Effect of Valproic Acid Concentration on Photic Response
Condition: Photosensitive Epilepsy
MeSH terms: Epilepsy; Epilepsy, Reflex
Study type: Interventional
Phase: Phase 4

Summary: 
      We are trying to learn if small changes in the amount of a valproate in the blood (given
      through an IV) will change the way the brain reacts to flashing lights.
    

Detailed description: 
      Photosensitive epilepsy is a form of epilepsy that is considered to have a genetic basis in
      most instances. It is a reflex type of epilepsy. Patients with this condition exhibit
      epileptic activity patterns (called photoparoxysmal response-PPR) on their EEG during
      intermittent photic stimulation with certain flash frequencies.

      Specific Aims

        1. To determine the extent of the pharmacodynamic effect of small changes in total and free
           VPA concentration via constant infusion of intravenous sodium valproate within the same
           photosensitive epilepsy patient.

        2. To determine the change in total and free VPA concentration required to achieve maximal
           effect on PPR in patients with photosensitive epilepsy.

      Hypothesis

        1. Valproic acid (VPA) demonstrates differential pharmacodynamic effect on PPR with small
           changes in VPA concentration (5-20 mg/L changes in total, or 0.5 to 2 mg/L changes in
           free VPA) within the same patient. In essence, the VPA concentration-response curve in
           patients with photosensitive epilepsy is relatively steep.

        2. Intravenously-administered VPA will demonstrate a reduction in standard photosensitive
           range (SPR) or abolition of PPR for at least 80% of patients studied, when the entire
           range of free VPA concentrations is considered.

      Photosensitivity, defined as a PPR on intermittent photic stimulation (IPS), is found in
      approximately 5% of all epileptic patients. Markedly photosensitive patients are usually
      sensitive to IPS within clearly defined limits of flash frequency (mostly between 10-30 Hz).
      This photosensitivity range, the difference between the highest and lowest flash rates that
      consistently elicit a photoparoxysmal response (PPR), can be used as a quantitative measure
      of photosensitivity.

      Administration of some antiepileptic drugs (AEDS) can diminish or even abolish PPR. With a
      standard set of tested frequencies, a standard photosensitive range (SPR) can be used to
      measure drug effect on photosensitivity. Combined with blood level monitoring, the model
      offers information about actual pharmacodynamic effect as measured with IPS related to the
      changes in blood levels.

      The standardized IPS procedure includes delivery of short (5 second-) trains of flashes. The
      stimulation starts with the lowest frequencies (which usually do not produce a PPR) only up
      to the limits of the photosensitivity range (the threshold frequencies for which the patient
      shows an epileptiform EEG response). After that the stimulation starts again with the highest
      frequencies (which also do not produce a PPR) down to the frequency that produces a definite
      PPR.

      The photic stimulator will be manually controlled for all stimulations in order to abort the
      stimulation when a clear PPR is elicited. With all stimulations, there is simultaneous
      recording of the EEG and direct observation of the patient for clinical changes. With all the
      safety measures in place, the likelihood of provoking prominent clinical seizures is
      extremely low.
    

Intervention name(s): Valproic Acid; Placebo
Intervention type(s): Drug; Drug
Intervention description(s): The investigators will utilize intravenous sodium valproate at visit 3. Dosage will be individualized to each patient's body weight, age, and hepatic-enzyme-inducing status. Intravenous VPA dose predictions will be based upon population VPA pharmacokinetic parameters (Dutta 2003).; Each patient will have a placebo-infusion (with 0.9% NS or D5W) of 12-hour duration at visit 2.
Other intervention name(s): Depacon; Normal Saline (NS) and 5% Dextrose in water (D5W)
Intervention MeSH terms: Valproic Acid
Intervention model: Single Group Assignment
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: epilepsy; photosensitive; valproic acid