What is the recommended work‑up and initial management for a patient with new‑onset fever, altered mental status, seizures, focal neurologic deficits, or headache suggestive of acute encephalitis?

Acute Encephalitis: Work-up and Initial Management

Immediately start intravenous acyclovir 10 mg/kg every 8 hours for all patients with suspected encephalitis while awaiting diagnostic confirmation, as this empiric treatment dramatically reduces mortality from HSV encephalitis from >70% to <30%. 1, 2

Immediate Actions (Within 6 Hours)

• Start empiric acyclovir 10 mg/kg IV every 8 hours immediately if initial CSF or imaging suggests viral encephalitis, or within 6 hours of admission if results are unavailable or the patient is deteriorating 1, 2
• Continue acyclovir even if initial CSF microscopy or imaging is normal but clinical suspicion remains high 1
• Assess airway protection urgently in patients with declining consciousness, as encephalitis causes rapid deterioration requiring ICU-level management of raised intracranial pressure, cerebral perfusion optimization, and electrolyte correction 1, 2
• Obtain immediate neurological specialist consultation, with clinical review within 24 hours of presentation 1, 2

Essential Diagnostic Work-up

Neuroimaging

• MRI brain with contrast is the imaging modality of choice and must be obtained within 48 hours, as it detects early cerebral changes in approximately 90% of cases versus only 25% sensitivity for CT 2
• Arrange imaging under general anesthesia if needed 1

Lumbar Puncture and CSF Analysis

• Perform lumbar puncture with CSF studies including PCR assays for HSV-1, HSV-2, VZV, enteroviruses, and West Nile virus as core testing 2, 3
• CSF PCR results should be available within 24-48 hours of lumbar puncture 1, 2
• HSV CSF PCR has very high sensitivity and specificity, especially with appropriate sample timing 4

Electroencephalography

• Obtain EEG when distinguishing psychiatric versus organic causes in patients with mildly altered behavior, or when subtle motor or non-convulsive seizures are suspected (abnormal in >80% of encephalitis cases) 2

Additional Testing

• Perform serologic testing and cultures of non-CNS sites to identify potential etiologic agents 1
• For returning travelers from malaria-endemic areas: obtain rapid blood malaria antigen tests and three thick/thin blood films immediately 1
• Consider testing for anti-NMDAR antibodies and other autoimmune encephalitis markers 2, 3

Critical Pitfalls to Avoid

Do not wait for diagnostic confirmation before starting acyclovir. Delays beyond 48 hours between hospital admission and treatment initiation significantly worsen outcomes, particularly in elderly patients or those with reduced consciousness 1

Do not assume bacterial meningitis is excluded. Mental status changes do not reliably differentiate encephalitis from bacterial meningitis—consider both diagnoses and treat accordingly 1

Do not discharge patients without lumbar puncture if clinical suspicion exists. Empirical antimicrobial use can prematurely halt the diagnostic pathway 1

Seizure Management

If seizures occur:

• First-line: IV valproate 20-30 mg/kg loading dose (88% seizure cessation within 20 minutes without hypotension) 2
• Alternative: Levetiracetam 30-60 mg/kg/day (73% seizure cessation rate) 2
• Avoid phenytoin as first-line (only 56% efficacy and causes hypotension in 12% of cases) 2

Etiology-Specific Treatment Duration

• HSV encephalitis: Continue acyclovir 10 mg/kg IV every 8 hours for 14-21 days 2
• VZV encephalitis: Consider increased acyclovir dosing 3
• Acute Disseminated Encephalomyelitis (ADEM): High-dose corticosteroids as first-line treatment 1, 2
• Autoimmune encephalitis (e.g., NMDAR-antibody): Rituximab as second-line immunotherapy 2

Multidisciplinary Care Requirements

Patients require access to:

• Neurological wards, high dependency units, or intensive care units for close monitoring 1
• Infectious disease physicians, virologists, microbiologists, neurophysiologists, neuroradiologists, neurosurgeons, and intensive care staff 1, 2
• Transfer to specialist neuroscience unit if diagnosis not rapidly established or patient fails to improve, ideally within 24 hours of request 1

Refractory Cases

If no diagnosis is made after the first week:

• Consider stereotactic brain biopsy if focal abnormalities on imaging 1
• Repeat brain MRI and imaging for occult malignancy 3
• Consider next-generation sequencing of CSF 3
• Empiric immunomodulatory treatment for suspected autoimmune conditions 3

Discharge Planning

• Do not discharge without definite or suspected diagnosis 1
• Arrange outpatient follow-up and rehabilitation assessment for all patients, as sequelae (anxiety, depression, cognitive deficits) often become evident after discharge rather than during acute illness 1, 2