• Survival with no or mild neurological impairment as measured by the Mattis Dementia Rating Scale [ Time Frame: 12 months ] [ Designated as safety issue: No ]
• Neuropsychological impairment [ Time Frame: one year post therapy ] [ Designated as safety issue: No ]

• Effect of antiviral therapy on HSV DNA in CSF (measured quantitatively by PCR). [ Time Frame: Day 0 and Day 90. ] [ Designated as safety issue: No ]
• Safety and tolerance of 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: 90 days and at 6 months. ] [ Designated as safety issue: No ]
• Effect of study medication on quality of life measurements. [ Time Frame: Days 0, 7, and 90; Months 6, 12, and 24. ] [ Designated as safety issue: No ]

• Survival with no or mild neurological impairment as measured by the MRDS and Glasgow Coma Scale [ Time Frame: 90 days and at 6, 12 and 24 months ] [ Designated as safety issue: No ]
• Quality of life [ Time Frame: 90 days ] [ Designated as safety issue: No ]
• Safety/tolerance [ Time Frame: One year post therapy ] [ Designated as safety issue: Yes ]
• HSV DNA in CSF [ Time Frame: 90 days ] [ Designated as safety issue: No ]

This study involves patients 12 years and older who have been diagnosed with Herpes Simplex Encephalitis (HSE) by a specific laboratory test and have completed treatment or are being treated with intravenous (given through a needle inserted into a vein) acyclovir. The purpose of the study is to determine if treatment with 4 tablets, 500 milligrams each, of valacyclovir given 3 times daily by mouth for 90 days is both effective and safe after completing intravenous acyclovir treatment and if it can increase survival with or without mild impairment of the brain and mental functions. Participants will be assigned to either drug or placebo (inactive substance) randomly (by chance). Study procedures will include blood samples and lumbar punctures (procedure in which a needle is inserted into the lower back to collect cerebral spinal fluid). Subjects will participate for up to 24 months.

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) 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. Tertiary endpoints include: frequency of symptomatic relapse/recurrence of HSE; survival with no or mild neuropsychological impairment at various time points, based on analysis of a disease-specific subset of questions from the test panel that measure frontal and/or temporal lobe dysfunction; survival with no or mild neuropsychological impairment at various time points assessed on an individual-subject basis using age, education, and IQ estimate, matched normative data for each subject as measured by the MDRS, MMSE, and tests of frontal/temporal lobe function; effect of antiviral therapy on HSV DNA in serum (measured quantitatively by PCR at clinical presentation, Day 0, and Day 90); and effect of antiviral therapy on HSV antibody in CSF as measured at clinical presentation, Day 0, and Day 90.

• Drug: Placebo
• Drug: Valacyclovir

Inclusion Criteria:

• Informed consent and/or assent must be obtained from the patient or legal guardian.
• Patients with encephalopathy consistent with herpes simplex encephalitis (HSE) whose cerebral spinal fluid (or brain biopsy sample) is positive for herpes simplex virus (HSV) deoxyribonucleic acid (DNA) by polymerase chain reaction (PCR).

NOTE: The purpose of this study is to assess patients with herpes simplex encephalitis, which is usually caused by HSV-1 and occasionally caused by HSV-2. A syndrome of HSV aseptic meningitis may also be encountered and is most often caused by HSV-2. HSV aseptic meningitis will result in a positive CSF PCR for HSV DNA. Investigators should not enroll subjects whose clinical and radiographic findings are suggestive of HSV meningitis without encephalitis. Investigators with questions about subject eligibility should contact one of the Protocol Chairs.

• Patients who are receiving and will have completed intravenous (IV) Acyclovir (ACV) therapy for a minimum duration of 14 days to a maximum of 21 days and a minimum dose of 30 mg/kg/day to a maximum of 60 mg/kg/day, or equivalent dose as adjusted for renal dysfunction.
• Patient is expected to be available for follow-up visits of study drug administration and through the 24 month study visit.
• Patients must be 12 years of age or older.
• Patient must weigh greater than or equal to 45.5kg (100 pounds).
• All female patients with childbearing potential must have a negative pregnancy test within 72 hours prior to initiation of study drug. If the pregnancy test is positive, the patient is ineligible for the study.
• Women must be post-menopausal, surgically sterile or willing to use adequate contraception (barrier method with spermicide, intrauterine device (IUD), oral contraceptives, implant or other licensed hormone method) from time of study enrollment through 1 month after the last dose of study treatment.
• Men must be surgically sterile or willing to use contraception (barrier method with spermicide) from time of study enrollment through 1 month after the last dose of study treatment.

Exclusion Criteria:

• Patients with herpes simplex virus (HSV) meningitis only, without evidence of HSV encephalitis.
• Patients with an anticipated life expectancy <90 days.
• Patients with creatinine clearance of less than or equal to 50ml/min./1.73m^2.
• Pregnant or breastfeeding females.
• Patients who have received any anti-herpesvirus medication (e.g. ganciclovir) other than intravenous Acyclovir (ACV) for acute therapy of the current episode of herpes simplex encephalitis (HSE).
• Patients who are unable to swallow oral medications at the time of study drug randomization (Day 0).
• Patients who are greater than 3 days beyond completion of treatment course with intravenous (IV) ACV.
• Patients who are expected to receive long-term (>30days/year) therapy with antiviral medications active against HSV [e.g. ACV, Valacyclovir (VACV), famciclovir).