What is the appropriate diagnostic work‑up and initial treatment for a patient with encephalitis who has multiple lesions on brain MRI?

Management of Encephalitis with Multiple MRI Lesions

Begin intravenous acyclovir 10 mg/kg every 8 hours immediately upon suspicion of encephalitis with multiple brain lesions, without waiting for diagnostic confirmation, as delayed treatment beyond 4 days increases mortality from 8% to 28%. 1, 2

Immediate Empiric Treatment

• Start IV acyclovir within 6 hours of admission for any patient with suspected encephalitis, regardless of imaging findings, as HSV encephalitis is the most common treatable cause (25-40% of sporadic encephalitis cases) and early treatment is critical for survival. 3, 1, 2
• Administer acyclovir at 10 mg/kg IV every 8 hours for adults and adolescents (20 mg/kg every 8 hours for children), adjusting for renal impairment. 1, 2
• Continue empiric antibacterial coverage until bacterial infection is excluded by CSF analysis. 3
• Treatment duration should be 14-21 days for confirmed HSV encephalitis. 1, 2

Diagnostic Work-Up (Performed Concurrently with Treatment)

Neuroimaging Priority

• MRI with and without contrast is the imaging modality of choice, with approximately 90% sensitivity within 48 hours compared to only 25% sensitivity for CT. 1, 2
• Look for characteristic patterns:
  • HSV encephalitis: Bilateral temporal lobe T2/FLAIR hyperintensities (present in >90% of cases), gyral edema, and involvement of cingulate gyrus. 3, 1, 2
  • Autoimmune encephalitis: Discrete hippocampal high signal with associated swelling (60% of VGKC-complex cases), may be bilateral or unilateral. 3
  • Other viral etiologies: Japanese B encephalitis affects thalamus/basal ganglia; enterovirus affects brainstem; VZV causes ischemic/hemorrhagic infarcts. 1
• If MRI is unavailable, perform CT to exclude structural causes of raised intracranial pressure, but do not rely on CT to rule out encephalitis due to poor sensitivity. 1, 2

Lumbar Puncture and CSF Analysis

• Perform lumbar puncture urgently (after imaging if concern for mass effect) with the following studies: 3, 1
  • HSV-1, HSV-2, and VZV PCR (sensitivity/specificity >95% when performed days 2-10 of illness). 2
  • Cell count with differential, protein, glucose, Gram stain, bacterial culture.
  • Opening pressure measurement.
  • Oligoclonal bands if autoimmune encephalitis suspected.
  • Consider enterovirus, parechovirus, CMV, HHV-6/7 PCR in immunocompromised patients. 2
• A single negative HSV PCR does not rule out HSE, especially if obtained <72 hours after symptom onset—repeat LP in 24-48 hours if clinical suspicion remains high. 2
• Typical viral CSF shows elevated protein with normal glucose and lymphocytic pleocytosis. 1

Additional Diagnostic Studies

• Obtain neurology consultation immediately for all suspected encephalitis cases. 3
• Perform EEG to detect periodic lateralizing epileptiform discharges (PLEDs) in temporal regions, present in ~80% of HSV encephalitis cases. 1, 2
• Check serum autoimmune encephalitis panel (VGKC-complex, NMDA receptor antibodies) if subacute presentation, hyponatremia, orofacial dyskinesia, choreoathetosis, or faciobrachial dystonic seizures present. 3
• Screen for malignancy in confirmed antibody-mediated encephalitis (thymoma, small cell lung cancer). 3
• Blood tests: B12, HIV, rapid plasma reagin, ANA, Ro/La, TSH, aquaporin-4 IgG, cortisol, ACTH. 3

Management Based on Etiology

Confirmed or Suspected HSV Encephalitis

• Continue IV acyclovir 10 mg/kg every 8 hours for 14-21 days. 1, 2
• Monitor renal function closely and maintain adequate hydration to prevent acyclovir-induced crystalluria and obstructive nephropathy. 2
• Even with treatment, mortality remains 25-28% at 18 months, and 20-60% of survivors develop neurological sequelae. 2

Autoimmune/Antibody-Mediated Encephalitis

• Once bacterial and viral infections are excluded, initiate immunosuppression: 3
  • Mild-moderate cases: Oral prednisone 0.5-1 mg/kg daily. 3
  • Severe cases or oligoclonal bands present: IV methylprednisolone 1 g daily for 3-5 days plus IVIG 2 g/kg over 5 days. 3
• For VGKC-complex antibody encephalitis: High-dose oral steroids (0.5 mg/kg/day) with antibody levels normalizing in 3-6 months, then taper over 12 months. 3
• If limited improvement with steroids/IVIG, consider rituximab or plasmapheresis in consultation with neurology. 3
• Remove any identified tumor (thymoma, small cell lung cancer). 3

Immune Checkpoint Inhibitor-Related Encephalitis

• Permanently discontinue the checkpoint inhibitor for grade 3-4 toxicity. 3
• Admit patient and initiate methylprednisolone 1 g daily for 3 days followed by oral corticosteroid taper. 3
• Consider IVIG 2 g/kg over 5 days for severe or progressive symptoms. 3

Critical Pitfalls to Avoid

• Never delay acyclovir while awaiting PCR or imaging results—this is the single most important factor affecting mortality and morbidity. 1, 2
• Do not discontinue acyclovir based on a single negative CSF PCR, especially if obtained early (<72 hours) or if clinical suspicion remains high. 2
• Do not use CT as the sole imaging modality to exclude encephalitis—its 25% sensitivity will miss most cases. 1, 2
• Do not start corticosteroids before excluding infectious causes, as this may worsen viral or bacterial encephalitis. 3
• In patients with multiple lesions, consider that this may represent either severe HSV encephalitis with extensive involvement, autoimmune encephalitis, or post-infectious ADEM—maintain broad differential until etiology confirmed. 3, 4, 5

Special Populations

• Immunocompromised patients: Expand PCR testing to include CMV, HHV-6/7, HIV; consider ganciclovir, foscarnet, or cidofovir for CMV encephalitis; prolonged acyclovir treatment may be needed for HSV clearance. 3, 2
• Renal impairment/dialysis patients: Significantly reduce acyclovir dosing based on creatinine clearance and maintain hydration. 6