|Year : 2020 | Volume
| Issue : 3 | Page : 303-308
Identification of predictors of cerebrovascular infarcts in patients with tuberculous meningitis
Jeneesh U Selvaraj1, Benin B Sujalini1, Moses S Rohitson1, Anu Anna George2, Vanjare Harshad Arvind3, Ajay Kumar Mishra4
1 Department of Internal Medicine, Christian Medical College, Vellore, Tamil Nadu, India
2 Department of Dermatology, Christian Medical College, Vellore, Tamil Nadu, India
3 Department of Radiology, Christian Medical College, Vellore, Tamil Nadu, India
4 Department of Internal Medicine, St. Vincent Hospital, Worcester, MA 01545, USA
|Date of Submission||04-Jun-2020|
|Date of Decision||01-Jul-2020|
|Date of Acceptance||03-Jul-2020|
|Date of Web Publication||28-Aug-2020|
Ajay Kumar Mishra
Department of Internal Medicine, St. Vincent Hospital, 123 Summer Street, Worcester, MA 01545
Source of Support: None, Conflict of Interest: None
Background: Tuberculous meningitis (TBM) remains common in developing countries. Cerebrovascular infarct (CI) in TBM occurs in 15%–57% of patients. Literature regarding the predictors of central nervous system (CNS) infarct in patients with TBM is scanty, and the outcome of these events is unknown. The aim of this study is to evaluate the predictors of CI among patients with TBM at a tertiary care center in South India and to compare the impact of CI on the prognosis and outcomes in terms of mortality and morbidity. Methods: All patients who were confirmed to have TBM and CNS infarcts/stroke were included in this study retrospectively. Forty-six patients had appropriate imaging, and they were enrolled in the study as cases. Patients without infarct were matched with age and sex as controls. Details of the course of the disease, the extent of CNS involvement, and treatment were compared between the two arms. Results: The mean age of patients with and without infarct was similar. The presence of basal meningeal inflammation, hydrocephalus, focal neurological deficit, and cranial nerve palsy, was higher in patients with infarct. Independent predictors of infarcts in a patient with TBM were Medical Research Council (MRC) staging of II or more, presence of focal neurological deficit, cranial nerve palsy, and presence of hydrocephalus, meningeal enhancement on neuroimaging. Presences of infarcts were independently associated with a higher odds ratio of 2.58 for poor outcome, 4.48 for a longer duration of hospital stay, and odds ratio of 8.85 for the requirement of multiple hospitalizations. Conclusion: CI involvement in TBM has higher morbidity, with longer stay, recurrent admission
Keywords: Infarcts, meningitis, outcome, tuberculosis
|How to cite this article:|
Selvaraj JU, Sujalini BB, Rohitson MS, George AA, Arvind VH, Mishra AK. Identification of predictors of cerebrovascular infarcts in patients with tuberculous meningitis. Int J Mycobacteriol 2020;9:303-8
|How to cite this URL:|
Selvaraj JU, Sujalini BB, Rohitson MS, George AA, Arvind VH, Mishra AK. Identification of predictors of cerebrovascular infarcts in patients with tuberculous meningitis. Int J Mycobacteriol [serial online] 2020 [cited 2020 Oct 26];9:303-8. Available from: https://www.ijmyco.org/text.asp?2020/9/3/303/293535
| Introduction|| |
Tuberculous meningitis (TBM) is the most common cause of subacute/chronic meningitis in developing countries. The projected incidence of central nervous system (CNS) tuberculosis is 20.6 per 100,000 populations. Complications following TBM are diverse. Cerebrovascular infarcts (CI) are uncommon complications following TBM which occurs in 15%–57% of patients. Literature regarding the risk factors and predictors of CI in patients with TBM are scanty. Similarly, the outcomes of CI in terms of both mortality and morbidity have not been studied. The primary objective of the study was as follows: (1) to assess the risk factors for CI involvement among patients with TBM, admitted in the Department of Internal Medicine department, at a tertiary care center in South India between the period of 2004–2016 (2) and to compare the outcomes in terms of morbidity and mortality of TBM patients with and without CI. The secondary objective was to discuss the demographic characteristics, clinical profile, imaging findings, and details of vascular territory involved among patients admitted with TBM and cerebral infarct from a tertiary care center.
| Methods|| |
This retrospective case–control study was conducted among the patients seen in the Department of General Medicine, and Radiology of Christian Medical College, Vellore, a tertiary care center in South India. All patients with a diagnosis of TBM based on the Lancet consensus score were eligible to be enrolled in the study, from April 2004 to September 2016 (12 years). To be enrolled, patient also needed to have appropriate CNS imaging. Patients with TBM and a radiological evidence of infarct during their hospitalization were included as cases. Moreover, age-matched patients with TBM who had no radiological evidence of infarct were included as controls. Patients who did not have neuroimaging, did not fulfil Lancet criteria, and were identified to have culture proven co-infections were excluded from the study. A new-onset infarct in the background of meningitis as demonstrated by neuroimaging was defined as cerebral infarct as per the definition of the World Health Organization. The outcome measures that were included were the duration of hospital stay, number of admissions, and morbidity and mortality.
Patient details were obtained retrospectively from the medical records department of our hospital. Following recruitment, those who fulfilled the inclusion criteria were enrolled in the study. Data regarding the baseline demography, comorbidities (hypertension, diabetes mellitus, and HIV), clinical symptoms, signs, laboratory parameters, inflammatory markers, details and duration of treatment, hospital stay, morbidity, and mortality were obtained. Data were collected by three independent investigators. The investigators underwent short training regarding the study methodology, several variables, and the pathological basis behind the study methodology. In case of any discrepancies, the senior investigator's opinion was sought. The senior investigator supervised the data acquisition, monitored the accuracy of the data. A preplanned questionnaire was used by the investigators for data recruitment. The neuroimaging parameters were interpreted by two independent radiologists, one of them being a trained neuroradiologist. Who documented the presence and absence of infarcts, basal exudates, meningeal enhancement, hydrocephalus, tuberculoma, and patterns of neurological involvement. Further details of the infarcts such as the number, size, side, site, and type were also obtained. The presence of more than one infarct was considered as multiple. The primary outcome of interest in this study was mortality and poor outcome. Poor outcome was defined as mortality and discharge in a moribund condition.
Institutional Review Board committee approval was obtained before initiating this study [IRB Min No. 10343]. In view of the retrospective nature of the study, patient consent was not required. All obtained data were anonymized to maintain patient privacy. Only the final author had access to the complete details of the data set and was responsible in keeping it secured. All three clinicians and the radiologists were blinded toward the outcome of interest. The principal author ensured the reliability, and the quality of the data with independent monitoring of data. Data were entered using Epidata and analyzed using the SPSS-16 (IBM, Armonk, New York, USA).
| Results|| |
A total of 1142 patients had a diagnosis of TBM. Among these, only 116 (10.2%) patients had a diagnosis of stroke documented in the records. Of these, only 46 fulfilled the inclusion criteria (Lancet's criteria) and were included in the study as cases. Forty-six age- and sex-matched controls were obtained from the patients with TBM without any definite evidence of CI in neuroimaging and fulfilling Lancet criteria, as shown in [Table 1]. The mean age of patients in both groups was 39. Males contributed to around 61% in both groups. The duration of symptoms before the presentation was equal in both the groups, with half of the patients presenting within 1 month of symptoms onset. Depressed sensorium was noted in more than 70% of patients in both groups. Focal neurological deficit and cranial nerve deficits were present in 65%, 50% of patients with TBM, and infarct as compared to 9%, 13% of patients with TBM without infarcts. The most common associated risk factor was HIV, which was present in 21.7% of patients of TBM with infarcts as compared to 28.3% of patients with TBM without infarcts. Risk factors such as diabetes, hypertension, and smoking were slightly higher among patients with TBM and infarct.
Hemoglobin, leukocyte count, cerebrospinal fluid details, including cell counts, protein, and glucose were similar in TBM patients with and without infarct.
Neuroimaging details: 60% of patients with TBM and infarcts underwent magnetic resonance imaging (MRI) as compared to 20% of patients with TBM without infarct [Table 2]. The presence of hydrocephalus, meningeal enhancement, tuberculoma, and basal exudates was present in 63%, 56.5%, 13%, and 13% of patients with TBM and infarcts as compared to 20.4%, 30.4%, 2.2%, and 6.5% of patients with TBM without infarcts, respectively. Among the patients with infarcts, 93.5% were acute, 74% of infarcts were multiple, and 26% were single. Infarcts were located in basal ganglia, lobar, subcortical white matter, and thalamus in 37%, 24%, 19.5%, and 19.5%, respectively[Figure 1].
|Figure 1: Magnetic resonance imaging brain of a 76-year-old male. T2 fluid-attenuated inversion recovery axial section shows hyperintense foci in bilateral centrum semiovale in the internal watershed territories. Diffusion and apparent diffusion coefficient images showing foci of restricted diffusion in these regions|
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The details of multidrug anti-tubercular therapy and steroid administered were available in most TBM patients with and without infarct. 87% of TBM with infarct and 84% of patients with TBM without infarct completed at least 9 months of antitubercular therapy. Twenty-eight percent of patients with TBM and infarct and 15% of patients with TBM without infarct were treated with an extended course of ATT of at least 12 months. Poor outcomes occurred in 17% of patients with TBM and infarct and 6.5% of patients with TBM without infarct. Mortality occurred in 8.7% of patients with TBM and infarct only. As compared to 30% of patients without infarct, 52% of patients with TBM and infarct had a hospital stay of 15 days or more. Similarly, as compared to 15% of patients without infarct, 43% of patients with infarct had recurrent hospital admissions.
Independent predictors of infarcts in a patient with TBM were MRC staging of II or more, presence of focal neurological deficit, cranial nerve palsy, and presence of hydrocephalus, meningeal enhancement on neuroimaging [Figure 2]. Mortality occurred in patients with TBM and infarct only. Presences of infarcts were independently associated with poor outcome (odds ratio [OR]: 2.58), a hospital stay of >15 days (OR: 4.48), and requirement of multiple hospital admission (OR: 8.85) and all these were statistically significant.
|Figure 2: Magnetic resonance imaging brain of a 28-year-old man. Postcontrast T1-weighted axial section shows enhancement along the basal cisterns. Arrows pointing to enhancement in the interpeduncular cistern along left middle cerebral artery. T2-weighted axial sections demonstrating focal hyperintensity involving the posterior aspect of the left lentiform nucleus. Diffusion and apparent diffusion coefficient images showing restricted diffusion in the posterior aspect of the lentiform nucleus|
Click here to view
| Discussion|| |
Meningitis caused by MTB is usually subacute. TBM is known to have diverse complications, infarcts being one of them. The reported incidence has been around 6%–47%., In our study, around 10.2% of patients had a clinical diagnosis of infarcts. However, this could still under-represent the true incidence, given that most patients did not undergo neuroimaging. A recent study including 559 patients with TBM who underwent a neuroimaging reported an incidence of 25.8%, among this 4.5% of patients developed infarcts during follow-up. While noncontrast computed tomography (CT) is usually performed, contrast-enhanced CT, MRI is better in differentiating tuberculomas, dilated Virchow robin spaces, and infarcts.,, Similar to prior studies in this present study, most infarcts were acute in nature and multiple in locations., The most common site of infarcts reported were basal ganglia, subcortical white matter, and thalamus simultaneously.,,, A predilection of these infarcts to basal ganglia, internal capsule and thalamus leads to the naming of these areas as “tubercular zone.” This is thought to be secondary to the presence of the significant and severe basal exudates over the circle of Willis in TBM.,, However, the involvement of a typical tubercular zone is seen in only 20% of patients.
Multiple mechanisms have been attributed to the development of infarctions. Which are (1) Inflammatory basal exudates lead to constriction, vasospasm, and thrombosis of vessels passing through. (2) Spread of meningeal inflammation to the vessels causing vasculitis and thrombosis. (3) Dilated ventricles causing stretching of inflamed vessels. (4) Intimal proliferation and pro-coagulant state late in the disease.,,, The presence of coinfection with HIV is also known to contribute to the presence of infarcts. Patients with HIV are prone to have a higher number of infarcts. In these patients, the presence of other neurological coinfections such as cryptococcal meningitis, syphilis, cytomegalovirus, herpes zoster virus, and toxoplasmosis can also lead to infarcts.,, However, in our study, HIV was present in around 22% and 29% of patients with and without infarcts simultaneously and no other coinfection was identified in these patients as well.
To identify the various predictors associated with cerebral infarct in patients with TBM, we did a review of the literature of all the existing studies on predictors of CIs in TBM. We only reviewed studies published on PubMed in English. All studies including adults with TBM and CIs which had a comparison arm were included as shown in [Table 3].,,,,,, We identified seven studies, including a total of 356 patients. Among these 6 were prospective, three studies had used MRI and the remaining 4 used CT or MRI. Independent predictors that have been identified in each of these studies have been shown in [Table 3]. The predictors associated with TBM in our study were stage of meningitis, focal neurological deficit, cranial nerve deficit, hydrocephalus, and meningeal enhancement.,, [Table 4] depicts the demographics, comorbidities, clinical, laboratory, and imaging-related predictors of infarcts in patients with TBM.,,,
|Table 3: Studies showing predictors of cerebral infarcts with tuberculous meningitis|
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Even though basal exudates are thought to be crucial in the pathogenesis in our study, basal exudates were noted in 13% of patients with TBM and infarcts, in keeping with prior studies. Meningeal enhancement and presence of hydrocephalus were higher and statistically significant among patients with TBM and infarct in our study. Prior studies have reported similar findings as well.,,, In our study, age could not be established as a predictor as our control groups were age matched. All except one study in the past have identified higher age as a predictor for CIs in TBM. In a recent study, vascular risk factors such as diabetes and hypertension were higher in patients with TBM and infarct. In our study, diabetes, hypertension, and smoking were higher among TBM patients with infarct, but these were not statistically significant., Peripheral vascular disease and family history of cerebrovascular events were similar among TBM patients with and without infarcts.
Similar to our study, most studies have shown poor outcomes in TBM patients with infarct as compared to patients without infarct. Poor outcome in such patients is usually defined as death or discharge with significant neurological deficit., In our study, we also identified that TBM patients with infarct require multiple hospitalizations and longer duration of hospital stay as compared to TBM patients without infarct. Patients in our study were treated with four drug antituberculous therapy and steroids.,, Although aspirin has been studied in patients with TBM, it has not shown to have a mortality benefit., In our study, most patients were not started on aspirin because of the absence of other cardiovascular risk factors. Our study had several limitations. This was a single-center study. As all neuroimaging was patient-financed, we did not have MRI brain of all the patients. Details of cardiac, pro-thrombotic, and autoimmune markers were not available., We did not have the details of functional status of these patients at the time of discharge. Details of long-term outcomes were also not available.,, The role of interaction of anti-tubercular therapy and antiretroviral therapy on patient disease and outcome were also not available.,,,,,
| Conclusion|| |
CIs are not uncommon in patients with TBM. These tend to be acute and multiple.,, The presence of focal neurological deficit, cranial nerve deficit, and higher TBM MRC grade should prompt the clinician to look for the presence of CIs. TBM patients with CIs tend to have a longer hospital stay, multiple admissions, and poorer outcomes.,,,
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[Figure 1], [Figure 2]
[Table 1], [Table 2], [Table 3], [Table 4]