Meningeal tuberculosis

Infectious Disease MONDO:0006042 Pathograph 24 Show in embeddings browser Bacterial meningitis Tuberculosis

Meningeal tuberculosis is central nervous system tuberculosis caused by Mycobacterium tuberculosis, in which inhaled bacilli establish a primary pulmonary or disseminated focus, seed the meninges hematogenously, and trigger rupture of a caseating Rich focus into the subarachnoid space, basal granulomatous exudate, vasculitic infarction, hydrocephalus, and subacute meningitis with high mortality and neurologic morbidity.

Ask OpenScientist

Ask a research question about Meningeal tuberculosis. OpenScientist will conduct autonomous deep research using the Disorder Mechanisms Knowledge Base and PubMed literature (typically 10-30 minutes).

Submitting...

Do not include personal health information in your question. Questions and results are cached in your browser's local storage.

🏷

Classifications

Harrison's Part
INFECTIOUS DISEASES
⚙

Pathophysiology

9
Pulmonary Mycobacterium tuberculosis entry
Inhaled bacilli reach alveolar macrophages and establish a pulmonary or disseminated tuberculous focus.
Downstream
Hematogenous CNS Tuberculous Seeding Bacilli disseminate from the primary site through the bloodstream toward meningeal or subependymal foci.
Hematogenous CNS Tuberculous Seeding
Bloodborne M. tuberculosis seeds the meninges or adjacent ependymal surfaces and creates a caseating subpial or subependymal Rich focus.
meninx UBERON:0002360 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in meninx (UBERON:0002360). UBERON:0002360 is an anatomical location from the Uberon multi-species anatomy ontology.
Downstream
Rich Focus Rupture Into CSF A caseating focus at a meningeal or ependymal surface can rupture into the subarachnoid space.
Show evidence (1 reference)
PMID:7610242 SUPPORT Other
"The mechanisms and the changes described herein typically begin with a dense basal meningeal exudate often resulting from a "Rich focus" along the basal surface of the cerebrum or ventricular ependyma."
Places the Rich focus at the basal cerebral or ventricular ependymal surface upstream of the basal meningeal exudate.
Rich Focus Rupture Into CSF
Rupture of the caseating Rich focus releases bacilli and mycobacterial antigens into cerebrospinal fluid and the basal subarachnoid space.
cerebrospinal fluid UBERON:0001359 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in cerebrospinal fluid (UBERON:0001359). UBERON:0001359 is an anatomical location from the Uberon multi-species anatomy ontology. subarachnoid space UBERON:0000315 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in subarachnoid space (UBERON:0000315). UBERON:0000315 is an anatomical location from the Uberon multi-species anatomy ontology.
Downstream
Basal Granulomatous Meningeal Exudate Bacilli and antigens in CSF elicit dense granulomatous inflammation around the basal cisterns.
Show evidence (1 reference)
PMID:7610242 SUPPORT INDIRECT Other
"The mechanisms and the changes described herein typically begin with a dense basal meningeal exudate often resulting from a "Rich focus" along the basal surface of the cerebrum or ventricular ependyma."
Places a Rich focus upstream of the basal meningeal exudate. The abstract does not itself state that the focus ruptures into the subarachnoid space; that step is inferred from the focus-to-exudate sequence.
Basal Granulomatous Meningeal Exudate
Mycobacterial antigens drive an epithelioid-macrophage-rich basal meningeal exudate around cranial nerves, basal cisterns, and cerebral vessels.
macrophage CL:0000235 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves macrophage (CL:0000235). CL:0000235 is a cell type from the Cell Ontology. epithelioid macrophage CL:0002150 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves epithelioid macrophage (CL:0002150). CL:0002150 is a cell type from the Cell Ontology.
inflammatory response GO:0006954 ↑ INCREASED Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased inflammatory response (GO:0006954). GO:0006954 is a biological process from the Gene Ontology.
meninx UBERON:0002360 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in meninx (UBERON:0002360). UBERON:0002360 is an anatomical location from the Uberon multi-species anatomy ontology.
Downstream
Tuberculous Cerebral Arteritis Basal exudate entraps and inflames adjacent cerebral arteries.
Obstructive Tuberculous Hydrocephalus Dense exudate blocks basal subarachnoid cisterns and obstructs CSF flow.
CSF MMP-9 Elevation Neutrophilic meningeal inflammation is accompanied by raised MMP-9 in cerebrospinal fluid.
CSF pleocytosis The leukocytic meningeal inflammatory infiltrate is sampled as a lymphocyte-predominant CSF pleocytosis.
Cranial nerve paralysis Basal exudate encases cranial nerve trunks crossing the basal cisterns, producing cranial nerve palsies, most often of the abducens nerve.
Nuchal rigidity Inflammation of the meninges produces meningeal irritation, seen clinically as neck stiffness.
Headache Meningeal inflammation produces the headache of the meningitic prodrome.
Fever The granulomatous inflammatory response is accompanied by systemic fever.
Show evidence (1 reference)
PMID:7610242 SUPPORT Other
"This exudate is made up of small and large mononuclear cells, including epithelioid cells, which also act as macrophages and may fuse to form Langhans' giant cells."
Defines the cellular composition of the basal granulomatous exudate in tuberculous meningitis.
Tuberculous Cerebral Arteritis
Basal exudate entraps large arteries and perforators, producing arteritis and arterial occlusion.
middle cerebral artery UBERON:0001627 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in middle cerebral artery (UBERON:0001627). UBERON:0001627 is an anatomical location from the Uberon multi-species anatomy ontology.
Downstream
Ischemic Cerebral Infarction Arteritic occlusion causes ischemic infarction in the supplied territory.
Show evidence (1 reference)
PMID:7610242 SUPPORT Other
"Entrapment and occasional arteritic occlusion of larger arteries, such as the middle cerebral in the Sylvian fissures, results in infarction."
Links tuberculous basal exudate to arteritic occlusion of large arteries such as the middle cerebral artery.
Ischemic Cerebral Infarction
Ischemic infarction downstream of tuberculous arteritis, most commonly in the basal ganglia, is a major determinant of morbidity and mortality.
collection of basal ganglia UBERON:0010011 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in collection of basal ganglia (UBERON:0010011). UBERON:0010011 is an anatomical location from the Uberon multi-species anatomy ontology.
Downstream
Hemiparesis Infarction of the basal ganglia and internal capsule produces focal motor weakness, most often hemiparesis.
Seizure Late seizures in tuberculous meningitis are associated with cerebral infarction, as well as with tuberculoma and hyponatremia.
Cognitive impairment Ischemic brain injury contributes to the neurodisability seen in survivors, including cognitive impairment.
Show evidence (1 reference)
PMID:28281443 SUPPORT REVIEW SYNTHESIS Other
"Vasculitis leading to infarcts in the basal ganglia occurs commonly and is a major determinant of morbidity and mortality."
Places tuberculous infarcts in the basal ganglia and links them to morbidity.
Obstructive Tuberculous Hydrocephalus
Basal exudate or tuberculoma-associated narrowing of the aqueduct and third ventricle blocks CSF pathways and causes hydrocephalus.
cerebrospinal fluid UBERON:0001359 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in cerebrospinal fluid (UBERON:0001359). UBERON:0001359 is an anatomical location from the Uberon multi-species anatomy ontology.
Downstream
Hydrocephalus Obstructed CSF pathways produce clinically and radiologically apparent hydrocephalus.
Coma Progressive hydrocephalus raises intracranial pressure, and patients deteriorate in consciousness until CSF is diverted.
Cognitive impairment Hydrocephalus and raised intracranial pressure contribute to brain injury and lasting neurodisability, including cognitive impairment.
Show evidence (1 reference)
PMID:7610242 SUPPORT Other
"Blockage of the basal subarachnoid cisterns around the midbrain and pons by the dense basal exudate or narrowing of aqueduct and third ventricle by a small tuberculoma causes consequent hydrocephalus."
Connects basal exudate and ventricular obstruction to hydrocephalus.
CSF MMP-9 Elevation
Matrix metalloproteinase-9 rises in cerebrospinal fluid early in tuberculous meningitis and tracks the CSF neutrophil count.
neutrophil CL:0000775 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves neutrophil (CL:0000775). CL:0000775 is a cell type from the Cell Ontology.
cerebrospinal fluid UBERON:0001359 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in cerebrospinal fluid (UBERON:0001359). UBERON:0001359 is an anatomical location from the Uberon multi-species anatomy ontology.
Downstream
Blood-Brain Barrier Disruption MMP-9 degrades extracellular matrix around the blood-brain barrier. The causal step is shown in a mouse CNS-TB model, not in patients.
Show evidence (1 reference)
PMID:19789647 SUPPORT Human clinical
"The strong correlation between CSF MMP-9 and neutrophil count suggests that polymorphonuclear leukocytes may play a central role in the early pathogenesis of TBM."
Links neutrophilic inflammation to CSF MMP-9 during early tuberculous meningitis pathogenesis.
Blood-Brain Barrier Disruption
Loss of blood-brain barrier integrity during CNS tuberculosis, accompanied by inflammatory cell infiltration and reactive gliosis. Direct evidence is from a mouse CNS-TB model.
maintenance of blood-brain barrier GO:0035633 ↓ DECREASED Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased maintenance of blood-brain barrier (GO:0035633). GO:0035633 is a biological process from the Gene Ontology.
blood-brain barrier UBERON:0000120 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in blood-brain barrier, annotated with blood brain barrier (UBERON:0000120). UBERON:0000120 is an anatomical location from the Uberon multi-species anatomy ontology.
Animal models
Mouse sonic-hedgehog CNS tuberculosis model Mouse partially recapitulates Infected mice develop blood-brain barrier breakdown with MMP-9 secretion when SHH signalling is pharmacologically blocked.
Show evidence (1 reference)
PMID:39536643 SUPPORT Model organism
"Immunohistochemistry demonstrated that CYC caused severe BBB breakdown and reactive gliosis, while PUR partially attenuated this response."
Shows blood-brain barrier breakdown in M. tuberculosis-infected mice.
⬡

Pathograph

Use Group by to collapse related nodes into one box. Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.
Pathograph: causal mechanism network for Meningeal tuberculosis Interactive directed graph showing how pathophysiology mechanisms, phenotypes, genetic factors and variants, experimental models, environmental triggers, and treatments relate through causal and linked edges.
●

Phenotypes

12
Digestive 1
Vomiting HP:0002013 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Vomiting (HP:0002013). HP:0002013 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:23757980 SUPPORT PRIMARY RESULT Human clinical
"The presenting complaints were fever 51 (98.1%), neck-stiffness 44 (84.61%), and altered level of consciousness 40 (76.9%), headache 31 (59.6%), vomiting 19 (36.5%) and focal weakness 10 (19.2%)."
Vomiting was a presenting complaint in 37% of 52 confirmed cases.
PMID:34100953 SUPPORT PRIMARY RESULT Human clinical
"however, headache (38.2% vs. 67.1%, P = 0.001), vomiting (18.2% vs. 35.6%, P = 0.030) and fever (80.0% vs. 91.8%, P = 0.052) were less common."
Vomiting was present in 36% of young adults and 18% of older adults with tuberculous meningitis in a prospective cohort.
Head and Neck 1
Nuchal rigidity HP:0031179 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Neck stiffness, annotated with Nuchal rigidity (HP:0031179). HP:0031179 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:23757980 SUPPORT PRIMARY RESULT Human clinical
"The presenting complaints were fever 51 (98.1%), neck-stiffness 44 (84.61%), and altered level of consciousness 40 (76.9%), headache 31 (59.6%), vomiting 19 (36.5%) and focal weakness 10 (19.2%)."
Neck stiffness was present in 85% of 52 confirmed tuberculous meningitis cases.
Metabolism 2
Fever HP:0001945 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Fever (HP:0001945). HP:0001945 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:28281443 SUPPORT REVIEW SYNTHESIS Other
"TBM predominates in the western world and presents as a subacute to chronic meningitis syndrome with a prodrome of malaise, fever, and headache progressing to altered mentation and focal neurologic signs, followed by stupor, coma, and death within five to eight weeks of onset."
Identifies fever as part of the prodrome of untreated tuberculous meningitis.
Hyponatremia HP:0002902 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Hyponatremia (HP:0002902). HP:0002902 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:34752323 SUPPORT PRIMARY RESULT Human clinical
"The prevalence rate of hyponatremia among TBM patients was 52% and the rate of death among those patients was 29%."
Meta-analysis of 42 studies gives a pooled hyponatremia prevalence of 52% in tuberculous meningitis.
Nervous System 8
Headache HP:0002315 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Headache (HP:0002315). HP:0002315 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:28281443 SUPPORT REVIEW SYNTHESIS Other
"TBM predominates in the western world and presents as a subacute to chronic meningitis syndrome with a prodrome of malaise, fever, and headache progressing to altered mentation and focal neurologic signs, followed by stupor, coma, and death within five to eight weeks of onset."
Identifies headache as part of the prodrome before altered mentation and focal neurologic signs.
Hydrocephalus HP:0000238 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Hydrocephalus (HP:0000238). HP:0000238 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:7610242 SUPPORT Other
"Blockage of the basal subarachnoid cisterns around the midbrain and pons by the dense basal exudate or narrowing of aqueduct and third ventricle by a small tuberculoma causes consequent hydrocephalus."
Provides a mechanism for hydrocephalus in tuberculous meningitis.
CSF pleocytosis HP:0012229 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is CSF pleocytosis (HP:0012229). HP:0012229 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:28281443 SUPPORT REVIEW SYNTHESIS Other
"The CSF formula typically shows a lymphocytic pleocytosis, and low glucose and high protein concentrations."
Identifies lymphocytic CSF pleocytosis as the typical cerebrospinal-fluid pattern in tuberculous meningitis.
Cognitive impairment HP:0100543 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Cognitive impairment (HP:0100543). HP:0100543 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:41629635 SUPPORT Other
"Cognitive impairment ranging from 12% to over 90% was found across studies, with severity ranging from mild deficits to severe global dysfunction."
Summarizes cognitive morbidity among adult tuberculous meningitis survivors.
Coma HP:0001259 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Coma (HP:0001259). HP:0001259 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:28281443 SUPPORT REVIEW SYNTHESIS Other
"TBM predominates in the western world and presents as a subacute to chronic meningitis syndrome with a prodrome of malaise, fever, and headache progressing to altered mentation and focal neurologic signs, followed by stupor, coma, and death within five to eight weeks of onset."
Places stupor and coma in the late course of untreated tuberculous meningitis.
Cranial nerve paralysis HP:0006824 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Cranial nerve palsy, annotated with Cranial nerve paralysis (HP:0006824). HP:0006824 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:41799630 SUPPORT PRIMARY RESULT Human clinical
"The pooled prevalence of CNP in TBM patients was 26.5 % (95 % CI: 22.4-31.1 %), while ONP prevalence was 23.9 % (95 % CI: 18.7-30.0 %)."
Meta-analysis of 47 studies gives a pooled cranial nerve palsy prevalence of 26.5% in tuberculous meningitis.
PMID:21570650 SUPPORT PRIMARY RESULT Human clinical
"Abducent nerve was the most frequently (32.3%) affected cranial nerve."
Identifies the abducens nerve as the cranial nerve most often involved in a cohort of 158 adults, 38% of whom had cranial neuropathy.
Seizure HP:0001250 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Seizure (HP:0001250). HP:0001250 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:30396007 SUPPORT PRIMARY RESULT Human clinical
"Seizures occurred in 34% patients with TBM and were associated with poor outcome at six months."
Seizures occurred in about a third of a prospective adult cohort.
Hemiparesis HP:0001269 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Hemiparesis (HP:0001269). HP:0001269 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:15206503 SUPPORT PRIMARY RESULT Human clinical
"Hemiparesis (35.7%), cranial nerve palsy (30.9%), and altered consciousness (26.9%) were the most common neurological deficits."
Hemiparesis was the most common neurological deficit in a 42-patient adult cohort.
💊

Medical Actions

3
Initial Four-Drug Antituberculous Therapy
Action: PharmacotherapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Pharmacotherapy (NCIT:C15986). NCIT:C15986 is a clinical intervention from the NCI Thesaurus. NCIT:C15986
Agent: isoniazide CHEBI:6030 Chemical Entities of Biological Interest (CHEBI) Relation: this treatment uses this therapeutic agent This treatment uses isoniazide (CHEBI:6030). CHEBI:6030 is a therapeutic agent from Chemical Entities of Biological Interest. rifampicin CHEBI:28077 Chemical Entities of Biological Interest (CHEBI) Relation: this treatment uses this therapeutic agent This treatment uses rifampicin (CHEBI:28077). CHEBI:28077 is a therapeutic agent from Chemical Entities of Biological Interest. pyrazinamide CHEBI:45285 Chemical Entities of Biological Interest (CHEBI) Relation: this treatment uses this therapeutic agent This treatment uses pyrazinamide, annotated with pyrazinecarboxamide (CHEBI:45285). CHEBI:45285 is a therapeutic agent from Chemical Entities of Biological Interest. ethambutol CHEBI:4877 Chemical Entities of Biological Interest (CHEBI) Relation: this treatment uses this therapeutic agent This treatment uses ethambutol (CHEBI:4877). CHEBI:4877 is a therapeutic agent from Chemical Entities of Biological Interest.
Platform: Small molecule
Initial TBM therapy uses isoniazid, rifampicin, pyrazinamide, and ethambutol to kill M. tuberculosis in the CSF and cover possible resistance while susceptibility testing is pending.
Mechanism Target:
INHIBITS Basal Granulomatous Meningeal Exudate — Bactericidal antituberculous therapy kills susceptible bacilli in the subarachnoid space, removing the antigenic drive of the basal exudate.
Show evidence (1 reference)
PMID:28281443 SUPPORT REVIEW SYNTHESIS Other
"The initial 4 drug regimen (isoniazid, rifampin, pyrazinamide, ethambutol) covers the possibility of infection with a resistant strain, maximizes antimicrobial impact, and reduces the likelihood of emerging resistance on therapy."
Supports initial four-drug tuberculosis therapy for CNS tuberculosis.
Adjunctive Dexamethasone
Action: PharmacotherapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Pharmacotherapy (NCIT:C15986). NCIT:C15986 is a clinical intervention from the NCI Thesaurus. NCIT:C15986
Agent: dexamethasone CHEBI:41879 Chemical Entities of Biological Interest (CHEBI) Relation: this treatment uses this therapeutic agent This treatment uses dexamethasone (CHEBI:41879). CHEBI:41879 is a therapeutic agent from Chemical Entities of Biological Interest.
Platform: Small molecule
Dexamethasone is recommended as adjunctive host-directed therapy and lowers early CSF MMP-9, but its survival benefit is modest and heterogeneous. A phase 3 trial in HIV-negative adults stratified by LTA4H genotype found no benefit over placebo in CC and CT genotypes and no better outcome in TT genotype, so genotype-guided steroid use is not established.
Mechanism Target:
INHIBITS CSF MMP-9 Elevation — Corticosteroid treatment lowers early CSF MMP-9 concentrations and dampens the inflammatory barrier injury branch.
Effect differs by subgroup:
genotype LTA4H TT genotype (open-label dexamethasone) vs LTA4H CC or CT genotype — no difference on all-cause death or new neurological event over 12 months cross stratum comparison
HIV-negative Vietnamese adults. TT-genotype participants were not randomized and all received dexamethasone, so this compares outcomes across genotype strata within one trial rather than a randomized treatment-by-genotype interaction. Among randomized CC and CT participants, dexamethasone and placebo outcomes did not differ, and no prespecified subgroup showed benefit or heterogeneity (NCT03100786).
Show evidence (2 references)
PMID:41540106 SUPPORT PRIMARY RESULT Human clinical
"Outcomes were not significantly better in TT-genotype participants versus CC- or CT-genotype participants."
Reports no outcome advantage for the hyperinflammatory TT genotype under dexamethasone.
PMID:41540106 SUPPORT PRIMARY RESULT Human clinical
"Benefit or heterogeneity of effect was not observed by any prespecified subgroup."
Reports no treatment-effect heterogeneity across the trial's prespecified subgroups.
Show evidence (2 references)
PMID:19789647 SUPPORT Human clinical
"Dexamethasone significantly reduced CSF MMP-9 concentrations in early follow up samples (median 5 days (range 3-8) of treatment), but had no significant influence on other MMPs/TIMPs."
Mechanistically links dexamethasone to lower early MMP-9 in CSF during tuberculous meningitis treatment.
PMID:41540106 SUPPORT BACKGROUND Human clinical
"Leukotriene A4 hydrolase (LTA4H) genotypes associate with distinct intracerebral inflammatory phenotypes and may determine corticosteroid response in tuberculous meningitis, with benefit observed in hyperinflammatory TT genotype but uncertain benefit in lower inflammation CC and CT genotypes."
The trial's framing of the LTA4H hypothesis it set out to test, based on earlier work. It is the rationale for the trial, not its result; the result is recorded under effect_modifiers.
BCG Vaccination
Action: VaccinationNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Vaccination (NCIT:C15346). NCIT:C15346 is a clinical intervention from the NCI Thesaurus. NCIT:C15346
Agent: BCG vaccine NCIT:C298 NCI Thesaurus (NCIT) Relation: this treatment uses this therapeutic agent This treatment uses BCG vaccine (NCIT:C298). NCIT:C298 is a therapeutic agent from the NCI Thesaurus.
Platform: Vaccine
Bacillus Calmette-Guerin vaccination in infants and young children reduces progression to disseminated meningeal or miliary tuberculosis.
Mechanism Target:
INHIBITS Hematogenous CNS Tuberculous Seeding — BCG-induced antituberculous immunity reduces progression to meningeal and miliary dissemination in early life.
Show evidence (1 reference)
PMID:24336911 SUPPORT Other
"Protection against meningeal and miliary tuberculosis was also high in infants (RR, 0.1; 95% CI, .01-.77) and children stringently tuberculin tested (RR, 0.08; 95% CI, .03-.25)."
Quantifies strong BCG protection against meningeal and miliary tuberculosis in infants and tuberculin-tested children.
🌍

Environmental Factors

1
HIV co-infection
HIV infection increases progression to active tuberculosis and CNS involvement, and TBM patients with HIV co-infection have higher mortality.
Show evidence (2 references)
PMID:30611205 SUPPORT PRIMARY RESULT Human clinical
"When multivariable analysis was applied, significant associations with in-hospital mortality were seen among patients with HIV (RR 2.06; Confidence Interval 95% (95% CI) 1.44-2.94)"
Quantifies HIV co-infection as a predictor of in-hospital mortality in a Peruvian adult TBM cohort.
PMID:36795648 SUPPORT PRIMARY RESULT Other
"the pooled case fatality rate among HIV positive and HIV negative TBM individuals was 53.39% (95%CI; 40.55-66.24) and 21.65% (95%CI;4.27-39.03) respectively."
A systematic review found higher pooled case fatality in HIV-positive TBM than in HIV-negative TBM.
Mechanism Target:
PREDISPOSES Hematogenous CNS Tuberculous Seeding — HIV infection increases the risk of active TB and CNS involvement among people with TB, but the cited sources do not pin the intervening steps to a single node in this graph.
Show evidence (1 reference)
PMID:30611205 SUPPORT BACKGROUND Human clinical
"HIV infection significantly increases the risk of developing active TB, the rate of progression from latent to active disease, and TB-associated morbidity and mortality"
Supports HIV infection as a risk factor for active tuberculosis and progression from latent infection.
🔬

Diagnosis

1
Composite CSF and Neuroimaging Diagnosis
TBM diagnosis combines CSF acid-fast smear or culture, nucleic-acid amplification such as Xpert Ultra, CSF inflammatory chemistry, and CT/MRI evidence of basal meningeal enhancement, hydrocephalus, infarction, or tuberculoma, because a negative molecular or culture result does not exclude disease.
Show evidence (2 references)
PMID:31924549 SUPPORT Human clinical
"Xpert Ultra detected tuberculous meningitis with higher sensitivity than Xpert and MGIT culture in this HIV-positive population."
Supports Xpert Ultra as a more sensitive CSF molecular assay than the earlier Xpert and MGIT culture comparators in suspected TBM.
PMID:28281443 SUPPORT REVIEW SYNTHESIS Other
"In a patient with compatible clinical features, the combination of meningeal enhancement and any degree of hydrocephalus is strongly suggestive of TBM."
Supports the diagnostic use of basal meningeal enhancement and hydrocephalus on neuroimaging.
📈

Progression

3
MRC grade I
Modified British Medical Research Council grade I: Glasgow Coma Scale score 15 with no focal neurological signs. The MRC grade at presentation is the standard staging of tuberculous meningitis severity.
Show evidence (1 reference)
PMID:29029055 SUPPORT BACKGROUND Other
"grade I (GCS score 15; no focal neurological signs), grade II (GCS score 11–14 or 15 with focal neurological signs), or grade III (GCS score ≤10)"
Defines the three modified MRC grades of tuberculous meningitis.
MRC grade II
Glasgow Coma Scale score 11-14, or 15 with focal neurological signs such as cranial nerve palsy.
Show evidence (1 reference)
PMID:29029055 SUPPORT BACKGROUND Other
"grade I (GCS score 15; no focal neurological signs), grade II (GCS score 11–14 or 15 with focal neurological signs), or grade III (GCS score ≤10)"
Defines MRC grade II.
MRC grade III
Glasgow Coma Scale score 10 or below. Mortality rises with grade; in a Peruvian inpatient cohort, grade III carried about three times the risk of in-hospital death.
Show evidence (2 references)
PMID:29029055 SUPPORT BACKGROUND Other
"grade I (GCS score 15; no focal neurological signs), grade II (GCS score 11–14 or 15 with focal neurological signs), or grade III (GCS score ≤10)"
Defines MRC grade III.
PMID:30611205 SUPPORT PRIMARY RESULT Human clinical
"significant associations with in-hospital mortality were seen among patients with HIV (RR 2.06; Confidence Interval 95% (95% CI) 1.44-2.94), BMRC II (RR 1.78; 95% CI 1.07-2.97), BMRC III (RR 3.11; 95% CI 1.78-5.45) and positive CSF cultures (RR 1.95; 95% CI 1.39-2.74)."
Higher BMRC grade at admission predicts in-hospital death.
📊

Prevalence

1
Active tuberculosis cases
Unknown Unknown
Tuberculous meningitis is reported as about 1% of active tuberculosis cases. This is a share of TB cases rather than a population prevalence or incidence rate, so no rate_per_100000 is asserted.
Show evidence (1 reference)
PMID:36795648 SUPPORT BACKGROUND Other
"Tuberculosis meningitis (TBM) accounts for approximately 1% of all active TB cases."
Reports the approximate TBM share among active tuberculosis cases.
🦠

Infectious Agent

1
Mycobacterium tuberculosis
Mycobacterium tuberculosis is the acid-fast intracellular bacterium that causes pulmonary tuberculosis and meningeal tuberculosis after dissemination to the central nervous system.
Mycobacterium tuberculosis NCBITaxon:1773 NCBI Taxonomy (NCBITaxon)
Show evidence (1 reference)
PMID:36795648 SUPPORT BACKGROUND Other
"Tuberculosis (TB) which is caused by Mycobacterium tuberculosis poses a significant public health global treat."
Establishes M. tuberculosis as the bacterial cause of tuberculosis, of which tuberculous meningitis is the CNS form.
↔️

Transmission

1
Airborne Mycobacterium tuberculosis acquisition
Humans acquire M. tuberculosis through inhalation of airborne bacilli; later dissemination from the primary infection can seed the central nervous system.
🐁

Animal Models

2
Zebrafish Mycobacterium marinum LTA4H inflammation model
The zebrafish M. marinum model links LTA4H-controlled eicosanoid balance to both inadequate and excessive mycobacterial inflammation. It motivated the LTA4H genotype hypothesis for steroid response in human TBM, which a later genotype-stratified phase 3 trial (PMID:41540106) did not confirm. It is a systemic mycobacterial infection model, not a CNS model.
Species
Zebrafish
Show evidence (1 reference)
PMID:22304914 SUPPORT Model organism
"In zebrafish, we find that susceptibility to Mycobacterium marinum can result from either inadequate or excessive acute inflammation."
Supports use of the zebrafish-M. marinum model for the inverted-U host inflammation branch relevant to TBM.
Mouse sonic-hedgehog CNS tuberculosis model
Sonic-hedgehog-pathway modulation in BALB/c mice with M. tuberculosis CNS infection models MMP-9-associated blood-brain-barrier injury and rapid brain bacillary expansion.
Species
Mouse
Pathograph links
Blood-Brain Barrier Disruption partially recapitulates fidelity: low observes: tissue Infected mice develop blood-brain barrier breakdown with MMP-9 secretion when SHH signalling is pharmacologically blocked.
Limitations: Barrier breakdown is produced under cyclopamine antagonism of SHH, an artificial accelerant with no counterpart in human TBM, in mice rather than humans; the basal exudate, arteritis and hydrocephalus are not reported.
Show evidence (1 reference)
PMID:39536643 SUPPORT Model organism
"Immunohistochemistry demonstrated that CYC caused severe BBB breakdown and reactive gliosis, while PUR partially attenuated this response."
Documents barrier breakdown in the infected-mouse model.
Show evidence (1 reference)
PMID:39536643 SUPPORT Model organism
"Further analysis revealed that CYC upregulated Matrix Metalloproteinase-9 (MMP-9) secretion, a key contributor to BBB disruption."
Links SHH antagonism to MMP-9-associated BBB disruption in a mouse CNS-TB model.
{ }

Source YAML

click to show 
name: Meningeal tuberculosis
creation_date: "2026-09-30T03:19:40Z"
description: >-
  Meningeal tuberculosis is central nervous system tuberculosis caused by
  Mycobacterium tuberculosis, in which inhaled bacilli establish a primary
  pulmonary or disseminated focus, seed the meninges hematogenously, and trigger
  rupture of a caseating Rich focus into the subarachnoid space, basal
  granulomatous exudate, vasculitic infarction, hydrocephalus, and subacute
  meningitis with high mortality and neurologic morbidity.
category: Infectious Disease
disease_term:
  preferred_term: meningeal tuberculosis
  term:
    id: MONDO:0006042
    label: meningeal tuberculosis
parents:
- Bacterial meningitis
- Tuberculosis
synonyms:
- tuberculous meningitis
- TB meningitis
- tuberculosis meningitis
notes: >-
  Seeded from `research/Meningeal_Tuberculosis-deep-research-openscientist.md`
  (OpenScientist, fallback from Falcon). Each claim is supported by its own
  evidence items, which quote primary studies, cohort meta-analyses and reviews
  of tuberculous meningitis.
infectious_agent:
- name: Mycobacterium tuberculosis
  infectious_agent_term:
    preferred_term: Mycobacterium tuberculosis
    term:
      id: NCBITaxon:1773
      label: Mycobacterium tuberculosis
  description: >-
    Mycobacterium tuberculosis is the acid-fast intracellular bacterium that
    causes pulmonary tuberculosis and meningeal tuberculosis after dissemination
    to the central nervous system.
  evidence:
  - reference: PMID:36795648
    reference_title: "Microbiological diagnosis and mortality of tuberculosis meningitis: Systematic review and meta-analysis."
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: BACKGROUND
    snippet: >-
      Tuberculosis (TB) which is caused by Mycobacterium tuberculosis poses a
      significant public health global treat.
    explanation: >-
      Establishes M. tuberculosis as the bacterial cause of tuberculosis, of
      which tuberculous meningitis is the CNS form.
agent_life_cycle:
  description: >-
    M. tuberculosis transmits between humans by airborne droplet nuclei, enters
    alveolar macrophages in the lung, persists in granulomatous foci, and can
    disseminate hematogenously to seed the meninges.
  hosts:
  - preferred_term: Homo sapiens
    role: reservoir and clinical host
    term:
      id: NCBITaxon:9606
      label: Homo sapiens
classifications:
  harrisons_chapter:
  - classification_value: INFECTIOUS_DISEASES
transmission:
- name: Airborne Mycobacterium tuberculosis acquisition
  description: >-
    Humans acquire M. tuberculosis through inhalation of airborne bacilli; later
    dissemination from the primary infection can seed the central nervous
    system.
prevalence:
- population: Active tuberculosis cases
  measure_type: UNKNOWN
  prevalence_class: UNKNOWN
  notes: >-
    Tuberculous meningitis is reported as about 1% of active tuberculosis cases.
    This is a share of TB cases rather than a population prevalence or incidence
    rate, so no rate_per_100000 is asserted.
  evidence:
  - reference: PMID:36795648
    reference_title: "Microbiological diagnosis and mortality of tuberculosis meningitis: Systematic review and meta-analysis."
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: BACKGROUND
    snippet: >-
      Tuberculosis meningitis (TBM) accounts for approximately 1% of all active
      TB cases.
    explanation: >-
      Reports the approximate TBM share among active tuberculosis cases.
environmental:
- name: HIV co-infection
  description: >-
    HIV infection increases progression to active tuberculosis and CNS
    involvement, and TBM patients with HIV co-infection have higher mortality.
  influences_mechanisms:
  - target: Hematogenous CNS Tuberculous Seeding
    environmental_effect: PREDISPOSES
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      HIV infection increases the risk of active TB and CNS involvement among
      people with TB, but the cited sources do not pin the intervening steps to
      a single node in this graph.
    evidence:
    - reference: PMID:30611205
      reference_title: Mortality in hospitalized patients with tuberculous meningitis.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: BACKGROUND
      snippet: >-
        HIV infection significantly increases the risk of developing active TB,
        the rate of progression from latent to active disease, and TB-associated
        morbidity and mortality
      explanation: >-
        Supports HIV infection as a risk factor for active tuberculosis and
        progression from latent infection.
  evidence:
  - reference: PMID:30611205
    reference_title: Mortality in hospitalized patients with tuberculous meningitis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: >-
      When multivariable analysis was applied, significant associations with
      in-hospital mortality were seen among patients with HIV (RR 2.06;
      Confidence Interval 95% (95% CI) 1.44-2.94)
    explanation: >-
      Quantifies HIV co-infection as a predictor of in-hospital mortality in a
      Peruvian adult TBM cohort.
  - reference: PMID:36795648
    reference_title: "Microbiological diagnosis and mortality of tuberculosis meningitis: Systematic review and meta-analysis."
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: PRIMARY_RESULT
    snippet: >-
      the pooled case fatality rate among HIV positive and HIV negative TBM
      individuals was 53.39% (95%CI; 40.55-66.24) and 21.65%
      (95%CI;4.27-39.03) respectively.
    explanation: >-
      A systematic review found higher pooled case fatality in HIV-positive TBM
      than in HIV-negative TBM.
pathophysiology:
- name: Pulmonary Mycobacterium tuberculosis entry
  role: trigger
  description: >-
    Inhaled bacilli reach alveolar macrophages and establish a pulmonary or
    disseminated tuberculous focus.
  biological_scale: ORGANISM
  downstream:
  - target: Hematogenous CNS Tuberculous Seeding
    causal_link_type: DIRECT
    description: >-
      Bacilli disseminate from the primary site through the bloodstream toward
      meningeal or subependymal foci.
- name: Hematogenous CNS Tuberculous Seeding
  description: >-
    Bloodborne M. tuberculosis seeds the meninges or adjacent ependymal surfaces
    and creates a caseating subpial or subependymal Rich focus.
  biological_scale: ORGANISM
  locations:
  - preferred_term: meninx
    term:
      id: UBERON:0002360
      label: meninx
  downstream:
  - target: Rich Focus Rupture Into CSF
    causal_link_type: DIRECT
    description: >-
      A caseating focus at a meningeal or ependymal surface can rupture into the
      subarachnoid space.
  evidence:
  - reference: PMID:7610242
    reference_title: Pathology and pathogenetic mechanisms in neurotuberculosis.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      The mechanisms and the changes described herein typically begin with a
      dense basal meningeal exudate often resulting from a "Rich focus" along
      the basal surface of the cerebrum or ventricular ependyma.
    explanation: >-
      Places the Rich focus at the basal cerebral or ventricular ependymal
      surface upstream of the basal meningeal exudate.
- name: Rich Focus Rupture Into CSF
  description: >-
    Rupture of the caseating Rich focus releases bacilli and mycobacterial
    antigens into cerebrospinal fluid and the basal subarachnoid space.
  biological_scale: ORGANISM
  locations:
  - preferred_term: cerebrospinal fluid
    term:
      id: UBERON:0001359
      label: cerebrospinal fluid
  - preferred_term: subarachnoid space
    term:
      id: UBERON:0000315
      label: subarachnoid space
  evidence:
  - reference: PMID:7610242
    reference_title: Pathology and pathogenetic mechanisms in neurotuberculosis.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      The mechanisms and the changes described herein typically begin with a
      dense basal meningeal exudate often resulting from a "Rich focus" along
      the basal surface of the cerebrum or ventricular ependyma.
    directness: INDIRECT
    explanation: >-
      Places a Rich focus upstream of the basal meningeal exudate. The abstract
      does not itself state that the focus ruptures into the subarachnoid
      space; that step is inferred from the focus-to-exudate sequence.
  downstream:
  - target: Basal Granulomatous Meningeal Exudate
    causal_link_type: DIRECT
    description: >-
      Bacilli and antigens in CSF elicit dense granulomatous inflammation around
      the basal cisterns.
- name: Basal Granulomatous Meningeal Exudate
  description: >-
    Mycobacterial antigens drive an epithelioid-macrophage-rich basal meningeal
    exudate around cranial nerves, basal cisterns, and cerebral vessels.
  biological_scale: TISSUE
  cell_types:
  - preferred_term: macrophage
    term:
      id: CL:0000235
      label: macrophage
  - preferred_term: epithelioid macrophage
    term:
      id: CL:0002150
      label: epithelioid macrophage
  biological_processes:
  - preferred_term: inflammatory response
    term:
      id: GO:0006954
      label: inflammatory response
    modifier: INCREASED
  locations:
  - preferred_term: meninx
    term:
      id: UBERON:0002360
      label: meninx
  evidence:
  - reference: PMID:7610242
    reference_title: Pathology and pathogenetic mechanisms in neurotuberculosis.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      This exudate is made up of small and large mononuclear cells, including
      epithelioid cells, which also act as macrophages and may fuse to form
      Langhans' giant cells.
    explanation: >-
      Defines the cellular composition of the basal granulomatous exudate in
      tuberculous meningitis.
  downstream:
  - target: Tuberculous Cerebral Arteritis
    causal_link_type: DIRECT
    description: >-
      Basal exudate entraps and inflames adjacent cerebral arteries.
  - target: Obstructive Tuberculous Hydrocephalus
    causal_link_type: DIRECT
    description: >-
      Dense exudate blocks basal subarachnoid cisterns and obstructs CSF flow.
  - target: CSF MMP-9 Elevation
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: >-
      Neutrophilic meningeal inflammation is accompanied by raised MMP-9 in
      cerebrospinal fluid.
  - target: CSF pleocytosis
    causal_link_type: DIRECT
    description: >-
      The leukocytic meningeal inflammatory infiltrate is sampled as a
      lymphocyte-predominant CSF pleocytosis.
    evidence:
    - reference: PMID:28281443
      reference_title: Central Nervous System Tuberculosis.
      supports: SUPPORT
      evidence_source: OTHER
      quote_role: REVIEW_SYNTHESIS
      directness: INDIRECT
      snippet: >-
        The CSF formula typically shows a lymphocytic pleocytosis, and low glucose
        and high protein concentrations.
      explanation: >-
        Reports the lymphocytic CSF pleocytosis that reflects the mononuclear
        meningeal exudate described in PMID:7610242.
  - target: Cranial nerve paralysis
    causal_link_type: DIRECT
    description: >-
      Basal exudate encases cranial nerve trunks crossing the basal cisterns,
      producing cranial nerve palsies, most often of the abducens nerve.
    evidence:
    - reference: PMID:32118118
      reference_title: "The current global situation for tuberculous meningitis: epidemiology, diagnostics, treatment and outcomes."
      supports: SUPPORT
      evidence_source: OTHER
      quote_role: REVIEW_SYNTHESIS
      snippet: >-
        Third, exudates encase cranial nerves, resulting in cranial nerve
        palsies.
      explanation: >-
        States that the basal exudate encasing cranial nerves is the cause of
        cranial nerve palsies in tuberculous meningitis.
  - target: Nuchal rigidity
    causal_link_type: DIRECT
    description: >-
      Inflammation of the meninges produces meningeal irritation, seen
      clinically as neck stiffness.
  - target: Headache
    causal_link_type: DIRECT
    description: >-
      Meningeal inflammation produces the headache of the meningitic prodrome.
  - target: Fever
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: >-
      The granulomatous inflammatory response is accompanied by systemic fever.
- name: Tuberculous Cerebral Arteritis
  description: >-
    Basal exudate entraps large arteries and perforators, producing arteritis
    and arterial occlusion.
  biological_scale: TISSUE
  locations:
  - preferred_term: middle cerebral artery
    term:
      id: UBERON:0001627
      label: middle cerebral artery
  evidence:
  - reference: PMID:7610242
    reference_title: Pathology and pathogenetic mechanisms in neurotuberculosis.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Entrapment and occasional arteritic occlusion of larger arteries, such as
      the middle cerebral in the Sylvian fissures, results in infarction.
    explanation: >-
      Links tuberculous basal exudate to arteritic occlusion of large arteries
      such as the middle cerebral artery.
  downstream:
  - target: Ischemic Cerebral Infarction
    causal_link_type: DIRECT
    description: >-
      Arteritic occlusion causes ischemic infarction in the supplied territory.
    evidence:
    - reference: PMID:28281443
      reference_title: Central Nervous System Tuberculosis.
      supports: SUPPORT
      evidence_source: OTHER
      quote_role: REVIEW_SYNTHESIS
      snippet: >-
        Vasculitis leading to infarcts in the basal ganglia occurs commonly and
        is a major determinant of morbidity and mortality.
      explanation: >-
        States that vasculitis leads to basal ganglia infarcts in CNS
        tuberculosis.
- name: Ischemic Cerebral Infarction
  description: >-
    Ischemic infarction downstream of tuberculous arteritis, most commonly in
    the basal ganglia, is a major determinant of morbidity and mortality.
  biological_scale: TISSUE
  locations:
  - preferred_term: collection of basal ganglia
    term:
      id: UBERON:0010011
      label: collection of basal ganglia
  evidence:
  - reference: PMID:28281443
    reference_title: Central Nervous System Tuberculosis.
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      Vasculitis leading to infarcts in the basal ganglia occurs commonly and
      is a major determinant of morbidity and mortality.
    explanation: >-
      Places tuberculous infarcts in the basal ganglia and links them to
      morbidity.
  downstream:
  - target: Hemiparesis
    causal_link_type: DIRECT
    description: >-
      Infarction of the basal ganglia and internal capsule produces focal
      motor weakness, most often hemiparesis.
    evidence:
    - reference: PMID:36048445
      reference_title: "Global Frequency and Clinical Features of Stroke in Patients With Tuberculous Meningitis: A Systematic Review."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: PRIMARY_RESULT
      directness: INDIRECT
      snippet: >-
        Moreover, patients with TBM experiencing stroke were more likely to
        present with focal weakness, which was found in 62% of patients in our
        analysis.
      explanation: >-
        Pooled analysis finds focal weakness in 62% of patients with
        tuberculous-meningitis stroke. Focal weakness is broader than
        hemiparesis, so the link to this phenotype is an inference.
  - target: Seizure
    causal_link_type: DIRECT
    description: >-
      Late seizures in tuberculous meningitis are associated with cerebral
      infarction, as well as with tuberculoma and hyponatremia.
    evidence:
    - reference: PMID:30396007
      reference_title: Seizures in tuberculous meningitis.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: PRIMARY_RESULT
      directness: INDIRECT
      snippet: >-
        Early seizures were associated with meningeal irritation and late
        seizures with tuberculoma, infarction and hyponatremia (P = 0.01).
      explanation: >-
        Reports an association between infarction and late seizures in a TBM
        cohort; the causal direction is inferred from the association.
  - target: Cognitive impairment
    causal_link_type: DIRECT
    description: >-
      Ischemic brain injury contributes to the neurodisability seen in
      survivors, including cognitive impairment.
    evidence:
    - reference: PMID:32118118
      reference_title: "The current global situation for tuberculous meningitis: epidemiology, diagnostics, treatment and outcomes."
      supports: SUPPORT
      evidence_source: OTHER
      quote_role: REVIEW_SYNTHESIS
      directness: INDIRECT
      snippet: >-
        Ischaemia, hydrocephalus and raised intracranial pressure frequently
        result, leading to extensive brain injury and neurodisability.
      explanation: >-
        States that ischemia leads to brain injury and neurodisability in TBM.
        Neurodisability is broader than cognitive impairment, so the link to
        this phenotype is an inference.
- name: Obstructive Tuberculous Hydrocephalus
  description: >-
    Basal exudate or tuberculoma-associated narrowing of the aqueduct and third
    ventricle blocks CSF pathways and causes hydrocephalus.
  biological_scale: TISSUE
  locations:
  - preferred_term: cerebrospinal fluid
    term:
      id: UBERON:0001359
      label: cerebrospinal fluid
  evidence:
  - reference: PMID:7610242
    reference_title: Pathology and pathogenetic mechanisms in neurotuberculosis.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Blockage of the basal subarachnoid cisterns around the midbrain and pons
      by the dense basal exudate or narrowing of aqueduct and third ventricle by
      a small tuberculoma causes consequent hydrocephalus.
    explanation: >-
      Connects basal exudate and ventricular obstruction to hydrocephalus.
  downstream:
  - target: Hydrocephalus
    causal_link_type: DIRECT
    description: >-
      Obstructed CSF pathways produce clinically and radiologically apparent
      hydrocephalus.
    evidence:
    - reference: PMID:7610242
      reference_title: Pathology and pathogenetic mechanisms in neurotuberculosis.
      supports: SUPPORT
      evidence_source: OTHER
      snippet: >-
        Blockage of the basal subarachnoid cisterns around the midbrain and pons
        by the dense basal exudate or narrowing of aqueduct and third ventricle by
        a small tuberculoma causes consequent hydrocephalus.
      explanation: >-
        States that cisternal or aqueductal obstruction causes hydrocephalus.
  - target: Coma
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: >-
      Progressive hydrocephalus raises intracranial pressure, and patients
      deteriorate in consciousness until CSF is diverted.
    evidence:
    - reference: PMID:35102984
      reference_title: Hydrocephalus in Tuberculous Meningitis - Pearls and Nuances.
      supports: SUPPORT
      evidence_source: OTHER
      quote_role: REVIEW_SYNTHESIS
      directness: INDIRECT
      snippet: >-
        Progressive hydrocephalus, clinically manifests with a potentially
        life-threatening high intracranial pressure. Patients with deteriorating
        vision loss and deteriorating consciousness, often need a surgical CSF
        diversion procedure
      explanation: >-
        Links progressive hydrocephalus to raised intracranial pressure and
        deteriorating consciousness. Coma is the endpoint of that decline, so
        the link to this phenotype is an inference.
  - target: Cognitive impairment
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: >-
      Hydrocephalus and raised intracranial pressure contribute to brain
      injury and lasting neurodisability, including cognitive impairment.
    evidence:
    - reference: PMID:32118118
      reference_title: "The current global situation for tuberculous meningitis: epidemiology, diagnostics, treatment and outcomes."
      supports: SUPPORT
      evidence_source: OTHER
      quote_role: REVIEW_SYNTHESIS
      directness: INDIRECT
      snippet: >-
        Ischaemia, hydrocephalus and raised intracranial pressure frequently
        result, leading to extensive brain injury and neurodisability.
      explanation: >-
        States that hydrocephalus and raised intracranial pressure lead to
        brain injury and neurodisability. Neurodisability is broader than
        cognitive impairment, so the link to this phenotype is an inference.
- name: CSF MMP-9 Elevation
  description: >-
    Matrix metalloproteinase-9 rises in cerebrospinal fluid early in
    tuberculous meningitis and tracks the CSF neutrophil count.
  biological_scale: MOLECULAR
  cell_types:
  - preferred_term: neutrophil
    term:
      id: CL:0000775
      label: neutrophil
  locations:
  - preferred_term: cerebrospinal fluid
    term:
      id: UBERON:0001359
      label: cerebrospinal fluid
  downstream:
  - target: Blood-Brain Barrier Disruption
    causal_link_type: DIRECT
    description: >-
      MMP-9 degrades extracellular matrix around the blood-brain barrier. The
      causal step is shown in a mouse CNS-TB model, not in patients.
    evidence:
    - reference: PMID:39536643
      reference_title: "Modulating sonic hedgehog (SHH) pathway to create a rapid CNS-TB model: Facilitating drug discovery."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        Further analysis revealed that CYC upregulated Matrix
        Metalloproteinase-9 (MMP-9) secretion, a key contributor to BBB
        disruption.
      explanation: >-
        Links raised MMP-9 secretion to blood-brain barrier disruption in a
        mouse CNS-TB model.
  evidence:
  - reference: PMID:19789647
    reference_title: Dexamethasone, cerebrospinal fluid matrix metalloproteinase concentrations and clinical outcomes in tuberculous meningitis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The strong correlation between CSF MMP-9 and neutrophil count suggests
      that polymorphonuclear leukocytes may play a central role in the early
      pathogenesis of TBM.
    explanation: >-
      Links neutrophilic inflammation to CSF MMP-9 during early tuberculous
      meningitis pathogenesis.
- name: Blood-Brain Barrier Disruption
  description: >-
    Loss of blood-brain barrier integrity during CNS tuberculosis, accompanied
    by inflammatory cell infiltration and reactive gliosis. Direct evidence is
    from a mouse CNS-TB model.
  biological_scale: TISSUE
  biological_processes:
  - preferred_term: maintenance of blood-brain barrier
    term:
      id: GO:0035633
      label: maintenance of blood-brain barrier
    modifier: DECREASED
  locations:
  - preferred_term: blood-brain barrier
    term:
      id: UBERON:0000120
      label: blood brain barrier
  evidence:
  - reference: PMID:39536643
    reference_title: "Modulating sonic hedgehog (SHH) pathway to create a rapid CNS-TB model: Facilitating drug discovery."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Immunohistochemistry demonstrated that CYC caused severe BBB breakdown
      and reactive gliosis, while PUR partially attenuated this response.
    explanation: >-
      Shows blood-brain barrier breakdown in M. tuberculosis-infected mice.
phenotypes:
- name: Fever
  phenotype_term:
    preferred_term: Fever
    term:
      id: HP:0001945
      label: Fever
  evidence:
  - reference: PMID:28281443
    reference_title: Central Nervous System Tuberculosis.
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      TBM predominates in the western world and presents as a subacute to
      chronic meningitis syndrome with a prodrome of malaise, fever, and
      headache progressing to altered mentation and focal neurologic signs,
      followed by stupor, coma, and death within five to eight weeks of onset.
    explanation: >-
      Identifies fever as part of the prodrome of untreated tuberculous
      meningitis.
- name: Headache
  phenotype_term:
    preferred_term: Headache
    term:
      id: HP:0002315
      label: Headache
  evidence:
  - reference: PMID:28281443
    reference_title: Central Nervous System Tuberculosis.
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      TBM predominates in the western world and presents as a subacute to
      chronic meningitis syndrome with a prodrome of malaise, fever, and
      headache progressing to altered mentation and focal neurologic signs,
      followed by stupor, coma, and death within five to eight weeks of onset.
    explanation: >-
      Identifies headache as part of the prodrome before altered mentation and
      focal neurologic signs.
- name: Hydrocephalus
  phenotype_term:
    preferred_term: Hydrocephalus
    term:
      id: HP:0000238
      label: Hydrocephalus
  evidence:
  - reference: PMID:7610242
    reference_title: Pathology and pathogenetic mechanisms in neurotuberculosis.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Blockage of the basal subarachnoid cisterns around the midbrain and pons
      by the dense basal exudate or narrowing of aqueduct and third ventricle by
      a small tuberculoma causes consequent hydrocephalus.
    explanation: >-
      Provides a mechanism for hydrocephalus in tuberculous meningitis.
- name: CSF pleocytosis
  phenotype_term:
    preferred_term: CSF pleocytosis
    term:
      id: HP:0012229
      label: CSF pleocytosis
  evidence:
  - reference: PMID:28281443
    reference_title: Central Nervous System Tuberculosis.
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      The CSF formula typically shows a lymphocytic pleocytosis, and low glucose
      and high protein concentrations.
    explanation: >-
      Identifies lymphocytic CSF pleocytosis as the typical cerebrospinal-fluid
      pattern in tuberculous meningitis.
- name: Cognitive impairment
  phenotype_term:
    preferred_term: Cognitive impairment
    term:
      id: HP:0100543
      label: Cognitive impairment
  evidence:
  - reference: PMID:41629635
    reference_title: "Unmasking the cognitive burden of adult tuberculous meningitis: A systematic review and meta analysis."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Cognitive impairment ranging from 12% to over 90% was found across
      studies, with severity ranging from mild deficits to severe global
      dysfunction.
    explanation: >-
      Summarizes cognitive morbidity among adult tuberculous meningitis
      survivors.
- name: Coma
  phenotype_term:
    preferred_term: Coma
    term:
      id: HP:0001259
      label: Coma
  evidence:
  - reference: PMID:28281443
    reference_title: Central Nervous System Tuberculosis.
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      TBM predominates in the western world and presents as a subacute to
      chronic meningitis syndrome with a prodrome of malaise, fever, and
      headache progressing to altered mentation and focal neurologic signs,
      followed by stupor, coma, and death within five to eight weeks of onset.
    explanation: >-
      Places stupor and coma in the late course of untreated tuberculous
      meningitis.
- name: Nuchal rigidity
  phenotype_term:
    preferred_term: Neck stiffness
    term:
      id: HP:0031179
      label: Nuchal rigidity
  evidence:
  - reference: PMID:23757980
    reference_title: "Clinical course, complications and predictors of mortality in patients with tuberculous meningitis--an experience of fifty two cases at Civil Hospital Karachi, Pakistan."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: >-
      The presenting complaints were fever 51 (98.1%), neck-stiffness 44
      (84.61%), and altered level of consciousness 40 (76.9%), headache 31
      (59.6%), vomiting 19 (36.5%) and focal weakness 10 (19.2%).
    explanation: >-
      Neck stiffness was present in 85% of 52 confirmed tuberculous
      meningitis cases.
- name: Vomiting
  phenotype_term:
    preferred_term: Vomiting
    term:
      id: HP:0002013
      label: Vomiting
  evidence:
  - reference: PMID:23757980
    reference_title: "Clinical course, complications and predictors of mortality in patients with tuberculous meningitis--an experience of fifty two cases at Civil Hospital Karachi, Pakistan."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: >-
      The presenting complaints were fever 51 (98.1%), neck-stiffness 44
      (84.61%), and altered level of consciousness 40 (76.9%), headache 31
      (59.6%), vomiting 19 (36.5%) and focal weakness 10 (19.2%).
    explanation: >-
      Vomiting was a presenting complaint in 37% of 52 confirmed cases.
  - reference: PMID:34100953
    reference_title: Tuberculous meningitis in the elderly.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: >-
      however, headache (38.2% vs. 67.1%, P = 0.001), vomiting (18.2% vs.
      35.6%, P = 0.030) and fever (80.0% vs. 91.8%, P = 0.052) were less
      common.
    explanation: >-
      Vomiting was present in 36% of young adults and 18% of older adults
      with tuberculous meningitis in a prospective cohort.
- name: Cranial nerve paralysis
  phenotype_term:
    preferred_term: Cranial nerve palsy
    term:
      id: HP:0006824
      label: Cranial nerve paralysis
  description: >-
    Around a quarter to a third of patients have a cranial nerve palsy. The
    abducens nerve is the most often affected.
  evidence:
  - reference: PMID:41799630
    reference_title: "Incidence of cranial and ophthalmic nerve palsy and associated risk factors in tuberculous meningitis: A systematic review and meta-regression analysis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: >-
      The pooled prevalence of CNP in TBM patients was 26.5 % (95 % CI:
      22.4-31.1 %), while ONP prevalence was 23.9 % (95 % CI: 18.7-30.0 %).
    explanation: >-
      Meta-analysis of 47 studies gives a pooled cranial nerve palsy
      prevalence of 26.5% in tuberculous meningitis.
  - reference: PMID:21570650
    reference_title: "Incidence, predictors and prognostic value of cranial nerve involvement in patients with tuberculous meningitis: a retrospective evaluation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: >-
      Abducent nerve was the most frequently (32.3%) affected cranial nerve.
    explanation: >-
      Identifies the abducens nerve as the cranial nerve most often involved
      in a cohort of 158 adults, 38% of whom had cranial neuropathy.
- name: Seizure
  phenotype_term:
    preferred_term: Seizure
    term:
      id: HP:0001250
      label: Seizure
  evidence:
  - reference: PMID:30396007
    reference_title: Seizures in tuberculous meningitis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: >-
      Seizures occurred in 34% patients with TBM and were associated with poor
      outcome at six months.
    explanation: >-
      Seizures occurred in about a third of a prospective adult cohort.
- name: Hemiparesis
  phenotype_term:
    preferred_term: Hemiparesis
    term:
      id: HP:0001269
      label: Hemiparesis
  evidence:
  - reference: PMID:15206503
    reference_title: Tuberculous meningitis in adults--experience from Turkey.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: >-
      Hemiparesis (35.7%), cranial nerve palsy (30.9%), and altered
      consciousness (26.9%) were the most common neurological deficits.
    explanation: >-
      Hemiparesis was the most common neurological deficit in a 42-patient
      adult cohort.
- name: Hyponatremia
  phenotype_term:
    preferred_term: Hyponatremia
    term:
      id: HP:0002902
      label: Hyponatremia
  evidence:
  - reference: PMID:34752323
    reference_title: "Hyponatremia in tuberculous meningitis: A systematic review and meta-analysis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: >-
      The prevalence rate of hyponatremia among TBM patients was 52% and the
      rate of death among those patients was 29%.
    explanation: >-
      Meta-analysis of 42 studies gives a pooled hyponatremia prevalence of
      52% in tuberculous meningitis.
progression:
- phase: MRC grade I
  notes: >-
    Modified British Medical Research Council grade I: Glasgow Coma Scale
    score 15 with no focal neurological signs. The MRC grade at presentation is
    the standard staging of tuberculous meningitis severity.
  evidence:
  - reference: PMID:29029055
    reference_title: Prognostic Models for 9-Month Mortality in Tuberculous Meningitis.
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: BACKGROUND
    snippet: >-
      grade I (GCS score 15; no focal neurological signs), grade II (GCS score
      11–14 or 15 with focal neurological signs), or grade III (GCS score ≤10)
    explanation: >-
      Defines the three modified MRC grades of tuberculous meningitis.
- phase: MRC grade II
  notes: >-
    Glasgow Coma Scale score 11-14, or 15 with focal neurological signs such as
    cranial nerve palsy.
  evidence:
  - reference: PMID:29029055
    reference_title: Prognostic Models for 9-Month Mortality in Tuberculous Meningitis.
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: BACKGROUND
    snippet: >-
      grade I (GCS score 15; no focal neurological signs), grade II (GCS score
      11–14 or 15 with focal neurological signs), or grade III (GCS score ≤10)
    explanation: >-
      Defines MRC grade II.
- phase: MRC grade III
  notes: >-
    Glasgow Coma Scale score 10 or below. Mortality rises with grade; in a
    Peruvian inpatient cohort, grade III carried about three times the risk of
    in-hospital death.
  evidence:
  - reference: PMID:29029055
    reference_title: Prognostic Models for 9-Month Mortality in Tuberculous Meningitis.
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: BACKGROUND
    snippet: >-
      grade I (GCS score 15; no focal neurological signs), grade II (GCS score
      11–14 or 15 with focal neurological signs), or grade III (GCS score ≤10)
    explanation: >-
      Defines MRC grade III.
  - reference: PMID:30611205
    reference_title: Mortality in hospitalized patients with tuberculous meningitis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: >-
      significant associations with in-hospital mortality were seen among
      patients with HIV (RR 2.06; Confidence Interval 95% (95% CI) 1.44-2.94),
      BMRC II (RR 1.78; 95% CI 1.07-2.97), BMRC III (RR 3.11; 95% CI
      1.78-5.45) and positive CSF cultures (RR 1.95; 95% CI 1.39-2.74).
    explanation: >-
      Higher BMRC grade at admission predicts in-hospital death.
diagnosis:
- name: Composite CSF and Neuroimaging Diagnosis
  description: >-
    TBM diagnosis combines CSF acid-fast smear or culture, nucleic-acid
    amplification such as Xpert Ultra, CSF inflammatory chemistry, and
    CT/MRI evidence of basal meningeal enhancement, hydrocephalus, infarction,
    or tuberculoma, because a negative molecular or culture result does not
    exclude disease.
  evidence:
  - reference: PMID:31924549
    reference_title: "Xpert MTB/RIF Ultra for the diagnosis of HIV-associated tuberculous meningitis: a prospective validation study."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Xpert Ultra detected tuberculous meningitis with higher sensitivity than
      Xpert and MGIT culture in this HIV-positive population.
    explanation: >-
      Supports Xpert Ultra as a more sensitive CSF molecular assay than the
      earlier Xpert and MGIT culture comparators in suspected TBM.
  - reference: PMID:28281443
    reference_title: Central Nervous System Tuberculosis.
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      In a patient with compatible clinical features, the combination of
      meningeal enhancement and any degree of hydrocephalus is strongly
      suggestive of TBM.
    explanation: >-
      Supports the diagnostic use of basal meningeal enhancement and
      hydrocephalus on neuroimaging.
treatments:
- name: Initial Four-Drug Antituberculous Therapy
  description: >-
    Initial TBM therapy uses isoniazid, rifampicin, pyrazinamide, and ethambutol
    to kill M. tuberculosis in the CSF and cover possible resistance while
    susceptibility testing is pending.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: isoniazide
      term:
        id: CHEBI:6030
        label: isoniazide
    - preferred_term: rifampicin
      term:
        id: CHEBI:28077
        label: rifampicin
    - preferred_term: pyrazinamide
      term:
        id: CHEBI:45285
        label: pyrazinecarboxamide
    - preferred_term: ethambutol
      term:
        id: CHEBI:4877
        label: ethambutol
  target_mechanisms:
  - target: Basal Granulomatous Meningeal Exudate
    treatment_effect: INHIBITS
    description: >-
      Bactericidal antituberculous therapy kills susceptible bacilli in the
      subarachnoid space, removing the antigenic drive of the basal exudate.
  evidence:
  - reference: PMID:28281443
    reference_title: Central Nervous System Tuberculosis.
    supports: SUPPORT
    quote_role: REVIEW_SYNTHESIS
    evidence_source: OTHER
    snippet: >-
      The initial 4 drug regimen (isoniazid, rifampin, pyrazinamide, ethambutol)
      covers the possibility of infection with a resistant strain, maximizes
      antimicrobial impact, and reduces the likelihood of emerging resistance on
      therapy.
    explanation: >-
      Supports initial four-drug tuberculosis therapy for CNS tuberculosis.
- name: Adjunctive Dexamethasone
  description: >-
    Dexamethasone is recommended as adjunctive host-directed therapy and lowers
    early CSF MMP-9, but its survival benefit is modest and heterogeneous. A
    phase 3 trial in HIV-negative adults stratified by LTA4H genotype found no
    benefit over placebo in CC and CT genotypes and no better outcome in TT
    genotype, so genotype-guided steroid use is not established.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: dexamethasone
      term:
        id: CHEBI:41879
        label: dexamethasone
  target_mechanisms:
  - target: CSF MMP-9 Elevation
    treatment_effect: INHIBITS
    description: >-
      Corticosteroid treatment lowers early CSF MMP-9 concentrations and dampens
      the inflammatory barrier injury branch.
  evidence:
  - reference: PMID:19789647
    reference_title: Dexamethasone, cerebrospinal fluid matrix metalloproteinase concentrations and clinical outcomes in tuberculous meningitis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Dexamethasone significantly reduced CSF MMP-9 concentrations in early
      follow up samples (median 5 days (range 3-8) of treatment), but had no
      significant influence on other MMPs/TIMPs.
    explanation: >-
      Mechanistically links dexamethasone to lower early MMP-9 in CSF during
      tuberculous meningitis treatment.
  - reference: PMID:41540106
    reference_title: "Genotype-stratified adjunctive dexamethasone for tuberculous meningitis in HIV-negative adults: a randomized controlled phase 3 trial."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: BACKGROUND
    snippet: >-
      Leukotriene A4 hydrolase (LTA4H) genotypes associate with distinct
      intracerebral inflammatory phenotypes and may determine corticosteroid
      response in tuberculous meningitis, with benefit observed in
      hyperinflammatory TT genotype but uncertain benefit in lower inflammation
      CC and CT genotypes.
    explanation: >-
      The trial's framing of the LTA4H hypothesis it set out to test, based on
      earlier work. It is the rationale for the trial, not its result; the
      result is recorded under effect_modifiers.
  effect_modifiers:
  - effect_modifier_type: GENOTYPE
    stratum: LTA4H TT genotype (open-label dexamethasone)
    comparator_stratum: LTA4H CC or CT genotype
    modified_outcome: all-cause death or new neurological event over 12 months
    effect_in_stratum: NO_DIFFERENCE
    modification_analysis: CROSS_STRATUM_COMPARISON
    description: >-
      HIV-negative Vietnamese adults. TT-genotype participants were not
      randomized and all received dexamethasone, so this compares outcomes
      across genotype strata within one trial rather than a randomized
      treatment-by-genotype interaction. Among randomized CC and CT
      participants, dexamethasone and placebo outcomes did not differ, and no
      prespecified subgroup showed benefit or heterogeneity (NCT03100786).
    evidence:
    - reference: PMID:41540106
      reference_title: "Genotype-stratified adjunctive dexamethasone for tuberculous meningitis in HIV-negative adults: a randomized controlled phase 3 trial."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: PRIMARY_RESULT
      snippet: >-
        Outcomes were not significantly better in TT-genotype participants
        versus CC- or CT-genotype participants.
      explanation: >-
        Reports no outcome advantage for the hyperinflammatory TT genotype
        under dexamethasone.
    - reference: PMID:41540106
      reference_title: "Genotype-stratified adjunctive dexamethasone for tuberculous meningitis in HIV-negative adults: a randomized controlled phase 3 trial."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: PRIMARY_RESULT
      snippet: >-
        Benefit or heterogeneity of effect was not observed by any prespecified
        subgroup.
      explanation: >-
        Reports no treatment-effect heterogeneity across the trial's
        prespecified subgroups.
- name: BCG Vaccination
  description: >-
    Bacillus Calmette-Guerin vaccination in infants and young children reduces
    progression to disseminated meningeal or miliary tuberculosis.
  therapeutic_modality: VACCINE
  treatment_term:
    preferred_term: Vaccination
    term:
      id: NCIT:C15346
      label: Vaccination
    therapeutic_agent:
    - preferred_term: BCG vaccine
      term:
        id: NCIT:C298
        label: BCG Vaccine
  target_mechanisms:
  - target: Hematogenous CNS Tuberculous Seeding
    treatment_effect: INHIBITS
    description: >-
      BCG-induced antituberculous immunity reduces progression to meningeal and
      miliary dissemination in early life.
  evidence:
  - reference: PMID:24336911
    reference_title: "Protection by BCG vaccine against tuberculosis: a systematic review of randomized controlled trials."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Protection against meningeal and miliary tuberculosis was also high in
      infants (RR, 0.1; 95% CI, .01-.77) and children stringently tuberculin
      tested (RR, 0.08; 95% CI, .03-.25).
    explanation: >-
      Quantifies strong BCG protection against meningeal and miliary
      tuberculosis in infants and tuberculin-tested children.
animal_models:
- name: Zebrafish Mycobacterium marinum LTA4H inflammation model
  species: Zebrafish
  description: >-
    The zebrafish M. marinum model links LTA4H-controlled eicosanoid balance to
    both inadequate and excessive mycobacterial inflammation. It motivated the
    LTA4H genotype hypothesis for steroid response in human TBM, which a later
    genotype-stratified phase 3 trial (PMID:41540106) did not confirm. It is a
    systemic mycobacterial infection model, not a CNS model.
  evidence:
  - reference: PMID:22304914
    reference_title: Host genotype-specific therapies can optimize the inflammatory response to mycobacterial infections.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      In zebrafish, we find that susceptibility to Mycobacterium marinum can
      result from either inadequate or excessive acute inflammation.
    explanation: >-
      Supports use of the zebrafish-M. marinum model for the inverted-U host
      inflammation branch relevant to TBM.
- name: Mouse sonic-hedgehog CNS tuberculosis model
  species: Mouse
  description: >-
    Sonic-hedgehog-pathway modulation in BALB/c mice with M. tuberculosis CNS
    infection models MMP-9-associated blood-brain-barrier injury and rapid brain
    bacillary expansion.
  modeled_mechanisms:
  - target: Blood-Brain Barrier Disruption
    relationship: PARTIALLY_RECAPITULATES
    fidelity: LOW
    model_scale: TISSUE
    description: >-
      Infected mice develop blood-brain barrier breakdown with MMP-9 secretion
      when SHH signalling is pharmacologically blocked.
    limitations: >-
      Barrier breakdown is produced under cyclopamine antagonism of SHH, an
      artificial accelerant with no counterpart in human TBM, in mice rather
      than humans; the basal exudate, arteritis and hydrocephalus are not
      reported.
    evidence:
    - reference: PMID:39536643
      reference_title: "Modulating sonic hedgehog (SHH) pathway to create a rapid CNS-TB model: Facilitating drug discovery."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        Immunohistochemistry demonstrated that CYC caused severe BBB breakdown
        and reactive gliosis, while PUR partially attenuated this response.
      explanation: >-
        Documents barrier breakdown in the infected-mouse model.
  evidence:
  - reference: PMID:39536643
    reference_title: "Modulating sonic hedgehog (SHH) pathway to create a rapid CNS-TB model: Facilitating drug discovery."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Further analysis revealed that CYC upregulated Matrix
      Metalloproteinase-9 (MMP-9) secretion, a key contributor to BBB
      disruption.
    explanation: >-
      Links SHH antagonism to MMP-9-associated BBB disruption in a mouse CNS-TB
      model.
📚

References & Deep Research

Deep Research

1

Deep research results are used as seeds for research; they do not undergo the same validation as the main records and may contain errors. How we use deep research.

Evaluations and curation notes (5)

Record notes

Seeded from `research/Meningeal_Tuberculosis-deep-research-openscientist.md` (OpenScientist, fallback from Falcon). Each claim is supported by its own evidence items, which quote primary studies, cohort meta-analyses and reviews of tuberculous meningitis.

Address OpenScientist report cross-check findings · 2026-10-25T07:32:00Z · View source

Replaced the stale notes sentence that said no deep-research report was committed after the branch added the original OpenScientist report and its artifact sidecar. Added a prevalence record for tuberculous meningitis representing about 1% of active tuberculosis cases, using already cached PMID:36795648, and left rate_per_100000 unset because the figure is a share of active TB cases rather than a population rate. Added HIV co-infection as an environmental risk and prognostic modifier, citing already cached PMID:30611205 for the adult hospitalized cohort risk ratio and PMID:36795648 for the HIV-stratified pooled case fatality rates.

Review round 3: rewrite notes that described an uncommitted deep-research report · 2026-10-25T07:03:46Z · View source

Addressed the one remaining blocker of the 2026-10-23 review (round 3) by the fallback the reviewer named. No deep-research report for this entry exists in the repository or on the PR branch history, and this runner has no deep-research provider, so a report could not be committed or generated. The entry-level notes previously described that uncommitted OpenScientist run in detail (35 references, 2 inexact quotes, PMID:35673608 flagged off-topic, the pyrazinamide quote and HPO pseudo-labels not curated, preflight-dr skipping gene checks because MONDO:0006042 records no causal gene). That description is preserved here and removed from notes, which now state only that no report is committed and that each claim rests on its own evidence items. Whether the entry may merge without a report is a maintainer decision. Optional suggestions were not taken: no cached source names meningeal irritation as the cause of nuchal rigidity, headache or fever, so those three exudate edges remain uncited.

Review round 2: add common phenotypes, MRC grade progression, causal wiring · 2026-10-23T23:07:21Z · View source

Addressed the 2026-10-21 review (round 2) of PR 14910. Phenotypes added, each with a cited frequency: nuchal rigidity (HP:0031179) and vomiting (HP:0002013) from a 52-patient Karachi cohort (PMID:23757980) and, for vomiting, a prospective Chandigarh cohort (PMID:34100953); cranial nerve paralysis (HP:0006824) from a 47-study meta-analysis (PMID:41799630, pooled 26.5%) with the abducens nerve as the most affected nerve (PMID:21570650); seizure (HP:0001250, 34%, PMID:30396007); hemiparesis (HP:0001269, 35.7%, PMID:15206503); hyponatremia (HP:0002902, pooled 52%, PMID:34752323). Progression: added modified MRC grades I-III as phases, with grade definitions from PMID:29029055 and grade-dependent in-hospital mortality from PMID:30611205. Pathograph: basal exudate now links to cranial nerve paralysis (PMID:32118118, exudates encase cranial nerves) and, without separate edge evidence, to nuchal rigidity, headache and fever. Ischemic cerebral infarction links to hemiparesis (PMID:36048445), seizure (PMID:30396007) and cognitive impairment (PMID:32118118). Obstructive hydrocephalus links to coma (PMID:35102984) and cognitive impairment (PMID:32118118). Edges that rest on an association or on a broader outcome (focal weakness, neurodisability, deteriorating consciousness) are marked directness INDIRECT. PMID:31082059 (StatPearls) was fetched but is abstract-only and carries no phenotype content, so it is not cited. Not done: no deep-research report is committed. No deep-research provider was available in the shepherd runner, and the OpenScientist report the entry notes describe is not in the repository. The optional suggestions (transmission evidence, HIV co-infection modifier, drug-resistant TBM and tuberculoma, LTA4H genetic row, NCT03100786) were not taken in this round. Validated with just validate (48/48 snippets, 0 issues).

Review round 1 fixes: dexamethasone LTA4H result, node splits, phenotype wiring · 2026-10-21T20:03:45Z · View source

Addressed the 2026-10-19 review of PR 14910. Dexamethasone: the LTA4H sentence from PMID:41540106 is the trial's stated hypothesis, now marked quote_role BACKGROUND. The trial's result (no outcome difference between TT and CC/CT genotypes; no benefit or heterogeneity in any prespecified subgroup) is recorded as a GENOTYPE effect_modifiers entry with NO_DIFFERENCE and CROSS_STRATUM_COMPARISON, because TT participants were not randomized. Treatment and zebrafish-model descriptions no longer state genotype-dependent benefit. Pathophysiology: split 'Tuberculous Arteritis and Infarction' into 'Tuberculous Cerebral Arteritis' (middle cerebral artery, PMID:7610242) and 'Ischemic Cerebral Infarction' (basal ganglia, PMID:28281443). Split 'MMP-9 Blood-Brain Barrier Breakdown' into 'CSF MMP-9 Elevation' (human, PMID:19789647) and 'Blood-Brain Barrier Disruption' (mouse, PMID:39536643, MODEL_ORGANISM). The Rich-focus rupture evidence is marked directness INDIRECT, since the abstract places the focus upstream of the exudate without naming rupture. Pathograph: wired Obstructive Tuberculous Hydrocephalus -> Hydrocephalus and Basal Granulomatous Meningeal Exudate -> CSF pleocytosis with cited edge evidence. Antituberculous therapy now targets the basal exudate instead of the rupture event. Added a Coma phenotype (HP:0001259) from PMID:28281443. The mouse SHH model links to Blood-Brain Barrier Disruption (PARTIALLY_RECAPITULATES, LOW fidelity, with limitations). BCG vaccination carries therapeutic_modality VACCINE and therapeutic_agent NCIT:C298 BCG Vaccine in place of the qualifier pair. Not done: no deep-research report is committed; MRC grade progression, transmission evidence, cranial-nerve palsy, seizures, hemiparesis, hyponatremia and HIV co-infection were not added because no cached source supports them. A hemiparesis edge from infarction was considered and dropped because no cached source names hemiparesis. Validated with just validate (30/30 snippets), validate-terms, check-entity-refs, check-causal-targets, check-duplicate-keys and model-scale-audit.

OpenScientist ▸
Meningeal Tuberculosis (Tuberculous Meningitis) — Comprehensive Disease Characterization Report
openscientist-autonomous 34 citations 2026-09-29T20:54:30.310057

Meningeal Tuberculosis (Tuberculous Meningitis) — Comprehensive Disease Characterization Report

Target Disease: Meningeal tuberculosis / Tuberculous meningitis (TBM) MONDO ID: MONDO:0006042 Category: Infectious Disease Report basis: 15 confirmed findings, 68 papers reviewed across 5 investigation iterations

Summary

Meningeal tuberculosis (tuberculous meningitis, TBM) is the most lethal and disabling form of tuberculosis, arising when Mycobacterium tuberculosis infects the meninges and subarachnoid space of the central nervous system. It is fundamentally an infectious disease with a strong immunopathological component: the initiating lesion is a subpial or subependymal caseous granuloma (the Rich focus) that ruptures into the subarachnoid space, seeding a dense basal meningeal exudate. This exudate drives the three cardinal complications that define the disease's morbidity and mortality — vasculitis with cerebral infarction, hydrocephalus, and cranial neuropathy — together with blood-brain-barrier (BBB) breakdown mediated by matrix metalloproteinase-9 (MMP-9) (PMID: 7610242; PMID: 19789647).

TBM accounts for roughly 1% of all active TB cases (1–5% of TB, ~14% of all meningitis) but carries an in-hospital mortality near 42%, rising toward 70% in HIV co-infection, and left ~78,200 adults dead in 2019 alone (PMID: 35288778; PMID: 36795648). Survivors frequently suffer multidomain cognitive impairment and focal neurological deficits. Diagnosis remains a central challenge because no single test is both sensitive and specific: clinicians rely on a composite of CSF findings (lymphocytic pleocytosis, elevated protein, low glucose, elevated adenosine deaminase), molecular testing (Xpert MTB/RIF Ultra, ~77% sensitive), and the neuroimaging triad of basal meningeal enhancement, hydrocephalus, and basal-ganglia infarction (PMID: 31924549; PMID: 28281443).

Treatment is prolonged multidrug antituberculous therapy — the WHO-standard 12-month HRZE-based regimen (2HRZE/10HR) — because standard 6-month pulmonary regimens penetrate the CNS poorly. Adjunctive corticosteroids are standard, but their survival benefit is now understood to be host-genotype-dependent: leukotriene A4 hydrolase (LTA4H) promoter genotype defines hyper-, intermediate-, and low-inflammatory phenotypes, and the phase 3 LAST ACT trial found no dexamethasone benefit in the CC/CT (lower-inflammation) genotypes (PMID: 41540106). Prevention rests principally on neonatal BCG vaccination, which is ~90% protective against the meningeal and miliary childhood forms (PMID: 24336911).

1. Disease Information

Overview. TBM is a subacute-to-chronic granulomatous meningitis caused by Mycobacterium tuberculosis reaching the CNS, usually via hematogenous dissemination from a primary (typically pulmonary) focus. It is the most severe manifestation of extrapulmonary TB. Untreated, it "presents as a subacute to chronic meningitis syndrome with a prodrome of malaise, fever, and headache progressing to altered mentation and focal neurologic signs, followed by stupor, coma, and death within five to eight weeks of onset" (PMID: 28281443).

Key identifiers: | Resource | Identifier | |---|---| | MONDO | MONDO:0006042 | | MeSH | Tuberculosis, Meningeal (D014390) | | ICD-10 | A17.0 (Tuberculous meningitis) | | ICD-11 | 1B41 (Tuberculosis of the nervous system) | | SNOMED CT | Tuberculous meningitis (disorder) |

Synonyms / alternative names: tuberculous meningitis, TB meningitis, TBM, meningeal tuberculosis, tuberculosis of the meninges, CNS tuberculosis (broader — includes tuberculoma and spinal arachnoiditis).

Information source type. This report aggregates disease-level evidence from systematic reviews, meta-analyses, randomized controlled trials, and cohort studies, supplemented by mechanistic model-organism and in-vitro work. It is not derived from individual EHR records.

2. Etiology

Primary cause (infectious). TBM is caused by Mycobacterium tuberculosis (NCBI Taxonomy 1773; complex 77643). The mechanistic trigger is the Rich focus — a caseating granuloma seeded during bacillemia that lodges subpially/subependymally and later ruptures into the subarachnoid space (PMID: 7610242).

Genetic risk factors (host susceptibility). Susceptibility and severity are shaped by host genetic polymorphisms and by pathogen lineage. "Pathogen lineage (Beijing genotype) and host genetics (polymorphisms in TLR2, TIRAP and LTA4H genes) can influence susceptibility to TBM" (PMID: 22953709). The LTA4H (leukotriene A4 hydrolase; HGNC:6710) promoter genotype is the best-characterized modifier, defining three intracerebral inflammatory phenotypes: TT (hyperinflammatory), CT (intermediate), CC (low inflammation) (PMID: 41540106).

Environmental / demographic risk factors. HIV co-infection is the dominant risk factor and outcome modifier. Other risks include young age (children <5 years present with more advanced disease), high community TB burden, low Human Development Index, malnutrition, and lack of BCG vaccination (PMID: 36795648; PMID: 41639788).

Protective factors. Neonatal BCG vaccination is strongly protective against meningeal/miliary TB (~90%) (PMID: 24336911). No robustly validated protective human genetic variant is established for TBM specifically.

Gene-environment interaction. The clearest GxE relationship is LTA4H genotype × corticosteroid therapy: the anti-inflammatory (steroid) intervention interacts with the host inflammatory set-point, so benefit is expected in the hyperinflammatory TT genotype but is uncertain/absent in CC/CT (PMID: 41540106; PMID: 22304914).

3. Phenotypes

TBM produces symptoms/signs (clinical), physical manifestations, behavioral/cognitive change, and laboratory abnormalities. Onset is subacute (typically days-to-weeks). Frequencies below are drawn from cohort and review data.

Phenotype Type Frequency / notes Suggested HPO
Fever Symptom ~67–80% HP:0001945
Headache Symptom ~33–63% HP:0002315
Vomiting / nausea Symptom ~52–92% (children higher) HP:0002013
Altered mental status / consciousness Sign ~55–78% HP:0011446
Meningismus / nuchal rigidity Sign ~38% + HP:0002829
Seizures Sign ~72% (children) HP:0001250
Cranial neuropathy (e.g., optic, oculomotor) Sign common (basal exudate entrapment) HP:0000496
Focal deficit / hemiparesis (stroke) Sign ~30% (stroke) HP:0001269
Hydrocephalus Manifestation 26–63% imaging HP:0000238
Cognitive impairment (memory, attention, executive) Behavioral/cognitive 12–>90% survivors HP:0100543
Lymphocytic CSF pleocytosis Lab classic HP:0012229 (abnormal CSF)
Hyponatremia Lab ~46–93% HP:0002902

Characteristics. Onset spans neonatal through geriatric, with a pediatric predilection for severe meningoencephalitis. Severity is graded by the British Medical Research Council (BMRC) stages I–III. Progression is typically progressive if untreated. Cognitive sequelae "most consistently affected memory, attention, and executive function" (PMID: 41629635). Younger children carry a disproportionate burden: "The < 5 years group had a higher proportion of TBM stage III cases (29.5% vs. 2.2%, p <0.001)" (PMID: 41639788).

Quality of life. Survivors face substantial disability from motor deficits, epilepsy, hydrocephalus-related morbidity, and cognitive dysfunction spanning mild deficits to severe global dysfunction (PMID: 41629635).

4. Genetic / Molecular Information

TBM is not a Mendelian genetic disease — there are no causal genes, pathogenic ACMG-classified variants, chromosomal abnormalities, or germline/somatic driver mutations. Host genetics act as susceptibility/modifier factors, not as causes:

  • LTA4H (HGNC:6710) — promoter polymorphism defines inflammatory phenotype and modifies corticosteroid response (PMID: 41540106).
  • TLR2 (Toll-like receptor 2) and TIRAP (TIR domain adaptor) — susceptibility polymorphisms (PMID: 22953709).

Epigenetic information: No TBM-specific human epigenomic signature is established in the reviewed literature.

The relevant "molecular" pathology is therefore host-inflammatory rather than genomic. The LTA4H-encoded enzyme sits at the eicosanoid branch point governing the balance of pro-inflammatory leukotriene B4 versus anti-inflammatory lipoxins (PMID: 22304914).

5. Environmental Information

  • Infectious agent: Mycobacterium tuberculosis (NCBI Taxon 1773); the Beijing lineage is associated with increased TBM susceptibility (PMID: 22953709). CHEBI-relevant host mediators include leukotriene B4 (CHEBI:15514) and lipoxins.
  • Environmental/lifestyle contributors: crowding and airborne transmission of TB, malnutrition, immunosuppression (notably HIV), and absence of BCG vaccination. HIV co-infection modifies presentation — persons living with HIV "exhibited lower frequencies of vomiting, nuchal rigidity, signs of meningeal inflammation, and coma, along with lower leukocyte counts in cerebrospinal fluid" (PMID: 40589807).

6. Mechanism / Pathophysiology

Ordered causal chain (initiating lesion → clinical manifestation)

  1. Inhalation of M. tuberculosis → primary (usually pulmonary) infection → hematogenous dissemination leads to seeding of subpial/subependymal caseous granulomas (Rich foci). (Demonstrated — classic neuropathology.)
  2. Rupture of a Rich focus into the subarachnoid space results in release of bacilli and antigen into CSF (PMID: 7610242).
  3. Antigen release triggers a dense basal meningeal exudate of mononuclear/epithelioid cells and Langhans giant cells around the basal cisterns (PMID: 7610242).
  4. The exudate branches into three parallel injury pathways:
  5. (4a) Vasculitis branch: exudate encases perforating arteries → arteritis → "arteritic occlusion of larger arteries, such as the middle cerebral" → infarction, characteristically in the basal ganglia (lateral striate, MCA, medial striate territory) (PMID: 7610242; PMID: 36048445).
  6. (4b) CSF-flow branch: "Blockage of the basal subarachnoid cisterns ... or narrowing of aqueduct and third ventricle by a small tuberculoma causes consequent hydrocephalus" (PMID: 7610242).
  7. (4c) Cranial-nerve branch: entrapment of optic nerves and other cranial nerves in the interpeduncular fossa → cranial neuropathies (PMID: 7610242).
  8. In parallel, neutrophil-driven and macrophage-driven secretion of MMP-9 (a zinc-dependent gelatinase) degrades basement membrane/extracellular matrix → blood-brain-barrier disruption and neuroinflammatory injury (PMID: 19789647; PMID: 39536643).
  9. Host inflammatory set-point (LTA4H genotype) modulates the magnitude of steps 3–5: both inadequate and excessive inflammation converge on dysregulated TNF, worsening outcome (inferred from zebrafish/human correlation) (PMID: 22304914).
  10. Combined ischemia, hydrocephalus, BBB breakdown and edema result in raised intracranial pressure, coma, and death, or — in survivors — cognitive and focal neurological sequelae (PMID: 41629635).

Detail by category

Cellular / immune processes. Granulomatous inflammation (epithelioid macrophages, Langhans giant cells, lymphocytes) is the dominant tissue response (PMID: 7610242). Early pathogenesis has a neutrophilic component: "The strong correlation between CSF MMP-9 and neutrophil count suggests that polymorphonuclear leukocytes may play a central role in the early pathogenesis of TBM" (PMID: 19789647). Specialized pro-resolving mediators (resolvins, lipoxins) decline with severity, and their CSF concentrations associate with 80-day survival (PMID: 31500466).

Protein dysfunction / biochemical abnormality. MMP-9 over-activity is central to matrix destruction. In a mouse CNS-TB model, SHH-pathway antagonism "upregulated Matrix Metalloproteinase-9 (MMP-9) secretion, a key contributor to BBB disruption," severe gliosis, and a 99% increase in brain bacillary load (PMID: 39536643). Dexamethasone "significantly reduced CSF MMP-9 concentrations in early follow up samples" (PMID: 19789647).

Molecular pathway. The eicosanoid/LTA4H axis (leukotriene B4 vs lipoxin balance) tunes TNF signaling: "inadequate inflammation caused by excess lipoxins and hyperinflammation driven by excess leukotriene B(4)" both cause susceptibility (PMID: 22304914). The sonic hedgehog (SHH) pathway is implicated in BBB integrity (PMID: 39536643).

Suggested ontology terms. GO: inflammatory response (GO:0006954), extracellular matrix disassembly (GO:0022617), blood-brain barrier maintenance (GO:0035633), leukotriene metabolic process (GO:0006691). CL: macrophage (CL:0000235), epithelioid cell, Langhans giant cell, neutrophil (CL:0000775), T lymphocyte (CL:0000084).

7. Anatomical Structures Affected

Organ / system level. Primary organ: brain and meninges (nervous system). The basal meninges, subarachnoid cisterns, and CSF pathways are the epicenter. Secondary involvement: cerebral parenchyma (infarcts, tuberculomas, encephalitis), ventricular system (hydrocephalus), cranial nerves, and spinal cord/arachnoid (spinal arachnoiditis). Systemic dissemination (miliary TB) is common in children.

Vascular territory. Basal-ganglia perforators are characteristically affected: "The lateral striate, middle cerebral, and medial striate arteries were typically affected" — the perforator "TB zone" encased by exudate (PMID: 36048445).

Tissue / cell level. Leptomeninges (pia-arachnoid), cerebral arterial walls (arteritis), ependyma, and choroid/aqueductal structures. Cell populations: macrophages, epithelioid and Langhans giant cells, lymphocytes, neutrophils.

Localization / UBERON: meninges (UBERON:0002360), leptomeninges/subarachnoid space (UBERON:0002450), basal cistern, brain (UBERON:0000955), cerebrospinal fluid (UBERON:0001359), middle cerebral artery (UBERON:0001627), basal ganglia (UBERON:0002420), cerebral ventricle (UBERON:0002285). Lateralization is typically bilateral/basal but infarcts may be focal/asymmetric.

8. Temporal Development

  • Onset: any age, with pediatric predilection; onset is subacute to chronic (prodrome of days to weeks).
  • Staging: BMRC grades I (alert, no deficit), II (altered consciousness/focal signs), III (stupor/coma, dense deficit). Advanced stage predicts poor outcome — up to 100% fatality in stage III in one pediatric series (PMID: 41288109).
  • Untreated course: progression from "malaise, fever, and headache progressing to altered mentation and focal neurologic signs, followed by stupor, coma, and death within five to eight weeks of onset" (PMID: 28281443).
  • Treated course: prolonged (≥12 months therapy); paradoxical reactions may occur during treatment in ~21% of CNS-TB (PMID: 42242389).
  • Critical period: early diagnosis and treatment initiation is the key intervention window; delay strongly worsens outcome.

9. Inheritance and Population (Epidemiology)

  • Proportion of TB: "Tuberculosis meningitis (TBM) accounts for approximately 1% of all active TB cases" (1–5% of TB) (PMID: 36795648).
  • Prevalence: CNS-TB ~2 per 100,000 inhabitants; represents "13.91% of all cases of meningitis and 4.55% of all cases of TB" (PMID: 35288778).
  • Mortality: in-hospital mortality "rose up to 42.12% in hospitalized patients" (PMID: 35288778); ~40% HIV-negative, up to ~70% with HIV. In 2019, "78,200 adults died of TB meningitis" (PMID: 36795648). An estimated 24,000 children <15 years developed TBM in 2019, of whom ~16,100 died (PMID: 39706662).
  • Inheritance: Not applicable (infectious disease). Host susceptibility is multifactorial/polygenic (TLR2, TIRAP, LTA4H).
  • Geographic distribution: burden concentrated in high-TB-incidence, low-HDI settings and areas of high HIV prevalence.
  • Demographics: male predominance in many cohorts; younger children over-represented among severe cases.

10. Diagnostics

No single test reliably rules TBM in or out; diagnosis is a composite.

CSF profile. "Cerebrospinal fluid (CSF) analysis showed lymphocytic pleocytosis, elevated protein, low glucose levels, and cobweb coagulum indicative of TBM" (PMID: 37915698).

Adenosine deaminase (ADA). A useful adjunct with high specificity but limited sensitivity: "ADA was the best performing parameter. It attained a specificity of 95%, a positive likelihood ratio of 10.7, and an area under the receiver operating characteristics curve of 82.1%, but had a low sensitivity (55%)" (PMID: 23973430).

Molecular tests. Xpert MTB/RIF Ultra is the WHO first-choice test: "Xpert Ultra had 76·5% sensitivity (95% CI 62·5-87·2 ...) and a negative predictive value of 92·7%," superior to Xpert (~56%) and MGIT culture (~61%) (PMID: 31924549). Metagenomic NGS reaches ~84% sensitivity and CSF pyrosequencing higher still, but "mNGS cannot be used as a rule-out test" (PMID: 35202495).

Culture. Confirmatory but insensitive: "The overall pooled estimates of CSF culture positive TBM was 29.72%" (PMID: 36795648).

Drug-resistance testing. Targeted NGS on CSF (e.g., Deeplex Myc-TB) enables rapid resistance detection: "Targeted next-generation sequencing (tNGS) produces high read depths, allowing the detection of DR-associated alleles with low frequencies" (PMID: 38466092).

Neuroimaging. The TBM triad — basal meningeal enhancement + hydrocephalus + basal-ganglia infarction — is diagnostically valuable: "the combination of meningeal enhancement and any degree of hydrocephalus is strongly suggestive of TBM" (PMID: 28281443). In a 559-case series: tuberculomas 40%, basal meningeal enhancement 41%, infarction 27%, hydrocephalus 26% (PMID: 31115112).

Test Sensitivity Specificity/NPV Source
CSF Xpert Ultra ~77% NPV 92.7% PMID:31924549
CSF Xpert (original) ~56% — PMID:31924549
MGIT culture ~25–61% culture-positive ~30% PMID:36795648
CSF mNGS ~84% not rule-out PMID:35202495
CSF pyrosequencing ~98% NPV ~98% PMID:33421910
CSF ADA ~55% ~95% spec PMID:23973430

Clinical criteria. The Marais/uniform case definition (definite/probable/possible) and Thwaites score are used to classify cases. Differential diagnosis includes cryptococcal meningitis, bacterial/partially-treated bacterial meningitis, viral meningoencephalitis, carcinomatous meningitis, and neurosarcoidosis (PMID: 41788392).

11. Outcome / Prognosis

  • Mortality: ~40% overall (HIV-negative), up to ~70% with HIV co-infection; in-hospital ~42% (PMID: 35288778).
  • Morbidity: high rates of long-term neurological and cognitive sequelae. "Cognitive impairment ranging from 12% to over 90% was found across studies ... The most consistently affected domains were memory, attention, and executive function" (PMID: 41629635).
  • Complications: stroke/infarction (~30%), hydrocephalus, seizures/epilepsy, cranial neuropathies, hyponatremia, paradoxical reactions, IRIS (in HIV).
  • Prognostic factors: BMRC stage at presentation (dominant), age (<5 years worse), HIV status, drug resistance, hyponatremia severity/persistence, low albumin/hemoglobin, delayed treatment. "Persistent hyponatraemia and increasing urinary output during treatment associate with worse clinical out[come]" (PMID: 42167495).
  • Stroke burden: "The frequency of stroke in TBM showed an estimate of 0.30 (95% CI, 0.26-0.33)" (PMID: 36048445).

12. Treatment

Standard antituberculous therapy. WHO recommends 12 months of therapy for TBM: "the World Health Organization recommends 12 months of treatment for TBM. The drugs used in the treatment are rifampicin, isoniazid, ethambutol, and pyrazinamide" (regimen 2HRZE/10HR) (PMID: 39752122). CNS penetration differs by drug: "pyrazinamide penetrates the brain better than other drugs and kills TB bacteria more effectively. In addition, ethambutol does not get into the brain" (PMID: 39752122). Rifampicin CNS penetration is limited, motivating high-dose (25–35 mg/kg) trials (PMID: 34494572). Suggested NCIT terms: Isoniazid (C557), Rifampicin/Rifampin (C608), Pyrazinamide (C777), Ethambutol (C486), Dexamethasone (C405).

Pediatric intensified regimen. A 6-month intensified regimen (higher-dose H/R, pyrazinamide, ethionamide replacing ethambutol; 6HRZEto) markedly improved outcomes: "death, 5.5% ... vs 23.9% ...; treatment success (survival with or without sequelae), 94.6% ... vs 75.4%" (PMID: 35673608).

Adjunctive corticosteroids (NCIT: dexamethasone, prednisolone). Standard of care for HIV-negative adults and children — but benefit is host-genotype-dependent. In the phase 3 LAST ACT trial (HIV-negative, CC/CT genotypes), "the primary endpoint of all-cause death or new neurological event over 12 months from randomization occurred in 108/305 (35.4%) given dexamethasone and 110/308 (35.7%) given placebo (hazard ratio of 0.99)" — i.e., no benefit in lower-inflammation genotypes (PMID: 41540106). In HIV-positive adults, adjunctive dexamethasone "did not confer a benefit with respect to survival" (PMID: 37819954).

Host-directed / adjunctive therapy. Aspirin, high-dose rifampicin, and linezolid are under trial (LASER-TBM, INTENSE-TBM, INSHORT, SURE). MMP inhibition (e.g., doxycycline) is a preclinical host-directed strategy (PMID: 41819159).

HIV co-management. ART improves survival but timing is critical — early ART increases IRIS/adverse events in TBM; prednisone "is effective in both preventing and treating the paradoxical tuberculosis-associated immune reconstitution inflammatory syndrome" (PMID: 31272663).

Supportive / surgical. Management of hydrocephalus (CSF diversion/shunting), seizure control, hyponatremia correction (distinguishing SIADH from cerebral salt wasting, which require opposite fluid strategies), and rehabilitation.

13. Prevention

  • Primary — BCG vaccination. The cornerstone. "Protection against meningeal and miliary tuberculosis was also high in infants (RR, 0.1; 95% CI, .01-.77)" — ~90% efficacy (PMID: 24336911). "the neonatal Bacillus Calmette-Guérin (BCG) is the only vaccine against TB and offers significant efficacy against disseminated and meningeal disease in children" (PMID: 40498907). Protection against pulmonary TB is weaker and more variable.
  • Secondary. Early case detection and prompt treatment initiation; TB preventive therapy in high-risk (e.g., HIV) individuals; contact tracing.
  • Tertiary. Corticosteroids to limit inflammatory injury (genotype-informed), hydrocephalus management, and prevention/treatment of IRIS.
  • Public health. TB control programs, HIV control, nutrition, and reduction of transmission.

14. Other Species / Natural Disease

TBM is fundamentally a human disease. M. tuberculosis has limited natural host range, though M. bovis (zoonotic) can cause CNS TB. Experimental infection with Mycobacterium marinum in zebrafish reproduces key inflammatory susceptibility biology (PMID: 22304914). Zoonotic potential exists for bovine TB. No dedicated companion-animal natural-TBM literature was identified in this review.

15. Model Organisms

  • Zebrafish (Danio rerio) / M. marinum. Establishes the "inverted-U" inflammation model: "susceptibility to Mycobacterium marinum can result from either inadequate or excessive acute inflammation," driven by the LTA4H eicosanoid balance; the human LTA4H polymorphism "is associated with inflammatory cell recruitment, patient survival and response to adjunctive anti-inflammatory therapy" (PMID: 22304914). Strength: models host-genotype-directed therapy. Limitation: does not reproduce full basal-exudate neuropathology.
  • Mouse CNS-TB model. SHH-modulated rapid CNS-TB model recapitulates MMP-9-driven BBB breakdown, reactive gliosis, and increased brain bacillary load (PMID: 39536643). Application: BBB pathology and drug/host-directed therapy discovery.

Mechanistic Model / Interpretation

 M. tuberculosis (Beijing lineage)
│  hematogenous spread
▼
   RICH FOCUS (subpial/subependymal caseous granuloma)
│  rupture into subarachnoid space
▼
   DENSE BASAL MENINGEAL EXUDATE ──────────────┐
│              │              │        │
   (4a) arteritis  (4b) CSF-flow  (4c) CN     (5) MMP-9 ↑
│              block       entrapment  │ (neutrophil/macrophage)
▼              ▼              ▼         ▼
   INFARCTION     HYDROCEPHALUS   CRANIAL     BBB DISRUPTION
   (basal ganglia)                NEUROPATHY  + neuroinflammation
└──────────────┴──────────────┴─────────┘
                ▼
RAISED ICP, COMA, DEATH  /  survivor sequelae
(cognitive impairment, focal deficit, epilepsy)

   HOST MODIFIER: LTA4H genotype (TT hyper- / CT / CC low-inflammation)
   → tunes exudate & MMP-9 magnitude, TNF balance
   → determines corticosteroid benefit

The disease is best understood as a two-hit process: (1) the mechanical/infectious hit of the Rich focus rupturing and generating a strategically located basal exudate, and (2) the immunopathological hit of dysregulated host inflammation (eicosanoid/TNF imbalance, MMP-9-mediated matrix destruction). The exudate's anatomical location — around the basal cisterns and perforating arteries — explains why the three cardinal complications are stereotyped (basal-ganglia stroke, obstructive hydrocephalus, cranial neuropathy). The host-inflammatory hit explains why anti-inflammatory adjunctive therapy helps some patients (hyperinflammatory TT) but not others (CC/CT), and why both too little and too much inflammation are harmful.

Evidence Base

PMID Contribution
7610242 Neuropathology — establishes Rich focus → basal exudate → vasculitis/hydrocephalus/CN entrapment chain
22953709 Host (TLR2, TIRAP, LTA4H) and pathogen (Beijing) susceptibility factors
41540106 LAST ACT phase 3 — genotype-stratified dexamethasone; null in CC/CT
22304914 Zebrafish LTA4H inverted-U inflammation model; links to human steroid response
19789647 Dexamethasone lowers CSF MMP-9; MMP-9/neutrophil link
39536643 Mouse model — MMP-9 drives BBB disruption
31924549 Xpert Ultra diagnostic performance (~77%)
23973430 CSF ADA performance (spec 95%, sens 55%)
35288778 Epidemiology & mortality meta-analysis
36795648 Microbiological diagnosis & mortality; 78,200 adult deaths (2019)
36048445 Stroke frequency (~30%) and vascular territory
41629635 Cognitive sequelae meta-analysis
35673608 Pediatric 6-month intensified regimen outcomes
39752122 WHO 12-month regimen & CNS drug penetration
42167495 Hyponatremia prevalence & prognostic value
34510291 SIADH vs cerebral salt wasting frequencies
24336911 BCG ~90% protection vs meningeal/miliary TB
28281443 Untreated temporal course; imaging triad value
31115112 Imaging finding frequencies (559 cases)
38466092 tNGS for rapid CSF drug-resistance detection
37819954 Dexamethasone no benefit in HIV-positive adults
42242389 Paradoxical reactions (~21%) in CNS-TB

Limitations and Knowledge Gaps

  1. Diagnostic gap. No test reliably excludes TBM; culture confirms only ~30%, and even Xpert Ultra misses ~1 in 4 cases. Delayed diagnosis remains a leading cause of death.
  2. Corticosteroid uncertainty. The genotype-stratified null result in CC/CT and the HIV-positive null challenge decades of blanket steroid use; optimal, genotype-informed anti-inflammatory strategy is unresolved.
  3. Drug penetration. Standard regimens penetrate the CNS poorly; optimal doses of rifampicin/linezolid and duration are still under trial.
  4. Host-directed therapy. MMP-9 inhibition, aspirin, and resolvin biology are promising but not yet standard.
  5. Pediatric/HIV evidence. Much mechanistic and trial data derive from adult, HIV-negative Vietnamese cohorts; generalizability to children and HIV-endemic African settings is incomplete.
  6. No omics disease signature. TBM-specific transcriptomic/proteomic/metabolomic diagnostic biomarkers are not yet validated for routine use.

Proposed Follow-up Experiments / Actions

  1. Genotype-guided steroid trials extending LAST ACT to pediatric and HIV-positive populations, testing whether the TT (hyperinflammatory) genotype specifically benefits.
  2. Host-directed therapy trials of MMP-9 inhibitors (doxycycline) and pro-resolving mediators, using CSF MMP-9 and resolvin profiles as pharmacodynamic biomarkers.
  3. Optimized antibiotic PK/PD — complete high-dose rifampicin + linezolid intensification trials (INTENSE-TBM, INSHORT, SURE) with CSF drug-exposure endpoints.
  4. Rapid molecular diagnostics scale-up — deploy CSF tNGS/pyrosequencing for simultaneous detection and resistance profiling; develop a rule-out biomarker panel.
  5. CSF biomarker discovery — multi-omic (proteomic/metabolomic/lipidomic) profiling to build a validated early-diagnosis and prognostic signature.
  6. Improved vaccines — evaluate next-generation TB vaccines specifically for prevention of childhood meningeal/miliary disease.

Report compiled from 15 confirmed findings and 68 reviewed papers. Evidence sources span human clinical (RCTs, cohorts, meta-analyses), model-organism (zebrafish, mouse), and in-vitro studies, as annotated by PMID throughout.

Artifacts

Reference Validation

Checked with linkml-reference-validator 0.3.0rc3.

Outcome Count
References checked 35
Resolved 35
Unresolved (possible confabulation) 0
Unverifiable 0
Quoted claims checked 27
Quoted claims found in source 25
Quoted claims not found in source 2
References weighed for topical relevance 35
On topic 15
Off topic 1

Quotes not found in the cited source

Searched the abstract, any retrieved full text, and the title. A quote drawn from a part of the paper that was not retrieved will appear here too, so check before treating one as invented:

Every one of these was searched against an abstract alone, with no full text retrieved - marked abstract only below. Where full text can be fetched, re-running with it will settle them; where the source publishes only a summary to PubMed, as GeneReviews chapters do, it will not, and the quote has to be checked by hand against the chapter itself.

  • PMID:41629635 (abstract only): "most consistently affected memory, attention, and executive function"
  • closest text in source: "The most consistently affected domains were memory, attention, and executive function, followed by language and visuospatial"
  • PMID:39752122 (abstract only): "pyrazinamide penetrates the brain better than other drugs and kills TB bacteria more effectively. In addition, ethambutol does not get into the brain"
  • closest text in source: "However, pyrazinamide, with higher penetration into the central nervous system, is generally overlooked"

References that may not be about this subject

These identifiers resolve, so they are not fabrications, but the records they resolve to share almost none of this report's vocabulary. That is a clue and not a verdict - a paper can be relevant in ways its title and abstract do not spell out - so read them before deciding:

  • PMID:35673608 (4 mentions) - Comparative Effectiveness of Regimens for Drug-Susceptible Tuberculous Meningitis in Children and Adolescents: A Systematic Review and Aggregate-Level Data Meta-Analysis.
  • shared terms: children

Weighed against this report's own most characteristic terms: tbm, disease, meningeal, csf, hydrocephalus, tuberculosis, therapy, hiv, lta4h, host, susceptibility, inflammatory, basal, children, inflammation, human, mmp-9, exudate, cns, cranial.

Term Validation

Checked with linkml-term-validator 0.4.5, through the ols: adapter.

Outcome Count
Terms checked 29
Resolved 28
Unresolved (possible confabulation) 0
Obsolete 0
Unverifiable 1
Terms whose name was checked 8
Terms named correctly 0
Terms named as a different term 7
Terms whose name is worth a second look 1

Terms the report names something else

These identifiers resolve, so nothing about them looks wrong, and the ontology calls them something unrelated to what the report calls them. That usually means the identifier is not the one the sentence needs:

  • MONDO:0006042 (2 mentions) - the report calls it "MONDO"; MONDO calls it meningeal tuberculosis
  • HP:0002013 (1 mention) - the report calls it "~52–92% (children higher)"; HP calls it Vomiting
  • HP:0001250 (1 mention) - the report calls it "~72% (children)"; HP calls it Seizure
  • HP:0001269 (1 mention) - the report calls it "~30% (stroke)"; HP calls it Hemiparesis
  • HP:0000238 (1 mention) - the report calls it "26–63% imaging"; HP calls it Hydrocephalus
  • HP:0100543 (1 mention) - the report calls it "12–>90% survivors"; HP calls it Cognitive impairment
  • HP:0012229 (1 mention) - the report calls it "abnormal CSF"; HP calls it CSF pleocytosis

Terms whose name is worth a second look

The report's name for these is recognisably related to the term's own name without being one of them. A loose paraphrase reads the same way as a citation of the wrong sibling term - and so does a related synonym, which the ontology records precisely because it names something adjacent rather than the same thing - so these are listed rather than judged:

  • HP:0000496 (1 mention) - the report calls it "common (basal exudate entrapment)"; HP calls it Abnormality of eye movement, and lists "Abnormal eye movement" among its other names