Neurometabolism in human epilepsy

Abstract

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.

Methods: We examine the evidence for neurometabolic dysfunction in epilepsy, integrating human studies of metabolic imaging, electrophysiology, microdialysis, as well as intracranial EEG and neuropathology.

Results: As an approach of noninvasive functional imaging, quantitative magnetic resonance spectroscopic imaging (MRSI) measured abnormalities of mitochondrial and energetic dysfunction (via 1H or 31P spectroscopy) are related to several pathophysiologic indices of epileptic dysfunction. With patients undergoing hippocampal resection, intraoperative 13C-glucose turnover studies show a profound decrease in neurotransmitter (glutamate-glutamine) cycling relative to oxidation in the sclerotic hippocampus. Increased extracellular glutamate (which has long been associated with increased seizure likelihood) is significantly linked with declining energetics as measured by 31P MR, as well as with increased EEG measures of Teager energy, further arguing for a direct role of glutamate with hyperexcitability.

Discussion: Given the important contribution that metabolic performance makes toward excitability in brain, it is not surprising that numerous aspects of mitochondrial and energetic state link significantly with electrophysiologic and microdialysis measures in human epilepsy. This may be of particular relevance with the self-propagating nature of mitochondrial injury, but may also help define the conditions for which interventions may be developed.

Figure 1

MRSI statistical map showing the bilateral but dominant left hippocampal abnormalities in NAA/Cr. The data are corrected for tissue content variability and are independent of cerebrospinal fluid (CSF) and parenchymal tissue volume. The color bar indicates level of statistical significance, starting at p < 0.05 (red). Epilepsia © ILAE

Figure 2

A limbic network of involved loci is seen in MTLE that heavily links the ipsilateral epileptogenic hippocampus with the ipsilateral anterior thalamus, and therein links with numerous other areas including contralateral limbic structures. For each pair of linked structures is shown its R value and significance. Epilepsia © ILAE

Figure 3

(A) 31P spectra from an epilepsy patient showing the ipsilateral depression of PCr/ATP in the epileptogenic hippocampus. The voxel size of the 31P measurement is ∼ 12 cc, for example, from a small sphere with a radius of ∼ 1.4 cm. (B) Preoperative PCr/ATP values determined from the ipsilateral mesial temporal lobe correlates significantly with electrophysiology from the resected tissue, that is, recovery of the membrane polarization after a sustained train of suprathreshold stimulation. Epilepsia © ILAE

Figure 4

Glutamate (A) and GABA (B) neurotransmission is directional involving multiple cellular compartments. Epilepsia © ILAE

Figure 5

(A) In vivo measures of extracellular glutamate increases with increasing teager energy, R = +0.75, p < 0.001. 95% confidence intervals and prediction bands are shown. (B) Ex vivo electrophysiology measures link hyperexcitability with in vivo extracellular glutamate concentrations. Epilepsia © ILAE

Figure 6

Relationship between preoperative PCr/ATP and microdialysis measurements of log extracellular Glutamate, R = − < 0.03. 95% confidence intervals and prediction bands are shown. Epilepsia © ILAE

Figure 7

(A) Electrophysiology of resected rat hippocampus with exposure to DON, an inhibitor of glutaminase. With progressive time of exposure, increasing hyperexcitability is seen. (B). Concentration of GABA and glutamate both fall with exposure to DON, with glutamate falling less rapidly than GABA. Data are from resected rat hippocampi. Epilepsia © ILAE