Tuberculous meningitis

• Meningeal infection by Mycobacterium tuberculosis
• High mortality, often needs empiric treatment even before confirmed diagnosis

Background

Classification

• Stage 1: normal level of consciousness, no focal neurological deficits
• Stage 2: decreased level of consciousness, significant focal neurological deficits
• Stage 3: seizures, comatose

Epidemiology

• About 1% of TB cases in Canada

Risk Factors

• Young
• Female
• Originally from endemic country
• Previous TB

Clinical Manifestations

History

• Prodrome (1-3 weeks)
  • Personality changes
  • Low-grade fever
  • Malaise
  • Weight loss
  • Gradual onset of worsening headache
• Headache
• Fevers
• Vomiting
• Confusion
• Personality changes
• Photophobia (only 5-10%)
• Seizures

Physical Exam

• Meningeal symptoms
• Fevers
• Vomiting
• Meningismus
• Focal neurological deficits
  • Cranial nerve palsies in VI, III, and IV
  • Hemiplegia, paraplegia
  • Urinary retention
• Confusion, coma

Thwaites Index

• Used to differentiate bacterial from tuberculous meningitis in adults before results of CSF culture are available1
• Tuberculous more likely if score ≤4; bacterial more likely if score ≥5
  • Sensitivity 86% and specificity 79%

Item	Score
Age ≥36 years	+2
Blood WBC ≥15	+4
≥6 days of illness	-5
CSF WBC ≥900x103	+3
CSF % PMN ≥75	+4

Complications and Prognosis

• Depends on stage at presentation
• Mortality is high
  • Stage 1: 10-20%
  • Stage 2: 20-40%
  • Stage 3: 60%
• Morbidity is high, with about 20% of patient being left with significant neurological sequelae
  • Mental retardation, psychiatric disorders, seizure, blindness, deafness, ophthalmoplegia, hemiparesis

Differential Diagnosis

• Fungal meningitis
• Sarcoidosis
• Neoplasm
• Other causes of chronic meningitis

Investigations

• Lumbar puncture
  • Increased lymphocytes, decreased glucose, and increased protein
  • Need 3-5mL of CSF for culture
  • May need serial LPs
• CT head

Diagnosis

• Gold standard is mycobacterial culture (71% sensitive, 100% specific)
  • Sensitivity increases with volume and number of samples
• Microscopy for acid-fast bacilli is 20-80% sensitive and 100% specific
• PCR is 85-95% sensitive and 98% specific
  • Used to confirm but not exclude the diagnosis

Management

• Rule out neoplasm and fungus, then start empiric treatment
• HIV test (delay antiretrovirals by 8 weeks, though)
• Standard HREZ x2mo then HR x7-10mo
  • Can replace ethambutol with a fluoroquinolone
• Adjunctive steroids for high risk of IRIS
  • Dexamethasone 3mg po qid x2wk then taper over 6-8wks
  • Prednisolone 120 mg PO daily x1wk, 90 mg x1wk, 60 mg x1wk, 30 mg x1wk, 15 mg x1wk, 5 mg x1wk

Drug	Dose	Duration	CSF penetration
Rifampin	10 mg/kg (max 600 mg)	12 months	10-20%
Isoniazid	5 mg/kg (max 300 mg)	12 months	80-90%
Pyrazinamide	25 mg/kg	2 months	90-100%
Ethambutol	15 mg/kg	2 months	20-30%
Second-line treatments
Levofloxacin	10-15 mg/kg	Throughout treatment	70-80%
Moxifloxacin	400 mg	Throughout treatment	70-80%
Amikacin	15 mg/kg (max 1 g)	Intensive phase only	10-20%
Kanamycin	15 mg/kg (max 1 g)	Intensive phase only	10-20%
Capreomycin	15 mg/kg (max 1 g)	Intensive phase only	Probably very low
Ethionamide or prothionamide	15-20 mg/kg (max 1 g)	Throughout treatment	80-90%
Cycloserine	10-15 mg/kg (max 1 g)	Throughout treatment	80-90%
Linezolid	600 mg	Throughout treatment	30-70%
Other drugs with uncertain benefit
Clofazimine	100 mg daily		Probably low
p-aminosalicylic acid	200-300 mg/kg		Probably very low
Bedaquiline			Probably very low
Delamanid			No data

Further Reading

• Treatment of Tuberculous Meningitis and Its Complications in Adults. Curr Treat Options Neurol. 2018;20(3):5. doi: 10.1007/s11940-018-0490-9