• Survival with no or mild neurological impairment after initiation of study medication, as measured by the Mattis Dementia Rating Scale (MDRS). [ Time Frame: 12 months. ] [ Designated as safety issue: No ]
  
• Assess the impact of valacyclovir therapy [following standard intravenous acyclovir (ACV) therapy] on neuropsychological impairment. [ Time Frame: One year post therapy. ] [ Designated as safety issue: No ]
  

• Effect of study medication on quality of life measurements. [ Time Frame: Days 0 and 90; Months 6, 12, and 24. ] [ Designated as safety issue: No ]
  
• Effect of antiviral therapy on herpes simplex virus (HSV) deoxyribonucleic acid (DNA) in cerebral spinal fluid (CSF) [measured quantitatively by polymerase chain reaction (PCR)]. [ Time Frame: Day 0 and Day 90. ] [ Designated as safety issue: No ]
  
• Safety and tolerance of valacyclovir (VACV) administered at a dose of 2.0 grams given orally 3 times a day for 90 days. [ Time Frame: Duration of study. ] [ Designated as safety issue: Yes ]
  
• Survival with no or mild neurological impairment as measured by the MRDS, the Mini-Mental Status Examination, and the Glasgow Coma Scale. [ Time Frame: At 90 days and at 6, 12 and 24 months. ] [ Designated as safety issue: No ]
  

Herpes simplex encephalitis (HSE) remains the most common cause of sporadic fatal encephalitis in the world. This study is a phase III, double-blind, placebo controlled study of long term therapy with valacyclovir as a treatment of herpes encephalitis. The primary objective of this study is to assess the impact of valacyclovir (VACV) therapy (following standard intravenous acyclovir therapy) on neuropsychological impairment at one year post therapy, based on the cumulative scores of the Mattis Dementia Rating Scale (MDRS). The secondary objectives of the study are to: assess the effect of therapy on neuropsychological impairment at various time points; assess the effect of therapy on quality of life, based on the SF-36 Quality of Life Assessment; measure the effect of therapy on herpes simplex virus (HSV) deoxyribonucleic acid (DNA) in the cerebral spinal fluid (CSF); and assess the safety and tolerability of long term VACV therapy in patients with HSE. The tertiary objective of the study is to determine the frequency of symptomatic relapse/recurrence of HSE. Study participants will include 120 males and females, 12 years of age and older, diagnosed with HSE; laboratory confirmed CSF positive for HSV DNA by polymerase chain reaction (PCR). Consenting study participants will be randomized (1:1) to either valacyclovir (active drug), 500 mg tablets, four tablets three times daily for 90 days or placebo (identical to active drug in appearance), 500 mg tablets, four tablets three times daily for 90 days. The primary endpoints of the study are to assess the impact of valacyclovir therapy [following standard intravenous acyclovir (ACV) therapy] on neuropsychological impairment at one year post therapy and survival with no or mild neuropsychological impairment at 12 months after initiation of study medication, as measured by the MDRS. The secondary endpoints include: survival with no or mild neuropsychological impairment at 90 days and at 6, 12 and 24 months, as measured by the MDRS, the Mini-Mental Status Examination (MMSE), and the Glasgow Coma Scale; effect of study medication on quality of life measurements; effect of antiviral therapy on HSV DNA in CSF (measured quantitatively by PCR at Day 0 and Day 90); and safety and tolerance of VACV administered at a dose of 2.0 grams given orally three times a day for 90 days. Each study participant will participate for approximately 24 months.