In February 2015, the US Institute of Medicine decided to re-name chronic fatigue syndrome (CFS) – also known as myalgic encephalomyelitis (ME) – as Systemic Exertion Intolerance Disease. Unsurprisingly, the new name does not appear to have caught on yet. Yet however it’s described, the causes of this debilitating syndrome remain a mystery that’s been argued over and researched for years.
Estimates of how many people suffer from CFS are also hazy, as there is no diagnostic test. In the US alone, figures range from 1m to 4m. While all CFS patients share a common unremitting fatigue that persists for six months or longer, additional symptoms can vary from patient to patient, and often overlap with those of other conditions.
‘CFS is one of the greatest scientific and medical challenges of our time,’ says Jose Montoya, professor of infectious diseases and geographic medicine at Stanford University School of Medicine, US. ‘Its symptoms often include not only overwhelming fatigue but also joint and muscle pain, incapacitating headaches, food intolerance, sore throat, enlargement of the lymph nodes, gastrointestinal problems, abnormal blood-pressure and heart-rate events, and hypersensitivity to light, noise or other sensations.’ The combination of symptoms can devastate a patient’s life for 10, 20 or even 30 years.
The fact that CFS patients experience different symptoms and multiple types of viral and bacterial infections has led researchers to believe CFS may have numerous causes. That lack of uniformity also complicates the diagnostic process and development of treatments.
One hypothesis is that a viral infection, which sometimes seems to trigger CFS, then goes on to produce an overactive immune response. This abnormal response causes ongoing symptoms, and could contribute to the brain inflammation found in other research.
Infectious hit and run
The past few months have seen renewed interest in the role of the immune system in CFS. Researchers at Columbia University’s Mailman School of Public Health in the US reported in February 2015 that they have found ‘what has eluded us for so long: unequivocal evidence of immunological dysfunction in CFS’. This, they say, is the ‘first robust evidence’ that CFS is a biological illness rather than a psychological disorder.
The team reported distinct changes in immune molecules in the blood of CFS patients at different stages of the disease. Then at the end of March 2015, they backed this up with evidence showing changes in immune markers called cytokines in the cerebrospinal fluid.
‘We now know that the same changes to the immune system that we recently reported in the blood of people with CFS with long-standing disease are also present in the central nervous system,’ comments Mady Hornig, director of translational research at Columbia’s Mailman School. ‘These immune findings may contribute to symptoms in both the peripheral parts of the body and the brain, from muscle weakness to brain fog.’
In the first study, the researchers determined the levels of 51 immune biomarkers in blood plasma samples from 298 CFS patients and 348 healthy controls (M. Hornig et al, Science Advances, doi: 10.1126/sciadv.1400121).
After controlling for other factors, they found specific patterns in patients who had CFS for three years or less that were not present in controls, or in patients who had the disease for more than three years. Patients who had been diagnosed with CFS for a short time had increased amounts of many cytokines. The association was unusually strong with a cytokine called interferon gamma that has been linked to the fatigue that follows many viral infections, including Epstein-Barr virus, the cause of glandular fever.
In the later study, Horning and colleagues used immunoassay testing methods to measure the levels of the same 51 immune biomarkers in the cerebrospinal fluid of 32 people with CFS, 40 patients with multiple sclerosis and 19 healthy controls, for an average of seven years (M. Hornig et al, Molecular Psychiatry, doi: 10.1038/mp.2015.29).
The researchers found that levels of most cytokines, including the inflammatory immune molecule interleukin 1, were depressed in CFS individuals, compared with the other two groups of patients (MS and healthy). This matched findings from the blood study. One cytokine – eotaxin – was elevated in the CFS and MS groups, but not in the control group.
Hornig says the studies support the idea that CFS may reflect an infectious ‘hit-and-run’ event. Patients often report getting ill, sometimes from something as common as glandular fever, and never fully recover. The new research suggests that these infections throw a wrench in the immune system; like a car stuck in high gear, the immune system’s response to the acute infection stays ramped up – until the three-year mark.
‘It appears that CFS patients are flush with cytokines until around the three-year mark, at which point the immune system shows evidence of exhaustion and cytokine levels drop,’ says Hornig. ‘Early diagnosis may provide unique opportunities for treatment that likely differ from those that would be appropriate in later phases of the illness.’
Ian Lipkin, director of the Center for Infection and Immunity, and co-author, believes their findings offer the hope of objective diagnostic tests as well as the potential for therapies that correct the imbalance in cytokine levels seen in people with CFS at different stages of their disease. There is precedent for using human monoclonal antibodies that regulate the immune response in a wide range of disorders from rheumatoid arthritis to multiple sclerosis, he says, but notes that additional work is needed to assess the safety and efficacy of this approach.
Charles Shepherd, medical advisor to the ME Association, welcomed the findings of the US team. ‘If distinctive patterns of cytokine abnormality can be linked to both stage and severity of the disease, this is a finding that could be used to aid diagnosis and open the door to the use of anti-inflammatory drug treatments that would dampen down the abnormal immune system response.’
The fact that CFS patients experience different symptoms and multiple types of viral and bacterial infections has led researchers to believe CFS could have numerous causes. That lack of uniformity also complicates the diagnostic process and development of treatments.
‘Part of the problem in trying to identify an agent or biomarkers for CFS is the extreme variability among people who say they have CFS. How to sort that out has held the field back a lot of years,’ says Ron Glaser, a virologist and director of the Institute for Behavioral Medicine Research at Ohio State University, US.
Glaser has studied the Epstein-Barr virus (EBV) for decades and believes there is a link between CFS and EBV (pictured, right), a human herpes virus that causes glandular fever. About 95% of Americans have been infected with the virus by adulthood, according to the Centers for Disease Control and Prevention (CDC), but fewer than half have experienced an active illness. Once a person is infected, the virus remains dormant in the body, and can be reactivated without causing symptoms of illness.
Back in 2012, following a pilot study of six CFS patients, Glaser and his colleagues suggested that a partly reactivated EBV can generate at least two viral proteins: DNA polymerase and dUTPase. CFS patients produced antibodies specifically designed to identify and neutralise one or both proteins for more than a year; 20 healthy people had no such antibodies (R. Glaser et al, PLoS ONE, 2012, 7(11): e47891). The scientists believe that, even in the absence of a complete active infection, these viral proteins are enough to induce inflammatory chemical signals that throw the immune system into a chaos that leads to CFS. The study was unprecedented because it had access to 16 months of blood samples for each patient.
The team has since run a larger, follow-up study and hopes to present its results at the annual meeting of the American Society of Virology in July 2015 in London, Ontario, Canada. Co-author Martin Lerner, an infectious diseases specialist, who runs a private CFS practice in Michigan, US, says he is can’t divulge the results, but is confident that the work will lead to identifying a biomarker and a diagnostic test for CFS.
Other researchers are investigating the possibility of using brain imaging as a diagnostic tool. Some studies, for example, have shown distinct differences between the brains of CFS patients and those of healthy people.
A recent paper by a Stanford University School of Medicine team reported that CFS patients’ brains differ in at least three distinct ways, suggesting that the disease has hijacked the central nervous system. They compared brain images of 15 CFS patients with those of 14 healthy volunteers matched for age and sex.
First, an MRI scan showed that overall ‘white matter’ content of CFS patients’ brains was reduced. White matter mainly describes the long, cable-like nerve tracts carrying signals among broadly dispersed concentrations of ‘grey matter’, which is involved in processing information. Lead author Michael Zeineh says this wasn’t entirely unexpected, as CFS is thought to involve chronic inflammation, quite possibly as a protracted immunological response to an as-yet unspecified viral infection, and inflammation affects white matter.
But a second finding was surprising. Using a technique called diffusion-tensor imaging, Zeineh identified a consistent abnormality in a particular part of a nerve tract in the right hemisphere of CFS patients’ brains. This tract, which connects the so-called frontal and temporal lobes of the brain, is called the right arcuate fasciculus, and in CFS patients looked abnormal. Furthermore, there was a fairly strong correlation between the degree of abnormality in this tract and the severity of the patient’s condition.
Finally, the team observed a thickening of the grey matter at the two areas of the brain connected by the right arcuate fasciculus in CFS patients, compared with controls. ‘This study was a start. It shows us where to look,’ Zeineh says. They are now planning a substantially larger study.
Other studies have also indicated differences in the brain. For example, researchers have shown decreased activation in the basal ganglia, which regulates motor activity and motivation, in the brains of CFS patients.
A team from Emory University School of Medicine, US, for example, used a brain scan technique that measures activity in various parts of the brain by blood flow, and compared 18 CFS patients with 41 controls, while they played a simple card game meant to stimulate feelings of reward (A. Miller et al, PLoS One, doi: 10.1371/journal.pone.0098156).
The researchers showed that CFS patients experienced significantly less change in basal ganglia blood flow between winning and losing than the healthy volunteers. They also found that the extent of a patient’s fatigue was tightly tied with the change in brain activity between winning and losing. Those with the most fatigue had the smallest change.
‘A number of previous studies have suggested that responses to viruses may underlie some cases of CFS,’ lead author Andrew Miller, professor of psychiatry and behavioral sciences at Emory. ‘Our data support the idea that the body’s immune response to viruses could be associated with fatigue by affecting the brain through inflammation.’ The study also suggests that, since the basal ganglia use the chemical dopamine as their major neurotransmitter, dopamine metabolism may play an important role in understanding and changing the course of this illness.
Maria Burke is a freelance science writer based in St Albans, Hertfordshire, UK