In a 39‑year‑old man with multifocal low‑attenuation supra‑ and infratentorial brain lesions, nasal cistern enhancement, normal laboratory studies, and presenting with confusion and headache, what is the most likely diagnosis and what is the recommended acute management?

Acute Management of Suspected Viral Meningoencephalitis

This 39-year-old man with multifocal brain lesions, meningeal enhancement, confusion, and headache most likely has viral meningoencephalitis (specifically HSV encephalitis until proven otherwise), and should be immediately started on empiric IV acyclovir 10 mg/kg every 8 hours while awaiting confirmatory testing. 1, 2

Immediate Diagnostic Workup

Urgent Lumbar Puncture (Do Not Delay)

• Perform LP immediately without waiting for CT/MRI if no signs of impending herniation 1, 2
• The imaging already shows multifocal lesions without significant mass effect, making LP safe to proceed 1
• CSF analysis must include: 1
  • Cell count with differential (expect lymphocytic pleocytosis in viral causes)
  • Protein and glucose levels
  • HSV-1/2 PCR (most critical test) 1, 2
  • VZV PCR, enterovirus PCR, West Nile virus IgM 1
  • Bacterial culture and Gram stain (to rule out partially treated bacterial meningitis) 3
  • CSF lactic acid level (elevated >4 mmol/L suggests bacterial; normal rules out bacterial meningitis) 3
  • Oligoclonal bands and IgG index 1
  • Cytology to exclude leptomeningeal metastases 1

Critical Blood Tests

• Autoimmune encephalitis panel (NMDAR, LGI1, CASPR2, AMPAR, GABA-B) 1
• Paraneoplastic antibody panel 1
• HIV serology, RPR/VDRL 1
• Thyroid function with anti-TPO and anti-thyroglobulin antibodies 1
• ANA, ENA, antiphospholipid antibodies 1

Additional Neuroimaging

• MRI brain with and without gadolinium contrast is superior to CT for detecting encephalitis 1
• T2 FLAIR sequences detect vasogenic edema 1
• Diffusion-weighted imaging (DWI) detects cytotoxic edema 1
• Post-contrast T1 and FLAIR detect meningeal enhancement 1
• HSV encephalitis classically involves temporal lobes but extratemporal involvement is common 1

EEG

• Perform urgently to evaluate for subclinical seizures and characteristic patterns 1
• HSV encephalitis may show periodic lateralized epileptiform discharges (PLEDs) 1

Immediate Empiric Treatment (Start Before Test Results)

First-Line Therapy

Begin IV acyclovir 10 mg/kg every 8 hours immediately upon clinical suspicion, even before LP results return 2, 4

• HSV encephalitis is rapidly fatal without treatment and has Level A evidence for acyclovir efficacy 2
• Continue acyclovir until HSV PCR returns negative 2, 4
• Ensure adequate hydration to prevent acyclovir-induced nephrotoxicity 2

Concurrent Antimicrobial Coverage

• Add empiric antibacterial coverage (ceftriaxone 2g IV q12h + vancomycin) until bacterial meningitis is definitively ruled out by CSF studies 4, 5
• The normal CBC does not exclude bacterial meningitis 3
• Discontinue antibiotics once CSF lactic acid is normal and cultures are negative at 48-72 hours 3

Consider Autoimmune Encephalitis Treatment

If CSF shows inflammatory changes but infectious workup is negative: 1

• Start IV methylprednisolone 1 gram daily for 3-5 days 1
• Do NOT delay steroids waiting for antibody results if infection is ruled out 1
• If no improvement after steroids, add IVIG 2 g/kg over 5 days (0.4 g/kg/day) or plasma exchange 1

Critical Pitfalls to Avoid

Do NOT Wait for Test Results to Start Acyclovir

• HSV encephalitis has dramatic mortality reduction with early acyclovir 2
• Prognosis depends critically on time to treatment initiation 2, 4
• Every hour of delay worsens neurological outcomes 2

Do NOT Assume Normal Labs Rule Out Serious Infection

• Normal CBC, electrolytes, and liver enzymes do not exclude meningoencephalitis 3
• CSF analysis is mandatory for diagnosis 1, 2

Do NOT Give Corticosteroids Before Ruling Out Infection

• Steroids are contraindicated in active HSV or bacterial infection 1, 2
• Only consider steroids after negative infectious workup 1

Do NOT Delay LP for Imaging Unless Signs of Herniation

• The described imaging already shows no significant mass effect 1
• LP delay increases mortality in treatable causes 2, 5

Disposition and Monitoring

ICU Admission Required

• All patients with suspected encephalitis require ICU-level monitoring 2, 6
• Monitor for: 2, 6
  • Seizure activity (continuous EEG if altered mental status)
  • Increased intracranial pressure
  • Respiratory failure
  • Dysautonomia

Neurosurgical Consultation

• Obtain early consultation for potential decompressive surgery if increased ICP refractory to medical management 2

Differential Diagnosis Considerations

Autoimmune Encephalitis

• The multifocal distribution and normal routine labs raise suspicion 1
• NMDAR encephalitis can present with confusion, seizures, and psychiatric symptoms 1
• FDG-PET may show bilateral occipito-parietal hypometabolism in NMDAR encephalitis if diagnosis remains unclear 1

Progressive Multifocal Leukoencephalopathy (PML)

• Consider if patient is immunosuppressed 7
• CSF JC virus PCR is diagnostic 7
• Lesions typically subcortical with irregular borders, no mass effect 7

CNS Vasculitis

• Multiple infarcts of varying ages would be more typical 7
• Consider if no improvement with antimicrobials and immunotherapy 7

The key to survival is immediate empiric acyclovir while pursuing rapid diagnostic confirmation through LP and comprehensive infectious/autoimmune workup. 2, 4