What are the etiologies of focal encephalitis and what is the recommended diagnostic work‑up?

Focal Encephalitis: Etiologies and Diagnostic Work-Up

Focal encephalitis is most commonly caused by HSV-1, followed by autoimmune etiologies (particularly antibody-mediated syndromes), with the diagnostic work-up centered on urgent MRI, CSF analysis with HSV PCR, and EEG, while empiric acyclovir should be started immediately pending results. 1

Primary Etiologies of Focal Encephalitis

Infectious Causes

The localized nature of inflammation points to specific pathogens:

• Herpes Simplex Virus Type 1 (HSV-1): The predominant cause of focal encephalitis, characteristically affecting the temporal lobes. HSV PCR can be falsely negative early in disease or in children, so repeat testing at 3-7 days is critical if initial CSF is negative but clinical suspicion remains high 1. EEG may show periodic lateralizing epileptiform discharges or repetitive sharp waves over temporal regions 1.

• Varicella-Zoster Virus (VZV): Can cause focal vasculopathy and localized inflammation, particularly in immunocompromised patients.

• Tuberculosis: Causes focal granulomatous inflammation, typically at the base of the brain. Multiple MTB PCR tests on large CSF volumes increase sensitivity, supplemented by systemic TB testing including interferon gamma release assays 1.

• Fungal infections: Geographic and travel history guide testing (Cryptococcus, Histoplasma, Coccidioides). Requires serology, CSF/urine antigen testing, and cultures 1.

• Free-living amoebae (Naegleria fowleri, Balamuthia mandrillaris, Acanthamoeba): Rare but devastating causes requiring specialized testing at reference laboratories, including CSF wet mount for Naegleria 1.

Autoimmune Causes

Autoimmune encephalitis now rivals infectious causes in frequency and must be systematically evaluated when viral work-up is negative 2, 3:

• Antibodies against cell surface antigens: NMDAR, LGI1 (associated with faciobrachial dystonic seizures), AMPA receptor, GABA-B receptor
• Antibodies against intracellular antigens: Hu, Ma2, CV2, amphiphysin (typically paraneoplastic)
• GFAP astrocytopathy: Steroid-responsive with characteristic imaging

Diagnostic Algorithm

Immediate First-Line Testing (All Patients)

These must be performed urgently unless contraindicated 1:

1. MRI brain with contrast (superior to CT for demonstrating CNS abnormalities; localization of inflammation suggests specific pathogens or autoimmune phenomena) 1

   • Temporal lobe involvement → HSV-1
   • Basal ganglia/thalamic → Arbovirus, autoimmune
   • Multifocal white matter → ADEM, autoimmune

2. Lumbar puncture (after imaging confirms safety):

   • Cell count with differential (pleocytosis ≥5 WBC/mm³ supports diagnosis, but absence does not exclude encephalitis, especially in immunocompromised patients or early infection) 1
   • Protein, glucose
   • HSV-1 and HSV-2 PCR (mandatory)
   • VZV PCR
   • Enterovirus PCR
   • Oligoclonal bands, IgG index, IgG synthesis rate 2
   • Bacterial culture and Gram stain
   • Neuronal autoantibody panel in CSF 2

3. EEG (identifies subclinical seizures causing altered mentation; may show pathogen-specific patterns) 1

4. Serum testing:

   • Neuronal autoantibody panel (serum and CSF together increase sensitivity) 2
   • Basic metabolic panel, liver function
   • HIV testing
   • Blood cultures

Geographic and Exposure-Tailored Testing

Customize based on patient's residence, travel history, and season 1:

• Arbovirus serology (IgM/IgG in serum and CSF): West Nile, Japanese encephalitis, tick-borne encephalitis, dengue, Zika
• Tick-borne disease serology: Borrelia, Ehrlichia, Rickettsia, Anaplasma
• Rabies testing (coordinate with public health): Serology, saliva RT-PCR, skin biopsy from nape of neck
• Respiratory virus PCR during appropriate seasons (influenza A/B, though role in CNS disease controversial) 1

Second-Tier Testing (If Initial Work-Up Negative)

Consider when first-line testing unrevealing but clinical suspicion persists 1, 2:

• Brain FDG-PET when MRI and other studies uninformative but AE suspected 2
• Repeat HSV PCR at 3-7 days if initially negative 1
• MTB testing with multiple large-volume CSF specimens, sputum cultures, tuberculin skin test
• Fungal studies tailored to geography
• Expanded autoimmune panel including VGKC, GAD, mGluR5 antibodies 1

Cancer Screening (For Autoimmune Encephalitis)

Perform CT chest/abdomen/pelvis with contrast; if negative, add mammogram/breast MRI, pelvic ultrasound, or whole-body FDG-PET based on antibody type and cancer risk factors 2.

Brain Biopsy

Reserved for patients with progressive clinical deterioration despite empiric treatment and negative comprehensive work-up 3, 4. Historical data shows low yield for alternative diagnoses (4/29 patients in one series), with significant complication risk including fatal hemorrhage 5. Consider metagenomic next-generation sequencing on CSF before proceeding to biopsy 3.

Critical Pitfalls to Avoid

• Do not wait for CSF results to start acyclovir: Empiric treatment must begin immediately given HSV's high mortality without treatment
• Do not accept single negative HSV PCR as definitive: Repeat at 3-7 days, especially in children 1
• Do not overlook autoimmune causes: If viral work-up negative by 48-72 hours, initiate autoimmune evaluation and consider empiric immunotherapy 2, 3
• Do not assume normal CSF excludes encephalitis: Immunocompromised patients and early infection may lack pleocytosis 1
• Do not forget to correct CSF WBC for traumatic tap: Use formula: True CSF WBC = actual CSF WBC - (WBC in blood × RBC in CSF)/RBC in blood 1

Focal Seizure Considerations

Focal seizures indicate localized process and warrant aggressive evaluation for HSV-1 and structural lesions 1. Subclinical seizures detected only on EEG may cause altered sensorium, making continuous EEG monitoring valuable in obtunded patients 1.