Abstract:TBM involves extensive pathology in the central nervous system. Severe infarction was predictive of poor outcome although this was not the case for angiographic abnormalities. Spinal disease occurs commonly and has important implications for diagnosis and treatment. Comprehensive imaging of the brain, spine and cerebral vessels adds insight into disease pathophysiology.
“…Imaging of M. tuberculosis -infected animals showed post-gadolinium enhancement of the tuberculomas on T 1 -weighted images and T 2 -weighted images demonstrated enlarged ventricles with enhancement ipsilateral to the tuberculoma. The post-gadolinium enhancement of TB lesions seen in this model is similar to enhancement of tuberculomas in individuals with CNS TB (Katti, 2004; Rohlwink et al, 2016b). Fig.…”
Section: Resultssupporting
confidence: 59%
“…However, these animal models do not evaluate the effect of TB meningitis and the host immune response on normal brain development, which would be crucial in the immature brain. Some studies suggest that there is a higher prevalence of cerebral infarcts and strokes in children with TB meningitis, which are associated with worse prognosis (Dastur et al, 1970; Kingsley et al, 1987; Rohlwink et al, 2016a,b). Therefore, more clinical and preclinical studies are needed to evaluate the potentially different host immune response in the younger and more immature brain.…”
Section: Discussionmentioning
confidence: 99%
“…MRI could also be utilized to monitor response to treatment or predict outcomes. A recent prospective pediatric study by Rohlwink et al (2016b) demonstrated that MRI evidence of severe infarcts from either vascular or non-vascular pathology, such as intracranial hypertension or hydrocephalus, was predictive of poor outcomes. Although we did not identify infarcts in our model at the time of imaging, enlarged ventricles were detected on MRI.…”
Central nervous system (CNS) tuberculosis (TB) is the most severe form of extra-pulmonary TB and disproportionately affects young children where the developing brain has a unique host response. New Zealand white rabbits were infected with Mycobacterium tuberculosis via subarachnoid inoculation at postnatal day 4-8 and evaluated until 4-6 weeks post-infection. Control and infected rabbit kits were assessed for the development of neurological deficits, bacterial burden, and postmortem microbiologic and pathologic changes. The presence of meningitis and tuberculomas was demonstrated histologically and by in vivo magnetic resonance imaging (MRI). The extent of microglial activation was quantified by in vitro immunohistochemistry as well as non-invasive in vivo imaging of activated microglia/macrophages with positron emission tomography (PET). Subarachnoid infection induced characteristic leptomeningeal and perivascular inflammation and TB lesions with central necrosis, a cellular rim and numerous bacilli on pathologic examination. Meningeal and rim enhancement was visible on MRI. An intense microglial activation was noted in M. tuberculosis-infected animals in the white matter and around the TB lesions, as evidenced by a significant increase in uptake of the tracer 124I-DPA-713, which is specific for activated microglia/macrophages, and confirmed by quantification of Iba-1 immunohistochemistry. Neurobehavioral analyses demonstrated signs similar to those noted in children with delayed maturation and development of neurological deficits resulting in significantly worse composite behavior scores in M. tuberculosis-infected animals. We have established a rabbit model that mimics features of TB meningitis in young children. This model could provide a platform for evaluating novel therapies, including host-directed therapies, against TB meningitis relevant to a young child's developing brain.
“…Imaging of M. tuberculosis -infected animals showed post-gadolinium enhancement of the tuberculomas on T 1 -weighted images and T 2 -weighted images demonstrated enlarged ventricles with enhancement ipsilateral to the tuberculoma. The post-gadolinium enhancement of TB lesions seen in this model is similar to enhancement of tuberculomas in individuals with CNS TB (Katti, 2004; Rohlwink et al, 2016b). Fig.…”
Section: Resultssupporting
confidence: 59%
“…However, these animal models do not evaluate the effect of TB meningitis and the host immune response on normal brain development, which would be crucial in the immature brain. Some studies suggest that there is a higher prevalence of cerebral infarcts and strokes in children with TB meningitis, which are associated with worse prognosis (Dastur et al, 1970; Kingsley et al, 1987; Rohlwink et al, 2016a,b). Therefore, more clinical and preclinical studies are needed to evaluate the potentially different host immune response in the younger and more immature brain.…”
Section: Discussionmentioning
confidence: 99%
“…MRI could also be utilized to monitor response to treatment or predict outcomes. A recent prospective pediatric study by Rohlwink et al (2016b) demonstrated that MRI evidence of severe infarcts from either vascular or non-vascular pathology, such as intracranial hypertension or hydrocephalus, was predictive of poor outcomes. Although we did not identify infarcts in our model at the time of imaging, enlarged ventricles were detected on MRI.…”
Central nervous system (CNS) tuberculosis (TB) is the most severe form of extra-pulmonary TB and disproportionately affects young children where the developing brain has a unique host response. New Zealand white rabbits were infected with Mycobacterium tuberculosis via subarachnoid inoculation at postnatal day 4-8 and evaluated until 4-6 weeks post-infection. Control and infected rabbit kits were assessed for the development of neurological deficits, bacterial burden, and postmortem microbiologic and pathologic changes. The presence of meningitis and tuberculomas was demonstrated histologically and by in vivo magnetic resonance imaging (MRI). The extent of microglial activation was quantified by in vitro immunohistochemistry as well as non-invasive in vivo imaging of activated microglia/macrophages with positron emission tomography (PET). Subarachnoid infection induced characteristic leptomeningeal and perivascular inflammation and TB lesions with central necrosis, a cellular rim and numerous bacilli on pathologic examination. Meningeal and rim enhancement was visible on MRI. An intense microglial activation was noted in M. tuberculosis-infected animals in the white matter and around the TB lesions, as evidenced by a significant increase in uptake of the tracer 124I-DPA-713, which is specific for activated microglia/macrophages, and confirmed by quantification of Iba-1 immunohistochemistry. Neurobehavioral analyses demonstrated signs similar to those noted in children with delayed maturation and development of neurological deficits resulting in significantly worse composite behavior scores in M. tuberculosis-infected animals. We have established a rabbit model that mimics features of TB meningitis in young children. This model could provide a platform for evaluating novel therapies, including host-directed therapies, against TB meningitis relevant to a young child's developing brain.
“…While neuroimaging studies may appear normal in early stages of disease, most patients will develop one or more neuroimaging abnormalities [41]. Meningeal enhancement in the basal brain and communicating hydrocephalus are the most common radiographic findings in patients with tuberculous meningitis [42–45]. Infarctions often occur despite anti-tuberculosis treatment, with the basal ganglia and internal capsule being most affected [41, 46].…”
Section: Diagnostic Approachmentioning
confidence: 99%
“…Hyponatremia is also more likely in children [78], due to either the syndrome of inappropriate anti-diuretic hormone or cerebral salt wasting [78, 83], which can be distinguished by extracellular fluid status [84]. Cerebrospinal fluid biomarkers of neuronal and astroglial injury predict survival at 6 months in South African children, with early changes (during the first 3 weeks) providing the greatest prognostic information [42]. …”
Purpose of Review
Tuberculous meningitis is the most devastating manifestation of infection with Mycobacterium tuberculosis and represents a medical emergency. Approximately one half of tuberculous meningitis patients die or suffer severe neurologic disability. The goal of this review will be to review the pathogenic, clinical, and radiologic features of tuberculous meningitis and to highlight recent advancements in translational and clinical science.
Recent Findings
Pharmacologic therapy includes combination anti-tuberculosis drug regimens and adjunctive corticosteroids. It is becoming clear that a successful treatment outcome depends on an immune response that is neither too weak nor overly robust, and genetic determinants of this immune response may identify which patients will benefit from adjunctive corticosteroids. Recent clinical trials of intensified anti-tuberculosis treatment regimens conducted in Indonesia and Vietnam, motivated by the pharmacologic challenges of treating M. tuberculosis infections of the central nervous system, have yielded conflicting results regarding the survival benefit of intensified treatment regimens. More consistent findings have been observed regarding the relationship between initial anti-tuberculosis drug resistance and mortality among tuberculous meningitis patients.
Summary
Prompt initiation of anti-tuberculosis treatment for all suspected cases remains a key aspect of management. Priorities for research include the improvement of diagnostic testing strategies and the optimization of host-directed and anti-tuberculosis therapies.
IMPORTANCE Stroke in tuberculous meningitis (TBM) is associated with significant morbidity and mortality.OBJECTIVE To determine the country-specific, regional, and overall prevalence of stroke among patients with TBM, including their clinical manifestations, stroke locations, and outcomes.EVIDENCE REVIEW This systematic review searched records in MEDLINE by PubMed, Scopus, and EMBASE until July 2020 for relevant articles on the occurrence and characteristics of stroke in TBM.Randomized clinical trials and cohort studies that included a population of patients with TBM were analyzed for clinical manifestations, type of stroke, area of stroke, vascular territory, and outcomes.Studies that did not report the occurrence of stroke, reported as abstract only with no full-texts available, and articles not in English were excluded. The country-specific, regional, and overall frequencies of stroke among patients with TBM were determined; secondary analysis enumerated the summary estimates of the clinical presentations, common locations of stroke, and outcomes. The Murad tool was used to assess methodological quality.FINDINGS From 852 articles identified, 71 studies involving 2194 patients with stroke in TBM were included. The sample size for each study ranged from 17 to 806 patients. The frequency of stroke in TBM showed an estimate of 0.30 (95% CI, 0.26-0.33). The most common clinical manifestations were fever and headache. The lateral striate, middle cerebral, and medial striate arteries were typically affected. The basal ganglia, cortex and lobar, and internal capsule were the frequently involved areas of the brain. The pooled proportions of mortality and poor outcomes were 0.22 (95% CI, 0.16-0.29) and 0.51 (95% CI, 0.37-0.66), respectively.
CONCLUSIONS AND RELEVANCEThe results of this systematic review suggest that stroke is considerably frequent among patients with TBM. The reported frequencies of stroke in TBM and its clinical features vary across the studies and populations.
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