In a 42‑year‑old man with fever and severe headache, cranial CT shows multiple low‑attenuation supratentorial and infratentorial lesions with basal cisternal enhancement, and CSF is clear with zero red blood cells, a white blood cell count of 453 cells/µL (≈87% lymphocytes) and protein >3 g/L; what is the most likely diagnosis?

Tuberculous Meningitis

Based on the clinical presentation of fever, headache, multifocal brain lesions with basal cisternal enhancement on CT, and CSF showing lymphocytic predominance (87.8% monocytes/lymphocytes), elevated WBC (453 cells/µL), and markedly elevated protein (>3 g/L), the most likely diagnosis is tuberculous meningitis with associated intracranial tuberculomas. 1, 2

Key Diagnostic Features Supporting TB Meningitis

The CSF profile is classic for tuberculous meningitis:

• Lymphocytic predominance (87.8%) with WBC count of 453 cells/µL falls within the typical range of 5-500 cells/µL for TB meningitis 3, 1, 2
• Markedly elevated protein (>3 g/L) is characteristic of TB meningitis, which typically shows protein >1 g/L; levels <0.6 g/L would make bacterial meningitis unlikely 3, 1, 2
• Clear, colorless CSF with zero RBCs excludes traumatic tap and is consistent with TB meningitis 3, 4

The imaging findings are pathognomonic:

• Multifocal low-attenuation lesions in both supratentorial and infratentorial regions represent intracranial tuberculomas, which occur at grey-white matter junctions due to hematogenous dissemination 5, 6
• Basal cisternal enhancement is strongly suggestive of TB meningitis and reflects the characteristic basal meningitis pattern 5, 4
• The combination of meningeal enhancement with any degree of hydrocephalus is highly specific for TB meningitis 5

The clinical presentation fits the subacute course:

• Febrile episodes and headache represent the typical prodrome of malaise, fever, and headache that progresses over weeks in TB meningitis 5, 4, 7

Critical Differential Diagnosis Considerations

Bacterial meningitis is effectively ruled out:

• Bacterial meningitis would show neutrophil predominance (80-95%), not the 87.8% lymphocytic predominance seen here 3, 1
• The clear CSF appearance argues strongly against bacterial meningitis, which typically shows turbid, cloudy, or purulent fluid 3
• CSF WBC in bacterial meningitis is typically >1000 cells/µL, not 453 cells/µL 3

Viral meningitis is unlikely:

• While viral meningitis can show lymphocytic predominance, the markedly elevated protein (>3 g/L) is atypical; viral meningitis typically shows only mildly raised protein 3, 8
• Viral meningitis does not explain the multifocal brain lesions and basal cisternal enhancement 3

Fungal meningitis (Cryptococcus, Histoplasma) remains in the differential:

• Fungal meningitis can present with identical CSF findings: lymphocytic pleocytosis (5-500 cells/µL), low glucose, and raised protein 3, 1, 8
• However, the imaging pattern of multifocal tuberculomas with basal cisternal enhancement is more characteristic of TB than fungal infection 5, 6

Partially treated bacterial meningitis must be considered:

• Prior antibiotics can shift bacterial meningitis to a lymphocytic profile 3, 8
• CSF may sterilize within 2 hours for meningococcus and 4 hours for pneumococcus after antibiotic administration 3
• However, the patient's normal CBC, CXR, and lack of systemic sepsis features make this less likely 1

Critical Missing Information Required Immediately

Calculate the CSF/plasma glucose ratio:

• This is the single most important missing value 3, 1, 2
• A ratio <0.5 is highly suggestive of TB meningitis 1, 2
• A ratio <0.36 would favor bacterial meningitis 3, 1
• A ratio >0.36 would favor viral meningitis 3, 1
• The absolute CSF glucose value can be misleading without knowing the serum glucose 3, 1

Obtain CSF opening pressure:

• TB meningitis typically shows raised opening pressure 3, 2

Perform confirmatory microbiological testing:

• CSF PCR for Mycobacterium tuberculosis has 87-100% sensitivity and 98-100% specificity 1, 7
• CSF acid-fast bacilli (AFB) smear and culture on 6 mL of CSF (sensitivity increases with multiple large-volume samples) 1, 4, 7
• CSF bacterial culture and Gram stain to definitively exclude bacterial meningitis 3, 1
• CSF HSV PCR to exclude herpes simplex encephalitis, which has >95% sensitivity 1
• CSF fungal studies including cryptococcal antigen, India ink staining, and fungal culture 1
• CSF lactate: levels >35 mg/dL would suggest bacterial meningitis with 93% sensitivity and 96% specificity 3, 1, 8

Additional essential workup:

• Chest X-ray or CT to identify pulmonary TB (primary source is usually the lung) 2, 4
• HIV testing (HIV-positive patients have higher incidence and mortality from TB meningitis) 1, 2
• Blood cultures 1
• MRI brain with contrast is superior to CT for detecting basal meningeal enhancement, tuberculomas, hydrocephalus, and vasculitic infarcts in the basal ganglia 3, 5, 6

Immediate Management Protocol

Start empiric four-drug anti-tuberculous therapy immediately without waiting for microbiological confirmation:

• Isoniazid, rifampin, pyrazinamide, and ethambutol (or streptomycin) for 2 months, followed by isoniazid and rifampin for 10 months (total 12 months) 1, 5, 4, 7
• Delay in treatment significantly worsens outcomes; treatment is most effective when started early 5, 4, 7
• The four-drug regimen covers resistant strains, maximizes antimicrobial impact, and reduces emergence of resistance 5, 7

Provide simultaneous empiric coverage for other life-threatening causes:

• IV acyclovir 500 mg/m² (or 10 mg/kg) every 8 hours until HSV encephalitis is excluded by negative PCR 1
• Ceftriaxone 2 g IV every 12 hours plus ampicillin 2 g IV every 4 hours (for patients >50 years or immunocompromised) until bacterial meningitis is definitively excluded 1
• Continue empiric therapy until bacterial cultures are negative at 48 hours, HSV PCR is negative, and TB studies are available 1

Adjunctive corticosteroid therapy:

• Corticosteroids reduce mortality in TB meningitis in all but late-stage disease 5, 7
• Consider dexamethasone as adjuvant therapy, particularly if tuberculomas enlarge paradoxically during treatment 9

Critical Clinical Pitfalls to Avoid

Do not wait for microbiological confirmation before starting treatment:

• CSF AFB smear has relatively low sensitivity (50-99% depending on organism and prior antibiotics) 3, 7
• Culture takes weeks and treatment delay significantly increases mortality 5, 4, 7
• Negative TB PCR does not rule out TB meningitis due to suboptimal sensitivity 7

Do not rely on absolute CSF glucose without the CSF/plasma ratio:

• Serum glucose abnormalities can make absolute CSF glucose misleading 3, 1
• Always calculate the ratio to properly interpret CSF glucose 1, 2

Monitor for complications:

• Hydrocephalus may require shunting procedures 5, 9
• Vasculitis leading to basal ganglia infarcts is a major determinant of morbidity and mortality 5
• Paradoxical enlargement of tuberculomas can occur during treatment and requires continued anti-TB therapy plus corticosteroids, not surgical intervention unless in high-risk locations 9

Repeat lumbar puncture if initial HSV PCR is negative but clinical suspicion persists:

• Approximately 5-10% of adults with HSV encephalitis may have initially normal CSF 8
• Repeat LP at 24-48 hours if suspicion remains high 1, 8