Development of a risk score to predict encephalitis by Herpes Simplex Virus and Varicella Zoster Virus

Encephalitis guidelines recommend repeating a lumbar puncture (LP) 3-7 days after an initial negative cerebrospinal fluid (CSF) herpes simplex virus (HSV) polymerase chain reaction (PCR) test in patients with high suspicion for HSV or varicella zoster virus (VZV), but this subgroup has not been specified. Retrospective observational study of 602 adults with encephalitis from 2002 to 2023 from two large U.S. healthcare systems. Multivariate logistic regression models were developed and internally validated to identify clinically relevant and statistically significant features predicting HSV, VZV, and combined HSV/VZV encephalitis. HSV and VZV encephalitis were diagnosed in 103 (17.1%) and 43 (7.14%), respectively. Independent predictors for HSV acute presentation, new temporal lobe abnormalities on MRI, and hemorrhage on brain MRI. For VZV, predictors were immunosuppression, Charles Comorbidity Index > 2, and absence of seizures on presentation. For HSV/VZV, predictors included age ≥ 50 years, immunocompromise, acute presentation, CSF lymphocytosis, new temporal lobe abnormalities on MRI, hemorrhage on brain MRI, and Glasgow Coma Scale (GCS) ≥ 13 (P < 0.05). Patients were classified into 3 categories: low-risk (0 points), intermediate-risk (1 point), and high-risk (≥ 2 points). The area under the receiver operating curve was 0.675, 0.734, and 0.583 for the HSV, VZV, and HSV/VZV models, respectively. The risk score can help identify patients with an initial negative PCR who would benefit from a repeat LP (intermediate- or high-risk) and may support discontinuing acyclovir in low-risk patients.