Jullie W. Pan

Cognitive effects of topiramate, gabapentin, and lamotrigine in healthy young adults

Objective: To study the acute and steady-state cognitive effects of three new antiepileptic drugs (AEDs): gabapentin, lamotrigine, and topiramate. Background: Several newer antiepileptic medications approved recently by the Food and Drug Administration are gaining attention as efficacious alternatives to established AEDs. Greater tolerability with fewer side effects are reported in some. However, the potential cognitive effects of these newer AEDs have received limited attention. Methods: Healthy young adults randomized to either of the three drugs were administered tests of attention, psychomotor speed, language, memory, and mood at baseline (predrug), acute single-dose period, and after 2 and 4 weeks on the drug. Results: Compared with baseline, the topiramate group had selective, statistically significant declines on measures of attention and word fluency at acute doses, whereas the other two AED groups had no performance changes. At the 2- and 4-week test periods, only the topiramate subjects continued to display neurocognitive effects from drug administration. Conclusions: Results demonstrate potential acute and steady-state adverse cognitive effects for topiramate, whereas minimal effects were displayed for either gabapentin or lamotrigine in young healthy adults.

Clinical Proton MR Spectroscopy in Central Nervous System Disorders

A large body of published work shows that proton (hydrogen 1 [(1)H]) magnetic resonance (MR) spectroscopy has evolved from a research tool into a clinical neuroimaging modality. Herein, the authors present a summary of brain disorders in which MR spectroscopy has an impact on patient management, together with a critical consideration of common data acquisition and processing procedures. The article documents the impact of (1)H MR spectroscopy in the clinical evaluation of disorders of the central nervous system. The clinical usefulness of (1)H MR spectroscopy has been established for brain neoplasms, neonatal and pediatric disorders (hypoxia-ischemia, inherited metabolic diseases, and traumatic brain injury), demyelinating disorders, and infectious brain lesions. The growing list of disorders for which (1)H MR spectroscopy may contribute to patient management extends to neurodegenerative diseases, epilepsy, and stroke. To facilitate expanded clinical acceptance and standardization of MR spectroscopy methodology, guidelines are provided for data acquisition and analysis, quality assessment, and interpretation. Finally, the authors offer recommendations to expedite the use of robust MR spectroscopy methodology in the clinical setting, including incorporation of technical advances on clinical units.

Modulation of cerebral GABA by topiramate, lamotrigine, and gabapentin in healthy adults

BackgroundAnticonvulsant drugs have multiple mechanisms of action. Recent in vivo MRS studies suggest that cerebral &ggr;-aminobutyric acid (GABA) increases occur with the administration of certain anticonvulsants in humans. ObjectiveTo investigate the effect of topiramate, gabapentin, and lamotrigine on cerebral GABA concentrations in healthy volunteers and correlate the GABA concentrations with serum drug levels. MethodsSeventeen healthy adults were randomly assigned to receive topiramate, gabapentin, and lamotrigine and underwent GABA measurements using a 4.1-T magnet from a 13.5-mL volume over the occipital region. GABA concentrations and serum levels were measured at 3 and 6 hours following administration of an acute single dose of one of the drugs. Thereafter, drugs were titrated over 4 weeks to target doses, with GABA measurements performed at 2 and 4 weeks. ResultsCerebral GABA concentrations rose 70% in the acute phase compared with baseline for topiramate. GABA rose 48% at 6 hours with gabapentin but not with lamotrigine. With long-term dosing and once target doses were achieved at 4 weeks, significant elevations in GABA were observed compared with baseline for all three drugs (topiramate 46%, gabapentin 25%, lamotrigine 25%). ConclusionThis study demonstrates that single doses of topiramate and gabapentin increase cerebral GABA concentrations acutely (hours) in healthy individuals, but all drugs at clinically utilized doses increase cerebral GABA at 4 weeks. These results suggest that the mechanisms of action of anticonvulsant drugs are more complex and are likely to be multiple in nature.

Topiramate increases cerebral GABA in healthy humans

Topiramate (TOP) is a novel anticonvulsant drug with multiple mechanisms of action used in the treatment of epilepsy. Measurements of cerebral GABA were obtained in six controls using 1H MRS at baseline and at 3 and 6 hours following the administration of 3 mg/kg of TOP. Brain GABA concentrations rose by 72% at 3 hours and by 64% at 6 hours compared with baseline (p < 0.004). This study demonstrates that TOP significantly increases human cerebral GABA concentrations in healthy individuals.

Proton spectroscopic imaging at 4.1 tesla in patients with malformations of cortical development and epilepsy

We used proton magnetic resonance spectroscopic imaging (MRSI) at 4.1 tesla in patients with malformations of cortical development (MCDs) and epilepsy. We compared the spectroscopic results with normative data using 2 SDs (95% confidence) above normal values for detection of significant abnormalities for creatine-N-acetylated compounds (Cr/NA) ratio and choline-N-acetylated compounds (Cho/NA). The results were correlated with clinical, EEG, and histologic findings. Patients with focal cortical dysplasia showed significant metabolic abnormalities in correspondence with the structural lesions, whereas patients with heterotopia and polymicrogyria demonstrated no subcortical MRSI abnormalities. Significant correlations were found between the metabolic abnormalities and the frequency of seizures but not with the degree of interictal EEG discharges. Quantitative neuronal and glial cell counts revealed no statistically significant correlation between cell loss and the abnormal metabolic ratios in those who underwent surgery. These preliminary findings suggest that MRSI-based metabolic abnormalities in patients with MCDs are variable and are likely to be associated with complex cellular mechanisms involving the regulation of NA, total Cr content, and Cho.

Quantitative 31P spectroscopic imaging of human brain at 4 Tesla: Assessment of gray and white matter differences of phosphocreatine and ATP

This report describes the implementation and application of a multicompartment analysis of 31P spectroscopic imaging data to determine the tissue‐specific heterogeneities in metabolite content in the human brain and surrounding tissue. Using this information and a multicompartment regression analysis the phosphocreatine and ATP content of “pure” cerebral gray and white matter, the cerebellum, and skeletal muscle was determined in a group of 10 healthy volunteers. The data were converted to mM units using previously reported values for the T1s of phosphocreatine and ATP at 4 T, the water content of human brain, and an external reference for absolute quantification. The phosphocreatine concentration in cerebral gray and white matter, the cerebellum, and skeletal muscle was 3.53 ± 0.33, 3.33 ± 0.37, 3.75 ± 0.66, and 25.8 ± 2.3 mM, respectively. The ATP concentration in cerebral gray and white matter, the cerebellum, and skeletal muscle was 2.19 ± 0.33, 3.41 ± 0.33, 1.75 ± 0.58, and 8.5 ± 1.9 mM, respectively. Magn Reson Med 45:46–52, 2001.

Ketosis and epilepsy: 31P spectroscopic imaging at 4.1 T.

Summary: Purpose: To determine whether changes in the high‐energy phosphates occur with use of the ketogenic diet in patients with intractable epilepsy.

Neurometabolism in human epilepsy

Purpose: Because of the large and continuous energetic requirements of brain function, neurometabolic dysfunction is a key pathophysiologic aspect of the epileptic brain. Additionally, neurometabolic dysfunction has many self‐propagating features that are typical of epileptogenic processes, that is, where each occurrence makes the likelihood of further mitochondrial and energetic injury more probable. Thus abnormal neurometabolism may be not only a chronic accompaniment of the epileptic brain, but also a direct contributor to epileptogenesis.

Human Brain β-Hydroxybutyrate and Lactate Increase in Fasting-Induced Ketosis:

Ketones are known to constitute an important fraction of fuel for consumption by the brain, with brain ketone content generally thought to be low. However, the recent observation of 1-mmol/L levels of brain β-hydroxybutyrate (BHB) in children on the ketogenic diet suggests otherwise. The authors report the measurement of brain BHB and lactate in the occipital lobe of healthy adults using high field (4-T) magnetic resonance spectroscopy, measured in the nonfasted state and after 2-and 3-day fasting-induced ketosis. A 9-mL voxel located in the calcarine fissure was studied, detecting the BHB and lactate upfield resonances using a 1H homonuclear editing sequence. Plasma BHB levels also were measured. The mean brain BHB concentration increased from a nonfasted level of 0.05 ± 0.05 to 0.60 ± 0.26 mmol/L (after second day of fasting), increasing further to 0.98 ± 0.16 mmol/L (after the third day of fasting). The mean nonfasted brain lactate was 0.69 ± 0.17 mmol/L, increasing to 1.47 ± 0.22 mmol/L after the third day. The plasma and brain BHB levels correlated well (r = 0.86) with a brain–plasma slope of 0.26. These data show that brain BHB rises significantly with 2-and 3-day fasting-induced ketosis. The lactate increase likely results from ketones displacing lactate oxidation without altering glucose phosphorylation and glycolysis.

Differentiation of Glucose transport in human brain gray and white matter

Localized 1H nuclear magnetic resonance spectroscopy has been applied to determine human brain gray matter and white matter glucose transport kinetics by measuring the steady-state glucose concentration under normoglycemia and two levels of hyperglycemia. Nuclear magnetic resonance spectroscopic measurements were simultaneously performed on three 12-mL volumes, containing predominantly gray or white matter. The exact volume compositions were determined from quantitative T1 relaxation magnetic resonance images. The absolute brain glucose concentration as a function of the plasma glucose level was fitted with two kinetic transport models, based on standard (irreversible) or reversible Michaelis-Menten kinetics. The steady-state brain glucose levels were similar for cerebral gray and white matter, although the white matter levels were consistently 15% to 20% higher. The ratio of the maximum glucose transport rate, Vmax, to the cerebral metabolic utilization rate of glucose, CMRGlc, was 3.2 ± 0.10 and 3.9 ± 0.15 for gray matter and white matter using the standard transport model and 1.8 ± 0.10 and 2.2 ± 0.12 for gray matter and white matter using the reversible transport model. The Michaelis-Menten constant Km was 6.2 ± 0.85 and 7.3 ± 1.1 mmol/L for gray matter and white matter in the standard model and 1.1 ± 0.66 and 1.7 ± 0.88 mmol/L in the reversible model. Taking into account the threefold lower rate of CMRGlc in white matter, this finding suggests that blood–brain barrier glucose transport activity is lower by a similar amount in white matter. The regulation of glucose transport activity at the blood–brain barrier may be an important mechanism for maintaining glucose homeostasis throughout the cerebral cortex.