More than one million people in the U.S. suffer from a poorly understood, difficult-to-diagnose condition that can leave them debilitated by unshakable exhaustion, pain, depression and cognitive trouble. Researchers, however, are still unsure what causes chronic fatigue syndrome (CFS), how to treat it, how best to diagnose it and even what to call it.

A new study is now providing hope for better understanding—and potentially better diagnosing—the disease. It has revealed a striking pattern of brain inflammation in CFS patients. Meanwhile, diagnosis and definition of the disease could soon be getting a major overhaul as a new $1-million Institute of Medicine (IOM) study gets underway at the request of the U.S. Department of Health and Human Services (HHS). Is the exhausting search for answers about CFS finally coming to an end?

In your head

Chronic fatigue syndrome was first formally described in the late 1980s. Soon thereafter it was lumped in with another perplexing condition known as myalgic encephalomyelitis (ME), which had been classified as a disease of the nervous system in the 1960s. A precise definition and diagnosis of CFS—sometimes called CFS/ME—has largely eluded doctors and researchers, however. Its subjectively described symptoms seem untestable: everyone is exhausted from time to time; many people suffer from occasional aches and pains; and, sure, we all have foggy days as well as down ones.

A large obstacle is that, unlike cancers or high blood pressure, researchers have no particular biomarkers that would allow them to test for the condition. Doctors rely exclusively on patient reports of the severity and duration of the symptoms—usually requiring the symptoms to be present for at least six consecutive months—along with the presence of extreme post-physical or mental exertion, fatigue and unrefreshing sleep, to diagnose the condition. Remissions and relapses confound clinicians further.

A change might be on the distant horizon, however, thanks in part to a new study of the brains of patients living with CFS.

Doctors have long suspected brain inflammation as a potential cause, but no definite traces of it had been detected. New research, in the June issue of the Journal of Nuclear Medicine, shows for the first time distinct increases in inflammation in particular regions of CFS patients' brains.

Yasuyoshi Watanabe, director of the RIKEN Center for Life Science Technologies and professor of physiology at Osaka City University Graduate School of Medicine, and his colleagues studied positron emission tomography (PET) scans of the brains of 10 health controls and nine patients with CFS. "Many researchers and clinicians, including our group, thought of this before, but apparently no one tried it using PET," Watanabe says.

The research team found increases in inflammatory markers in regions including the amygdala, thalamus and midbrain in CFS patients who had more severe cognitive troubles. They found more of these markers in thalamus and cingulate cortex in individuals who reported worse pain. And they found higher traces of inflammation in the hippocampus in patients with severe depression.

More than a decade ago, Watanabe's group found tantalizing suggestions that certain neurotransmitters were not being synthesized as well in people with CFS. These patients also had lower levels of serotonin transporters in particular brain areas. Other research had found higher levels of inflammatory cell-signaling proteins called cytokines circulating in the blood. All of these results led Watanabe to look closer for inflammation.

These PET-scan correlations do not precisely explain the symptoms, Watanabe notes. And only a handful of patients were in the study. But the work opens a new trail researchers can follow. Watanabe and his team are now looking into the amount of neuroinflammation in patients with CFS as well as the levels of circulating cytokines, which could both lead to the development of tests for the condition. Having a biologically based test could help those who do have the disease as well as patients who might have a different condition that has similar symptoms, such as depression, fibromyalgia or late-stage Lyme disease, which would be managed differently and potentially be cured with antidepressants, pain relievers or antibiotics. "Most important," Watanabe says, is "how to treat [CFS] patients and how to prevent this disorder." Currently, clinicians can only try to treat the symptoms—not the disease—with medications or lifestyle recommendations. "We are now planning to study therapeutics, such as anti-inflammatory agents, including herbal medicine," which might treat the underlying pathology, Watanabe says.

By any other name

Watanabe's study, and other new and forthcoming findings, however, may not be included in the current IOM review of the disease. "It is possible that the committee could examine new research that comes out during the study," says Jennifer Walsh, a spokesperson for the IOM. But, she notes, it depends on the study.

The study committee members will largely be assessing major research efforts and definitions developed previously for the disorder. "There were a number of case definitions that had come up over the years," says Nancy Lee, director of the Office on Women's Health at HHS and the department's designated federal officer of the Chronic Fatigue Syndrome Advisory Committee. Bringing so much of the work together to come up with a unified definition would help researchers not only better understand the illness, as well as help to convey information to clinicians so they can make faster, more definitive diagnoses. As Lee points out, "most U.S. physicians do not have a good understanding of how to make the diagnosis of ME/CFS." The IOM will try to develop new evidence-based criteria for diagnosing CFS, decide whether the condition should be renamed and come up with a way to best get the new recommendations to health care providers. It will not, however, be making recommendations on treatment, for now. The report is due by spring 2015.

The group's conclusions could have far-reaching consequences for how patients are diagnosed and treated in the U.S. and worldwide. Another recent study in Australia, published April 30 in the journal of Health and Quality of Life Outcomes, showed a large discrepancy in severity of illness for 45 CFS patients and 30 healthy volunteers who met the U.S. Centers for Disease Control and Prevention criteria set in 1994 versus international standards revised in 2011. Better definitions could prevent some patients from being underdiagnosed.