Glutamate imaging for epileptic foci determination

Researchers have piloted a new method using advanced non-invasive neuroimaging to recognise the neurotransmitter glutamate, thought to be the culprit in the most common form of medication-resistant epilepsy.

The findings are published today in Science Translational Medicine.

“Identification of the brain region generating seizures in location-related epilepsy is associated with significantly increased chance of seizure freedom after surgery,” said lead author Kathryn Davis, MD, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania. “The aim of the study was to investigate whether a novel imaging method, developed at Penn, could use glutamate to localise and identify the epileptic lesions and map epileptic networks in these most challenging patients.”

“We theorised that if we could develop a technique which allows us to track the path of and make non-invasive measurements of glutamate in the brain, we would be able to better identify the brain lesions and epileptic foci that current methods miss,” said senior author Ravinder Reddy, PhD, University of Pennsylvania Perelman School of Medicine.

Dr. Reddy’s lab developed the glutamate chemical exchange saturation transfer (GluCEST) imaging method -- a very high resolution magnetic resonance imaging contrast method -- to measure how much glutamate was in different regions of the brain including the hippocampi.

The study tested 4 patients with medication-resistant epilepsy and 11 controls. In all 4 patients, concentrations of glutamate were found to be higher in one of the hippocampi, and confirmatory methods (electroencephalography and magnetic resonance spectra) verified independently that the hippocampus with the elevated glutamate was located in the same hemisphere as the epileptic focus/lesion. Consistent lateralisation to one side was not seen in the control group.

While preliminary, this work indicates the ability of GluCEST to detect asymmetrical hippocampal glutamate levels in patients thought to have non-lesional temporal lobe epilepsy. The authors said this approach could reduce the need for invasive intracranial monitoring, which is often associated with complications, morbidity risk, and added expense.

“This demonstration that GluCEST can localise small brain hot spots of high glutamate levels is a promising first step in our research,” said Dr. Davis. “By finding the epileptic foci in more patients, this approach could guide clinicians toward the best therapy for these patients, which could translate to a higher rate of successful surgeries and improved outcomes from surgery or other therapies in this difficult disease."

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Kathryn Adamiak Davis,Ravi Prakash, Reddy Nanga,Sandhitsu Das,Stephanie H. Chen,Peter N. Hadar, John R. Pollard, Timothy H. Lucas, Russell T. Shinohara, Brian Litt, Hari Hariharan, Mark A. Elliott, John A. Detre, Ravinder Reddy. Glutamate imaging (GluCEST) lateralizes epileptic foci in nonlesional temporal lobe epilepsy.  Science Translational Medicine  14 Oct 2015:  Vol. 7, Issue 309, pp. 309ra161

Toward visualizing the focus

Many seizures, especially those that originate in the brain’s temporal lobe, start at a single spot in the brain. If drugs fail, excision of this region can often provide relief from seizures. A new imaging method that harnesses the power of a 7-T magnet shows promise in locating hard-to-find epileptic foci by visualizing the neurotransmitter glutamate.

In a pilot study, the authors used glutamate chemical exchange saturation transfer (GluCEST), a very high resolution magnetic resonance imaging contrast method, to measure how much glutamate was in the hippocampi of four patients with epilepsy. Glutamate is elevated in epileptic foci. The amount of glutamate was clearly higher in one of the hippocampi in all four patients, and confirmatory methods (electroencephalography or magnetic resonance spectra) verified independently that the hippocampus with the elevated glutamate was located in the same hemisphere as the epileptic focus.

Although the authors have only taken a first step toward noninvasively finding epileptic foci, their demonstration that GluCEST can localize small brain hot spots of high glutamate is promising. This approach can potentially allow a higher rate of successful surgeries in this difficult disease.

Abstract

When neuroimaging reveals a brain lesion, drug-resistant epilepsy patients show better outcomes after resective surgery than do the one-third of drug-resistant epilepsy patients who have normal brain magnetic resonance imaging (MRI). We applied a glutamate imaging method, GluCEST (glutamate chemical exchange saturation transfer), to patients with nonlesional temporal lobe epilepsy based on conventional MRI. GluCEST correctly lateralized the temporal lobe seizure focus on visual and quantitative analyses in all patients. MR spectra, available for a subset of patients and controls, corroborated the GluCEST findings. Hippocampal volumes were not significantly different between hemispheres. GluCEST allowed high-resolution functional imaging of brain glutamate and has potential to identify the epileptic focus in patients previously deemed nonlesional. This method may lead to improved clinical outcomes for temporal lobe epilepsy as well as other localization-related epilepsies.