What are the diagnosis and management guidelines for acute encephalitis syndrome?

Acute Encephalitis Syndrome: Diagnosis and Management

Immediate Actions and Initial Assessment

All patients with suspected acute encephalitis require immediate neurological specialist assessment within 24 hours and should be managed in appropriate settings (neurological wards, high dependency units, or ICU depending on severity) to optimize morbidity and mortality outcomes. 1, 2

Critical Initial Interventions

• Start empiric acyclovir 10 mg/kg IV every 8 hours immediately for all adults with suspected encephalitis, particularly those with seizures or altered consciousness, while awaiting diagnostic confirmation 1
• Assess airway protection and ventilatory support needs urgently in patients with declining consciousness, as encephalitis can cause rapid deterioration requiring ICU-level management of raised intracranial pressure and cerebral perfusion optimization 1, 2
• Administer appropriate antiepileptic medications for seizure control alongside acyclovir 1

Diagnostic Workup

Neuroimaging (Priority #1)

MRI 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. Key patterns include:

• Frontotemporal lesions suggest HSV encephalitis 3
• Thalamic and basal ganglia lesions suggest Japanese encephalitis 3
• Neuroimaging changes predict longer recovery time 4

Cerebrospinal Fluid Analysis (Priority #2)

Perform lumbar puncture with results ideally available within 24-48 hours 2, 4. Essential CSF studies include:

• Cell count and differential (pleocytosis favors infectious etiology; normal CSF suggests encephalopathy or non-infectious causes) 3
• PCR assays for HSV and other viral pathogens 2
• Oligoclonal bands, IgG index, and IgG synthesis rate 5
• Neuronal autoantibodies in CSF (critical for autoimmune encephalitis diagnosis) 5

Additional Diagnostic Studies

• EEG should be obtained 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, 4
• Serum neuronal autoantibodies testing 5
• For patients returning from malaria-endemic areas: rapid blood malaria antigen tests and three thick/thin blood films 2
• Brain FDG-PET when high clinical suspicion exists but other studies are uninformative 5

Etiology-Specific Treatment

Infectious Encephalitis

Herpes Simplex Virus (Most Important Western Cause):

• Acyclovir 10 mg/kg IV every 8 hours for 14-21 days in adults and children 1
• Neonates require higher dosing: 20 mg/kg IV every 8 hours for 21 days 1
• Treatment has decreased mortality to 5% 1
• Adjunctive corticosteroids remain controversial but one retrospective study showed better outcomes 1

Varicella-Zoster Virus:

• Acyclovir 10-15 mg/kg IV three times daily 1
• Consider short course of corticosteroids, particularly if vasculitic component is present 1

Cytomegalovirus:

• Combination therapy: ganciclovir 5 mg/kg IV every 12 hours plus foscarnet 60 mg/kg IV every 8 hours (or 90 mg/kg IV every 12 hours) for 3 weeks 1

Cerebral Malaria (Plasmodium falciparum):

• Quinine, quinidine, or artemether 2
• Exchange transfusion recommended for ≥10% parasitemia 2
• Corticosteroids are NOT recommended 2

Toxoplasma gondii:

• Pyrimethamine plus either sulfadiazine or clindamycin 2

Autoimmune Encephalitis

First-Line Immunotherapy Algorithm:

1. Once infection is ruled out based on CSF results, start high-dose corticosteroids immediately (or IVIG/PLEX if steroids contraindicated) 5

2. If no improvement by end of initial treatment cycle, add IVIG or PLEX: 5

   • Choose IVIG first in agitated patients and those with bleeding disorders 5
   • Choose PLEX first in patients with severe hyponatremia, high thromboembolic risk, cancer risk, or associated brain/spinal demyelination 5

3. For severe initial presentations (NMDAR-antibody encephalitis, new onset refractory status epilepticus, severe dysautonomia), start combination therapy (steroids/IVIG or steroids/PLEX) from the beginning rather than sequentially 5

Second-Line Immunotherapy (if no improvement 2-4 weeks after combined acute therapy):

• Rituximab for known or highly suspected antibody-mediated autoimmunity (e.g., NMDAR-antibody encephalitis) 5, 1
• Cyclophosphamide for known or highly suspected cell-mediated autoimmunity (e.g., classical paraneoplastic syndrome) 5
• Novel approaches (tocilizumab, bortezomib) if conventional therapies fail, though minimal evidence supports their use 5

Bridging/Maintenance Therapy:

• Gradual oral prednisone taper, or monthly IV immunoglobulin, or IV methylprednisolone 5

Cancer Screening in Autoimmune Encephalitis:

• CT chest/abdomen/pelvis with contrast (or MRI if CT contraindicated) 5
• If negative, consider mammogram/breast MRI, pelvic ultrasound, and/or whole body FDG-PET guided by clinical presentation and cancer risk factors 5
• Screen for neoplasm in all patients with VGKC complex or NMDA receptor antibody-associated encephalitis 1

Acute Disseminated Encephalomyelitis (ADEM)

• High-dose corticosteroids as first-line treatment 2
• Alternatives include plasma exchange or intravenous immunoglobulin 2

Management of Refractory Seizures

Second-Line Antiepileptic Medications

For refractory seizures not responding to benzodiazepines:

• IV valproate 20-30 mg/kg loading dose achieves 88% seizure cessation within 20 minutes without associated hypotension 1
• Levetiracetam 30-60 mg/kg/day demonstrates 73% seizure cessation rate 1
• Phenytoin 18-20 mg/kg IV (or fosphenytoin equivalent) has only 56% efficacy following benzodiazepines and causes hypotension in 12% of cases 1

Refractory Status Epilepticus

• Consider continuous EEG monitoring 1
• Escalate to anesthetic agents under ICU care 1
• Consider antibody-mediated encephalitis in all patients with intractable seizures, particularly with subacute presentation, orofacial dyskinesia, choreoathetosis, or hyponatremia 1
• Early immune suppression and tumor removal (if present) improves outcomes in VGKC-complex or NMDA receptor antibody-associated encephalitis 1

Critical Care Considerations

ICU Management Priorities

• Airway protection and ventilatory support 2
• Management of raised intracranial pressure 2
• Optimization of cerebral perfusion pressure 2
• Correction of electrolyte imbalances 2
• Particular attention to status epilepticus, cerebral edema, and dysautonomia 6

Plasma Exchange Technical Considerations

• 5-10 sessions every other day 5
• Particularly effective in refractory cases 5
• No known psychiatric side effects 5
• Does not increase thromboembolism risk except line-related thrombosis 5
• Major limitations: increased bleeding risk, volume shifts (problematic in dysautonomic patients), need for central line placement, less suitable for agitated patients 5

Discharge Planning and Follow-Up

Critical discharge requirements:

• Do not discharge without either definite or suspected diagnosis 2
• Formulate arrangements for outpatient follow-up and ongoing therapy/rehabilitation at discharge meeting 2
• All patients require access to rehabilitation assessment, as sequelae may not be immediately apparent at discharge and commonly include anxiety, depression, and cognitive deficits 1, 2, 4
• Monitor for drug interactions between antimicrobials and antiepileptic medications 1

Common Pitfalls to Avoid

• Never delay acyclovir while awaiting diagnostic confirmation - start empirically in all suspected cases 1
• Do not rely on CT alone; MRI sensitivity is vastly superior (90% vs 25%) 2
• Do not assume normal CSF rules out encephalitis; it may indicate non-infectious causes or encephalopathy requiring different management 3
• Avoid discharging patients without adequate follow-up planning, as many experience ongoing complications 2
• In malaria-endemic exposure, do not delay antimalarial treatment if there will be delay in obtaining film results 2