Despite the negative result on a herpes simplex virus (HSV) polymerase chain reaction (PCR) test, herpes simplex encephalitis remains the most likely cause of this patient's illness. HSV type 1 infection of the central nervous system causes a necrotizing infection of the temporal lobes, although atypical presentations may occur. Localization of inflammation to one or both temporal lobes on neuroimaging strongly suggests herpes simplex encephalitis and should prompt diagnostic testing and empiric therapy for this life-threatening infection. The sensitivity and specificity of cerebrospinal fluid (CSF) PCR for the diagnosis of herpes simplex encephalitis are greater than 95%, and PCR has replaced brain biopsy as the gold standard for laboratory confirmation of that condition. However, early in the course of infection, the PCR result may be falsely negative. Therefore, when clinical suspicion for herpes simplex encephalitis is high on the basis of the clinical presentation, acyclovir should be continued with repeat CSF PCR 3 to 7 days later. Delay in initiation of acyclovir therapy or premature cessation of treatment for herpes simplex encephalitis is associated with a significantly worse prognosis.

Enteroviruses are a common cause of lymphocytic meningitis but rarely cause meningoencephalitis in adults. In the case of enterovirus, no anatomic localization would be seen on imaging.

Pneumococcal meningitis is a life-threatening infection most commonly affecting the very old or very young; however, the absence of a neutrophilic pleocytosis (typically a CSF leukocyte count >1000/µL [1000 × 10⁶/L]) and the focal involvement of brain parenchyma would essentially exclude this diagnosis.

West Nile virus may cause meningoencephalitis that is more common and severe in older adults, but neuroimaging findings are typically normal or show abnormalities of the thalami, basal ganglia, or spinal cord.