Successful Treatment of Multidrug-Resistant Tuberculous Meningitis in a Young Chinese Woman: A Case Study From Japan

Introduction

In Japan, despite a decreasing overall trend of tuberculosis (TB) incidence, imported TB has increased notably, accounting for 11.9% of new TB cases in 2022 [1]. Among young adults in their twenties with TB, 77.5% have imported TB [1]. Drug resistance is common in these populations, requiring clinicians to consider the TB epidemiology of the patient’s country of origin when formulating treatment plans. According to the 2024 World Health Organization (WHO) Global Tuberculosis Report, an estimated 400 000 people developed multidrug-resistant or rifampicin-resistant TB (MDR/RR-TB) in 2023, accounting for approximately 3.2% of new TB cases and 16% of previously treated cases globally [2]. Notably, 5 countries – India (27%), the Russian Federation (7.4%), Indonesia (7.4%), China (7.3%), and the Philippines – accounted for over half of the global MDR/RR-TB burden [2]. In Japan in 2022, there were 531 cases of culture-positive pulmonary TB reported, including 26 cases of MDR-TB, 14 of which were imported [1].

Additionally, TB meningitis (TBM), a form of extrapulmonary TB, can be fatal without proper treatment. Patients with TBM frequently experience altered consciousness, which complicates oral medication administration. Thus, treatment regimens must consider and prioritize both central nervous system (CNS) penetration and adaptable routes of administration.

Herein, we report the case of a Chinese woman in her twenties who was diagnosed with MDR-TB and presented with concurrent TBM and pulmonary TB.

This report describes a 24-year-old woman with multidrug-resistant pulmonary tuberculosis and tuberculous meningitis successfully treated with pyrazinamide, levofloxacin, cycloserine, and linezolid.

Case Report

A woman in her twenties from Jilin Province, China, presented with progressive symptoms during the previous 2 weeks, which began with fatigue followed by fever, left-arm weakness, and subsequent lower-limb weakness. On the day of admission, she was unable to move and was brought to the hospital by ambulance. She had no significant medical history, although her father had a history of TB treatment. She had been residing in Japan for 3 years as a university student.

Upon admission, her vital signs were as follows: Glasgow Coma Scale (GCS) E4V4M6, body temperature 38°C, blood pressure 104/66 mmHg, pulse 120 bpm (regular), respiratory rate 22 per minute, and SpO2 96% on room air. Physical examination demonstrated clear bilateral breath sounds without adventitious sounds. Neurological examination revealed nuchal rigidity, positive left Barre sign, and marked weakness in the upper and lower extremities. Blood tests showed the following: white blood cell count 16 000/μL, hemoglobin 13 g/dL, platelets 416 000/μL, C-reactive protein 11.62 mg/dL, glucose 120 mg/dL, and hemoglobin A1c of 6.1%. Viral markers for hepatitis B surface antigen, hepatitis C virus antibody, and human immunodeficiency virus antigen/antibody were absent. The T-SPOT.TB test result was positive. Cerebrospinal fluid analysis revealed the following: a clear, colorless fluid with no opening pressure elevation; protein 173 mg/dL (reference range: 15–45 mg/dL); glucose 56 mg/dL (reference range: 45–80 mg/dL); cell count 313/μL (reference range: 0–5/μL), including 179/μL neutrophils and 132/μL monocytes; and cerebrospinal fluid adenosine deaminase (ADA) activity 18.4 U/L (reference range: <9 U/L). Gram and Ziehl-Neelsen stains were negative. Chest computed tomography (CT) demonstrated diffuse granular and nodular opacities with tree-in-bud appearances – characterized by centrilobular bronchial dilatation and filling with mucus, pus, or fluid, resembling a budding tree (Figure 1). Non-contrast brain CT and magnetic resonance imaging (MRI) were normal.

On day 1, acid-fast bacilli (AFB) cultures of sputum, cerebrospinal fluid, blood, gastric fluid, and urine were obtained. Due to suspicion of pulmonary TB and TBM, standard anti-TB treatment with isoniazid (INH) 300 mg/d (5 mg/kg/d), rifampicin (RFP) 600 mg/d (10 mg/kg/d), ethambutol (EB) 750 mg/d (15 mg/kg/d), and pyrazinamide (PZA) 1300 mg/d (25 mg/kg/d) was initiated. On day 2, ocular motor disturbances and worsening of limb weakness were observed, suggesting TBM, prompting the addition of dexamethasone (DEXA) 19.8 mg/d (0.35 mg/kg/d). By day 5, contrast-enhanced MRI of the cervicothoracic spine and brain revealed basal meningeal enhancement and multiple small nodules, consistent with TBM and tuberculomas (Figure 2). On day 6, she had impaired consciousness (GCS E2V2M4), and a cerebral CT scan revealed hydrocephalus, necessitating nasogastric tube insertion. On day 9, a seizure was observed and the hydrocephalus worsened, which led to external ventricular drainage (Figure 3). An AFB smear from the drainage fluid was positive, and levofloxacin (LVFX) 750 mg/d was added due to its known ability to penetrate the CNS, which was considered essential in managing TB meningitis. On day 10, TB-polymerase chain reaction of the drainage fluid confirmed TB. GeneXpert testing for cerebrospinal fluid samples was not available at our institution at the time of diagnosis. On day 27, due to persistent hydrocephalus, a ventriculoperitoneal shunt was placed. On day 44, external laboratory results indicated potential drug-resistant TB. Given the emerging possibility of multidrug-resistant TB, RFP was replaced by rifabutin 300 mg/d (5 mg/kg/d), with the addition of cycloserine (CS) (500 mg/d) and linezolid (LZD) (600 mg/d), which were selected for their adequate CNS penetration and compatibility with nasogastric administration. DEXA was gradually tapered and discontinued by day 56. Despite these measures, the patient remained comatose, and hydrocephalus persisted, necessitating a left ventricular peritoneal shunt insertion on day 62. On day 89, MDR-TB was confirmed by liquid culture (Table 1). Sequencing-based diagnostics were not available at our institution. Drug resistance was confirmed by conventional culture-based drug susceptibility testing at a reference laboratory. The patient continued treatment with PZA, LVFX, CS, and LZD. At that time, bedaquiline and pretomanid were not used because sufficient evidence of their CNS penetration was lacking, and additionally, pretomanid was not available in Japan. She experienced blood count reductions as adverse effects, which were managed with blood transfusions alone, and these were considered likely to be adverse effects of linezolid. Although her level of consciousness did not improve, there was no further worsening of hydrocephalus or progression of pulmonary lesions, and her respiratory and circulatory status remained stable. She remained on mechanical ventilation via tracheostomy and was in a minimally conscious state (GCS E1VTM3). After 541 days of hospitalization, she was discharged to home-based care with support from her family.

Discussion

This case illustrates the complexities of treating MDR-TB with CNS involvement, emphasizing the importance of selecting drugs based on both CNS penetration and feasibility of enteral administration. A young woman in her twenties survived pulmonary TB and TBM caused by MDR-TB following successful treatment with a 4-drug regimen consisting of PZA, LVFX, CS, and LZD. In this case, the diagnosis of pulmonary TB was based on clinical symptoms and characteristic CT findings, despite negative sputum cultures. Radiological features such as “tree-in-bud” appearance are known to correlate with active pulmonary tuberculosis, especially in cases with endobronchial involvement [3]. The diagnosis of tuberculous meningitis was established based on a positive cerebrospinal fluid (CSF) culture for Mycobacterium tuberculosis, in accordance with the imaging findings and clinical presentation.

Given the high global burden of MDR/RR-TB, particularly in countries such as China, where our patient originated, it is essential to consider regional drug resistance patterns when managing imported TB cases. In China, MDR-TB accounts for 6% of new TB cases and 26% of retreatment cases. Drug resistance prevalence varies between developed and developing regions; developed areas have a higher rate of drug-resistant cases among retreatment patients, whereas in developing areas, new cases are more likely to be drug-resistant [4,5]. Factors contributing to this issue include poor sanitation, poverty, and the misuse of anti-TB medications. Specifically, in Jilin Province, China, 8.6% of new TB cases and 23.2% of retreatment cases are identified as MDR-TB [6]. This report describes a patient from a region in China with a particularly high prevalence of MDR-TB. We anticipated a strong likelihood of DR-TB; thus, early identification and discussions regarding appropriate treatment options were essential. Understanding the TB epidemiology of the patient’s country or region of origin is critical in managing imported TB cases.

Multidrug-resistant tuberculosis (MDR-TB) remains a persistent global health threat due to increasing incidence and limited treatment options worldwide [7]. Regarding MDR-TB treatment, the World Health Organization (WHO) recommends short-term treatment with a 6-month regimen as an alternative to conventional long-term therapy. This is called the BPaLM regimen, which includes bedaquiline, pretomanid, LZD, and moxifloxacin [8]. However, this regimen is not currently recommended for cases involving the CNS, as clinical trials have excluded patients with CNS tuberculosis, and data on the CNS penetration of bedaquiline and pretomanid remain limited. Therefore, individualized treatment strategies are necessary for MDR-TB with CNS involvement. The treatment for drug-susceptible TBM is based on regimens used for pulmonary TB. The WHO recommends the same regimen: 2 months of RFP, INH, PZA, and EB, followed by 10 months of RFP and INH [9]. In contrast, when TBM is caused by MDR-TB, drug selection must prioritize both CNS penetration and the feasibility of nasogastric or enteral administration due to the frequent presence of impaired consciousness in affected patients. Our case is consistent with the findings reported by DeVincenzo et al, who also emphasized the importance of CNS penetration of second-line anti-TB drugs in MDR-TB meningitis [10]. Table 2 outlines anti-TB drugs with CNS penetration and compatibility with feeding tube administration [11,12], guiding the selection of PZA, LVFX, CS, and LZD. For the present case, these were the only feasible options under the given conditions.

Bedaquiline is an innovative anti-TB drug that inhibits the adenosine triphosphate synthase enzyme in mycobacteria and provides a unique mechanism without cross-resistance to existing TB medications [13]. Although it can be administered for 6 months or longer, its potential adverse effects include QT prolongation, gastrointestinal symptoms, arthralgia, and hepatotoxicity [14]. At the time of treatment in this case, sufficient data regarding CNS penetration were not available. However, recent case reports and small series have demonstrated the effectiveness of bedaquiline in CNS penetration and feeding tube administration [15]. This trend suggests the potential usefulness of bedaquiline in similar cases in the future. Pretomanid is another novel anti-TB agent, included in the BPaLM regimen, which shows strong bactericidal activity against MDR-TB strains. At the time of treatment, Pretomanid had not yet been approved in Japan, and clinical data regarding its CNS penetration were insufficient. Although animal models have indicated a certain degree of CNS penetration, further clinical data are awaited to better define its potential role in the management of MDR-TBM [16].

Conclusions

This case highlights the importance of individualized drug selection for MDR-TB with CNS involvement, taking into account both CNS penetration and the feasibility of enteral administration. Early diagnosis and appropriate treatment were critical to survival despite significant neurological sequelae. In managing TB, clinicians should also consider the patient’s country of origin.