At Last, Medical Evidence for a 'Psychological Disease'

Jose Montoya, MD

Every now and then the publication of a scientific study makes a patient community go wild with enthusiasm. For patients with chronic fatigue syndrome, a recent study led by Jose Montoya, MD, professor of infectious diseases, was their eureka moment.

More than 1 million people in the United States suffer from chronic fatigue syndrome, also known as myalgic encephalomyelitis, or ME/CFS.

Many patients with ME/CFS experience flulike symptoms common in inflammation-driven diseases. But because the symptoms of this disease are so diffuse and heterogeneous—sometimes manifesting as heart problems, sometimes as mental impairment nicknamed “brain fog,” other times as indigestion, diarrhea, constipation, muscle pain, tender lymph nodes, and so forth—it often goes undiagnosed, even among patients who’ve visited a half-dozen or more different specialists to determine what’s wrong with them.

Montoya believes that in around 80 percent of the ME/CFS patients he treats, the condition developed as a result of infection. But because few of them get to see a specialist until they have been ill for many years or even decades, the bacteria or viruses responsible have long gone into hiding inside the body’s cells, meaning that many standard blood tests show nothing wrong.

“This is one major reason why so many doctors have dismissed this as psychological in the past,” he says.

Supporting Evidence

Previously, there has been little or no correlation between science and patient complaints, but the findings from Montoya’s study provide evidence that inflammation is a powerful driver of this mysterious condition, whose underpinnings have eluded researchers for 35 years.

The research found that people with ME/CFS had abnormal levels of 17 cytokines, substances from the immune system, in their blood. The higher the levels of certain pro-inflammatory cytokines, the more severe the symptoms of chronic fatigue syndrome, which led Montoya and his colleagues to suggest a link between excess inflammation and the disease.

Another significant finding concerned one cytokine that has been implicated in development and promotion of lymphoma. ME/CFS patients have a higher predisposition to develop lymphoma, and that finding may lead to the biological link between ME/CFS and lymphoma.

Previous efforts to identify immunological abnormalities behind the disease have met with conflicting and confusing results, says Montoya, who oversees the Stanford ME/CFS Initiative.

That’s what spurred him to undertake a systematic study to see if the inflammation that’s been a will-o’-the-wisp in those previous searches could be definitively pinned down. The study’s findings, published August 22, 2017, in the Proceedings of the National Academy of Sciences, could lead to further understanding of this condition and be used to improve the diagnosis and treatment of the disorder.

ME/CFS is a disease with no known cure or even reliably effective treatments. It characteristically arises in two major waves: among adolescents between 15 and 20, and in adults between 30 and 35. The condition typically persists for decades.

Three of every four ME/CFS patients are women, for reasons that are not understood. However, Montoya’s study found that leptin, one of the 17 cytokines correlating with severity and produced at higher levels in women, may explain why ME/CFS is more common in females.

'The Suffering of These Patients'

What got Montoya interested in ME/CFS was “purely the suffering of these patients,” he says.

He recalls seeing a young, 35-year-old female patient in 2004 who had been experiencing debilitating symptoms for eight years without a compelling explanation from any medical expert.

“Her circumstances convinced me that there was no reason for her to fake her symptoms, and because one of the major reasons I became a doctor was to empathize with patients and ease their suffering, I just couldn’t walk away from a case like that, even though that’s what many of my colleagues were doing.

“I couldn’t believe that the causes for their symptoms were psychological; there had to be some biological reason why these patients were so sick,” he adds.

Montoya observes that physicians, lacking proper tools or knowledge at the time, have discounted other diseases that we now understand. During the 19th century people were dying by the thousands in London, and the cause was thought to be bad air or even a punishment from God. Only after the invention of the microscope and the foundation of certain principles of epidemiology did scientists realize the cause was a bacterium we now know as cholera.

For decades patients with ME/CFS were describing symptoms that suggest inflammation, but doctors tended to ignore that.

The medical community has blood tests, imaging studies, and many other methods to determine why somebody is sick. In the case of ME/CFS they were unable to come up with any technique that was applicable.

“Because CFS is complex, falls between specialties, and doesn’t fit into a diagnosis, doctors thought it must be something that the patient was inventing. They didn’t want to think we weren’t smart enough to understand it or that we weren’t applying the right technology,” Montoya explains.

A Group Effort

He began working with experts in several other disciplines, notably Mark Davis, PhD, professor of immunology and microbiology and director of Stanford’s Institute for Immunity, Transplantation and Infection.

Finally, these patients have a BIOLOGICAL reason for their suffering.

“This was a group effort, and the major piece was that the correlation between 17 cytokines and severity of symptoms was something that was not appreciated before. The importance of that is that this disease has been viewed as a psychological disease, something that lived in the patient’s imagination, and through that they have been humiliated and ostracized,” Montoya explains.

“Now, for the first time, the findings from this study fit very well with what patients have been telling us all along. Finally, these patients have a biological reason for their suffering, and the beauty is that it correlates nicely. The more severe their symptoms, the higher the cytokines are,” says Montoya.

For patients, this research is validation. They can now say: “My symptoms correlate with biological measures in my blood, so I’m not crazy!”

The Future

Another benefit of the study is the patient cohort. The research community now has blood that was collected from this patient population that can be used for other studies.

Having “hit the jackpot” with the results from this patient population, Montoya explains that they now can view this population from many different angles.

This initial study focused on the immune system. In the same patients, scientists can study their genes, for example, with the expectation of making equally astounding findings.

“What we’ve done is put together a group of about 30 people at Stanford. These are faculty and staff of various disciplines who are looking at these data and this patient cohort. So, we will have, within a year, results of other assays, where we apply other technologies to this same patient population where we found this initial amazing correlation,” says Montoya.