Proton magnetic resonance spectroscopy of malformations of cortical development causing epilepsy

https://doi.org/10.1016/j.eplepsyres.2007.02.002Get rights and content

Summary

Purpose

To use proton magnetic resonance spectroscopy (MRS) to measure concentrations of gamma-aminobutyric acid (GABA) and glutamate plus glutamine (GLX) in adult patients with refractory epilepsy associated with malformations of cortical development (MCD).

Methods

We used MRS to measure N-acetyl aspartate (NAA), creatine plus phosphocreatine (Cr) and choline containing compounds (Cho), as well as GLX, and GABA. Fifteen patients with epilepsy attributable to MCD and 15 healthy controls were studied. Nine of the MCD group had heterotopia and six had polymicrogyria. Quantitative short echo time MRS [echo time (TE) = 30 ms, repetition time (TR) = 3000 ms] was performed in the MRI evident MCD and in the occipital lobes of the control group and the concentrations of NAA, Cr, Cho, and GLX were measured. GABA plus homocarnosine (GABA+) was measured in the same regions using a double quantum filter.

Results

The dominant abnormalities in the patient group were elevation of Cho and GLX and reduction in NAAt compared to the control group. The ratios GLX/NAAt and GABA+/Cr were also increased in the patient group whilst the ratio NAAt/Cr was decreased. NAAt was significantly lower in polymicrogyria than heterotopia.

Conclusions

Large cortical malformations had abnormal levels of both GLX and GABA+/Cr. Low NAAt and high Cho were also observed. These results indicate that MCD show spectroscopic features of primitive tissue and abnormal metabolism of both inhibitory and excitatory neurotransmitters.

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)

  • F. Cendes et al.

    Proton magnetic resonance spectroscopic imaging and magnetic resonance imaging volumetry in the lateralization of temporal lobe epilepsy: a series of 100 patients

    Ann. Neurol.

    (1997)
  • P.G. Henry et al.

    Brain GABA editing without macromolecule contamination

    Magn. Reson. Med.

    (2001)
  • T.R. Henry et al.

    Homocarnosine elevations: a cause or a sign of seizure control?

    Neurology

    (2001)
  • K.M. Jacobs et al.

    Focal epileptogenesis in a rat model of polymicrogyria

    J. Neurophysiol.

    (1999)
  • J.R. Keltner et al.

    In vivo detection of GABA in human brain using a localized double-quantum filter technique

    Magn. Reson. Med.

    (1997)
  • R.D. Kok et al.

    Maturation of the human fetal brain as observed by 1H MR spectroscopy

    Magn. Reson. Med.

    (2002)
  • S.V. Kothare et al.

    Seizure onset from periventricular nodular heterotopias: depth-electrode study

    Neurology

    (1998)
  • R. Kreis et al.

    Brain metabolite composition during early human brain development as measured by quantitative in vivo 1H magnetic resonance spectroscopy

    Magn. Reson. Med.

    (2002)
  • D.M. Kullmann et al.

    Glutamatergic modulation of GABAergic signaling among hippocampal interneurons: novel mechanisms regulating hippocampal excitability

    Epilepsia

    (2002)
  • R. Kuzniecky et al.

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

    Neurology

    (1997)
  • R. Kuzniecky et al.

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

    Neurology

    (2002)
  • L.M. Li et al.

    Neuronal metabolic dysfunction in patients with cortical developmental malformations: a proton magnetic resonance spectroscopic imaging study

    Neurology

    (1998)
  • J. Lynch et al.

    Nuclear magnetic resonance study of cerebrospinal fluid from patients with multiple sclerosis

    Can. J. Neurol. Sci.

    (1993)
  • L. Marsh et al.

    Proton magnetic resonance spectroscopy of a gray matter heterotopia

    Neurology

    (1996)
  • D. Mattia et al.

    Seizure-like discharges recorded in human dysplastic neocortex maintained in vitro

    Neurology

    (1995)
  • M.A. McLean et al.

    In vivo GABA+ measurement at 1.5 T using a PRESS-localized double quantum filter

    Magn. Reson. Med.

    (2002)
  • Cited by (0)

    1

    Tel.: +44 1494 601 360; fax: +44 1494 874 666.

    View full text