phosphocreatine and Epilepsy

Magnetic resonance spectroscopy (MRS) is noninvasive and may be readily combined with magnetic resonance imaging (MRI). Attention has focussed on proton (1H) and phosphorus (31P) MRS, and studies have been undertaken by using single voxels or many voxels simultaneously (chemical-shift imaging, magnetic resonance spectroscopic imaging). The latter is more difficult and prone to artefact but potentially yields significantly more information. 1H MRS has principally yielded data on concentrations of N-acetyl aspartate (NAA), choline, creatine, and phosphocreatine. NAA is located primarily within neurons, and reduction of the ratio of NAA to choline, creatine, and phosphocreatine is a marker of neuronal loss and dysfunction. This technique may be useful as a noninvasive tool for localizing epileptogenic foci, but its role requires further evaluation. As with all functional imaging methods, coregistration with high-quality MRI is essential for interpreting data. 1H MRS can be used also to estimate cerebral concentrations of several neurotransmitters: glutamate, glutamine, and gamma-aminobutyric acid (GABA). This may prove useful for characterizing the neurometabolic profiles of patients with different epilepsy syndromes and for evaluating the effects of medical and surgical treatments. 31P MRS can detect adenosine triphosphate, phosphodiesters, phosphomonoesters, phosphocreatine, and inorganic phosphate, and estimate intracerebral pH. Abnormalities that have been associated with epileptogenic brain areas include increased inorganic phosphate, reduced phosphomonoesters, and increased pH. Only small numbers of patients have been studied, however, so that conclusions are not definitive, and the clinical role of this technique is not yet established.

Topics: Aspartic Acid; Brain; Creatinine; Epilepsy; Epilepsy, Complex Partial; Epilepsy, Temporal Lobe; gamma-Aminobutyric Acid; Hippocampus; Humans; Magnetic Resonance Imaging; Magnetic Resonance Spectroscopy; Neurotransmitter Agents; Phosphocreatine; Phosphorus Isotopes; Protons; Sclerosis; Temporal Lobe; Tissue Distribution

In patients with malformations of cortical development (MCD), widespread structural abnormalities of the brain have been demonstrated using volumetric MRI, and associated with poor post-surgical outcome in patients with localization-related epilepsy. Proton magnetic resonance spectroscopic imaging (1H-MRSI) studies permit the non-invasive measurement of concentrations of a variety of cerebral metabolites implicated in cerebral structure and function. There is a dearth of quantitative 1H-MRSI studies of MCD. Ten controls and 10 patients with localization-related epilepsy who were found to have MCD on high resolution MRI underwent 1H-MRSI on a 1.5 T GE Signa scanner [TE (echo time) = 30 ms, TR (repetition time) = 3 s]. In all patients, the axial area studied contained lesional and perilesional tissue. In seven unilaterally affected patients, the area studied contained also apparently normal contralateral grey and white matter; in three patients with bilateral but asymmetrical MCD, it contained visually normal and abnormal tissue from both hemispheres. N-acetyl aspartate + N-acetyl aspartyl glutamate (NAA), creatine + phosphocreatine (Cr), choline-containing compounds (Cho), glutamate + glutamine (Glx) and myo-inositol (Ins) were automatically quantified in voxels covering these different regions. Metabolite concentrations were corrected for CSF content and correlated with the grey and white matter of the MRSI voxels. In control subjects, there were significant positive correlations between grey matter content and concentrations of NAA, Glx, Ins and Cr. Compared with a normal range that took grey matter content into account, defined as the control mean +/- 2 SD, all lesions but one showed metabolic abnormalities. The most common abnormality was a decrease in NAA, but findings were heterogeneous and there was increased NAA in one lesion. Perilesional tissue was abnormal in eight patients, with increased NAA in three. Tissue contralateral to the main MCD was abnormal in all three patients with bilateral but asymmetrical MCD, and in six of the seven apparently unilaterally affected patients. Spectroscopic grey and white matter abnormalities in patients with MCD exceeded the apparently focal abnormality shown by MRI, indicating widespread abnormalities of cerebral function.

Topics: Adult; Analysis of Variance; Aspartic Acid; Cerebral Cortex; Choline; Creatine; Dipeptides; Epilepsy; Female; Glutamic Acid; Glutamine; Humans; Inositol; Magnetic Resonance Imaging; Male; Middle Aged; Nervous System Malformations; Phosphocreatine; Reference Values

Vigabatrin (VGB) is a new antiepileptic drug that increases the human brain gamma-aminobutyric acid (GABA) level by irreversibly inhibiting GABA transaminase. Although some patients respond to VGB with a significant seizure reduction, others do not. The aim of this study was to identify possible responders before or in an early phase of VGB treatment by measuring the GABA and homocarnosine contaminated with macromolecules/creatine and phosphocreatine ratio (GABA+/Cr) signal by means of proton-nuclear magnetic resonance (1H NMR) spectroscopy.. Measurements were performed immediately before and after a titration period of 1 month (2 g/day during the past 2 weeks). A third measurement followed a maintenance period of 3 months (2 or 3 g/day). In 14 patients with drug-resistant temporal lobe epilepsy and 3 patients with occipital lobe epilepsy, GABA+/Cr was measured in the ipsilateral (i.e., epileptogenic) hemisphere and contralateral (i.e., nonepileptogenic) hemisphere in a volume of 8 cm3.. Depending on the therapeutic efficacy of VGB, we defined three groups: (a) full responders (n = 7), (b) nonresponders (n = 7), and (c) partial responders (n = 3). The nonresponders had no significant change in the GABA+/Cr signal during the treatment compared with baseline. The full responders had a significant increase of the GABA+/Cr signal during the whole treatment phase and a lower ipsilateral level at baseline. The partial responders had also a lowered ipsilateral GABA+/Cr signal at baseline and an increase during treatment but a decrease when the seizures started again.. Responders to VGB could be identified by a lower ipsilateral baseline GABA+/Cr signal and a steeper increase during VGB treatment. However, it was not possible to predict the duration of the response (full versus partial responder) with these criteria.

Topics: Adolescent; Adult; Anticonvulsants; Brain; Brain Chemistry; Carnosine; Creatine; Epilepsy; Epilepsy, Temporal Lobe; Female; Functional Laterality; gamma-Aminobutyric Acid; Humans; Magnetic Resonance Spectroscopy; Male; Middle Aged; Occipital Lobe; Phosphocreatine; Treatment Outcome; Vigabatrin

This study aimed to identify noninvasive biomarkers of human epilepsy that can reliably detect and localize epileptic brain regions. Having noninvasive biomarkers would greatly enhance patient diagnosis, patient monitoring, and novel therapy development. At the present time, only surgically invasive, direct brain recordings are capable of detecting these regions with precision, which severely limits the pace and scope of both clinical management and research progress in epilepsy.. We compared high versus low or nonspiking regions in nine medically intractable epilepsy surgery patients by performing integrated metabolomic-genomic-histological analyses of electrically mapped human cortical regions using high-resolution magic angle spinning proton magnetic resonance spectroscopy, cDNA microarrays, and histological analysis.. We found a highly consistent and predictive metabolite logistic regression model with reduced lactate and increased creatine plus phosphocreatine and choline, suggestive of a chronically altered metabolic state in epileptic brain regions. Linking gene expression, cellular, and histological differences to these key metabolites using a hierarchical clustering approach predicted altered metabolic vascular coupling in the affected regions. Consistently, these predictions were validated histologically, showing both neovascularization and newly discovered, millimeter-sized microlesions.. Using a systems biology approach on electrically mapped human cortex provides new evidence for spatially segregated, metabolic derangements in both neurovascular and synaptic architecture in human epileptic brain regions that could be a noninvasively detectable biomarker of epilepsy. These findings both highlight the immense power of a systems biology approach and identify a potentially important role that magnetic resonance spectroscopy can play in the research and clinical management of epilepsy.

Topics: Adolescent; Biomarkers; Brain; Child; Child, Preschool; Choline; Creatine; Epilepsy; Female; Genetic Markers; Humans; Infant; Lactic Acid; Magnetic Resonance Spectroscopy; Male; Metabolomics; Oligonucleotide Array Sequence Analysis; Phosphocreatine

Neuroimaging studies demonstrate that not only the lesions of malformations of cortical development (MCD) but also the normal-appearing parenchyma (NAP) present metabolic impairments, as revealed with (1)H-MRS. We have previously detected biochemical disturbances in MCD lesions with phosphorus-31 magnetic resonance spectroscopy (31P-MRS). Our hypothesis is that pH abnormalities extend beyond the visible lesions.. Three-dimensional 31P-MRS at 3.0 T was performed in 37 patients with epilepsy and MCD, and in 31 matched-control subjects. The patients were assigned into three main MCD subgroups: cortical dysplasia (n=10); heterotopia (n=14); schizencephaly/polymicrogyria (n=13). Voxels (12.5 cm3) were selected in five homologous regions containing NAP: right putamen; left putamen; frontoparietal parasagittal cortex; right centrum semiovale; and left centrum semiovale. Robust methods of quantification were applied, and the intracellular pH was calculated with the chemical shifts of inorganic phosphate (Pi) relative to phosphocreatine (PCr).. In comparison to controls and considering a Bonferroni adjusted p-value <0.01, MCD patients presented significant reduction in intracellular pH in the frontoparietal parasagittal cortex (6.985±0.022), right centrum semiovale (7.004±0.029), and left centrum semiovale (6.995±0.030), compared to controls (mean values±standard deviations of 7.087±0.048, 7.096±0.042, 7.088±0.045, respectively). Dunnet and Dunn tests demonstrated that the differences in pH values remained statistically significant in all MCD subgroups. No significant differences were found for the putamina.. The present study demonstrates widespread acidosis in the NAP, and reinforces the idea that MCD visible lesions are only the tip of the iceberg.

Topics: Adult; Analysis of Variance; Brain; Case-Control Studies; Epilepsy; Female; Humans; Hydrogen-Ion Concentration; Imaging, Three-Dimensional; Magnetic Resonance Spectroscopy; Male; Malformations of Cortical Development; Middle Aged; Phosphocreatine; Phosphorus; Young Adult

This study examined the biochemical metabolism by proton magnetic resonance spectroscopy ('H-MRS) in order to explore the value of 'H-MRS in idiopathic epilepsy in children.. Thirty-three children with idiopathic epilepsy (14 cases with history of febrile seizures and 19 cases without) and six normal controls experienced MRI of the skull and brain and single-voxel 'H-MRS examinations of the hippocampi-temporal lobe. The signal intensities of N-acetylaspartate (NAA), eatine+phosphocreatine (Cr), choline-containing compounds (Cho) and lactate (Lac) and the ratios of NAA/ (Cho+Cr) and Lac/Cr were compared between the patients and normal controls.. MRI examination showed that only one child with epilepsy had myelin dysplasia. 'H-MRS examination showed that the ratio of NAA/ (Cho+Cr) in the epilepsy group was lower than that in the control group (0.64+/-0.07 vs 0.73+/-0.05; P<0.01). The epileptic children with history of febrile seizures had a more decreased ratio of NAA/ (Cho+Cr) compared with those without the history (0.61+/-0.07 vs 0.66+/-0.06; P<0.05). There were no significant differences in the ratio of Lac/Cr between the epilepsy and the control groups.. 'H-MRS may provide early information on brain injury sensitively and non-invasively in children with epilepsy. It may be used for diagnosis and prognosis evaluation of epilepsy.

Topics: Aspartic Acid; Child; Child, Preschool; Choline; Epilepsy; Female; Humans; Magnetic Resonance Imaging; Magnetic Resonance Spectroscopy; Male; Phosphocreatine; Protons

There is increasing evidence for a dysfunctional metabolic network in human mesial temporal lobe epilepsy (MTLE). To further describe this, we evaluated the bioenergetic status in unilateral MTLE inter-regionally and in relation to neuropathology.. We used whole brain high field (4 T) 31P MR spectroscopic imaging to determine in vivo PCr and ATP, studying n=22 patients (all candidates for hippocampal resection) and n=14 control volunteers. The degree of bioenergetic impairment was assessed by calculating the ratio of PCr to ATP.. Compared to controls, patients demonstrated significant decreases in PCr/ATP from the ipsilateral amygdala and pes (0.84 +/- 0.14, 0.87 +/- 0.10, respectively, patients vs 0.97 +/- 0.15, 0.98 +/- 0.16, controls). In patients, the ipsilateral thalamic energetics positively correlated with contralateral hippocampal energetics. In addition, the ipsilateral thalamic and striatal energetics negatively correlated with hippocampal total glial counts.. These data are consistent with a view that in MTLE, the bilateral hippocampi, ipsilateral thalamus and striatum are linked in their energetic depression, possibly reflecting the propagation of seizures throughout the brain.

Topics: Adenosine Triphosphate; Adolescent; Adult; Brain Chemistry; Case-Control Studies; Corpus Striatum; Epilepsy; Female; Hippocampus; Humans; Magnetic Resonance Spectroscopy; Male; Middle Aged; Phosphocreatine; Phosphorus Radioisotopes; Thalamus

Cortical malformations (CMs) are increasingly recognized as the epileptogenic substrate in patients with medically refractory neocortical epilepsy (NE). The aim of this study was to test the hypotheses that: 1. CMs are metabolically heterogeneous. 2. The structurally normal appearing perilesional zone is characterized by similar metabolic abnormalities as the CM.. Magnetic resonance spectroscopic imaging (MRSI) in combination with tissue segmentation was performed on eight patients with NE and CMs and 19 age matched controls. In controls, NAA, Cr, Cho,NAA/Cr and NAA/Cho of all voxels of a given lobe were expressed as a function of white matter content and thresholds for pathological values determined by calculating the 95% prediction intervals. These thresholds were used to identify metabolically abnormal voxels within the CM and in the perilesional zone.. 30% of all voxels in the CMs were abnormal, most frequently because of decreases of NAA or increases of Cho. Abnormal voxels tended to form metabolically heterogeneous clusters interspersed in metabolically normal regions. Furthermore, 15% of all voxels in the perilesional zone were abnormal, the most frequent being decreases of NAA and Cr.. In CMs metabolically normal regions are interspersed with metabolically heterogeneous abnormal regions. Metabolic abnormalities in the perilesional zone share several characteristics of CMs and might therefore represent areas with microscopic malformations and/or intrinsic epileptogenicity.

Topics: Adolescent; Adult; Aspartic Acid; Cerebral Cortex; Choline; Creatine; Epilepsy; Humans; Image Processing, Computer-Assisted; Magnetic Resonance Imaging; Magnetic Resonance Spectroscopy; Phosphocreatine

Although MRS measurements are useful in assessing the biochemical alterations underlying human epilepsy, to date their use has been limited primarily by three factors: (a) the lack of widespread methods and appropriate hardware for acquiring high-resolution spectroscopic imaging data, (b) difficulties in spectral interpretation associated with metabolic heterogeneity, and (c) difficulties in biological interpretation due to a lack of correlative histologic studies. In this work, we (a) describe approaches to overcome these hurdles, and (b) discuss the biological interpretation of the spectroscopic findings in TLE.

Topics: Adult; Amygdala; Aspartic Acid; Brain; Choline; Creatine; Epilepsy; Epilepsy, Temporal Lobe; Female; Functional Laterality; Glial Fibrillary Acidic Protein; Hippocampus; Humans; Hydrogen; Magnetic Resonance Spectroscopy; Male; Neurons; Phosphocreatine; Phosphorus

To determine whether changes in the high-energy phosphates occur with use of the ketogenic diet in patients with intractable epilepsy.. 31P magnetic resonance spectroscopic imaging studies were performed at 4.1 T in seven patients with intractable epilepsy (four Lennox-Gastaut syndrome, one absence, one primary generalized tonic-clonic, and one partial complex) before and after institution of the ketogenic diet. Coronal 1H anatomic imaging also was performed to provide correlation to the 31P data.. Taking the patients as a group, the ratio of phosphocreatine (PC)/gamma-adenosine triphosphate (ATP) measured at baseline (regular diet) compared with that measured after the ketogenic diet showed a small but significant increase from 0.61+/-0.08 to 0.69+/-0.08 (p < 0.05). Comparing the ratio of PCr inorganic phosphorus (Pi) measured at baseline with the postketogenic diet, there was a significant increase from 2.45+/-0.27 to 2.99+/-0.44 (p < 0.05).. As a group, improvement of energy metabolism occurs with use of the ketogenic diet. This is in agreement with the chronic ketosis studies performed earlier in rodents.

Topics: Adenosine Triphosphate; Adolescent; Brain; Child; Child, Preschool; Epilepsy; Food, Formulated; Humans; Ketosis; Magnetic Resonance Spectroscopy; Phosphocreatine; Phosphorus; Phosphorus Isotopes

An association between complex febrile convulsions and the development of hippocampal atrophy, which is characterized by neuron loss and gliosis, has been suggested but is still controversial. In proton magnetic resonance spectroscopy (1H-MRS) a reduction in N-acetylaspartate (NAA), a neuron marker, or in its ratio to other metabolites, that is, creatine and phospocreatine (Cr) and choline-containing compounds (Cho), is considered a sensitive method for detecting neuron loss. We performed 1H-MRS of mesial temporal regions, including hippocampi, in two different groups of children with epilepsy: in children with a history of complex febrile convulsions (CFCs) (n = 7; mean age 7.1 years) and in children without any history of CFCs, referred to herein as the non-CFC group (n = 6; mean age 7.6 years). Changes in the metabolite ratios were detected in 57% of children in the CFC group and in 67% of children in the non-CFC group. In both groups, NAA/(Cho + Cr), NAA/Cho, and NAA/Cr were significantly decreased ipsilaterally to the seizure focus when compared with the control group, but no significant differences were detected between the CFC and non-CFC groups. Also on the contralateral side, NAA/(Cho + Cr) and NAA/Cr were significantly decreased in both patient groups, but the differences were not significant between the CFC and non-CFC groups. Metabolite abnormalities in the mesial temporal region were detected in children with intractable epilepsy and in children whose epilepsy is well controlled by antiepileptic medication. The noninvasive 1H-MRS can be considered an additional diagnostic method to promote early detection of mesial temporal abnormalities that, in the light of this study, seem to be underdiagnosed in children with either temporal lobe epilepsy or other seizure types.

Topics: Aspartic Acid; Child; Child, Preschool; Choline; Electroencephalography; Epilepsy; Hippocampus; Humans; Magnetic Resonance Imaging; Magnetic Resonance Spectroscopy; Phosphocreatine; Seizures, Febrile; Temporal Lobe

Proton magnetic resonance spectra include signals from N-acetylaspartate, creatine + phosphocreatine, and choline-containing compounds. Abnormalities in these signals can be used in the assessment of patients with intractable epilepsy. In particular, they provide a means of identifying metabolic abnormalities within the temporal lobes, detecting bilateral and diffuse pathology, and aiding lateralization of the seizure focus. The pathology demonstrated on MRS can also be related to cognitive dysfunction.

Topics: Adult; Aspartic Acid; Brain Damage, Chronic; Brain Mapping; Child; Choline; Creatine; Dominance, Cerebral; Energy Metabolism; Epilepsy; Epilepsy, Temporal Lobe; Female; Humans; Image Processing, Computer-Assisted; Magnetic Resonance Imaging; Magnetic Resonance Spectroscopy; Male; Neuropsychological Tests; Phosphocreatine; Temporal Lobe

Topics: Acoustic Stimulation; Adenosine; Adenosine Triphosphate; Animals; Blood Pressure; Brain Chemistry; Caffeine; Dose-Response Relationship, Drug; Electroencephalography; Epilepsy; gamma-Aminobutyric Acid; Hypnotics and Sedatives; Male; Mice; Mice, Inbred Strains; NAD; Niacinamide; Norepinephrine; Phosphocreatine; Phosphorus Radioisotopes; Time Factors

Topics: Acidosis; Adenosine Diphosphate; Adenosine Triphosphate; Animals; Bicarbonates; Blood Flow Velocity; Brain; Carbon Dioxide; Cats; Cerebrovascular Circulation; Dogs; Electric Stimulation; Energy Metabolism; Epilepsy; Flurothyl; Hydrogen-Ion Concentration; Lactates; Mice; NAD; Oxygen; Oxygen Consumption; Pentylenetetrazole; Phosphocreatine; Pyruvates; Rats; Seizures