What is the recommended initial assessment, diagnostic workup, and empiric treatment for a child with suspected central nervous system infection, including infants and older children?

Central Nervous System Infection in Pediatrics: Initial Assessment, Diagnostic Workup, and Empiric Treatment

All children with suspected CNS infection should receive immediate intravenous acyclovir (500 mg/m² every 8 hours for ages 3 months-12 years, or 10 mg/kg every 8 hours for >12 years) plus empiric antibiotics (ceftriaxone and vancomycin, with ampicillin added for infants <3 months) until bacterial meningitis and HSV encephalitis are definitively excluded. 1, 2, 3

Initial Clinical Assessment

Key Clinical Features to Identify

• Fever is present in 67-80% of cases, though its absence does not exclude CNS infection 3
• Altered mental status (confusion, irritability, behavioral changes) occurs in 40-76% of cases 3
• Seizures occur in 33-78% of patients with encephalitis 3
• Focal neurological signs suggest parenchymal involvement (encephalitis) rather than pure meningitis 4
• Neck stiffness is present in only 22% of cases, making it an unreliable sign in children 3
• Infants often present with non-specific symptoms including poor feeding, lethargy, and irritability rather than classic meningeal signs 3, 5

Contraindications to Immediate Lumbar Puncture

Do not perform LP immediately if any of the following are present: 1

• Glasgow Coma Score <13 or fall in GCS >2 points
• Focal neurological signs (excluding cranial nerve palsies)
• Abnormal posturing
• Papilledema
• Active or recent seizures until patient stabilized
• Relative bradycardia with hypertension
• Coagulation abnormalities (platelets <100×10⁹/L, abnormal coagulation studies, anticoagulant therapy)
• Respiratory insufficiency
• Signs of shock or hemodynamic instability

If LP is contraindicated, obtain CT scan first, but do not delay empiric treatment while awaiting imaging. 1, 4

Immediate Empiric Treatment (Start Within 6 Hours)

Antiviral Therapy

Acyclovir dosing: 1, 2, 3

• Children 3 months-12 years: 500 mg/m² IV every 8 hours
• Children >12 years: 10 mg/kg IV every 8 hours
• Adjust dose for renal impairment and ensure adequate hydration to prevent crystalluria 2
• Continue for 14-21 days if HSV confirmed; discontinue if HSV definitively excluded 1, 2

Critical timing: Delays beyond 48 hours in starting acyclovir significantly worsen outcomes; HSV encephalitis has 70% mortality without treatment, reduced to 20-30% with treatment 2

Empiric Antibacterial Therapy

Standard regimen: 2, 3

• Ceftriaxone (50 mg/kg IV every 12-24 hours, max 2g/dose)
• Vancomycin (15 mg/kg IV every 6 hours)
• Add ampicillin (50 mg/kg IV every 6 hours) for infants <3 months to cover Listeria monocytogenes

Continue antibiotics until bacterial meningitis excluded by culture and clinical course. 2, 3

Adjunctive Dexamethasone

Dexamethasone 0.15 mg/kg IV every 6 hours for 4 days can be given when treating empirical bacterial meningitis, administered with or within 24 hours of first antibiotic dose 2

Diagnostic Workup

Lumbar Puncture and CSF Analysis (When Safe to Perform)

Essential CSF studies: 1, 3

• Cell count with differential (lymphocytic pleocytosis suggests viral etiology but does not exclude partially treated bacterial meningitis, TB, or Listeria)
• Protein and glucose levels
• Gram stain and bacterial culture
• PCR for HSV-1, HSV-2, VZV, and enteroviruses (these represent 90% of viral CNS infections) 3
• PCR for EBV and CMV in immunocompromised patients 1

Optimal timing for HSV PCR: Days 2-10 of illness for best sensitivity (96-98% sensitivity, 95-99% specificity) 4

If initial CSF obtained early was negative or not tested, repeat LP at 10-14 days for HSV-specific IgG antibody testing to detect intrathecal antibody synthesis 1

Additional Microbiological Samples

Ancillary investigations to identify systemic infection or carriage: 1

• Throat and rectal swabs for enterovirus PCR (especially important as enteroviruses cause ~20% of febrile illness in infants <90 days) 3
• Nasopharyngeal aspirate for respiratory viruses (influenza, RSV, adenovirus)
• Blood cultures for bacteria and Listeria
• Vesicle swabs (if present) for HSV/VZV PCR and culture
• Parotid duct or buccal swabs if mumps suspected 1

Neuroimaging

MRI is the imaging modality of choice with ~90% sensitivity within 48 hours, compared to CT with only ~25% sensitivity. 4

MRI should be performed as soon as possible in all patients to identify: 1, 4

• Bilateral temporal lobe hyperintensities on T2/FLAIR (seen in >90% of HSV encephalitis, nearly pathognomonic) 4
• Cingulate gyrus involvement (early HSV finding)
• Alternative diagnoses (stroke, abscess, tumor)
• Basal meningeal enhancement (TB or fungal meningitis)

CT scan role: 1, 4

• Perform CT before LP only if contraindications to LP exist
• CT cannot reliably diagnose or exclude raised intracranial pressure
• Do not rely on CT alone to rule out encephalitis due to poor sensitivity
• CT may suggest alternative diagnoses (abscess, hemorrhage) that obviate LP

Electroencephalography (EEG)

Obtain EEG if: 4

• Subtle motor or non-convulsive seizures suspected
• Need to differentiate psychiatric from organic causes in patients with mildly altered behavior
• Periodic lateralizing epileptiform discharges in temporal regions occur in ~80% of HSV encephalitis cases 4

Serology and Additional Testing

HIV testing should be performed on all patients with suspected encephalitis, regardless of apparent risk factors. 1

Acute and convalescent serum samples (10-14 days apart) for viral antibodies when EBV, arboviruses, Lyme disease, or atypical pathogens suspected 1

For immunocompromised patients, expanded workup includes: 1

• CSF acid-fast bacillus staining and culture for Mycobacterium tuberculosis
• Indian ink staining and/or cryptococcal antigen (CRAG) testing of CSF and serum
• Toxoplasma serology and CSF PCR if seropositive
• Syphilis serology
• Consider CSF PCR for HHV-6, HHV-7, JC/BK virus, measles, Erythrovirus B19

Special Populations

Immunocompromised Children

Consider encephalitis even with prolonged history, subtle features, or absence of fever. 1

Broader pathogen differential includes: 1

• CMV (most frequent in HIV with CD4 <50)
• EBV
• Toxoplasma
• Cryptococcus
• Listeria
• Mycobacterium tuberculosis
• Progressive multifocal leukoencephalopathy (JC virus)

Modified treatment for immunocompromised: 1

• HSV encephalitis: Acyclovir 10 mg/kg IV three times daily for at least 21 days, then reassess with CSF PCR; consider long-term oral suppression until CD4 >200×10⁶/L
• VZV encephalitis: Acyclovir 500 mg/m² IV for at least 10 days, longer if immunocompromised
• CMV CNS infection: Ganciclovir, valganciclovir, foscarnet, or cidofovir

Returning Travelers

Additional considerations for children with travel history: 1

• Perform rapid malaria antigen test and three thick/thin blood films for all patients from malaria-endemic areas (thrombocytopenia or malaria pigment in neutrophils/monocytes may be clue even if films negative) 1
• Start antimalarial treatment if cerebral malaria likely and diagnostic delays expected
• Consider TB meningitis in children with TB contact or family from high-incidence areas
• Consult regional pediatric infectious diseases for arbovirus testing (Japanese encephalitis, West Nile, dengue, tick-borne encephalitis) based on geographic exposure 1

Critical Care and Supportive Management

Indications for Intensive Care Consultation

Early ICU involvement essential for: 2

• Patients requiring inotropic or ventilatory support
• Continued deterioration despite appropriate treatment
• Signs of shock (administer 20 mL/kg isotonic crystalloid boluses up to 60 mL/kg total, reassessing after each bolus) 2

Monitoring

• Close monitoring for neurological deterioration, seizures, and signs of raised intracranial pressure 6
• Monitor for acyclovir nephrotoxicity with serial creatinine measurements 2
• Ensure adequate hydration to prevent acyclovir-induced crystalluria 2

Common Pitfalls to Avoid

1. Delaying acyclovir while awaiting imaging or laboratory confirmation increases mortality and morbidity 4, 2

2. Relying on a single negative CSF PCR to rule out HSV encephalitis—false negatives occur, especially early in disease; if clinical suspicion remains high, continue acyclovir and repeat LP at 10-14 days for antibody testing 1, 4

3. Using CT as the only imaging modality—CT has only ~25% sensitivity for early encephalitis changes; MRI is required 4

4. Assuming lymphocytic CSF excludes bacterial infection—partially treated bacterial meningitis, TB, and Listeria can present with lymphocytic pleocytosis 2

5. Discontinuing acyclovir prematurely if initial CSF or imaging normal but clinical suspicion remains high 4

6. Failing to add ampicillin for infants <3 months—Listeria coverage is essential in this age group 2, 3

7. Performing LP in presence of contraindications—this risks cerebral herniation; obtain CT first and start empiric treatment immediately 1

8. Assuming absence of fever excludes CNS infection—fever is absent in 20-33% of cases 3