Hydrocephalus and vasculitis delay therapeutic responses in tuberculous meninigitis: Results of Haydarpasa-III study
Correspondence Address: Source of Support: None, Conflict of Interest: None DOI: 10.4103/0028-3886.190258
Source of Support: None, Conflict of Interest: None
Keywords: Clinical; meningitis; response; tuberculosis
Tuberculosis (TB) can affect many organs of the body and remains an important cause of morbidity and mortality worldwide. Despite antimycobacterial treatment, 15–50% of patients still die of tuberculous meningitis (TBM)., According to the World Health Organization (WHO), there were approximately 9.6 million cases of tuberculosis in 2014 resulting in 1.5 million deaths (http://apps.who.int/iris/bitstream/10665/191102/1/9789241565059_eng.pdf?ua = 1). Involvement of the central nervous system (CNS) occurs in 1% of patients with active tuberculosis and in 5–10% of those with extrapulmonary tuberculosis.
The clinical presentation of TBM can be classified into three distinct prognostic stages, as defined by the British Medical Research Council criteria.,,, Grade I is characterized by the insidious onset of malaise, lassitude, headache, low-grade fever, a normal mental status, and no focal neurological deficits. Grade II follows with worsening neurologic features such as meningismus, severe headache, vomiting, lethargy, confusion, a Glasgow coma score of 11 to 14, or a Glasgow coma score of 15 with focal neurological deficits. Finally, grade III is characterized by a Glasgow coma score of 10 or less with or without focal neurological deficits. In general, fever, headache, and altered mental status are the three most prominent symptoms of TB meningitis., To the best of our knowledge, there are no studies evaluating predictors for an early clinical response in TBM as well as on the resolution of classical meningitis symptoms such as fever, headache, and altered consciousness. This study examined the course of these parameters after the start of antibiotic therapy, and evaluated the factors affecting the early treatment response in patients with microbiologically confirmed TBM. Our ultimate aim was to provide more insight to the treating clinician regarding the course of the disease under therapy, with special emphasis on the study of parameters delaying the therapeutic response.
This retrospective, international Haydarpasa-3 study included 88 patients who were hospitalized with TBM between 2000 and 2012. Tuberculous meningitis was diagnosed by the clinicians at the participating centers. In the Haydarpasa study, a standard data collection form was used for patients suffering from TBM older than 14 years of age. The demographic features and the clinical and laboratory data of the patients were obtained. In this Haydarpasa-3 study, we used the same database obtained with the Haydarpasa-1 study that evaluated the diagnostic accuracy of laboratory tests; and, the Haydarpasa-2 analysis that provided a novel prognostic index for predicting an unfavorable outcome. Haydarpasa-4 study, one of the major components of these consecutive Haydarpasa studies, evaluated antibiotic resistance patterns and is published elsewhere. The Haydarpasa database includes 507 patients with microbiologically confirmed TBM. In this substudy, the data from 94 patients that were found to be eligible for analysis was submitted from 24 participating centers. Six out of 94 patients died during the hospitalization and the statistical analysis was performed with 88 survivors to determine the therapeutic responses [Figure 1]. The median values of the duration of fever, loss of consciousness, headache, and complete resolution of symptoms between the initiation of treatment and recovery in 507 TBM patients were calculated as 7, 9, 11, and 13 days, respectively, and were used to form the 'early' and 'late responder' groups. Only the 88 TBM cases with follow-up data for fever, headache and mental changes, and having computed tomography/magnetic resonance imaging (CT/MRI) scans were included in the Haydarpasa-3 study. The TBM patients, whose follow-up data could not retrieved from the hospital records, were excluded from the study. The Haydarpasa study protocol was initially approved by the institutional review board of Fatih Sultan Mehmet Training and Research Hospital in Istanbul.
The patients meeting all of the following criteria were included: 1. Clinical and laboratory evidence of CNS infection and microbiological confirmation of TBM in the cerebrospinal fluid (CSF) by one of the following: (a) Positive Ehrlich–Ziehl–Neelsen (EZN) staining, (b) positive mycobacterial culture and, (c) positive polymerase chain reaction (PCR) analysis. 2. Patients with available data of cranial MRI or cranial CT scan; 3. TBM patients with regular follow-up with respect to the clinical response towards fever, headache, and alterations in consciousness during the course of anti TB treatment.
Some of the definitions utilized in the series included the following:
Stage of the disease: It was determined according to the classical British Medical Research Council system.
Vasculitis: The classical histopathological change for vasculitis essentially consists of an inflammatory infiltrate within the vessel wall associated with destructive changes, occlusion, and infarction. These radiological findings were grouped together in one block as vasculitis.
Motor deficit: Hemiplegia-hemiparesis, paraplegia-paraparesis, and quadriplegia-quadriparesis were expressed as motor deficits.
Elapsed time: The period between the onset of symptoms and the initiation of anti-tuberculous therapy was considered as the elapsed time.
Immunosuppression: Use of immunosuppressive drugs, including corticosteroids, connective tissue disorders, and malignancies were included in this category
Follow-up of patients: The initial evaluation was performed on admission to the hospital. The patients were evaluated on a daily basis during their hospitalization. The clinical improvement, specifically including that in fever, headache, and alteration in conscious, was monitored and recorded. Response to antimycobacterial treatment was regularly noted at follow-up visits as follows:
Complete resolution of symptoms: Improvement in the clinical response including complete disappearance of fever, alteration in consciousness, and headache.
Paradoxical reaction: Effective killing of Mycobacterium tuberculosis (MTB) may worsen pre-existing tuberculous lesions or induce new lesions that produce fresh neurological symptoms, despite an initial improvement. These events are called paradoxical reactions. In these cases, the initial resolution of TBM symptoms followed by the development of fresh ones were considered to be a part of the paradoxical response.
Statistical analyses were done by using the Statistical Package for the Social Sciences, Version 20 software (IBM; SPSS Inc., Chicago, IL, USA). The median values of the duration of fever, loss of consciousness, headache, and complete resolution of all symptoms after the initiation of treatment were calculated from the Haydarpasa database study that included 507 patients. Accordingly, the median values were 7, 9, 11, and 13 days, respectively, for the duration of fever, loss of consciousness, headache, and complete resolution of all symptoms. These median values were used to form the 'early' and 'late response' groups in this study. We further analyzed various categorical clinical and laboratory data in the subset of 88 patients by using the chi-square test or Fisher's exact test. Numerical or ordinal data showing an abnormal distribution in groups were compared using the Mann–Whitney U-test. All possible factors identified (P ≤ 0.05) in predicting the response to treatment in the previous analyses were further included in the multivariate analysis for assessment of independent predictors using logistic regression analysis.
The patient groups were formed based on the presence of variables and the clinical response times and were compared using the Mann–Whitney U-test. A multivariate linear regression model was used to assess the independent effects of various predictors on the treatment response. P values less than 0.05 were considered statistically significant.
The study included 88 patients who were treated between 2000 and 2012. The mean age of the patients was 33.9 ± 16.4 years (range 14–87 years; median 30 years). Female gender comprised half of the patients (n = 44). CSF EZN staining was positive in 18 out of 86, CSF culture for MTB was positive in 73 of 88, and CSF for MTB PCR was positive in 12 of 27 patients. At least one of the parameters, EZN, culture, or PCR was positive in each patient. As the initial therapy, five anti-tuberculosis drugs were used in 13, four drugs were used in 70, and 3 drugs were used in five TBM patients. The mean prednisolone equivalent dose of steroids used in TBM patients was 116.28 ± 59.08 mg and the mean duration of steroid usage was 39.76 ± 18.17 days.
In this study, 6 out of 94 patients died of various complications related to TBM during the treatment. One of these patients died without a clinical response at day 28 despite institution of treatment. The clinical response of the other five patients was observed for fever in 6 ± 2.68 days, for headache in 18.4 ± 12.33 days, and for mental alteration in 12.8 ± 7.3 days.
On univariate analysis, late deffervescence (duration of fever >7 days) was seen more frequently in those patients who presented with vasculitis (P = 0.015) and in patients who waited longer to be treated after the onset of symptoms (14 vs. 20 days) [P = 0.011; [Table 1]. In multivariate analysis, the presence of vasculitis (P = 0.029, OR = 10.491 [95% CI, 1.27–86.83]) was found to be the only significant variable associated with late deffervescence [Table 2]. Likewise, the presence of hydrocephalus (P = 0.003) and the use of five medications was associated with a persistent altered mental status >9 days (P = 0.044) [Table 3]. In multivariate analysis, only the presence of hydrocephalus (P = 0.005, OR = 5.740 [95% CI, 1.68–19.57]) was found to be significantly associated with persistent altered mental status [Table 2]. We found no factors that had a statistically significant effect on the recovery of headache [Table 4].
The median duration of complete recovery showed that only the presence of hydrocephalus (P = 0.066) was significantly associated with a delayed clinical response [Table 5]. Fever was significantly prolonged in the presence of convulsions (15 days vs. 7 days, P = 0.036), vasculitis (17.5 days vs. 7 days, P = 0.02), and hydrocephalus (11 days vs. 7 days, P = 0.031) whereas it was shorter in those with chronic renal insufficiency (3 days vs. 8 days, P = 0.047). On further analysis with linear regression, vasculitis (P < 0.001) and hydrocephalus (P = 0.029) were significant predictors. Overall, the presence of hydrocephalus was significantly associated with the persisting headache (21 days vs. 12 days, P = 0.025), delayed recovery of consciousness (19.5 days vs. 7 days, P = 0.001), and a delay in the complete recovery (21 days vs. 14 days, P = 0.007) [Table 6].
A paradoxical response was seen 2 (2.3%) and toxicity due to antimycobacterial drugs were seen 6 (6.8%) out of 88 patients. Therapy in patients experiencing adverse events was not stopped but modified to intermittent antimycobacterial therapy. Drug resistant MTB was detected in 5 (5%) of 88 cases. Brainstem vasculitis was observed in 4 (4.5%) out of 88 patients.
The treatment consisted of four anti-tuberculous drugs in 70, and three anti-tuberculous drugs in 5 survivors. However, five drugs were initially given to 13 patients. Of these 13 patients, 5 patients were infected with drug resistant MTB and 5 patients experienced drug toxicity; although the antibiotic susceptibility pattern was not known, 3 other patients had a previous history of tuberculosis. As expected, the duration of response to treatment in these cases was longer than that of the patients receiving a four-drug regimen. However, this difference was not statistically significant in the multivariate analysis.
CNS infections are life-threatening infections with serious sequelae. The clinical response to antibiotic therapy is evaluated after 48 h of the start of antibiotics in bacterial meningitis. To the best of our knowledge, there are no data assessing the efficacy of anti-tuberculous drugs in the resolution of TBM symptoms. Obviously, exploring the clinical response and the factors affecting the duration of this period (during which the resolution of TBM symptoms takes place) may be helpful for the treating clinician. The existing studies on TBM have only included assessement of factors associated with an unfavorable outcome. In the present study, we found that the presence of either vasculitis or hydrocephalus resulted in a delayed resolution of symptoms of meningitis in TBM patients.
The incidence of hydrocephalus, which has been known to result in a poor prognosis, was reported to be 52–84% in TBM patients.,, Serial neuroimaging assessment disclosed that 40% of TBM cases with hydrocephalus had complete cure and 38% displayed partial resolution in due course of treatment. In our study, the presence of hydrocephalus was found to be the most prominent parameter related to a delay in the normalization of consciousness, resolution of headache, and fever, and finally in achieving complete recovery. In routine medical practice, visual impairment, cranial nerve palsies, and the presence of basal exudates were reported to be significant predictors of hydrocephalus. Thus, close monitoring of TBM patients for the development of hydrocephalus; as well in assessing the increase the increase in hydrocephalus, particularly in its early stages, in collaboration with neurosurgeons, may contribute to the improvement of the neurological status of patients suffering from TBM. On the other hand, vasculitis is a commonly observed autopsy finding in TBM patients. Arteritis, arterial thrombosis, arterial spasm, and compression of larger arteries caused by thick exudates are vascular abnormalities in TBM, and hence, cerebral perfusion reduces as vascular changes and infarcts develop. It has long been known that vasculitic lesions may produce high and persisting fever even in noninfectious disorders  along with their noteworthy contributions towards a poor prognosis in TBM., In this study, 4.5% of the cases had vasculitic involvement at the level of the brainstem, whereas the majority of vasculitic lesions were mainly distributed within the cerebrum. Consequently, the presence of these lesions extended the febrile period in TBM patients in this study.
Although the advanced stage of the disease was reported as a risk factor for an unfavorable outcome in TBM patients, result of this study indicated that the classical TBM staging developed by the British Medical Council in 1948 did not directly affect the clinical responses. The current data also corroborates that this staging system does not adequately correlate with the clinical outcomes, as had been perceived in the past.,,, Rather, we found that the basic parameters such as vasculitis and hydrocephalus, which both result in an advancement of the clinical staging in TBM patients, were the main predictors of a delayed clinical response. As expected, old age, diabetes mellitus, immunosuppression, and neurological deficits were not associated with a significant clinical improvement in this study. This is probably due to the existing complex interactions between immunity and eradication of infection wherein strong immune responses have been implicated in increasing the neural damage. Hence, in this study, we could not irrefutably demonstrate that TBM patients with the potential to have weakened immunity had delayed clinical responses.
The major limitation of this study is its retrospective design. However, it is difficult to provide a prospective cohort with microbiologically confirmed TBM, as was recruited for this study. In conclusion, vasculitis, and particularly hydrocephalus, seem to be associated with a delay in the clinical response in TBM patients. In addition, the clinical symptoms of TBM patients under antimycobacterial treatment seem to recover in up to 2 weeks, on an average, among survivors, according to our data. In the absence of hydrocephalus and vasculitis, a week of anti-tuberculous treatment seems to be adequate for detecting the resolution of major symptoms and to assess the efficacy of anti-tuberculous treatment in TBM patients. Even in the small proportion of patients exhibiting a subsequent paradoxical reaction (2.3%), the presence of hydrocephalus and vasculitis apparently delay the initial resolution of major symptoms of TBM.
Financial support and sponsorship
Conflicts of interest
We neither have competing interests to declare nor did we receive a fund of any kind.
[Table 1], [Table 2], [Table 3], [Table 4], [Table 5], [Table 6]