Clinical scoring systems for diagnosing tuberculous meningitis: A systematic review

Table 1 Details of scores with external validation

Ref.	Country	Internal validation	Clinical criteria	Laboratory criteria	Microbiological/histopathological criteria	Radiological criteria	Interpretation
Thwaites et al[31], 2002	Vietnam	AUC of ROC: 0.990	Age: (1) ≥ 36 years: 2 points; and (2) < 36 years: 0 points	CSF analysis (103/mL)	None	None	TDI: DI (age) + DI (blood white-cell count) + DI (history of illness) + DI (cerebrospinal fluid white-cell count) + DI (cerebrospinal fluid% neutrophils)
		Sensitivity 97.0%; specificity: 91.0%		CSF total white cell count
				≥ 900: 3 points; < 900: 0 points			TBM: TDI ≤ 4
				CSF% neutrophils: ≥ 75: 4 points; < 75: 0 points
		After internal validation with test data population (n = 75)	History of illness: (1) ≥ 6 days: -5 points; and (2) < 6 days: 0 points	Blood white cell count (103/mL): (1) ≥ 15000: 4 points; and (2) < 15000: 0 points			BM: TDI > 4
		Sensitivity: 86.0%; specificity: 79.0%
Marais et al[32], 2010	NIL	NIL	Entry criteria: Symptoms and signs of meningitis including at least one: Headache, irritability, vomiting, fever, neck stiffness, convulsions, focal neurological deficits, altered consciousness, or lethargy	CSF analysis 1 point each, maximum score: 4 points	Extraneural TB: Maximum score: 4 points. Imaging suggestive of extraneural TB (see next column). AFB identified or M.TB cultured from another source (e.g., sputum, lymph node, gastric washing, urine, blood culture): 4 points. Positive commercial M.TB NAAT from extra-neural specimen: 4 points	Cerebral imaging: Maximum score: 6 points: (1) Hydrocephalus: 1 point; (2) Basal meningeal enhancement: 2 points; (3) Tuberculoma: 2 points; (4) Infarct: 1 point; (5) Pre-contrast basal hyperdensity: 2 points; and (6) Imaging suggestive of extraneural TB: Chest radiograph suggestive of active TB: Signs of TB: 2 points. Miliary TB: 4 points. CT/MRI/ultrasound evidence for TB outside CNS: 2 points	Definite TBM
							Clinical entry criteria
							At least 1: (1) AFB seen in CSF; (2) M.TB cultured from CSF; and (3) CSF positive commercial NAAT
			Clinical criteria: Maximum score: 6 points	Clear appearance			“AND/OR” AFB seen in context of histological changes consistent with TB in the brain or spinal cord with suggestive symptoms or signs and CSF changes, or visible meningitis (on autopsy)
			Symptom duration > 5 days: 4 points	Cells: 10-500 per μL			Probable TBM
							Clinical entry criteria: (1) Total diagnostic score (with ≥ 2 point from laboratory or radiological criteria); (2) Score ≥ 10 (when cerebral imaging unavailable); and (3) Score ≥ 12 (when cerebral imaging available)
			Systemic symptoms suggestive of TB (at least 1): 3 points: (1) Weight loss or poor weight gain in children; (2) Night sweats; and (3) Persistent cough > 2 weeks	Lymphocytic predominance (> 50%)			Exclusion of alternative diagnoses
			History of recent (within past year) close contact with an individual with pulmonary TB or positive TST or IGRA (only in children < 10 years old): 2 points	Protein concentration > 1 g/L			Probable TBM
							Clinical entry criteria: (1) Total diagnostic score (with ≥ 2 points from laboratory or radiological criteria); (2) Score ≥ 10 (when cerebral imaging unavailable); and (3) Score ≥ 12 (when cerebral imaging available)
			Focal neurological deficit (excluding cranial nerve palsies): 1 point	CSF: Plasma glucose ratio < 50% or an absolute CSF glucose concentration < 2.2 mmol/L			Exclusion of alternative diagnoses
			Cranial nerve palsy: 1 point				Possible TBM: (1) Clinical entry criteria; (2) Total diagnostic score: Score: 6-9 (when cerebral imaging is not available); score: 6-11 (when cerebral imaging is available); and (3) Exclusion of alternative diagnoses. Possible TB cannot be diagnosed or excluded without doing a lumbar puncture or cerebral imaging
			Altered consciousness: 1 point				Non-TBM: Alternative diagnosis established, without a definitive diagnosis of TBM or other convincing signs of dual disease
Hristea et al[33], 2012	Romania	AUC of ROC: 0.977	DSBA ≥ 5 days: Fever; headache; vomiting; neck stiffness	CSF analysis	None	None	For patients with clear CSF meningitis, use this equation to calculate the probability of TBM: Ln (ODDS) = 3.615 × DSBA + 2.680 × (neurological stage) + 3.414 × (glucose ratio) + 1.669 × (CSF protein) - 7.612
		Sensitivity: 92.0%; specificity: 94.0%	Neurological stage II and III (defined based on Medical Research Council Definitions)	CSF/blood glucose ratio < 0.5
			Stage II: Lethargy, confusion, mild focal signs (cranial nerve palsy, hemiparesis)	CSF protein level > 100 mg/dL			Scoring system: (1) DBSA ≥ 5 days: 3 points; (2) Neurological stages II/III (instead of I): 2 points; (3) Glucose ratio < 0.5: 3 points; and (4) CSF protein > 100 mg/dL: 1 point
		PPV: TBM: 89.1%; VM: 95.6%	Stage III: Delirium, stupor, coma, seizures, multiple cranial nerve palsies, dense hemiplegia or paraparesis
Kumar et al[34], 19991	India	One or more predictor variables present: Total n = 100; TBM n = 65; non-TBM n = 35; sensitivity: 98.4%; specificity: 43.5%	Prodromal stage ≥ 7 days	CSF analysis: CSF leukocytes < 50% polymorphs	None	None	TBM ruled in with high degree of certainty: ≥ 3 of 5 criteria present
		Two or more predictor variables present: Total n = 59; TBM n = 51; non-TBM n = 8; sensitivity: 77.2%; specificity: 87.0%	Fundal optic atrophy				Highly unlikely TBM: None of the 5 criteria present
		Three or more predictor variables present: Total n = 37; TBM n = 36; non-TBM n = 1; sensitivity: 54.5%; specificity: 98.3%	Focal neurological deficits				Use scoring system and ROC plot if ≥ 2 out of 5 criteria present (best cut off: 34): (1) Prodromal stage ≥ 7 days: 23; (2) Fundal optic atrophy: 2; (3) Focal deficits: 18; (4) EP movements: 29; and (5) CSF leucocytes < 50% polymorphs: 34
			Extrapyramidal movements

¹Formulated with paediatric population.

AUC: Area under the receiver operating characteristic curve; ROC: Receiver operating characteristic; CSF: Cerebrospinal fluid; TDI: Total diagnostic index; DI: Diagnostic index; TBM: Tuberculous meningitis; BM: Bacterial meningitis; NIL: Zero; TST: Tuberculosis skin test; IGRA: Interferon gamma release assay test; TB: Tuberculosis; NAAT: Nucleic acid amplification test; CT: Computed tomography; MRI: Magnetic resonance imaging; CNS: Central nervous system; AFB: Acid fast bacilli; DSBA: Duration of symptoms before admission; non-TBM: Non-tuberculous meningitis; EP: Epileptic.

Table 2 Overview of scores with external validation

Ref.	Sensitivity (%)	Specificity (%)	Country of external validation population	Clinical criteria	Laboratory criteria	Microbiological/histopathological criteria	Radiological criteria
Thwaites et al[31], 2002	Cut off of ≤ 3.5: TBM vs non-TBM: 78.0	Cut off of ≤ 3.5: TBM vs non-TBM: 63.0	Malawi	√	√	X	X
	TBM vs PM: 95.0	TBM vs PM: 23.5	Pakistan
	Cut off of ≤ 4: TBM vs non-TBM: 78.0-100	Cut off of ≤ 4: TBM vs non-TBM: 40.8-43.0	Malawi, Turkey, Qatar
	TBM vs BME: 95.8	TBM vs BME: 0.680	Turkey
	TBM vs PM: 96.0	-	India
	TBM vs BM: 95.8-98.2	TBM vs BM: 43.6-87.9	China, Turkey, India
Marais et al[32], 2010	Cut off of ≥ 6: TBM vs non-TBM: 66.7-100	Cut off of ≥ 6: TBM vs non-TBM: 48.7-85.5	Brazil, Turkey, China, Qatar	√	√	√	√
	TBM vs BM: 93.0-97.0	TBM vs BM: 56.0-68.0	China
	TBM vs BME: 96.8	TBM vs BME: 3.06	Turkey
	Cut off of ≥ 8: TBM vs non-TBM: 84.9	Cut off of ≥ 8: TBM vs non-TBM: 77.2	Brazil
	Cut off of ≥ 10: TBM vs non-TBM: 100	Cut off of ≥ 10: TBM vs non-TBM: 40.8	Brazil
Hristea et al[33], 20121	Cut off of ≥ 6: TBM vs non-TBM: 100	Cut off of ≥ 6	Turkey	√	√	X	X
	TBM vs VM: 96.7	TBM vs VM: 81.1	Romania
	TBM vs CM: 86.6	TBM vs CM: 27.7	Romania
	Cut off of ≥ 9: TBM vs VM: 51.6	Cut off of ≥ 9: TBM vs VM: 100	Romania
Kumar et al[34], 19991	Cut off of ≥ 3: TBM vs non-TBM: 37.0	Cut off of ≥ 3: TBM vs non-TBM: 58.1	India	√	√	X	X

¹Validated in the paediatric population.

TBM: Tuberculous meningitis; non-TBM: Non-tuberculous meningitis; BME: Bacterial meningoencephalitis; BM: Bacterial meningitis; VM: Viral meningitis; CM: Cryptococcal meningitis; PM: Pyogenic meningitis.

Table 3 Overview of scores without external validation

Ref.	Sensitivity	Specificity	Clinical criteria	Laboratory criteria	Microbiological/histopathological criteria	Radiological criteria	Country
Yang et al[35], 2019	97.0-98.0	81.0-82.0	√	√	X	X	China
Goenka et al[36], 2018	93.0-100	89.0-93.0	√	√	√	X	South Africa
Wen et al[37], 2022	96.0	86.0	√	√	X	X	China
Vibha et al[10], 2012	95.7	97.6	√	√	X	X	India
Ersoy et al[38], 2012	95.5	100	√	√	X	X	Turkey
Solari et al[39], 2018	94.9	52.6-94.7	√	√	X	X	Peru
Chusri et al[40], 2018	92.0	89.0	√	√	X	√	Thailand
Lee et al[41], 2018	89.4	80.4	√	√	X	X	South Korea
Solomons et al[42] 20161	97.0	48.0-78.0	√	√	√	√	South Africa
	79.0	48.0-78.0	√	√	√	√
He et al[43], 2021	87.0	94.0	√	√	X	X	China
Dendane et al[44], 2013	86.0-88.0	93.0-95.0	√	√	√	√	Morocco
Lu et al[45], 2021	81.0-85.8	86.3-87.7	√	√	X	√	China
Luo et al[46], 2021	81.6	91.8	X	√	X	X	China
Fong et al[24], 2023	81.5	88.1	√	√	X	√	China
Handryastuti et al[47], 20231	47.1	95.1	√	X	X	√	Indonesia
Patel et al[48], 2010	38.0	93.0	√	√	X	X	South Africa

¹Validated in the paediatric population. Refer to Supplementary Table 3 for further details.