Gulf War Syndrome may lead to new brain MR spectroscopy

Could extend to similar tests for “diseases of ill repute”

MRI scans of Gulf War veterans show evidence of brain-cell loss, which could substantiate the claims of military personnel who say they have Gulf War Syndrome--actually at least three syndromes typified by combinations of joint pain, fatigue, dizziness, and mental confusion.

Documentation of a brain deficit accompanying Gulf War Syndrome has spurred GE Medical Systems to begin developing MRI software that quantifies this deficit. Early development of a test for the malady has been focused at 1.5 tesla, but a key collaborator on the project, Dr. James L. Fleckenstein, believes the greatest benefit might be derived from very high field studies.

“The standard deviation (with 3 tesla) may be smaller. This would make the measurements more reliable,” said Fleckenstein, a professor of radiology at the University of Texas Southwestern Medical Center in Dallas. “You wouldn’t need as big a difference (from control values) to declare results abnormal.”

Fleckenstein and his colleagues at UT were the first to document a quantifiable brain deficit associated with Gulf War Syndrome. Preliminary results were first released at last year’s annual RSNA meeting. They created a sensation in the lay press this spring when the data were published in the June 2000 issue of the peer-reviewed journal, Radiology.

In the wake of this news, many people who believed they had symptoms of Gulf War Syndrome turned to MR services for answers, according to Fleckenstein. Unfortunately, technological limitations and a lack of expertise with MR spectroscopy all but guarantee inexact results, he said.

“We may be looking at a very small difference—10% to 15%—in one metabolite,” he said. “Almost all general radiology practices are incapable of detecting or knowing whether that’s a biological difference or a machine difference.”

For this reason, Fleckenstein encouraged the industry to develop a spectroscopic tool that could be used by the mainstream MRI practitioner, yet deliver the quantitative data needed to document the deficit associated with Gulf War Syndrome. He said GE has taken him up on the challenge.

The spectroscopic technique revolves around the ratio of two chemicals, N-acetylaspartate (NAA) to creatine, in the basal ganglia and brainstem. Finding less NAA in the deep brain structures of sick veterans implies that many brain cells have either been destroyed or become too damaged to function properly. A significantly low ratio of the two metabolites and, therefore, a lower functional mass of neurons, have been associated in Gulf War veterans with impaired cognition, confusion-ataxia, and central pain.

“That these brain abnormalities may be related to chemical exposure during the Gulf War was supported by strong epidemiologic associations between the three primary syndromes and risk factors for wartime exposures to combinations of low-level organophosphate chemical nerve agents, pesticides, pyridostigmine, and diethyltoluamide (DEET)-containing insect repellents,” the researchers wrote in Radiology.

The veterans manifesting symptoms had been exposed to pesticide-containing flea collars, anti-nerve-gas tablets, or certain insect repellents, according to the study.

When compared with 18 healthy veterans of the Gulf War, 22 veterans complaining of these symptoms showed significantly less functional neuron mass in the brain stem, right basal ganglia, and left basal ganglia. The magnitude of biochemical unbalance varied among veterans, which may explain why some veterans are sicker than others. Those with the greatest deficits, veterans exhibiting confusion and ataxia, demonstrated less NAA in the right basal ganglia and the brain stem compared with healthy veterans of the same age, sex, and education level.

Over the past several weeks, GE has provided Fleckenstein with software that quantifies the metabolites whose measurements may indicate the presence of Gulf War Syndrome. Although the spectral data must still be processed off-line, just being able to gather such data is a sign of substantial progress, he said. The technical roadblocks have been overcome. Usable data can be obtained quickly and without a physicist.

“What we need now is to be able to have a patient come out of the scanner with a piece of paper that says how his values compare to the normal population,” Fleckenstein said. “That requires at least a database that’s updatable and data that are automatically pushed from the spectroscopy analysis package to the database. If you can do that, you can give a metabolic study to patients and have their doctors give them an answer.”

Determining the critical mass of comparison data will depend on the precision of the spectroscopic measurement. The more exact the measurement, the less “normal” data are needed. Fleckenstein and his UT colleagues are exploring this issue with grants from the Department of Defense. A proposal now in review at the DOD would provide the money needed to install and use a 3-tesla system at Southwestern Medical Center.

The researchers are awaiting the arrival of this system to determine the variation in data between very high field and 1.5 tesla, the field strength at which the groundbreaking research was conducted. Preliminary results have been gathered on a GE 3-tesla system operating at the Mayo Clinic and a Siemens 3-tesla unit at the Mallinckrodt Institute. Other questions relate to optimizing such variables as the pulse sequence.

Success in developing a mainstream test for Gulf War Syndrome based on MR spectroscopy could lead to similar tests for other psychiatric disorders that have thus far eluded documentation. These diagnostic quandaries, which include chronic fatigue syndrome, are “diseases of ill repute,” Fleckenstein said.

“They are viewed skeptically by physicians, but if you ask the patients, they are very seriously concerned about their health,” he said. “Gulf War Syndrome is a classic example of that kind of patient-doctor interaction.”

Fleckenstein hopes that MR spectroscopy will provide quantitative results that can be used to discriminate between patients with organic brain disease and those who have symptoms of disease but no apparent organic basis. If this happens, the research will provide a much needed boost to MR spectroscopy, which has generated signs of increased interest from the imaging community but has so far failed to rally a strong following.