Proton magnetic resonance spectroscopy of malformations of cortical development causing epilepsy
Introduction
Malformations of cortical development (MCD) are an important cause of refractory focal epilepsy. MCD include a heterogeneous range of conditions that arise at different points along the process of normal cortical development, which have characteristic histopathological features and recognisable appearance on MRI. Microscopic structure of these MCD sub-types can range from heterotopic aggregates of relatively normal neurons to abnormalities of cortical lamination or neuronal differentiation. Invasive EEG studies have demonstrated that MCD are intrinsically epileptogenic (Kothare et al., 1998, Mattia et al., 1995, Palmini et al., 1995) or that surrounding normal appearing tissue is epileptogenic (Jacobs et al., 1999).
Proton magnetic resonance spectroscopy (MRS) is a sensitive measure of neuronal loss or dysfunction (Cendes et al., 1997, Tasch et al., 1999, Urenjak et al., 1992) or neuronal maturation (Kreis et al., 2002, Tkac et al., 2003), and recent MRS studies have reported the reliable quantification of metabolites relevant to the study of epilepsy (McLean et al., 2000, McLean et al., 2002, Petroff et al., 2000). Most MRS studies in subjects with MCD have used long echo times (TE), and reported only the ratios of the main visible metabolites, N-acetyl aspartate (NAA), creatine plus phosphocreatine (Cr), and choline containing compounds (Cho) (Kuzniecky et al., 1997, Li et al., 1998, Marsh et al., 1996, Mueller et al., 2005, Simone et al., 1999, Widjaja et al., 2003). These studies have typically shown reduction in NAA/Cr and NAA/Cho in the region of focal cortical dysplasia whilst heterotopia and polymicrogyria may have normal or reduced NAA/Cr (Kuzniecky et al., 1997, Li et al., 1998, Marsh et al., 1996, Widjaja et al., 2003). There is evidence for metabolic heterogeneity within the visible lesions as well as within normal appearing surrounding tissue (Mueller et al., 2005). In a quantitative multi voxel MRS study of MCD with correction for tissue composition we found abnormal metabolite concentrations within MCD, within peri-lesional tissue and also in contralateral normal appearing tissue (Woermann et al., 2001).
Elevation of glutamate is a feature of epileptic tissue (Petroff et al., 1995) and elevations in GLX have been observed in the frontal lobes in subjects with idiopathic generalised epilepsy (IGE) (Simister et al., 2003b) and in the temporal lobe in temporal lobe epilepsy (Woermann et al., 1999).
The role of GABA in the developing brain and in epileptic tissue is the subject of much current research. Reduction in GABA inhibition may cause seizures (Olsen and Avoli, 1997) and several potent anti-epileptic drugs (AED) enhance GABA function. However, in immature or epileptic tissue, activation of GABAergic synapses may be excitatory rather than inhibitory (Ben Ari, 2002, Ben Ari and Holmes, 2005). Although in vivo identification of GABA via MRS is difficult due to overlapping metabolite peaks, methods such as spectral editing have been developed to separate the GABA signal to allow quantification (Henry et al., 2001, Kuzniecky et al., 2002, Mescher et al., 1998, Mueller et al., 2001, Petroff et al., 1996, Petroff et al., 1999a, Petroff et al., 1999b, Petroff et al., 2000, Petroff et al., 2001). We have reported the reliable measurement of GABA+ using a double quantum filter (DQF) (Simister et al., 2003b). As with spectral editing methods the resulting “GABA” peak includes homocarnosine, glutathione and some macromolecule signal so we designate our measures as GABA+. Homocarnosine is a dipeptide of GABA and histidine. Its localization appears to be the cytosol of a sub-group of GABAergic neurons and it may act as a GABA reservoir (Henry and Theodore, 2001). Measurements in subjects with epilepsy without MRI evidence of MCD have shown low (Petroff et al., 1996, Petroff et al., 2000, Petroff et al., 2001) or unchanged GABA+ levels (Simister et al., 2003b, Simister et al., 2003a) compared to a control population. Levels of GABA+ (Petroff et al., 1996) and homocarnosine (Petroff et al., 2000, Petroff et al., 2001) increased with improved seizure control or following the administration of vigabatrin, topiramate (TPM) or gabapentin (GBP) (Kuzniecky et al., 2002, Mueller et al., 2001, Petroff et al., 2000). In contrast, GABA concentrations were elevated in ex vivo measurements of focal cortical dysplasia (Aasly et al., 1999). Animal models of MCD have shown increased GABAergic function associated with impaired GABA transporter function (Calcagnotto et al., 2002), down-regulation of GABAA receptors (Prince et al., 1997) or decreased neuronal sensitivity to GABA (Benardete and Kriegstein, 2002).
The aim of the current study was to measure the profiles in large MCD of GABA+ and GLX concentrations together with concentrations of the other main MRS visible metabolites.
Section snippets
Subjects
Fifteen controls (seven female, with median age 27 years and range 18–40 years) and 15 subjects with MCD (five female, with median age 30 years and range 21–51 years) were studied. Ethical approval by the Joint Research Ethics Committee of the Institute of Neurology and the National Hospital for Neurology and Neurosurgery was obtained, and all subjects gave informed consent. All 15 patients had refractory focal epilepsy, and were taking one or more AED. Diagnosis was based upon full clinical
Group results
The proportion of grey matter in the studied voxels was similar in both groups (Table 2). Inter-group comparison for the individual metabolites identified significant variation for NAAt, Cho and GLX. Cho (p < 0.001), GLX (p < 0.05) and GLX/NAAt (p < 0.001) were all elevated in MCD. NAAt (p < 0.05) and NAAt/Cr (p = 0.01) were reduced in the patient group (Figure 3).
Following removal of patients taking VPA from the Ins analysis and patients taking TPM or GBP from the GABA+ analysis no significant variation
Discussion
This is the first MRS study to measure GABA+ concentrations in MCD. We observed a modest elevation in GABA+/Cr together with more marked elevation in GLX, Cho and GLX/NAAt in large MCD. Low NAAt was observed but may be a feature of PMG rather than HT. The results indicate highly abnormal metabolism in these lesions.
Quantification of GABA+ remains technically difficult and the low sensitivity of the DQF method requires relatively large volumes of interest to be studied. This necessitated
Acknowledgements
RJS was supported by a Brain Neurology Scholarship and The National Society for Epilepsy. JSD is supported by The National Society for Epilepsy. MAM was supported by the Medical Research Council. GJB was supported by the Multiple Sclerosis Society for Great Britain and Northern Ireland.
We are grateful to Dr. B.E. Kendall and Dr. J.M. Stevens, Consultant Neuroradiologists for their review of MRI data. We are also grateful to Dr. L.L. Wald, Dr. S.R. Williams, and Dr. A. Busza for their
References (53)
- et al.
Proton magnetic resonance spectroscopy of brain biopsies from patients with intractable epilepsy
Epilepsy Res.
(1999) - et al.
In vivo short echo time 1H-magnetic resonance spectroscopic imaging (MRSI) of the temporal lobes
Neuroimage
(2001) - et al.
Symbiosis between in vivo and in vitro NMR spectroscopy: the creatine, N-acetylaspartate, glutamate, and GABA content of the epileptic human brain
Magn. Reson. Imaging
(1995) - et al.
Effects of valproate and other antiepileptic drugs on brain glutamate, glutamine, and GABA in patients with refractory complex partial seizures
Seizure
(1999) Wiring, dysmorphogenesis and epilepsy: a hypothesis
Seizure
(1995)N-acetylaspartate in the vertebrate brain: metabolism and function
Neurochem. Res.
(2003)Excitatory actions of gaba during development: the nature of the nurture
Nat. Rev. Neurosci.
(2002)- et al.
The multiple facets of gamma-aminobutyric acid dysfunction in epilepsy
Curr. Opin. Neurol.
(2005) - et al.
Increased excitability and decreased sensitivity to GABA in an animal model of dysplastic cortex
Epilepsia
(2002) - et al.
Heterotopic neurons with altered inhibitory synaptic function in an animal model of malformation-associated epilepsy
J. Neurosci.
(2002)
Proton magnetic resonance spectroscopic imaging and magnetic resonance imaging volumetry in the lateralization of temporal lobe epilepsy: a series of 100 patients
Ann. Neurol.
Brain GABA editing without macromolecule contamination
Magn. Reson. Med.
Homocarnosine elevations: a cause or a sign of seizure control?
Neurology
Focal epileptogenesis in a rat model of polymicrogyria
J. Neurophysiol.
In vivo detection of GABA in human brain using a localized double-quantum filter technique
Magn. Reson. Med.
Maturation of the human fetal brain as observed by 1H MR spectroscopy
Magn. Reson. Med.
Seizure onset from periventricular nodular heterotopias: depth-electrode study
Neurology
Brain metabolite composition during early human brain development as measured by quantitative in vivo 1H magnetic resonance spectroscopy
Magn. Reson. Med.
Glutamatergic modulation of GABAergic signaling among hippocampal interneurons: novel mechanisms regulating hippocampal excitability
Epilepsia
Proton spectroscopic imaging at 4.1 tesla in patients with malformations of cortical development and epilepsy
Neurology
Modulation of cerebral GABA by topiramate, lamotrigine, and gabapentin in healthy adults
Neurology
Neuronal metabolic dysfunction in patients with cortical developmental malformations: a proton magnetic resonance spectroscopic imaging study
Neurology
Nuclear magnetic resonance study of cerebrospinal fluid from patients with multiple sclerosis
Can. J. Neurol. Sci.
Proton magnetic resonance spectroscopy of a gray matter heterotopia
Neurology
Seizure-like discharges recorded in human dysplastic neocortex maintained in vitro
Neurology
In vivo GABA+ measurement at 1.5 T using a PRESS-localized double quantum filter
Magn. Reson. Med.
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