Polish Journal of Radiology. 2018;83:e524–e535. DOI: 10.5114/pjr.2018.81408

[31] 31. Soni N, Kumar S, Shimle A, Ora M, Bathla G, Mishra P. Cerebrovascular complications in tuberculous meningitis—A magnetic resonance imaging study in 90 patients from a tertiary care hospital. The Neuroradiology Journal. 2020;33(1):3–16. DOI: 10.1177/1971400919881188

[32] 32. Trivedi R, Saksena S, Gupta RK. Magnetic resonance imaging in central nervous system tuberculosis. Indian Journal of Radiology and Imaging. 2009;19(4):256–265. DOI: 10.4103/0971-3026.57205

[33] 33. Ibrahim IG, Osman AA, Shikhow MG, Celik C, Mutlu E, Hassan Qalaf MS, Tahtabaşı M, Garad Mohamed Y. Magnetic resonance imaging findings of intracranial tuberculoma patients in a tertiary hospital in Mogadishu, Somalia: A retrospective study. Annals of Medicine and Surgery (2012). 2022;78:103812. DOI: 10.1016/j.amsu.2022.103812

[34] 34. Baloji A, Ghasi RG. MRI in intracranial tuberculosis: Have we seen it all? Clin. Imag. 2020;68:263–277. DOI: 10.1016/j.clinimag.2020.08.028

[35] 35. Dian S, Hermawan R, van Laarhoven A, Immaculata S, Achmad TH, Ruslami R, Anwary F, Soetikno RD, Ganiem AR, van Crevel R. Brain MRI findings in relation to clinical characteristics and outcome of tuberculous meningitis. PLoS One. 2020; 15(11):e0241974. DOI: 10.1371/journal.pone.0241974

[36] 36. Saxena D, Pinto DS, Tandon AS, Hoisala R. MRI findings in tubercular radiculomyelitis. eNeurologicalSci. 2021;22:100316. DOI: 10.1016/j.ensci.2021.100316

[37] 37. Rodriguez-Takeuchi SY, Renjifo ME, José Medina FJ. Extrapulmonary Tuberculosis: Pathophysiology and Imaging Findings. RadioGraphics. 2019;39(7):2023–2037. DOI: 10.1148/rg.2019190109

[38] 38. Imron A, Hermanto Y, Rizal A, Yunivita V, Ruslami R. Cerebrospinal fluid analysis in tuberculous meningitis: A literature review. Surgical Neurology International. 2025;16:246. DOI: 10.25259/SNI_1131_2024

[39] 39. Thomas J, Mishra U, Tavisetty C, Mandloi D. The spectrum of cerebrospinal fluid findings in tuberculous meningitis and their relation to severity, radiological features, and outcome. Journal of Neurosciences in Rural Practice. 2023;14:717–722

[40] 40. Ssebambulidde K, Gakuru J, Ellis J, Cresswell FV, Bahr NC. Improving Technology to Diagnose Tuberculous Meningitis: Are We There Yet? Frontiers in Neurology. 2022;13:892224. DOI: 10.3389/fneur.2022.892224

[41] 41. Jain SK, Tobin DM, Tucker EW, et al. Tuberculous meningitis: A roadmap for advancing basic and translational research. Nature Immunology. 2018;19:521–525

[42] 42. Ramachandra V, Brammacharry U, Muralidhar A, Muthukumar A, Mani R, Muthaiah M, Soundappan G, Frederick A. Assess the diagnostic accuracy of genexpert to detect mycobacterium tuberculosis and rifampicin-resistant tuberculosis among presumptive tuberculosis and presumptive drug resistant tuberculosis patients. Microbiology Research. 2023;15:91–108. DOI: 10.3390/microbiolres15010006

[43] 43. Lin F. Tuberculous meningitis diagnosis and treatment: Classic approaches and high-throughput pathways. Frontiers in Immunology. 2025;15:1543009

[44] 44. Cao W-F, Leng E-L, Liu S-M, Zhou Y-L, Luo C-Q, Xiang Z-B, Cai W, Rao W, Hu F, Zhang P, et al. Recent advances in microbiological and molecular biological detection techniques of tuberculous meningitis. Frontiers in Microbiology. 2023;14:1202752

[45] 45. Bahr NC, Nuwagira E, Evans EE, Cresswell FV, Bystrom PV, Byamukama A, Bridge SC, Bangdiwala AS, Meya DB, Denkinger CM, Muzoora C, Boulware DR. ASTRO-CM trial team. Diagnostic accuracy of xpert MTB/RIF ultra for tuberculous meningitis in HIV-infected adults: A prospective cohort study. The Lancet Infectious Diseases. 2018;18(1):68–75. DOI: 10.1016/S1473-3099(17)30474-7

[46] 46. Donovan J, et al. Xpert MTB/RIF ultra versus Xpert MTB/RIF for the diagnosis of tuberculous meningitis: A prospective, randomised, diagnostic accuracy study. The Lancet Infectious Diseases. 2020;20(3):299–307. DOI: 10.1016/s1473-3099(19)30649-8

[47] 47. Dorman SE, et al. Xpert MTB/RIF ultra for detection of Mycobacterium tuberculosis and rifampicin resistance: A prospective multicentre diagnostic accuracy study. The Lancet Infectious Diseases. 2018;18(1):76–84. DOI: 10.1016/s1473-3099(17)30691-6

[48] 48. World Health Organization. WHO Consolidated Guidelines on Tuberculosis. Module 3: Diagnosis - Rapid Diagnostics for Tuberculosis Detection, 2021 Update. Licence: CC BY-NC-SA 3.0 IGO, World Health Organization, Geneva, 2021. Available from: https://www.who.int/publications/i/item/9789240029415 [Accessed: 2025-September]

[49] 49. Yu G, Shen Y, Zhong F, Ye B, Yang J, Chen G. Diagnostic accuracy of the loop-mediated isothermal amplification assay for extrapulmonary tuberculosis: A meta-analysis. PLoS One. 2018; 13(6):e0199290. DOI: 10.1371/journal.pone.0199290

[50] 50. Ashkin A, Lindner D. The Challenges of Diagnosing Tuberculous Meningitis and Importance of Early Intervention. Journal of Community Hospital Internal Medicine Perspectives. 2023;13(4):84–87. DOI: 10.55729/2000-9666.1196

[51] 51. Garg RK. Tuberculous meningitis. Acta Neurologica Scandinavica. 2010;122:75–90. DOI: 10.1111/j.1600-0404.2009.01316.x

[52] 52. Song J, Kim SH, Jung YR, Choe J, Kang CI, Min JH. 10-year retrospective review of the etiologies for meningitis with elevated adenosine deaminase in cerebrospinal fluid: Etiologies other than TB. Frontiers in Cellular and Infection Microbiology. 2022;12:858724. DOI: 10.3389/fcimb.2022.858724

[53] 53. Lan Y, Chen W, Yan Q, Liu W. Interferon-γ release assays for tuberculous meningitis diagnosis: A meta-analysis. Archives of Medical Science. 2021;17(5):1241–1250. DOI: 10.5114/aoms.2019.86994

[54] 54. Caliman-Sturdza OA, Mihalache D, Luca CM. Performance of an interferon-gamma release assay in the diagnosis of tuberculous meningitis in children. Revista Romana De Medicina De Labor. 2015;23:199–212. DOI: 10.1515/rrlm-2015-0016

[55] 55. Yin X, Ye -Q-Q, Wu K-F, Zeng J-Y, Li N-X, Mo -J-J, Huang P-Y, Xie L-M, Xie L-Y, Guo X-G. Diagnostic value of Lipoarabinomannan antigen for detecting Mycobacterium tuberculosis in adults and children with or without HIV infection. Journal of Clinical Laboratory Analysis. 2022; 36(2):e24238. DOI: 10.1002/jcla.24238

[56] 56. Songkhla MN, Tantipong H, Tongsai S, Angkasekwinai N. Lateral flow urine lipoarabinomannan assay for diagnosis of active tuberculosis in adults with human immunodeficiency virus infection: A prospective cohort study. Open Forum Infectious Diseases. 2019; 6(4):ofz132. DOI: 10.1093/ofid/ofz132

[57] 57. Yan L, Sun W, Lu Z, Fan L. Metagenomic Next-Generation Sequencing (mNGS) in cerebrospinal fluid for rapid diagnosis of Tuberculosis meningitis in HIV-negative population. International Journal of Infectious Diseases. 2020;96:270–275. DOI: 10.1016/j.ijid.2020.04.048

[58] 58. Chen Y, Tang H, Zheng J, Yang Q, Han DO. Transforming tuberculosis diagnosis with clinical metagenomics: Progress and roadblocks. Journal of Clinical Microbiology. 2025;19:e00537–25. DOI: 10.1128/jcm.00537-25

[59] 59. Huang M, Ding Z, Li W, Chen W, Du Y, Jia H, Sun Q, Du B, Wei R, Xing A, Li Q, Chu N, Pan L. Identification of protein biomarkers in host cerebrospinal fluid for differential diagnosis of tuberculous meningitis and other meningitis. Frontiers in Neurology. 2022;13:886040. DOI: 10.3389/fneur.2022.886040

[60] 60. Gigase FAJ, Smith E, Collins B, Moore K, Snijders GJLJ, Katz D, Bergink V, Perez-Rodriquez MM, De Witte LD. The association between inflammatory markers in blood and cerebrospinal fluid: A systematic review and meta-analysis. Molecular Psychiatry. 2023;28(4):1502–1515. DOI: 10.1038/s41380-023-01976-6

[61] 61. Yao X-P, Hong J-C, Jiang Z-J, Pan -Y-Y, Liu X-F, Wang J-M, Fan R-J, Yang B-H, Zhang W-Q, Fan Q-C, L-x L, B-w L, Zhao M. Systemic and cerebrospinal fluid biomarkers for tuberculous meningitis identification and treatment monitoring. Microbiology Spectrum. 2024; 12(1):e0224623. DOI: 10.1128/spectrum.02246-23

[62] 62. Tomalka J, Sharma A, Smith AGC, Avaliani T, Gujabidze M, Bakuradze T, Sabanadze S, Jones DP, Avaliani Z, Kipiani M, Kempker RR, Collins JM. Combined cerebrospinal fluid metabolomic and cytokine profiling in tuberculosis meningitis reveals robust and prolonged changes in immunometabolic networks. Tuberculosis (Edinburgh). 2024;144:102462. DOI: 10.1016/j.tube.2023.102462

[63] 63. Lu W, Li Y, Deng J, Su Y, Fan H, Huang K. Advancements in the identification and utilization of cerebrospinal fluid immunological biomarkers for the diagnosis of tuberculous meningitis. Microbial Pathogenesis. 2025;206:107826. DOI: 10.1016/j.micpath.2025.107826

[64] 64. Bharucha T, Gangadharan B, Kumar A, de Lamballerie X, Newton PN, Winterberg M, Dubot-Pérès A, Zitzmann N. Mass spectrometry-based proteomic techniques to identify cerebrospinal fluid biomarkers for diagnosing suspected central nervous system infections. A systematic review. Journal of Infection. 2019;79(5):407–418. DOI: 10.1016/j.jinf.2019.08.005

[65] 65. Ahlawat S, Chaudhary R, Dangi M, Bala K, Singh M, Chhillar AK. Advances in tuberculous meningitis diagnosis. Expert Review of Molecular Diagnostics. 2020;20:1229–1241. DOI: 10.1080/14737159.2020.1858805

[66] 66. Foppiano Palacios C, Saleeb PG. Challenges in the diagnosis of tuberculous meningitis. Journal of Clinical Tuberculosis and Other Mycobacterial Diseases. 2020;20:100164. DOI: 10.1016/j.jctube.2020.100164

[67] 67. Janssen S, Murphy M, Upton C, Allwood B, Diacon AH. Tuberculosis: An Update for the Clinician. Respirology. 2025;30:196–205. DOI: 10.1111/resp.14887

[68] 68. Thwaites GE, Lan NTN, Dung NH, et al. Effect of antituberculosis drug resistance on response to treatment and outcome in adults with tuberculous meningitis. The Journal of Infectious Diseases. 2005;192(1):79–88. DOI: 10.1086/430616

[69] 69. World Health Organization. Key Updates to the Treatment of Drug-Resistant Tuberculosis: Rapid Communication. Geneva: World Health Organization; 2024. https://iris.who.int/handle/10665/378472 [Accessed: 2025-September-01]

[70] 70. Cresswell FV, Te Brake L, Atherton R, Ruslami R, Dooley KE, Aarnoutse R, Van Crevel R. Intensified antibiotic treatment of tuberculosis meningitis. Expert Review of Clinical Pharmacology. 2019;12(3):267–288. DOI: 10.1080/17512433.2019.1552831

[71] 71. Heemskerk AD, Nguyen MTH, Dang HTM, et al. Clinical outcomes of patients with drug-resistant tuberculous meningitis treated with an intensified antituberculosis regimen. Clinical Infectious Diseases. 2017;65(1):20–28. DOI: 10.1093/cid/cix230

[72] 72. Lienhardt C, Dooley K, Nahid P, et al. Target regimen profiles for tuberculosis treatment. Bulletin of the World Health Organization 2024;102:600–607

[73] 73. Dartois VA, Rubin EJ. Anti-tuberculosis treatment strategies and drug development: Challenges and priorities. Nature Reviews Microbiology. 2022;20(11):685–701

[74] 74. Gillespie SH, Crook AM, McHugh TD, et al. Four-month moxifloxacin-based regimens for drug-sensitive tuberculosis. New England Journal of Medicine. 2014;371(17):1577–1587. DOI: 10.1056/NEJMoa1407426

[75] 75. Wasserman S, Davis A, Wilkinson RJ, Meintjes G. Key considerations in the pharmacotherapy of tuberculous meningitis. Expert Opinion on Pharmacotherapy. 2019;20(15):1791–1795. DOI: 10.1080/14656566.2019.1638912

[76] 76. Maitre T, Bonnet M, Calmy A, Raberahona M, Rakotoarivelo RA, Rakotosamimanana N, Ambrosioni J, Miró JM, Debeaudrap P, Muzoora C, Davis A, Meintjes G, Wasserman S, Wilkinson R, Eholié S, Nogbou FE, Calvo-Cortes M-C, Chazallon C, Machault V, Anglaret X, Bonnet F. Intensified tuberculosis treatment to reduce the mortality of HIV-infected and uninfected patients with tuberculosis meningitis (INTENSE-TBM): Study protocol for a phase III randomized controlled trial. Trials. 2022;23(1):928. DOI: 10.1186/s13063-022-06772-1

[77] 77. Navaneethapandian P, Chandrasekaran P. Treatment of tuberculosis and the drug interactions associated with HIV-TB co-infection treatment. Frontiers in Tropical Diseases. 2022;3:2022. DOI: 10.3389/fitd.2022.834013

[78] 78. Le X, Shen Y. Advances in antiretroviral therapy for patients with human immunodeficiency virus-associated tuberculosis. Viruses. 2024;16(4):494. DOI: 10.3390/v16040494

[79] 79. Quinn CM, Poplin V, Kasibante J, Yuquimpo K, Gakuru J, Cresswell FV, NC B. Tuberculosis IRIS: Pathogenesis, presentation, and management across the spectrum of disease. Life (Basel). 2020;10(11):262. DOI: 10.3390/life10110262

[80] 80. Davis AG, Donovan J, Bremer M, Van Toorn R, Schoeman J, Dadabhoy A, Lai RPJ, Cresswell FV, Boulware DR, Wilkinson RJ, Thuong NTT, Thwaites GE, Bahr NC. Tuberculous meningitis international research consortium. Host directed therapies for tuberculous meningitis. Wellcome Open Research. 2021;5:292. DOI: 10.12688/wellcomeopenres.16474.2

[81] 81. Schutz C, Davis AG, Sossen B, Lai RP-J, Ntsekhe M, Harley YX, Wilkinson RJ. Corticosteroids as an adjunct to tuberculosis therapy. Expert Review of Respiratory Medicine. 2018;12(10):881–891. DOI: 10.1080/17476348.2018.1515628

[82] 82. Li R, Yin R, Li Y, Wei Y, Zhao B, Ge C. Advances in the treatment and clinical management strategies of tuberculous meningitis. International Journal of General Medicine. 2025;18:3267–3276. DOI: 10.2147/IJGM.S516998

[83] 83. Diallo A, BD D, OH D, Carlos-Bolumbu M, Camara M, Sidikiba S. Corticosteroids for reducing tuberculosis mortality in persons living with HIV: A systematic review and meta-analysis using reconstructed individual patient data. BMJ Global Health. 2025; 10(8):e017923. DOI: 10.1136/bmjgh-2024-017923

[84] 84. World Health Organization. WHO Consolidated Guidelines on Tuberculosis. Module 4: Treatment-drug-resistant Tuberculosis Treatment, 2022 Update. Geneva, Switzerland: World Health Organization; 2022

[85] 85. Prasad K, Singh MB, Ryan H. Corticosteroids for managing tuberculous meningitis. The Cochrane Database of Systematic Reviews. 2016; 4(4):CD002244. DOI: 10.1002/14651858.CD002244.pub4

[86] 86. Donovan J, Bang ND, Imran D, et al. Adjunctive dexamethasone for tuberculous meningitis in HIV-positive adults. New England Journal of Medicine. 2023;389:1357–1367

[87] 87. Thwaites GE, DB N, HD N, et al. Dexamethasone for the treatment of tuberculous meningitis in adolescents and adults. New England Journal of Medicine. 2004;351:1741–1751

[88] 88. Amin A, Vartanian A, Yegiazaryan A, Al-Kassir AL, Venketaraman V. Review of the effectiveness of various adjuvant therapies in treating Mycobacterium tuberculosis. Infectious Disease Reports. 2021;13(3):821–834. DOI: 10.3390/idr13030074

[89] 89. Murthy J. Management of intracranial pressure in tuberculous meningitis. Neurocritical Care. 2005;2(306-12. 10.1385/NCC:2:3):306. DOI: 10.1385/NCC:2:3:

[90] 90. Dharmana SN, Singla N, Sharma K, Modi M, Goyal M. Prevalence of seizures in patients with tuberculous meningitis (TBM) and their clinical outcomes. Cureus. 2025; 17(1):e77210. DOI: 10.7759/cureus.77210

[91] 91. Bhatia R, Shree R, Modi M, Anand A, Garg A, Haldar P, Padma Srivastava MV, Singla N, Goyal M, Supriya S, Sharma K, Wig N, Singh MB, Fatima S, Longkumer I, Bindal T, Srivastava A, Vishnu VY, Biswas A, Sinha S, Vikram NK, Vishnubhatla S, Sharma N, Singh P, Medhi B, Ahuja C. A randomised trial to assess the efficacy of add on therapy with aspirin or clopidogrel to the standard medical therapy alone in patients with tubercular meningitis: ACT TBM. The Lancet Regional Health - Southeast Asia. 2025;37:100604. DOI: 10.1016/j.lansea.2025.100604

[92] 92. Davis AG, Wilkinson RJ. Aspirin in tuberculous meningitis. Eclinicalmedicine. 2021;35:100871. DOI: 10.1016/j.eclinm.2021.100871

[93] 93. Rohilla R, Shafiq N, Malhotra S. Efficacy and safety of aspirin as an adjunctive therapy in tubercular meningitis: A systematic review and meta-analysis. EClinicalMedicine. 2021;34:100819. DOI: 10.1016/j.eclinm.2021.100819

[94] 94. Blackmore T, Manning L, Taylor W, Wallis R. Therapeutic use of infliximab in tuberculosis to control severe paradoxical reaction of the brain and lymph nodes. Clinical Infectious Diseases. 2008;47:e83–5. DOI: 10.1086/592695

[95] 95. Yuk J-M, Kim JK, Kim IS, Jo E-K. TNF in human tuberculosis: A double-edged sword. Immune Network. 2024;24(1):e4. DOI: 10.4110/in.2024.24.e4

[96] 96. van Toorn R, Zaharie S-D, Seddon JA, van der Kuip M, Marceline van Furth A, Schoeman JF, Solomons RS. The use of thalidomide to treat children with tuberculosis meningitis: A review. Tuberculosis (Edinburgh). 2021;130:102125. DOI: 10.1016/j.tube.2021.102125

[97] 97. Marais BJ, Cheong E, Fernando S, Daniel S, Watts MR, Berglund LJ, Barry SE, Kotsiou G, Headley AP, Stapledon RA. Use of infliximab to treat paradoxical tuberculous meningitis reactions. Open Forum Infectious Diseases. 2021; 8(1):ofaa604. DOI: 10.1093/ofid/ofaa604

[98] 98. Santin M, Escrich C, Majós C, et al. Tumor necrosis factor antagonists for paradoxical inflammatory reactions in the central nervous system tuberculosis Case report and review. Medicine. 2020;99. DOI: 10.1097/MD.0000000000022626

[99] 99. Ledingham D, El-wahsh S, Sebire D, Cappelen-Smith C, Hodgkinson SJ, McDougall AJ, Maley M, Cordato DJ. Adjuvant immunosuppression for paradoxical deterioration in tuberculous meningitis including one case responsive to cyclosporine. A tertiary referral hospital experience. Journal of the Neurological Sciences. 2019;404:58–62. DOI: 10.1016/j.jns.2019.07.002

[100] 100. Domínguez-Moreno R, García-Grimshaw M, Medina-Julio D, Cantú-Brito C, González-Duarte A. Paradoxical manifestations during tuberculous meningitis treatment among HIV-negative patients: A retrospective descriptive study and literature review. Neurological Sciences. 2022;43(4):2699–2708. DOI: 10.1007/s10072-021-05693-2

[101] 101. Dutta NK, Bruiners N, Zimmerman MD, Tan S, Dartois V, Gennaro ML, Karakousis PC. Adjunctive host-directed therapy with statins improves tuberculosis-related outcomes in mice. The Journal of Infectious Diseases. 2020;221(7):1079–1087. DOI: 10.1093/infdis/jiz517

[102] 102. Solima S, Bongani M, Mumin O, Mafu Trevor S, Wilkinson Robert J, Friedrich T, Reto G. Immunomodulatory effects of atorvastatin on peripheral blood mononuclear cells infected with Mycobacterium tuberculosis. Frontiers in Immunology. 2025;16:2025. DOI: 10.3389/fimmu.2025.1597534

[103] 103. Jaganath D, Mupere E. Childhood tuberculosis and malnutrition. The Journal of Infectious Diseases. 2012;206(12):1809–1815. DOI: 10.1093/infdis/jis608

[104] 104. Guo C, Liu K-W, Tong J, Gao M-Q. Prevalence and prognostic significance of malnutrition risk in patients with tuberculous meningitis. Frontiers in Public Health. 2025;12:1391821. DOI: 10.3389/fpubh.2024.1391821

[105] 105. Omoteso OA, Fadaka AO, Walker RB, Khamanga SM. Innovative strategies for combating multidrug-resistant tuberculosis: Advances in drug delivery systems and treatment. Microorganisms. 2025;13:722. DOI: 10.3390/microorganisms13040722

[106] 106. Song H-W, Tian J-H, Song H-P, Guo S-J, Lin Y-H, Pan J-S. Tracking multidrug resistant tuberculosis: A 30-year analysis of global, regional, and national trends. Frontiers in Public Health. 2024;12:1408316

[107] 107. Gygli SM, Borrell S, Trauner A, Gagneux S. Antimicrobial Resistance in Mycobacterium tuberculosis: Mechanistic and Evolutionary Perspectives. FEMS Microbiology Reviews. 2017;41:354–373

[108] 108. Brode SK, Dwilow R, Kunimoto D, Menzies D, Khan FA. Chapter 8: Drug-resistant tuberculosis. Canadian Journal of Respiratory, Critical Care, and Sleep Medicine. 2022;6(sup1):109–128. DOI: 10.1080/24745332.2022.2039499

[109] 109. Espinosa-Pereiro J, Sánchez-Montalvá A, Aznar ML, Espiau M. MDR Tuberculosis Treatment. Medicina (Kaunas). 2022;58(2):188. DOI: 10.3390/medicina58020188

[110] 110. Jang JG, Chung JH. Diagnosis and treatment of multidrug-resistant tuberculosis. Yeungnam University Journal of Medicine. 2020;37(4):277–285. DOI: 10.12701/yujm.2020.00626

[111] 111. Maranchick Nicole F, Alshaer Mohammad H, Smith Alison GC, Avaliani T, Gujabidze M, Bakuradze T, Sabanadze S, Avaliani Z, Kipiani M, Peloquin Charles A, Kempker Russell R. Cerebrospinal fluid concentrations of fluoroquinolones and carbapenems in tuberculosis meningitis. Frontiers in Pharmacology. 2022;13. DOI: 10.3389/fphar.2022.1048653

[112] 112. Ignatius EH, Dooley KE. New drugs for the treatment of tuberculosis. Clinics in Chest Medicine. 2019;40(4):811–827. DOI: 10.1016/j.ccm.2019.08.001

[113] 113. Fei ZT, Huang W, Zhou DP, et al. Clinical efficacy of linezolid in the treatment of tuberculous meningitis: A retrospective analysis and literature review. BMC Infectious Diseases. 2025;25:467

[114] 114. Liu X, Tang D, Qi M, He J. Efficacy of linezolid in the treatment of tuberculous meningitis: A meta-analysis. Archives of Medical Science. 2024;20(3):1038–1042. DOI: 10.5114/aoms/189905

[115] 115. Davis AG, Wasserman S, Stek C, Maxebengula M, Jason Liang C, Stegmann S, Koekemoer S, Jackson A, Kadernani Y, Bremer M, Daroowala R, Aziz S, Goliath R, Lai Sai L, Sihoyiya T, Denti P, Lai RPJ, Crede T, Naude J, Szymanski P, Vallie Y, Banderker IA, Moosa MS, Raubenheimer P, Candy S, Offiah C, Wahl G, Vorster I, Maartens G, Black J, Meintjes G, Wilkinson RJ. A phase 2A trial of the safety and tolerability of increased dose rifampicin and adjunctive linezolid, with or without aspirin, for human immunodeficiency virus–associated tuberculous meningitis: The LASER-TBM trial. Clinical Infectious Diseases. 2023;76(8):1412–1422. DOI: 10.1093/cid/ciac932

[116] 116. Mudde SE, Upton AM, Lenaerts A, Bax HI, De Steenwinkel JEM. Delamanid or pretomanid? A Solomonic judgement! Journal of Antimicrobial Chemotherapy. 2022;77(4):880–902. DOI: 10.1093/jac/dkab505

[117] 117. Tucker EW, Pieterse L, Zimmerman MD, Udwadia ZF, Peloquin CA, Gler MT, Ganatra S, Tornheim JA, Chawla P, Caoili JC, Ritchie B, Jain SK, Dartois V, Dooley KE. Delamanid central nervous system pharmacokinetics in tuberculous meningitis in rabbits and humans. Antimicrobial Agents and Chemotherapy. 2019;63. DOI: 10.1128/AAC.00913-19

[118] 118. Alao MA, Ibrahim OR, Ogunbosi BO. Trends of Xpert MTB/RIF in the diagnosis of Mycobacterium tuberculosis and rifampicin resistance in Southwest Nigeria: A 4-year retrospective study. Journal of the Pan African Thoracic Society. 2023;4(1):31–41. DOI: 10.25259/JPATS_25_2022

[119] 119. Conradie F, Bagdasaryan TR, Borisov S, Howell P, Mikiashvili L, Ngubane N, Samoilova A, Skornykova S, Tudor E, Variava E, Yablonskiy P, Everitt D, Wills GH, Sun E, Olugbosi M, Egizi E, Li M, Holsta A, Timm J, Bateson A, Crook AM, Fabiane SM, Hunt R, McHugh TD, Tweed CD, Foraida S, Mendel CM, Spigelman M. ZeNix trial team. Bedaquiline-pretomanid-linezolid regimens for drug-resistant tuberculosis. New England Journal of Medicine. 2022;387(9);810–823. DOI: 10.1056/NEJMoa2119430

[120] 120. Nyang’wa BT, Kloprogge F, Moore DAJ, et al. Population pharmacokinetics and pharmacodynamics of investigational regimens’ drugs in the TB-PRACTECAL clinical trial (the PRACTECAL-PKPD study): A prospective nested study protocol in a randomized controlled trial. BMJ Open. 2021;11:e047185

[121] 121. WHO. WHO consolidated guidelines on tuberculosis: Module 4: Treatment - drug-resistant tuberculosis treatment, 2022 update [Internet]. Geneva: World Health Organization; 2022. Recommendations. Available from: https://www.ncbi.nlm.nih.gov/books/NBK588557/ [Accessed: 2025-September-01]

[122] 122. Vanino E, Granozzi B, Akkerman OW, et al. Update of drug-resistant tuberculosis treatment guidelines: A turning point. International Journal of Infectious Diseases. 2023;130(1):S12–S15. DOI: 10.1016/j.ijid.2023.03.013

[123] 123. Korotych O, Achar J, Gurbanova E, et al. Effectiveness and safety of modified fully oral 9-month treatment regimens for rifampicin-resistant tuberculosis: A prospective cohort study. The Lancet Infectious Diseases. 2024;24(10):1151–1161. DOI: 10.1016/S1473-3099(24)00228-7

[124] 124. Guglielmetti L, Khan U, Velásquez GE, et al. endTB-Q Clinical Trial Team. Bedaquiline, delamanid, linezolid, and clofazimine for rifampicin-resistant and fluoroquinolone-resistant tuberculosis (endTB-Q): An open-label, multicentre, stratified, non-inferiority, randomised, controlled, phase 3 trial. The Lancet Respiratory Medicine. 2025;13(9):809–820. DOI: 10.1016/S2213-2600(25)00194-8

[125] 125. Ravikoti S, Bhatia V, Mohanasundari SK. Recent advancements in tuberculosis (TB) treatment regimens. Journal of Family Medicine and Primary Care. 2025;14(2):521–525. DOI: 10.4103/jfmpc.jfmpc_1237_24

[126] 126. Bishop EL, Ismailova A, Dimeloe S, Hewison M, JH W. Vitamin D and immune regulation: Antibacterial, antiviral, anti-inflammatory. JBMR Plus. 2020; 5(1):e10405. DOI: 10.1002/jbm4.10405

[127] 127. Bouzeyen R, Javid B. Therapeutic vaccines for tuberculosis: An overview. Frontiers in Immunology. 2022;13:878471. DOI: 10.4103/jfmpc.jfmpc_1237_24

[128] 128. Nasiri MJ, Lutfy K, Venketaraman V. Challenges of multidrug-resistant tuberculosis meningitis: Current treatments and the role of glutathione as an adjunct therapy. Vaccines (Basel). 2024;12(12):1397. DOI: 10.3390/vaccines12121397

[129] 129. Lourens R, Singh G, Arendse T, Thwaites G, Rohlwink U. Tuberculous meningitis across the lifespan. The Journal of Infectious Diseases. 2025;231(5):1101–1111. DOI: 10.1093/infdis/jiaf181

[130] 130. Miftode EG, Dorneanu OS, Leca DA, et al. Tuberculous meningitis in children and adults: A 10-year retrospective comparative analysis. PLoS One. 2015;10:e0133477

[131] 131. Chiang SS, Khan FA, Milstein MB, et al. Treatment outcomes of childhood tuberculous meningitis: A systematic review and meta-analysis. The Lancet Infectious Diseases. 2014;14:947–957

[132] 132. Tobin EH, Tristram D Tuberculosis Overview. In: StatPearls. Treasure Island (FL): StatPearls Publishing; 2025. Available from: https://www.ncbi.nlm.nih.gov/books/NBK441916/ [Accessed: 2024-December-22]

[133] 133. Daniel BD, Grace GA, Natrajan M. Tuberculous meningitis in children: Clinical management & outcome. Indian Journal of Medical Research. 2019;150(2):117–130. DOI: 10.4103/ijmr.IJMR_786_17

[134] 134. Mezochow A, Thakur K, Vinnard C.Tuberculous meningitis in children and adults: New insights for an ancient foe. Current Neurology and Neuroscience Reports. 2017;17(11):85

[135] 135. Aulakh R, Chopra S. Pediatric tubercular meningitis: A review. Journal of Pediatric Neurosciences. 2018;13(4):373–382. DOI: 10.4103/JPN.JPN_78_18

[136] 136. Katwal S, Thapa A, Adhikari A, Baral P, Alam Ansari M. Tuberculous meningitis with stroke: A case report of diagnostic dilemma and therapeutic triumph. Radiology Case Reports. 2024;19(5):1847–1850. DOI: 10.1016/j.radcr.2024.01.073

[137] 137. Huynh J, Donovan J, Phu NH, Nghia HDT, Thuong NTT, Thwaites GE. Tuberculous meningitis: Progress and remaining questions. The Lancet Neurology. 2022;21:450–464. DOI: 10.1016/S1474-4422(21)00435-X

[138] 138. Palacios CF, Saleeb PG. Challenges in the diagnosis of tuberculous meningitis. Journal of Clinical Tuberculosis and Other Mycobacterial Diseases. 2020;20:100164. DOI: 10.1016/j.jctube.2020.100164

[139] 139. Rahman SMM, Nasrin R, Kabir S, et al. Performance of Xpert MTB/RIF ultra for the diagnosis of tuberculous meningitis in children using cerebrospinal fluid. Scientific Reports. 2025;15:13060

[140] 140. Pradhan NN, et al. Performance of Xpert ® MTB/RIF and Xpert ® Ultra for the diagnosis of tuberculous meningitis in children. The International Journal of Tuberculosis and Lung Disease. 2022;26(4):317–325. DOI: 10.5588/ijtld.21.0388

[141] 141. Fatema K, Rahman MM, Akhter S, Akter N, Paul B, Begum S, Begum F. Clinicoradiologic profile and outcome of children with tubercular meningitis in a Tertiary Care Hospital in Bangladesh. Journal of Child Neurology. 2019;35:088307381988416. DOI: 10.1177/0883073819884169

[142] 142. Munakomi S, Grasso G, Chapagain R. Multi-spectral pattern of clinical presentation and the resultant outcome in central nervous system tuberculosis: A single center study on the ubiquitous pathogen. Advances in Experimental Medicine and Biology. 2020;1271:29–35

[143] 143. Chaudhary V, Bano S, Garga UC.Central Nervous System Tuberculosis: An Imaging Perspective. Canadian Association of Radiologists Journal. 2017;68(2):161–170

[144] 144. Garg RK, Malhotra HS, Jain A.Neuroimaging in tuberculous meningitis. Neurology India. 2016;64(2):219–227

[145] 145. El Aggari H, Ahsayen FZ, Aichouni N, Nasri S, Kamaoui I, Skiker I. Miliary brain tuberculomas and tuberculous meningitis presenting with stroke. Radiology Case Reports. 2024;19(2):798–801. DOI: 10.1016/j.radcr.2023.10.004

[146] 146. Radtke KK, Dooley KE, Dodd PJ, Garcia-Prats AJ, McKenna L, Hesseling AC, Savic RM. Alternative dosing guidelines to improve outcomes in childhood tuberculosis: A mathematical modelling study. The Lancet Child & Adolescent Health. 2019;3(9):636–645. DOI: 10.1016/S2352-4642(19)30196-8

[147] 147. Ramachandran G, Kumar H, Swaminathan S. Pharmacokinetics of Anti-tuberculosis Drugs in Children. The Indian Journal of Pediatrics. 2011;78:435–442. DOI: 10.1007/s12098-010-0304-x

[148] 148. Solans BP, Béranger A, Radtke K, Mohamed A, Mirzayev F, Gegia M, Linh NN, Schumacher SG, Nahid P, Savic RM. Effectiveness and pharmacokinetic exposures of first-line drugs used to treat drug-susceptible tuberculosis in children: A systematic review and meta-analysis. Clinical Infectious Diseases. 2023;76(9):s1658–1670fc. DOI: 10.1093/cid/ciac973

[149] 149. Schaaf HS, Seddon JA.Management of tuberculous meningitis in children. Paediatrics and International Child Health. 2021;41(4):231–236

[150] 150. Hill J, Marais B.Improved treatment for children with tuberculous meningitis: Acting on what we know. Archives of Disease in Childhood. 2022;107(1):68–69

[151] 151. Kumar K, Mathew JL.World Health Organization guideline on the management of tuberculosis in children: Critical appraisal, concerns, and caution. Indian Journal of Pediatrics. 2023;90(8):811–816

[152] 152. Nataprawira HM, Gafar F, Risan NA, Wulandari DA, Sudarwati S, Marais BJ, Stevens J, Alffenaar JC, Ruslami R. Treatment outcomes of childhood tuberculous meningitis in a real-world retrospective cohort, Bandung, Indonesia. Emerging Infectious Diseases. 2022;28(3):660–671. DOI: 10.3201/eid2803.212230

[153] 153. Maphalle LNF, Michniak-Kohn BB, Ogunrombi MO, Adeleke OA. Pediatric tuberculosis management: A global challenge or breakthrough? Children. 2022;9:1120. DOI: 10.3390/children9081120

[154] 154. Abdella A, Deginet E, Weldegebreal F, Ketema I, Eshetu B, Desalew A. Tuberculous meningitis in children: Treatment outcomes at discharge and its associated factors in eastern Ethiopia: A five years retrospective study. Infection and Drug Resistance. 2022;15:2743–2751

[155] 155. Wang M-G, Luo L, Zhang Y, Liu X, Liu L, He J-Q. Treatment outcomes of tuberculous meningitis in adults: A systematic review and meta-analysis. BMC Pulmonary Medicine. 2019;19:200

[156] 156. Wen L, Li M, Xu T, Yu X, Wang L, Li K. Clinical features, outcomes and prognostic factors of tuberculous meningitis in adults worldwide: Systematic review and meta-analysis. Journal of Neurology. 2019;266:3009–3021

[157] 157. van Toorn R, Solomons R. Update on the diagnosis and management of tuberculous meningitis in children. Seminars in Pediatric Neurology. 2014;21(1):12–18. DOI: 10.1016/j.spen.2014.01.006

[158] 158. Wilkhoo HS, Gundaniya P, Visvanathan H, Chatterjee S, Dzagnidze A. A case report of acute ischaemic stroke associated with tuberculous meningitis. Annals of Neurosciences. 2025;32(4):295–301. DOI: 10.1177/09727531251322546

[159] 159. Schoeman JF, Janse van Rensburg A, Laubscher JA, Springer P. The role of aspirin in childhood tuberculous meningitis. Journal of Child Neurology. 2011;26:405–408. DOI: 10.1177/0883073811398132

[160] 160. Yang H, Liu Q, Wu Y, et al. Paradoxical tuberculosis-associated immune reconstitution inflammatory syndrome in initiating ART among HIV-Infected patients in China-risk factors and management. BMC Infectious Diseases. 2024;24(5). DOI: 10.1186/s12879-023-08897-3

[161] 161. Chiang S, Faiz AK, Milstein M, Tolman A, Benedetti A, Starke J, Becerra M. Treatment outcomes of childhood tuberculous meningitis: A systematic review and meta-analysis. The Lancet Infectious Diseases. 2014;14. DOI: 10.1016/S1473-3099(14)70852-7

[162] 162. du Preez K, Jenkins HE, Donald PR, Solomons RS, Graham SM, Schaaf HS, Starke JR, Hesseling AC, Seddon JA. Tuberculous meningitis in children: A forgotten public health emergency. Frontiers in Neurology. 2022;13:751133. DOI: 10.3389/fneur.2022.751133

[163] 163. Kegne TW, Anteneh ZA, Bayeh TL, Shiferaw BM, Tamiru DH. Survival rate and predictors of mortality among TB-HIV co-infected patients during tuberculosis treatment at public health facilities in Bahir Dar city, northwest Ethiopia. Infection and Drug Resistance. 2024;17:1385–1395. DOI: 10.2147/IDR.S446020

[164] 164. Maleki Rad M, Haddad M, Sheybani F, Shirazinia M, Dadgarmoghaddam M. Mortality predictors and diagnostic challenges in adult tuberculous meningitis: A retrospective cohort of 100 patients. Tropical Medicine and Health. 2025;53(1):58. DOI: 10.1186/s41182-025-00738-0

[165] 165. Nacarapa E, Munyangaju I, Osório D, Ramos-Rincon J-M. Predictors of tuberculous meningitis mortality among persons with HIV in Mozambique. Tropical Medicine and Infectious Disease. 2025;10:276. DOI: 10.3390/tropicalmed10100276

[166] 166. Pontali E, Raviglione M. Updated treatment guidelines for drug-resistant TB: How safe are clofazimine-based regimens? IJTLD Open. 2024;1(11):486–489. DOI: 10.5588/ijtldopen.24.0490

[167] 167. Sotgiu G, Nahid P, Loddenkemper R, et al. The ERS-endorsed official ATS/CDC/IDSA clinical practice guidelines on treatment of drug-susceptible tuberculosis. European Respiratory Journal. 2016;48:963–971

[168] 168. Rashid S, van TR, Seddon James A, Solomons Regan S. The impact of hyponatremia on the severity of childhood tuberculous meningitis. Frontiers in Neurology. 2022;12:2021. DOI: 10.3389/fneur.2021.703352

[169] 169. Burke RM, Rickman HM, Singh V, Corbett EL, Ayles H, Jahn A, Hosseinipour MC, Wilkinson RJ, MacPherson P. What is the optimum time to start antiretroviral therapy in people with HIV and tuberculosis coinfection? A systematic review and meta-analysis. Journal of the International AIDS Society. 2021; 24(7):e25772. DOI: 10.1002/jia2.25772

[170] 170. Zhang X, Li P, Wen J, et al. Ventriculoperitoneal shunt for tuberculous meningitis-associated hydrocephalus: Long-term outcomes and complications. BMC Infectious Diseases. 2023;23:742

[171] 171. Costa M, Caria J, Caiano J, et al. Tuberculous meningitis: An endemic cause of intracranial hypertension. Cureus. 2024;16(1):e51532. DOI:10.7759/cureus.51532

[172] 172. Oo N, DK D. Epidemiology, pathogenesis, clinical manifestations, and management strategies of tuberculous meningitis. Archives of Internal Medicine Research. 2025;8(1):48–58. DOI: 10.26502/aimr.0195

[173] 173. Donovan J, Cresswell FV, Tucker EW, Davis AG, Rohlwink UK, Huynh J, Solomons R, Seddon JA, Bahr NC, van Laarhoven A, Anderson ST, Jain SK, Chow FC, Pattison S, Scriven JE, Singh G, Aarnoutse RE, Alffenaar JC, Dian S, Manesh A, Basu Roy R, Singh V, van Toorn R, Upton CM, van Crevel R, Dooley KE, Gibb D, Meya D, Wilkinson RJ, Rogozińska E, Misra UK, Figaji A, Thwaites GE. A clinical practice guideline for tuberculous meningitis. The Lancet Infectious Diseases. 2025;1473–3099. DOI: 10.1016/S1473-3099(25)00364-0

[174] 174. Selvakumar S, Vishwanath V. Editorial: Advances in the management of tuberculosis meningitis. Frontiers in Immunology. 2024;15:2024. DOI: 10.3389/fimmu.2024.1433345

[175] 175. World Health Organization. WHO Consolidated Guidelines on Tuberculosis Module 4: Treatment: Drug-Susceptible Tuberculosis Treatment. Geneva, Switzerland: World Health Organization; 2022. https://www.who.int/publications/i/item/9789240048126 [Accessed: 2025-September-10]