Treatment of Flu-Associated Necrotizing Encephalitis
Initiate immediate empiric treatment with intravenous acyclovir 10 mg/kg every 8 hours while simultaneously starting high-dose corticosteroids (methylprednisolone 1 g IV daily for 3-5 days) and oseltamivir, as this triple-therapy approach addresses both HSV (which must be empirically covered) and the inflammatory cascade specific to influenza-associated acute necrotizing encephalopathy. 1, 2
Immediate Critical Care Management
All patients require urgent ICU assessment for:
- Airway protection and mechanical ventilation if consciousness is declining 1
- Management of raised intracranial pressure with mannitol 3
- Optimization of cerebral perfusion pressure 1
- Aggressive seizure control with anticonvulsants 3, 4
- Correction of electrolyte imbalances and coagulopathy 1
The mortality from cerebral herniation occurs rapidly (median 3 days from symptom onset), making aggressive intracranial pressure management critical 4.
Antiviral Therapy
Oseltamivir dosing should be high-dose (150 mg twice daily in adults, weight-based equivalent in children) rather than standard dosing:
- Standard oseltamivir penetrates poorly into CSF 5
- A case report demonstrated successful treatment with high-dose oseltamivir (150 mg BID) combined with methylprednisolone, with relapse occurring after switching to standard dosing 2
- Continue high-dose therapy for at least 2 weeks, potentially longer if clinical response is incomplete 2
Acyclovir 10 mg/kg IV every 8 hours must be given empirically because HSV encephalitis cannot be excluded clinically and delays in treatment significantly worsen mortality 1, 5. Discontinue only after HSV PCR returns negative and influenza is confirmed 5.
Immunomodulatory Therapy
High-dose corticosteroids are the cornerstone of treatment for influenza-associated ANE:
- Methylprednisolone 1 g IV daily for 3-5 days (or prednisone 1 mg/kg/day equivalent) 1, 3, 2, 6
- The inflammatory cascade in ANE differs from direct viral invasion—it represents a cytokine storm requiring immunosuppression 3, 4
- Most survivors in recent case series received methylprednisolone 4
Intravenous immunoglobulin (IVIG) 2 g/kg divided over 2-5 days:
- Used in 66% of patients in the largest US case series 4
- Should be added to corticosteroids, not used as monotherapy 1, 4
Additional immunomodulatory agents for refractory cases:
- Tocilizumab (IL-6 inhibitor) was used in 51% of recent US cases 4
- Plasmapheresis in 32% of cases, particularly for those failing initial therapy 4
- Anakinra (IL-1 inhibitor) in select cases 4
Diagnostic Priorities
Neuroimaging must be obtained immediately:
- MRI with contrast is superior to CT for identifying bilateral thalamic involvement (the hallmark of ANE) 5, 1
- Symmetrical multifocal brain lesions with bilateral thalamic necrosis are characteristic 5
- CT may appear normal early but can reveal cerebral edema 5
Laboratory workup:
- Influenza PCR from respiratory specimens 4
- CSF analysis typically shows elevated protein (63% of cases) but may be normal early 5, 6, 4
- Liver transaminases are elevated in 78% of cases 4
- Thrombocytopenia occurs in 63% 4
- Genetic testing for RANBP2 mutations should be sent (present in 34% of cases) 3, 4
Critical Pitfalls to Avoid
Do not delay acyclovir while awaiting diagnostic confirmation—empiric treatment must begin immediately as HSV cannot be clinically excluded 1, 5. The IDSA guidelines explicitly state this as a performance measure 5.
Do not use standard-dose oseltamivir—CSF penetration is poor and case reports suggest high-dose therapy may be necessary 5, 2.
Do not withhold corticosteroids due to concern about viral replication—the pathophysiology is inflammatory/cytokine-mediated, not direct viral invasion of the CNS 3, 2, 4.
Monitor for rapid deterioration—27% mortality in recent series, with most deaths from cerebral herniation within days 4. Transfer to a neurological ICU within 24 hours if not improving 1.
Recognize that most patients (76%) have no significant medical history and 84% were unvaccinated against influenza 4. This is not a disease limited to immunocompromised hosts.
Prognosis and Follow-up
Among survivors with 90-day follow-up, 63% have at least moderate disability (modified Rankin Scale ≥3) 4. Cognitive impairment is common even in survivors 6. Median hospital length of stay is 22 days 4.
Survivors with RANBP2 mutations require: