Abstracts

RATIONALE: The ability of magnetic resonance spectroscopy (MRS) to measure amino acids, GABA and other metabolites in vivo has lead to several investigations of the neuropharmacology of antiepileptic drugs (AED) and pathophysiology of epilepsy. Valproic acid (VPA)(2-PROPYLPENTANOIC ACID) is an AED that achieves blood concentrations of 0.3 to 1.0 mM at therapeutic doses. If brain concentrations are comparable, the proton signals from VPA should be visible on proton MRS of the human brain. We performed localized proton MRS to determine whether this compound can be observed in the human brain using this technique. METHODS: Ten studies on 6 subjects with epilepsy on valproic acid were performed. Proton spectra were acquired on a 2.1 Tesla, 1 meter bore magnet equipped with an extensively modified Biospec I spectrometer. Prior to the MRS measurement a T1 weighted, inversion recovery MRI was obtained from which a 12-18 cc volume in the occipital lobe was chosen for proton MRS measurement. A short spin echo pulse sequence (TE=16ms) optimized to measure amino acids, ketone bodies, intracellular pH and macromolecules was used. Proton spectra obtained after subtraction of macromolecule resonances were analyzed for presence of the proton signals of VPA. These were compared to proton spectra obtained from a phantom of VPA using the same pulse sequence. RESULTS: The protons of the methyl groups of VPA between 0.8 and 1.4 ppm were observed in 6 of the 10 studies. The VPA signal was seen in subjects whose serum VPA concentration was usually > 0.5 mM. The signals had a complex multiplet structure as expected for this compound. The subtraction of the macromolecule signals at 0.9 and 1.4 ppm was critical to detect these proton MRS signals. CONCLUSIONS: Valproic acid can be observed in localized proton MRS of human brain in vivo. This study demonstrates that proton MRS can be used to study the neuropharmacology of VPA in the human brain. Studies on the pharmacokinetics and mechanism of action of this AED in the human can be performed. Correlative studies of brain VPA levels and changes in GABA and other amino acids are underway. Supported by PHS grants from NINDS (NS-38175) and Children's Clinical Research Center (RR-06022)