Diagnostic Approach for HSV Encephalitis

Core Diagnostic Triad

The Infectious Diseases Society of America recommends that all patients with suspected HSV encephalitis require immediate lumbar puncture for CSF HSV PCR, brain MRI, and EEG, even if initial results are normal, because HSV PCR can be falsely negative early in disease 1, 2, 3
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, according to the Infectious Diseases Society of America 1, 2
If the first LP is negative but temporal lobe involvement is seen on neuroimaging, repeat LP within 3-7 days with repeat HSV PCR, as recommended by the Infectious Diseases Society of America 1, 2, 4
Protein and glucose levels should be checked in CSF analysis, as recommended by the Infectious Diseases Society of America 5
Gram stain and bacterial culture, as well as broad viral PCR panel including VZV, enteroviruses, EBV, CMV, HHV-6, HHV-7, should be performed in CSF analysis, according to the Infectious Diseases Society of America 6, 7

MRI brain should 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, according to the Infectious Diseases Society of America 5, 3
Diffusion-weighted imaging (DWI) should be included in the MRI protocol, as it is especially sensitive for early changes, as recommended by the Infectious Diseases Society of America 3
Classic findings on MRI include bilateral temporal lobe involvement, medial temporal lobe and cingulate gyrus edema, T2/FLAIR hyperintensities, according to the Infectious Diseases Society of America 5, 3

EEG should be performed in all patients to confirm encephalitis diagnosis and detect seizure activity, as recommended by the Infectious Diseases Society of America 1, 2, 4
EEG may show focal abnormalities, periodic lateralized epileptiform discharges (PLEDs), or slow wave activity, according to the Infectious Diseases Society of America 2, 4

Throat and rectal swabs should be sent for enterovirus PCR/culture in all patients, as recommended by the Infectious Diseases Society of America 6, 7
Vesicle sampling (if present) should be sent for electron microscopy, PCR, and culture for HSV/VZV, according to the Infectious Diseases Society of America 6, 7
Blood tests should include acute and convalescent serology for EBV, arboviruses, Mycoplasma, Chlamydophila, as recommended by the Infectious Diseases Society of America 6, 7
Respiratory virus testing should be considered during influenza season, according to the Infectious Diseases Society of America 2, 8

Immunocompromised patients should have additional testing, including CMV PCR, HHV-6/7 PCR, HIV PCR, Toxoplasma testing, and fungal studies, as recommended by the Infectious Diseases Society of America 3
Pregnant women should have MRI benefits weighed against risks, though typically avoided in first trimester unless no alternative, according to the Infectious Diseases Society of America 3

HSV‑1 is the most frequent cause of infectious encephalitis in developed countries, whereas enteroviruses are the leading cause of viral meningitis and account for a smaller proportion of encephalitis cases. (Clinical Microbiology and Infection guideline, 2017) 9
Guideline consensus states that the most common pathogen in infectious encephalitis is HSV (predominantly HSV‑1), reflecting long‑standing recognition of its predominance. (Clinical Microbiology and Infection guideline, 2017) 9

Untreated HSV‑1 encephalitis carries a mortality of up to 70 %, markedly higher than the typically self‑limited course of enteroviral encephalitis. (Clinical Microbiology and Infection guideline, 2017) 9

The guideline recommends that all patients with suspected encephalitis receive immediate cerebrospinal‑fluid HSV PCR testing, because HSV‑1 is the primary treatable cause. (Clinical Microbiology and Infection guideline, 2017) 9
In addition to CSF testing, the guideline advises collection of throat and rectal swabs for enterovirus PCR in every encephalitis work‑up, recognizing enteroviruses as a relevant differential diagnosis. (Clinical Microbiology and Infection guideline, 2017) 9