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

Viral Encephalitis: Diagnostic Work-Up and Initial Management

Immediate Empiric Treatment

Start intravenous acyclovir 10 mg/kg every 8 hours immediately—within 6 hours of admission—for any patient with suspected encephalitis, even before obtaining lumbar puncture, imaging, or PCR results. 1

• Delaying acyclovir beyond 48 hours after presentation significantly increases mortality and morbidity 1
• Early acyclovir reduces HSV encephalitis mortality from >70% to 20–30% 1
• Do not wait for diagnostic confirmation if it would postpone acyclovir beyond 6 hours 1
• Continue acyclovir for 14–21 days in confirmed HSV encephalitis 1
• Adjust dosing in renal impairment 1

Clinical Recognition: When to Suspect Encephalitis

Suspect encephalitis in any patient presenting with fever plus altered mental status (confusion, disorientation, behavioral changes, personality changes) plus any of the following: new seizures, focal neurological signs, or altered consciousness 2

Key Clinical Features by Etiology:

HSV encephalitis (most common treatable cause):

• Fever (91% of cases), though some present with only low-grade pyrexia 2
• Disorientation (76%), speech disturbances (59%), behavioral changes (41%) 2
• Seizures (one-third of patients) 2
• Temporal lobe involvement on imaging 1

Antibody-mediated encephalitis (critical not to miss):

• Subacute onset over weeks to months 2
• Orofacial dyskinesia, choreoathetosis, faciobrachial dystonic seizures 2
• Intractable seizures often without fever 2
• Hyponatremia (60% of VGKC-complex cases) 2
• Profound amnesia and confusion 2

Flavivirus infections (West Nile, Japanese encephalitis):

• Movement disorders, tremor, basal ganglia signs 1
• Acute flaccid paralysis 1

Common Pitfalls to Avoid:

• Behavioral changes can be mistaken for primary psychiatric illness, drug intoxication, or alcohol withdrawal—leading to tragic delays 2, 3
• Normal Glasgow Coma Score does not exclude encephalitis; it is too crude to detect subtle cognitive changes 2
• Elderly patients may present atypically, mimicking stroke or systemic sepsis 1

Diagnostic Work-Up Algorithm

Step 1: Immediate Stabilization & Neuroimaging

Before lumbar puncture, many patients require CT to exclude contraindications 2:

• Obtain urgent CT if: focal neurological signs, papilledema, reduced consciousness (GCS <12), new-onset seizures, or immunocompromised status 2
• MRI is strongly preferred over CT when feasible—detects early changes in ~90% of cases versus only 25% for CT 4
• MRI should be obtained within 48 hours 4

Step 2: Lumbar Puncture & CSF Analysis

Perform lumbar puncture as soon as possible after admission unless contraindicated 1:

Essential CSF studies 1:

• Opening pressure
• Cell count with differential
• Protein and glucose (with paired serum glucose)
• HSV-1/2 PCR (most critical test)
• Varicella-zoster virus (VZV) PCR
• Enterovirus PCR
• West Nile virus serology/PCR (if epidemiologically relevant)
• Bacterial culture and Gram stain
• Consider: CMV PCR, EBV PCR, HHV-6 PCR (especially in immunocompromised)
• Consider: paired oligoclonal bands
• Lactate

If initial HSV PCR not sent or negative but suspicion remains high: Repeat lumbar puncture at 24 hours and send second HSV PCR 2

Critical caveat for immunocompromised patients: CSF may be acellular despite active CNS infection—still obtain full microbiological panel regardless of cell count 2, 1

Step 3: Serum Studies

All patients should have serum tested for 2:

• VGKC-complex antibodies
• NMDA-receptor antibodies
• Basic metabolic panel (check sodium—hyponatremia suggests antibody-mediated encephalitis) 2

Additional serum tests based on exposure history 4:

• Malaria rapid antigen and thick/thin blood films (three sets) if travel to endemic area
• Arbovirus serology if appropriate exposure
• HIV testing
• Toxoplasma serology if immunocompromised

Step 4: Electroencephalography (EEG)

• EEG is abnormal in >80% of encephalitis cases 4
• Obtain EEG when: distinguishing organic from psychiatric causes, or when subtle motor activity or non-convulsive seizures suspected 4
• Periodic lateralized epileptiform discharges (PLEDs) may appear in HSV but are not specific 1

Step 5: Consider Brain Biopsy (Rarely)

Brain biopsy is not indicated during initial assessment 1

Consider stereotactic biopsy after the first week only if 1:

• No diagnosis despite comprehensive work-up
• Focal imaging abnormalities present
• Patient deteriorates despite empiric therapy
• HSV PCR negative but clinical suspicion remains very high

Etiology-Specific Treatment Modifications

HSV Encephalitis (Confirmed)

• Acyclovir 10 mg/kg IV every 8 hours for 14–21 days 1
• In immunocompromised: extend to at least 21 days, repeat CSF PCR to confirm clearance, consider long-term oral suppressive therapy 1

VZV Encephalitis

• Acyclovir 10–15 mg/kg IV three times daily 1
• Consider short course of corticosteroids if vasculitic component suspected 1

VGKC-Complex Autoimmune Encephalitis

• High-dose oral corticosteroids (0.5 mg/kg/day) for 3–6 months, then taper over 12 months 2
• If acutely unwell: add IV immunoglobulin (0.4 g/kg/day) or plasma exchange to accelerate improvement 2
• Screen for underlying malignancy (thymoma, small-cell lung cancer in <10%) 2

NMDAR Encephalitis

• Remove underlying tumor when present—improves outcomes 2
• High-dose corticosteroids as first-line 4
• Alternatives: plasma exchange or IV immunoglobulin 4

Acute Disseminated Encephalomyelitis (ADEM)

• High-dose corticosteroids first-line 4
• Alternatives: plasma exchange or IV immunoglobulin 4

Cerebral Malaria (Plasmodium falciparum)

• Quinine, quinidine, or artemether 4
• Exchange transfusion if ≥10% parasitemia 4
• Do not use corticosteroids 4

Toxoplasma Encephalitis

• Pyrimethamine plus either sulfadiazine or clindamycin 4

Special Populations

Immunocompromised Patients

• Manage HIV-positive patients in specialized HIV centers 2
• Broader differential includes: HHV-6, CMV, EBV, toxoplasmosis, cryptococcus, tuberculosis, listeriosis 1
• Obtain CT before lumbar puncture given higher risk of mass lesions 1
• Presentations may be atypical with prolonged subtle symptoms, absent fever, or normal CSF white-cell count 1

Returning Travelers

• Consider region-specific pathogens: Japanese encephalitis, West Nile virus, tick-borne encephalitis, cerebral malaria, African trypanosomiasis 1
• Involve tropical medicine specialists for targeted testing 1

Critical Care & Supportive Management

Patients with falling level of consciousness require urgent ICU assessment for 4:

• Airway protection and ventilatory support
• Management of raised intracranial pressure
• Optimization of cerebral perfusion pressure
• Correction of electrolyte imbalances (especially hyponatremia)

Disposition & Follow-Up

• Manage patients in settings where neurological specialist review is available within 24 hours 4
• Appropriate settings include: neurological wards, high-dependency units, or ICU depending on severity 4
• Do not discharge without a definite or suspected diagnosis 4
• Formulate discharge plans including outpatient follow-up, ongoing therapy, and rehabilitation 4
• All patients require access to rehabilitation assessment—sequelae may not be immediately apparent at discharge 4