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Comparison of cerebrospinal fluid characteristics in patients with tuberculous meningitis with and without cranial nerve palsy
*Corresponding author: Robiah Al Adawiyah, Department of Neurology, Faculty of Medicine - Universitas Airlangga, Dr. Soetomo General Academic Hospital, Surabaya, Indonesia. robiah.robbi@gmail.com
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Received: ,
Accepted: ,
How to cite this article: Al Adawiyah R, Sugianto P. Comparison of cerebrospinal fluid characteristics in patients with tuberculous meningitis with and without cranial nerve palsy. J Neurosci Rural Pract. doi: 10.25259/JNRP_147_2025
Abstract
Objectives:
Tuberculous meningitis (TBM) represents the most severe form of extrapulmonary tuberculosis. One of the common complications of TBM is cranial nerve palsy. This study assessed the characteristics of cerebrospinal fluid (CSF) in patients with TBM and cranial nerve palsy, particularly in a tertiary care hospital in Surabaya, East Java, Indonesia.
Materials and Methods:
A retrospective analysis of patients diagnosed with TBM from January 2022 to December 2024 was conducted, collecting demographic details, clinical features, and laboratory results of 37 patients. Patients with TBM diagnosed with CSF Xpert Mycobacterium tuberculosis/Rifampicin. Analysis of CSF characteristics using nominal data represented using frequency tables while continuous variables were described using mean ± standard deviation. Comparisons of CSF profiles in TBM patients with and without cranial nerve palsy were analyzed using Fisher’s exact test. A p-value <0.05 was considered statistically significant.
Results:
A total of 37 patients enrolled in this study. Cranial nerve palsy was noted in 9 (24.3%) of patients with TBM. Of the patients, 4 (10.8%) had multiple cranial nerve palsies including the 3rd, 4th, and 6th nerves, 2 (5.4%) presented with 2nd and 3rd cranial nerve palsies, 1 (2.7%) had isolated 3rd cranial nerve palsy, 1 (2.7%) had 3rd and 6th cranial nerve palsy, and 1 (2.7%) had 7th and 12th cranial nerve palsy. Chi-square analysis indicated that lymphocyte levels exceeding 50% in CSF are significant factors for cranial nerve palsy.
Conclusion:
The prevalence of cranial nerve palsy was 24.3%, with lymphocyte levels >50% in CSF representing a significant predictor of cranial nerve palsy in patients with TBMs.
Keywords
Cerebrospinal fluid
Cranial nerve palsy
Meningitis
Tuberculosis
Tuberculous meningitis
INTRODUCTION
Tuberculous meningitis (TBM) refers to the infection of the meninges by Mycobacterium Tuberculosis (MTB). It typically arises as a spreading disease caused by an initial pulmonary tuberculosis (TB) infection.[1] TBM represents the most severe manifestation of extrapulmonary TB, affecting approximately 1–5% of pulmonary TB patients worldwide.[2] The World Health Organization (WHO) provides global estimates indicating that 30.000–490.000 people are diagnosed with TBM each year.[3] The reported mortality rate is at 50% among adult patients, accompanied by a significant occurrence of long-term neurological symptoms.[2]
With a population of over 274.859.100, Indonesia is the largest archipelagic nation in South-East Asia and the second-highest country in the world, after India, in terms of cases of TBM. The estimated incidence of TBM in Indonesia is 969.000 cases in 2021, or an incidence rate of 354 per 100.000 population.[4]
Due to the rapid but uneven population growth, the island of Java is home to 58% of Indonesia’s population, which has led to a high population density. One of the elements causing the high rate of TB transmission is population density. In densely populated urban areas, the poverty rate is also elevated by the increase in urbanization, which will have an impact on health levels and treatment methods.[5] Differences in demographics, economics, and disease management strategies among countries determine the incidence rates of TB. Developing countries such as Indonesia significantly differ from the United States, which globally contributed 2.9%, and Europe, with only 2.2%.[4]
The high prevalence of TBM in Indonesia may be attributed to insufficient TB screening. The TB screening rate among individuals in close contact with TB patients is reported to be only 52% of those screened. Reports indicated that only 3% of diabetes mellitus patients underwent TB screening, while 74% of HIV patients were screened. This inadequate screening has contributed to the elevated prevalence of TB and the delay of its treatment. Another concern is the implementation of TB preventative therapy, which is merely 9% for individuals with HIV and 1.3% for close contacts with TB patients.[4] In patients with pulmonary TB, the risk of TBM increases by 30–50%, whereas it increases by 10% in patients with a history of TB and 10% in patients with spinal TB.[6]
Cranial nerve palsy is a frequent outcome of TBM. Recent studies indicate that patients with TBM with cranial nerve palsy are associated with poor prognosis and higher mortality.[7] A study from Wen et al. showed that CSF white cell count (WCC) is an important predictor of cranial nerve palsy in patients with TBM.[8] Nonetheless, no research has evaluated the prevalence of cranial nerve palsy in individuals with TBM and its related variables in Indonesia. This study evaluated the characteristics of cerebrospinal fluid (CSF) in patients with TBM with cranial nerve palsy in tertiary health care in Indonesia.
MATERIALS AND METHODS
Study design
This study was an observational, cross-sectional, retrospective, single-institutional study in adult patients with TBM, admitted to the Department of Neurology, Dr. Soetomo General Hospital, from January 2022 to December 2024. This study evaluated the CSF characteristics in TBM with and without cranial nerve palsy. This data also presented clinical characteristics of patients, including age, gender, disease onset, headache, consciousness level, neck rigidity, hemiparesis, hyponatremia (<135 mmoL/L), and pulmonary TB status.
Participants
The inclusion criteria for this study were patients aged 18 years or older with a diagnosis of TBM confirmed by CSF Xpert MTB/Rifampicin (RIF). Eligible patients must have undergone head imaging with contrast-enhanced computed tomography (CT) scan or magnetic resonance imaging (MRI), routine blood and electrolyte testing, CSF analysis, and chest X-ray examination. The exclusion criterion was the presence of secondary bacterial infection confirmed by CSF culture.
The required sample size for estimating sensitivity in a population is calculated using the formula from the book on sample size determination in health studies.[9]
The diagnosis of TBM in this study was confirmed with the use of Xpert MTB/RIF.[3] Xpert MTB/RIF is an automated cartridge-based polymerase chain reaction test that facilitates rapid diagnostics for TB. A review conducted by the WHO in 2014 focused on TBM and determined that Xpert MTB/RIF shows a sensitivity of 80.5% (95% confidence interval [CI] 59.0–92.2%) and a specificity of 97.8% (95% CI 95.2–99.0%) as compared to culture results.[10] Although CSF culture is considered the gold standard for diagnosing TBM, the process is time-consuming and requires several weeks, making it impractical for timely diagnosis. In addition, the guidelines from the Indonesian national medical service regarding TBM support the testing of Xpert MTB/RIF from CSF specimens for all types of central nervous system TB (Recommendation IIA).[11]
Study methods
All subjects in the medical records that fulfilled the inclusion and exclusion criterion had their basic demographic data documented in the data collection sheet. Data collection for the research subjects was conducted by two assistant researchers; one assistant documented the CSF results, while the other assistant computed the clinical characteristics. From this, we collected data regarding clinical characteristics of patients, including age, gender, disease onset, headache, consciousness level, neck rigidity, hemiparesis, hyponatremia (<135 mmoL/L), head imaging data from CT-scan or MRI, and pulmonary TB status.
Statistical analysis
Statistical analysis was performed using Statistical Package for the Social Sciences version 29.0 (IBM Corp, Armonk, NY, USA). For numerical variables, mean and standard deviation (SD) were used to represent the data. Nominal variables were represented by count and percentages. The CSF criteria from the Lancet Consensus Scoring System served as a reference for the CSF under research. The criteria include: Clear appearance, cell count of 10–500/mL, lymphocytic predominance exceeding 50%, protein concentration >1 g/L, and a CSF to plasma glucose ratio of <50%. All samples showed protein levels below 1 g/L; therefore, this variable was excluded from the analysis.
Nominal data will be represented through frequency tables and diagrams, while continuous data will be defined by mean ± SD. The comparison of CSF profiles and TBMs associated with cranial nerve palsy will use the Fisher-Exact Test. P < 0.05 qualifies as statistically significant.
A completed strengthening of the reporting of observational studies in epidemiology checklist for cross-sectional studies is provided as supplementary material to ensure compliance with reporting standards.
RESULTS
A total of 70 patients were enrolled in this study; however, 33 patients were excluded, as their CSF culture showed bacterial findings in the CSF. Among the 37 patients, 20 (54.1%) were female and 17 (45.9%) were male, with a range of ages between 18 and 57 years old. We found that 26 (70.3%) patients with TBM had onset ≥5 days before diagnosis with CSF Xpert MTB/RIF. The clinical findings among these patients are mostly 32 (86.5%) with decreased of consciousness, 29 (78.4%) with hyponatremia, 24 (64.9%) with headache, 22 (59.5%) with nuchal rigidity, 18 (48.6%) with pulmonary TB and leukocytosis, 11 (29.7%) presented with weight loss, 8 (21.6%) with seizure and cranial nerve palsy, 7 (18.9%) with hemiparesis, 6 (16.2%) with fever, 3 (8.1%) with persistent cough for more than 2 weeks, and 2 (5.4%) with night sweats [Table 1].
| Demographic data | n(%) |
|---|---|
| Age | |
| Mean±SD | 30.65±10.41 |
| Range (year) | 18–57 |
| Gender | |
| Female | 20 (54.1) |
| Male | 17 (45.9) |
| Onset | |
| <5 days | 11 (29.7) |
| ≥5 days | 26 (70.3) |
| Headache | 24 (64.9) |
| Cranial nerve palsy | 9 (24.3) |
| Decreased of consciousness | 32 (86.5) |
| Nuchal rigidity | 22 (59.5) |
| Hemiparesis | 7 (18.9) |
| Hyponatremia | 29 (78.4) |
| Pulmonary TB | 18 (48.6) |
TB: Tuberculosis, SD: Standard deviation
CSF analysis was performed in all patients, with examination of CSF Xpert MTB/RIF used as a diagnostic tool for TBM. On CSF examination, all the TBM patients with cranial nerve palsy 9 (100%) had clear appearance and glucose CSF: Plasma ratio <50%, 5 (55.6%) had lymphocyte predominant for more than 50% and 8 (88.9%) had cell 10–500/mL [Table 2]. The main findings of lymphocyte dominant more than 50% was found to be significantly associated with cranial nerve palsy in TBM.
| Features of CSF | Meningitis TB, n(%) | P-value | OR (95% CI) | |
|---|---|---|---|---|
| With cranial nerve palsy (n=9) (%) | Without cranial nerve palsy (n=28) (%) | |||
| Clear appearance | 9 (100) | 28 (100) | 0.568a | 0.929 (0.838–1.029) |
| Lymphocyte predominant >50% | 5 (55.6) | 25 (89.3) | 0.045a* | 0.150 (0.025–0.888) |
| Cells (10–500/μL ) | 8 (88.9) | 27 (96.4) | 0.432a | 0.296 (0.017–5.288) |
| Glucose CSF: Plasma ratio <50% | 9 (100) | 21 (75) | 0.115a | 0.750 (0.606–0.929) |
Cranial nerve palsy presents in 9 (24.3%) of the 37 patients with TBM in this study. Multiple cranial nerve palsies involvement is more frequent compared to singled cranial nerve palsy, cranial nerve 3rd, 4th, and 6th is the most affected cranial nerve (10.8%) resulting ophthalmoplegia, followed by 2nd and 3rd cranial nerve (5.4%) palsy resulting pupil anisochoria, single 3rd cranial nerve palsy (2.7%) reported as medial rectus muscle palsy, 3rd and 6th (2.7%) as horizontal gaze palsy, and the 7th and 12th cranial nerve palsies (2.7%) [Table 3].
| Cranial nerve involvement | n(%) |
|---|---|
| 2nd and 3rd nerve | 2 (5.4) |
| 3rd nerve | 1 (2.7) |
| 3rd and 6th nerve | 1 (2.7) |
| 3rd, 4th , and 6th nerve | 4 (10.8) |
| 7th and 12th nerve | 1 (2.7) |
DISCUSSION
The clinical signs of TBM arise from a dysregulated immune response triggered by the infiltration of MTB into the meninges.[3] MTB has the capability to penetrate the blood-brain barrier (BBB) and form a rich focus, which may subsequently rupture into the subarachnoid space, eliciting a significant inflammatory response.[12]
Cranial nerve palsy occurs in 20–30% of TBM cases.[13] In a study from Wen et al., cranial nerve palsy was identified in 33.3% of the recruited patients, with the oculomotor nerve (the third nerve) being the most commonly affected at 52.2%.[8] That study showed the total WCC in CSF may be correlated with cranial nerve palsy. Our study provides a more detailed analysis by demonstrating the predominance of lymphocytes in CSF, in line with the findings of Wen et al.[8] After MTB’s passage through the central nervous system, the immune system attempts to manage the infection. Immune cells, particularly microglia, macrophages, and T lymphocytes, play a role in identifying and eliminating MTB. As a result, the prevalence of significant lymphocytes in the CSF may indicate TBM.[1]
The cranial nerve palsy in TBM includes those that follow. TBM essentially induces exudative and proliferative lesions in the central nervous system, the exudate accumulates in the subarachnoid space at the base of the brain and the lateral cistern, surrounding the brainstem and exerting pressure on the cranial nerves, which leads to palsy. It can also happen due to the direct inflammatory action of cranial nerves in the subarachnoid space or due to tuberculoma or abscess may serve as a cause. Intracranial hypertension and brain herniation may potentially impair the cranial nerves in advanced cases. Overproduction of CSF results in communicating hydrocephalus, leading to the distension of cranial nerves and subsequent paralysis. On the other hand, occlusive vasculitis may result in cerebral stem infarction and stroke, leading to cranial nerve impairment.[8]
In a study conducted in India, Sharma et al. included 158 patients with TBM and found that cranial nerve palsy was observed in 38% of these patients and was associated with poor outcome.[7] Another study from Li et al. performed a study indicating that the association of TBM with cranial nerve palsy occurred in merely 14.8% of patients during follow-up. The oculomotor nerve palsy (56.9%) was the most frequent among these.[14] The distribution of cranial nerve palsy predominantly affected the anterior cranial nerve group, with the oculomotor nerve being the most frequently involved, followed by the optic nerve and abducens nerve. The occurrence of cranial nerve palsy within the posterior cranial nerve group is infrequent.[8]
The impairment of the BBB can lead to protein leakage into the CSF.[15] Low glucose levels in the CSF, particularly compared to plasma glucose, indicate TBM, as MTB uses glucose as its metabolic substrate.[1] Hyponatremia is another symptom observed in TBM patients. It is believed that the anti-diuretic hormone plasma is secreted in response to increased intracranial pressure, which causes elevated mean arterial pressure and maintains cerebral perfusion pressure within normal limits.[16] Headache and decreased consciousness are signs of increased intracranial pressure. Prolonged rise of intracranial pressure may result in ventricular displacement and cerebral herniation, potentially resulting in coma and death.[17]
Limitations
The present study revealed certain limitations. Initially, our study used a retrospective design with a small sample size. Information on recruited patients was confined to medical records, which consequently led to selection bias. This study also did not possess long-term follow-ups and did not perform multivariate analysis.
CONCLUSION
Cranial nerve palsy is a frequent clinical symptom of TBM, with a CSF lymphocyte count over 50% serving as a significant predictor of this condition. There were no significant differences between clear appearance, cell count of 10–500/mL, and CSF to plasma glucose ratio of <50%. Given those limitations, the next step was to conduct a multi-center prospective cohort research with a larger sample size.
Ethical approval:
The research/study approved by the Institutional Review Board at Dr. Soetomo General Hospital, number 1948/LOE/301.4.2.III/2025, dated March 19th, 2025.
Declaration of patient consent:
Patient’s consent was not required, as there are no patients in this study.
Conflicts of interest:
There are no conflicts of interest.
Use of artificial intelligence (AI)-assisted technology for manuscript preparation:
The authors confirm that there was no use of artificial intelligence (AI)-assisted technology for assisting in the writing or editing of the manuscript and no images were manipulated using AI.
Financial support and sponsorship: Nil.
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