This study described the early features that distinguish TBM patients and discriminated them from the patients with CNS infection from other causes including virus, bacteria, and cryptococcus. A new diagnostic score of TBM was developed by supplementing early observations, eliminating non-independent predictors, and re-balancing the weight of each indicator, and it validated the score in a prospective population.
TBM mostly manifests as subacute onset[21]. Previous studies have defined the duration of TBM as longer than 5-10 days[12, 14, 15, 17], which did not distinguish TBM from CM. In our study, 66.5% of patients in the TBM group had a symptom duration of 10-30 days. The results suggest that a symptom duration of more than 10 days can help discriminate between TBM and acute meningitis including VM and BM, and a symptom duration of less than 30 days can help differentiate TBM from CM effectively. CM presents with a more insidious onset of symptoms, and it even has minimal or nonspecific symptoms at presentation, especially in patients with immunosuppression. The median duration of CM from the symptom onset to presentation is 6-12 weeks in non-HIV cases[22]. Therefore, the dichotomized variable of 10-30 days can help diagnose TBM more specifically and accurately.
CSF laboratory data are a vital part of the diagnosis of CNS infections. Similar to previous observations, patients with TBM were more likely to show features of high protein[15, 19, 23-25], and hyponatremia (the manifestation in CSF was a decrease in chloride concentration)[13, 17, 26]. We focus on the differences between this score and previous TBM score studies. Most of the previous studies[14, 15, 17, 19, 21] only limited the CSF leukocyte count in TBM to a cut-off value (>10-20*106/ml) rather than a range, which was of little significance for the differential diagnosis of confusing CNS infection, especially between TBM and BM. The reference range of CSF leukocyte count was limited to 100-500*106/ml in our study, which may more reasonable than that in the other prior scoring model settings. However, it was worth noting that CSF leukocyte count and classification as well as CSF biochemistry should be combined to have greater reference significance.
The unique element of our TBM scoring system is the proportion of CSF neutrophils and not the predominance of lymphocytes. Before treatment, the typical CSF cytology in TBM is characterized as a mixed cellular response with neutrophils, monocytes, and lymphocytes. Specifically, 47% of the patients had more than 50% neutrophils and 66.4% of the patients had more than 40% neutrophils. Using a cut-off value for a neutrophil proportion of 20%-75%, the sensitivity and specificity were 75.5% and 86.7%, respectively, with an AUC of 0.885. VM most commonly presents with a CSF lymphocytic predominance and rare neutrophils, and acute BM commonly presents with neutrophilic pleocytosis in the CSF (usually more than 80% before treatment), while CM usually presents with a mixed cell response pattern dominated by lymphocytes. The neutrophil proportion is overwhelmingly the strongest diagnosis predictor of TBM, therefore, weighting this component of the TBM score more than others is justified. It was worth noting that the application of the neutrophils proportion in the diagnosis of TBM was not consistent in previous studies. Based on cytological examination of CSF, several studies point out that in the acute phase of untreated TBM, the increase in the proportion of neutrophils was the early characteristic, which can exceed 50%, and in the subacute phase, whether effective treated or not, it changes into a mixed cytological reaction[27-31]. Recently, there are few studies on the CSF cytology of the TBM series. Some studies only put forward that CSF lymphocyte predominance (> 50%) was the characteristic manifestation of TBM, but did not classify the cells in detail[21, 23, 24]. Therefore, the reasons for the inconsistencies may be due to differences in the methodology used for CSF classification. Since the cellular component of CSF obtained from the lumbar area is generally scant, and considering the potential for cell loss, the clarity of cellular detail and the spectrum of stains offered, cytological examination of CSF has effectively addressed these aspects, ensuring the integrity of cell collection and the accuracy of classification[32]. Among all studies of this type, CSF cytology plays a central, indispensable role. Therefore, the score of lymphocyte > 50% in the expert consensus remains to be further studied and confirmed on a large scale.
TBM has several mechanisms to raise CSF neutrophils. The central pathogenesis of TBM has been widely believed to be the basal inflammatory exudate[33, 34]. Pathological studies found that early TBM without anti-tuberculosis treatment was exudative inflammation, and the inflammatory changes were mainly located at the basicranial with a large number of neutrophils[33]. Moreover, there were consistent reports that the earliest immune response during mycobacterial infection was a migration of neutrophils to the site of infection[35-37], with neutrophils having functions of phagocytosis, chemotaxis and killing pathogenic bacteria[38, 39]. Thus, an increase in neutrophils was first seen in CSF of TBM, and a subsequent mixed cytological response was seen in CSF cytology due to the chemotactic effect of neutrophils on other immune cells.
Imaging outcomes of CNS including meningeal enhancement and brain parenchyma nodules (tuberculomas) were independent predictors of TBM diagnosis, which was consistent with previous studies[21, 40-43]. In contrast to several reports which demonstrated hydrocephalus among the patients with TBM[41-43], this study failed to identify this parameter as a suitable parameter to distinguish TBM from other causes of meningitis. The reason may be that the pathological process of this study cohort was in the early stage of onset, and the disease did not develop to hydrocephalus. Of note, among the patients who underwent spinal cord imaging, 18 patients of TBM had spinal meningeal enhancement features, which were less common in the non-TBM group (2-5 cases). Considering that not all patients included in this study routinely undergo spinal cord MRI, this index was not included in the scoring system. However, the incidence of spinal meningeal enhancement in TBM should not be ignored. Gupta et al. reported that 46.4% (30/71) of TBM cases showed spinal involvement [44]. And Rohlwink et al. described spinal cord disease associated with TBM in a large pediatric cohort, and enhancement of the cord was present in over 70% of patients[45]. The mechanism of spinal involvement was considered to be related to M. tuberculosis hematogenous spread to the spinal cord or infiltration of the tuberculous exudate into the lumbosacral region[46]. Recently, Liu, Y et al. [47] found that spinal involvement of TBM might be significantly associated with paradoxical reactions[48]. Our study suggests that extended contrast-enhanced spinal cord MRI should be performed as part of the assessment of TBM in patients with particularly high or progressively increased CSF protein content and/or symptoms involving the spinal cord, such as paraparesis, hemiparesis, paresthesia in lower limbs, sphincter dysfunction, and sensory loss.
Several limitations of this study should be acknowledged. First, this was a retrospective study, and data for some of the variables were inaccessible and could not be introduced into the logistic regression analysis. As a result, 104 patients were excluded due to insufficient data. Second, the TBM score model included only the risk factors available at the time of admission. However, changes in biomarkers measured repeatedly during the disease duration may provide important information in the whole process of TBM development. Additional studies might improve the accuracy of the score by updating the risk score, such as dynamic changes in CSF parameters and neuroimages. Third, the data in the present study were derived from the Chinese setting. The model needs to be tested prospectively at multiple centers to substantiate its broad applicability.