New Tool Detects Epileptic Foci

Pauline Anderson

November 24, 2015

Researchers are using a powerful imaging tool to locate hard-to-find epileptic foci. Glutamate chemical exchange saturation transfer (GluCEST) is a high-resolution MRI technique that measures how much glutamate is in the hippocampus.

Glutamate is the most common excitatory neurotransmitter in the central nervous system. Studies show that it is increased ictally (during seizures), interictally (between seizures), and post-mortem in the epileptic focus.

"In epilepsy, the central underlying hypothesis is that when someone has a seizure, there is some mismatch between how much inhibition of glutamate there is and how much excitation there is," explained Kathryn Adamiak Davis, MD, assistant professor, neurology, University of Pennsylvania, Philadelphia.

Dr Kathryn Adamiak Davis

Dr Davis was first author of a new study suggesting that this new tool is more sensitive than currently available imaging methods to detect the area in the hippocampus that contains the epileptic network.

The study, published October 14 in Science Translational Medicine, was very small, including only four patients with epilepsy, but had "such striking results" that the researchers decided it was "important to get it out there," said Dr Davis.

They also decided to publish the results because they're now enrolling patients in a larger study using a more sophisticated multislice MRI technique rather than the single-slice approach used in the current study. Study coauthors Ravinder Reddy and Hari Hariharan, both at the Center for Magnetic Resonance & Optical Imaging, Department of Radiology, University of Pennsylvania, hold the patent on CEST MRI methods for imaging metabolites and the use of these as biomarkers.

Temporal Lobe Epilepsy

Being better able to detect seizure foci could significantly improve patient care and quality of life for people with epilepsy, the authors say.

Localization-related epilepsy (LRE), also called partial-onset epilepsy, is the most common type of epilepsy, occurring in 80% of drug-resistant patients. In adults, temporal lobe epilepsy (TLE) accounts for 65% of LRE. Mesial temporal sclerosis can be identified on structural MRI in about two thirds of patients with TLE and is associated with the most favorable outcomes from resective epilepsy surgery.

Patients with drug-resistant epilepsy now typically undergo multimodel structural and functional imaging for surgical planning. In addition to MRI, this may include 18-fluoro-deoxyglucose positron emission computed tomography and magnetoencephalography. These methods, however, don't adequately localize the seizure focus in a large percentage of patients.

About a third of patients with TLE show no lesion by conventional MRI. But in those who undergo resective surgery, histopathology is abnormal in 87%, suggesting that lesions are present but current imaging technology lacks the sensitivity to detect them.

The new study included one male and three female adult patients with what was determined to be nonlesional TLE (mean age, 40 years) and 11 adult healthy controls (three men and eight women; mean age, 35 years).

Half of the patients with epilepsy had seizures from the left hippocampus and the other half from the right hippocampus. All were resistant to multiple antiepileptic medications, having tried and not responded to between two and seven of these medications.

Imaging with GluCEST was done for each participant at one time point. With this CEST technique, researchers can measure the difference in hydrogen concentrations in water as an indirect measure of glutamate.

"You see how much hydrogen is exchanged and that's an indirect measure of the glutamate concentration," said Dr Davis.

Axial sections from a patient with temporal lobe epilepsy, showing GluCEST signal. Courtesy of University of Pennsylvania

CEST imaging was done with MRI scanners at a magnetic field strength of 7 T. GluCEST has at least two orders of magnitude higher sensitivity than traditional MRI methods of measuring glutamate, according to the authors. It also images glutamate in vivo at a much higher spatial resolution than can be achieved with magnetic resonance spectroscopy (MRS) or spectroscopic imaging.

In this study, the researchers had access to just one slice cut through the hippocampus, although they're now launching a study using a technique that allows them to get 60 slices. "So we can get images of glutamate concentration throughout most of the brain," said Dr Davis.

Results showed that in the four patients with epilepsy, concentrations of glutamate measured by GluCEST were higher in the epileptogenic (ipsilateral) hippocampus than in the contralateral hippocampus, both qualitatively and quantitatively, so researchers were able to get an actual number to create an area of interest, Dr Davis said.

"The scans were presented to blinded epilepsy specialists and they also were able to identify the area of increased glutamate in all the patients," she said.

In the study patients, the GluCEST signal in the ipsilateral (to seizure onset) head was significantly different from that of the contralateral head (one-tail, P = .03). Similar comparisons of the hippocampal tail, whole hemisphere, and hemisphere not including the occipital lobe (consisting largely of temporal lobe and mesial temporal structures) showed no significant differences.

One of the patients with epilepsy subsequently underwent intracranial electroencephalographic evaluation and right temporal lobectomy. In this patient, the pathology of the removed region was consistent with mesial temporal sclerosis.

This, said the authors, lends "further confidence in the GluCEST technique." Surgery is being planned for the other three cases.

The promising new approach has several advantages over MRS, the only other imaging test that noninvasively measures brain glutamate in humans. In addition to having higher resolution, it is less time-intensive and less subject to movement artefacts. GluCEST also has higher spatial resolution than positron emission tomography, which has been used to measure glutamate receptors only in healthy controls.

This new imaging tool could reduce the need for invasive intracranial monitoring, which is associated with morbidity, mortality, and expense. "Right now, in patients pursuing surgery in whom we think the seizures are coming from the hippocampus but it's unclear what side, and they don't have a lesion on MRI, we will often insert intracranial electrodes under the skull and do a very invasive evaluation," said Dr Davis.

As well, the test may yield prognostic information that can help determine the best form of treatment. "Our current MRI methods are missing very subtle lesions," said Dr Davis. "The hope is that adding this technique that's looking at the underlying function of the excitatory network in the brain will help guide us to the right therapy, and perhaps spare people from very invasive procedures."

Epilepsy affects about 65 million people worldwide. About a third of patients with epilepsy have seizures that are not controlled by medications.

Most current antiepileptic drugs work by increasing inhibition or decreasing excitation of glutamate, said Dr Davis. "It is thought that all of our treatments are working on this inhibitory–excitatory balance that is tripped the wrong way in epilepsy."

As well as doing a larger study using a multislice protocol, Dr Davis and her colleagues are expanding their investigation to all types of drug-resistant epilepsy. They're also doing work on animal models using an even stronger MRI (9.4 T).

High Level of Glutamate

Reached for comment, Richard Conroy, PhD, director, Division of Applied Sciences & Technology, National Institute of Biomedical Imaging and Bioengineering (NIBIB), which funded the study, said that even though the study was small, it had two important strengths.

One is that it demonstrated, for the first time, "what has been suspected — that there are high level of glutamate in regions where the focus of epileptic seizure occurs," he told Medscape Medical News.

The second important element of the study is that it uses a much higher-strength scanner and imaging approach that removed some of the "background features" that accompany MRS, said Dr Conroy. MRS, he added, typically images only one region of the brain, which may be "challenging."

Dr Conroy acknowledged that supportive evidence was available on only one patient. "Part of their argument is that they're showing abnormal levels of glutamate that correspond to abnormal pathology in that region," he said. "But it's only one patient, so it's hard to build a strong case."

He said another challenge is accessing 7-T scanners, which are available only at academic centers; Dr Davis said she estimates there are 20 to 25 such scanners across the country.

Dr Conroy also commented that different kinds of epilepsy fall into this category of not being focal and being drug-resistant. "So the question is, once they start looking at larger populations, will it turn out that they can only see this in a subset of that subset?" he said.

Another question, he said, is whether MRIs with lower magnetic field strengths — for example, 1.5 T or 3 T — which are much more widely available, can also detect a measurable difference in glutamate.

"Once you know what you're looking for, it might become easier to demonstrate this on more common MRI systems."

The study was funded by the National Institutes of Health's National Institute of Neurological Disorders and Stroke, McCabe Pilot Award (University of Pennsylvania), and Center for Biomedical Image Computing and Analytics Seed Award (University of Pennsylvania). Coauthors Ravinder Reddy and Hari Hariharan hold the patent (US 20120019245 A1) on CEST MRI methods for imaging metabolites and the use of these as biomarkers.

Sci Transl Med. 2015;7:309RA161. Abstract

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