Workup for HSV Encephalitis
All patients with suspected HSV encephalitis require immediate lumbar puncture for CSF HSV PCR, brain MRI (preferably within 24-48 hours), and EEG, even if initial results are normal, because HSV PCR can be falsely negative early in disease and a second lumbar puncture should be performed within 3-7 days if clinical suspicion remains high. 1, 2
Core Diagnostic Triad
1. Lumbar Puncture and CSF Analysis
Primary CSF Testing:
- HSV PCR is the diagnostic gold standard, but can be falsely negative in up to 22% of cases, particularly in children and within the first 72 hours of symptom onset 1, 3
- Critical caveat: If the first LP is negative but temporal lobe involvement is seen on neuroimaging, repeat LP within 3-7 days with repeat HSV PCR 1
- Normocellular CSF occurs in 22% of HSV encephalitis cases and should not exclude the diagnosis 3
Additional CSF Studies:
- Cell count with differential (though may be normal) 3
- Protein and glucose levels 1
- Gram stain and bacterial culture 1
- Broad viral PCR panel including VZV, enteroviruses, EBV, CMV, HHV-6, HHV-7 1
- HSV-specific IgG antibodies (useful after day 10-14 of illness, but not for acute management) 1
2. Neuroimaging
MRI Brain (Preferred):
- Must be performed within 24-48 hours of admission as it is abnormal in approximately 90% of HSV encephalitis cases, while early CT may be normal in 69% of cases 1, 2, 3
- Include diffusion-weighted imaging (DWI) in the protocol, as it is especially sensitive for early changes 2
- Classic findings: Bilateral temporal lobe involvement (nearly pathognomonic), medial temporal lobe and cingulate gyrus edema, T2/FLAIR hyperintensities 1, 2
- Atypical presentations can include extensive global brain swelling and severe brainstem involvement 3
CT Brain (Only if MRI Unavailable):
- Less sensitive than MRI and often normal early in disease 1, 3
- Should only be used if MRI is unavailable, impractical, or contraindicated 1
3. Electroencephalography (EEG)
- Perform in all patients to confirm encephalitis diagnosis and detect seizure activity 1
- EEG abnormalities are highly sensitive for HSV encephalitis independent of CSF cell count 3
- May show focal abnormalities, periodic lateralized epileptiform discharges (PLEDs), or slow wave activity 1
Ancillary Investigations
Throat and Rectal Swabs:
- Send for enterovirus PCR/culture in all patients 1
Vesicle Sampling (if present):
- Electron microscopy, PCR, and culture for HSV/VZV 1
Blood Tests:
- Acute and convalescent serology for EBV, arboviruses, Mycoplasma, Chlamydophila 1
- Consider respiratory virus testing during influenza season 1
Critical Clinical Pitfalls
Do Not Delay Treatment:
- Start empiric acyclovir immediately upon clinical suspicion; do not wait for confirmatory testing 4, 5, 6
- Negative initial HSV PCR does not rule out HSV encephalitis 7, 5, 8
- Normal CSF analysis does not exclude HSV encephalitis 3, 8
- Normal CT scan does not exclude HSV encephalitis 3
When to Repeat Testing:
- If first HSV PCR is negative but clinical presentation (fever, altered mental status, focal neurologic deficits) and imaging (temporal lobe involvement) suggest HSV encephalitis, repeat LP in 3-7 days 1
- Intrathecal HSV antibody testing after day 10-14 can help establish diagnosis retrospectively when early PCR was negative 1
High-Risk Presentations:
- Altered mental status (78%), focal neurologic deficits (72%), fever (72%) 3
- Temporal lobe seizures or refractory seizures should heighten suspicion 7
- New-onset neuropsychiatric symptoms in elderly patients 7
Special Populations
Immunocompromised Patients:
- Add CMV PCR, HHV-6/7 PCR, HIV PCR, Toxoplasma testing, and fungal studies 2
Pregnant Women:
- MRI benefits likely outweigh risks in suspected encephalitis, though typically avoided in first trimester unless no alternative 2