What is the recommended diagnostic work‑up and initial treatment for a patient of any age presenting with acute altered mental status, fever, headache, seizures, focal neurologic deficits, or new psychiatric symptoms suggestive of encephalitis?

Approach to Suspected Encephalitis

Immediate Treatment - Start Before Diagnostic Confirmation

Intravenous acyclovir 10 mg/kg every 8 hours must be initiated immediately in all patients with suspected encephalitis, within 6 hours of admission, even before diagnostic results are available. 1, 2 This empiric therapy should continue while awaiting HSV PCR results, as delays beyond 48 hours significantly worsen mortality and morbidity. 1

• Acyclovir reduces HSV encephalitis mortality from >70% to 20-30%, making early treatment critical regardless of diagnostic uncertainty. 1
• Do not wait for lumbar puncture, imaging, or PCR confirmation if these will delay treatment beyond 6 hours. 1
• Dose adjustment is required in renal impairment. 1

Critical Initial Assessment

All patients require neurological specialist assessment within 24 hours and should be managed where ICU-level care is immediately accessible. 2

• Assess airway protection urgently in patients with declining consciousness, as encephalitis causes rapid deterioration requiring intubation and ventilatory support. 2, 3
• Evaluate for raised intracranial pressure and optimize cerebral perfusion pressure. 2
• Look for specific clinical patterns that suggest etiology:
  • Temporal lobe involvement, behavioral changes, seizures → HSV encephalitis 1
  • Subacute onset, orofacial dyskinesia, choreoathetosis, faciobrachial dystonic seizures, hyponatremia → antibody-mediated encephalitis (VGKC-complex, NMDAR) 1, 4
  • Movement disorders (tremors, basal ganglia signs) → flaviviruses (West Nile, Japanese encephalitis) 1
  • Acute flaccid paralysis → enteroviruses, flaviviruses 1
  • Brainstem signs, autonomic dysfunction, cranial neuropathies → listeriosis, tuberculosis 1

Diagnostic Workup - Prioritized by Urgency

Lumbar Puncture (Perform Immediately Unless Contraindicated)

LP should be performed as soon as possible after admission unless clinical contraindications exist. 1

Contraindications requiring CT first: 1

• Focal neurological deficits suggesting mass effect
• Papilledema
• Significantly reduced or declining Glasgow Coma Scale
• New-onset seizures

If CT is needed, perform it emergently and then reassess LP safety on a case-by-case basis unless imaging shows significant brain shift or tight basal cisterns. 1

Essential CSF studies: 1, 2

• HSV-1 and HSV-2 PCR (most critical)
• VZV PCR
• Enterovirus PCR
• West Nile virus serology/PCR
• Cell count, protein, glucose
• Bacterial culture
• Opening pressure

Additional CSF tests in specific populations: 1

• Immunocompromised patients: Add EBV PCR, CMV PCR, HHV-6 PCR, cryptococcal antigen, toxoplasma serology, acid-fast bacilli staining/culture, JC/BK virus PCR 1
• Travel history: Consider arbovirus panels based on geographic exposure 1

Critical caveat: In immunocompromised patients, CSF may be acellular despite active infection—perform full microbiological workup regardless of cell count. 1

Neuroimaging

MRI brain is the imaging modality of choice and must be obtained within 48 hours. 2, 3

• MRI detects early cerebral changes in approximately 90% of encephalitis cases versus only 25% sensitivity for CT. 2
• If MRI unavailable and CT performed before LP, repeat imaging (preferably MRI) as soon as possible after LP. 1
• Characteristic MRI findings:
  • HSV: Temporal lobe high signal, often bilateral 1
  • VGKC-complex encephalitis: Hippocampal high signal with swelling (60% of cases) 1

Electroencephalography

EEG should be obtained when: 1, 2

• Distinguishing psychiatric versus organic causes in patients with mildly altered behavior (abnormal in >80% of encephalitis) 1, 2
• Subtle motor or non-convulsive seizures suspected 1
• Monitoring refractory status epilepticus 4

EEG findings: Periodic lateralized epileptiform discharges (PLEDs) occur in HSV encephalitis but are not pathognomonic. 1

Autoimmune Encephalitis Testing

All patients with suspected encephalitis should have serum tested for: 1, 4

• VGKC-complex antibodies
• NMDA receptor antibodies
• Consider additional antibody panels if subacute presentation, psychiatric features, movement disorders, or hyponatremia present 1

If antibody-positive, screen for underlying malignancy (thymoma, small cell lung cancer). 1, 4

Seizure Management

For acute seizures in encephalitis: 2, 4

First-line: Benzodiazepines (standard protocol)

Second-line options (in order of preference):

1. IV valproate 20-30 mg/kg loading dose → 88% seizure cessation within 20 minutes, no hypotension 2, 4
2. Levetiracetam 30-60 mg/kg/day → 73% seizure cessation rate 2, 4
3. Phenytoin 18-20 mg/kg IV → Only 56% efficacy, causes hypotension in 12% (least preferred) 2, 4

For refractory status epilepticus: Continuous EEG monitoring and escalation to anesthetic agents under ICU care. 4

Etiology-Specific Treatment Duration

HSV Encephalitis

• Adults/children: Acyclovir 10 mg/kg IV every 8 hours for 14-21 days 1, 2, 4
• Neonates: Acyclovir 20 mg/kg IV every 8 hours for 21 days 4
• Immunocompromised: Acyclovir 10 mg/kg IV every 8 hours for at least 21 days, then reassess with repeat CSF PCR; consider long-term oral suppression until CD4 >200 cells/μL in HIV patients 1

VZV Encephalitis

• Acyclovir 10-15 mg/kg IV three times daily 1, 4
• Consider short course of corticosteroids, especially if vasculitic component suspected 1, 4

CMV Encephalitis (Immunocompromised)

• Combination therapy: Ganciclovir 5 mg/kg IV every 12 hours PLUS foscarnet 60 mg/kg IV every 8 hours for 3 weeks 4

Autoimmune Encephalitis

VGKC-complex encephalitis: 1

• High-dose oral corticosteroids (0.5 mg/kg/day) for 3-6 months, then taper over 12 months
• If acutely unwell: Add IVIg (0.4 g/kg/day) or plasma exchange to accelerate improvement
• IVIg alone without steroids is less effective at reducing antibody levels

NMDAR encephalitis: 2, 4

• First-line: High-dose corticosteroids, IVIg, or plasma exchange
• Second-line (refractory cases): Rituximab 2
• Remove underlying tumor if present (improves outcomes) 1, 4

Plasma exchange is particularly effective in refractory autoimmune cases: 5-10 sessions every other day. 2

Acute Disseminated Encephalomyelitis (ADEM)

• High-dose intravenous methylprednisolone as first-line therapy 2, 3

When to Consider Brain Biopsy

Brain biopsy has no role in initial assessment. 1

Consider stereotactic biopsy after the first week if: 1

• No diagnosis established despite comprehensive workup
• Focal abnormalities on imaging present
• Patient deteriorating despite empiric treatment
• HSV PCR negative but clinical suspicion remains high

If imaging shows no focal lesion, open biopsy from non-dominant frontal lobe may be preferable. 1 In one series, biopsy identified alternative treatable diagnoses in 10% of suspected HSV cases. 1

Special Populations

Elderly Patients

• HSV encephalitis is more common in elderly than younger adults. 1
• Presentation may be atypical with stroke-like features or systemic sepsis confounding diagnosis. 1
• Maintain high index of suspicion and low threshold for empiric acyclovir. 1

Immunocompromised Patients

• Consider encephalitis even with prolonged history, subtle features, absence of fever, or normal CSF white cell count. 1
• Broader differential includes HHV-6, CMV, EBV, toxoplasmosis, cryptococcus, tuberculosis, listeriosis. 1
• HIV patients should be managed in specialized HIV centers. 1
• CT before LP should be considered given higher risk of mass lesions. 1

Returning Travelers

• Consider geographic-specific pathogens: Japanese encephalitis, West Nile virus, tick-borne encephalitis, cerebral malaria, African trypanosomiasis. 1
• Liaison with tropical medicine specialists for appropriate diagnostic testing. 1

Discharge Planning and Rehabilitation

No patient should be discharged without either definitive or suspected diagnosis and arranged outpatient follow-up. 2

All patients require comprehensive rehabilitation assessment before discharge: 2, 3

• 30-50% develop long-term neurological or psychiatric sequelae 3
• Common sequelae include anxiety, depression, obsessive behaviors, cognitive deficits, memory impairment 2, 3
• Sequelae may not be immediately apparent during acute illness 3
• Multidisciplinary input needed: neuropsychology, neuropsychiatry, speech/language therapy, physiotherapy, occupational therapy 1