KATIE HART HAS BEEN sick most of her life, but it took more than three decades for her to find out what was behind her debilitating fatigue, persistent headaches, muscle pain and dizziness. During her adolescence, medical tests didn’t point to any clear answers, and her symptoms were dismissed as hypochondria. It wasn’t until 15 years later, in 1988, that she was diagnosed, first with fibromyalgia and then with chronic fatigue syndrome. “But even those names were met with more resistance than validation,” Hart says. She was later misdiagnosed with depression and treated as a psychiatric patient. But the medications she was prescribed only made her feel worse. It wasn’t until Hart was in her mid-thirties and living in the United Kingdom that she received a diagnosis of myalgic encephalomyelitis, a disease that the Centers for Disease Control and Prevention and most medical institutions now recognize as myalgic encephalomyelitis/chronic fatigue syndrome, or ME/CFS.

Hart’s experience is typical for this condition, which has remained enigmatic since it first drew widespread attention in the 1980s. Because the symptoms of ME/CFS can sometimes be vague and overlap with those of other common diseases, getting to a diagnosis is a painstaking process that largely involves excluding other conditions. There have been no offical blood tests or other diagnostic tools, which means that physicians sometimes turn to psychological explanations. Often enough, as in Hart’s case, they point to depression or overwork as the likely culprits.

Even today, ME/CFS resists easy categorization. Hart’s symptoms came on gradually, but in many cases a single trigger sets the disease in motion. It might be an infection such as influenza or mononucleosis, the physical trauma of a car accident or surgery or psychological trauma, such as the death of a loved one. A cascade of symptoms follows and lasts for months or years. Unrelenting fatigue is always one of them, but a long list of others includes enlarged lymph nodes in the neck or armpits, impaired short-term memory, poor concentration, unrefreshing sleep and joint pain. It often causes “orthostatic intolerance,” in which sitting or standing interferes with blood pressure and blood flow to the brain. And patients suffer from a severe crash in energy levels lasting days or weeks after physical activity—which may, in some cases, involve nothing more than leaving the house to do an errand or walking to the bathroom.

Having the disease also means coping with its persistent stigma. Many people, including physicians, have simply not believed that ME/CFS is a real physiological condition, even with an estimated 1 million to 2.5 million people in the United States thought to be suffering from it. This may stem from the uncertainty that still swirls around its diagnosis. Physicians now have multiple sets of criteria for identifying ME/CFS—some that may be overly broad, others overly restrictive and almost all hotly debated among medical and lay groups. Researchers now also believe that hidden beneath what has ultimately been described as a “clinical syndrome”—in which symptoms tend to occur together—several subtypes may exist, with varying ranges and severity of symptoms and diverse underlying causes, each of which may call for a different approach to treatment.

In recent years, however, research on ME/CFS has turned a corner. Greater awareness has led to a few tantalizing clues about how people with ME/CFS differ from their healthy counterparts. Some of these were covered in a landmark gathering of ME/CFS researchers at the National Institutes of Health in April. Abnormalities in the immune system, impaired cellular metabolism and other problems affecting blood pressure and heart rate regulation seem to be hallmarks of the disease. More powerful tools are helping scientists search for molecular pathways that may set those problems in motion, and collaboration among researchers in pulmonology, neuroimmunology and other disciplines is leading to new insights. One major goal is to find biomarkers that could produce definitive laboratory tests for diagnosis and help tease apart underlying mechanisms that may split what is currently a clinical syndrome into several clearly-defined disorders. And a few of these may have the promise to move toward effective treatments—a promise that, in some cases, is already heading into clinical trials.


UNTIL RECENTLY, VERY LITTLE was known about what might cause post-exertional malaise (PEM), a defining symptom of ME/CFS. Symptoms of ME/CFS often worsen after minimal exertion, and even getting up for a glass of water may leave someone exhausted for days or longer. New tests have shown that PEM may result from cardiopulmonary and nervous system abnormalities. David Systrom, director of the Invasive Cardiopulmonary Exercise Laboratory at Brigham and Women’s Hospital in Boston, has been chasing these down with the help of his invasive cardiopulmonary exercise test, or iCPET.

Normally, blood depleted of oxygen returns to the right side of the heart, filling the atrium and then the ventricle. The right ventricle pumps blood to the lungs, and that blood, filled with oxygen, returns to the left side of the heart. From there it is sent out to the muscles, where the blood unloads its oxygen to feed mitochondria, which in turn provide cells with energy. Breathing hard during exercise steps up this process, delivering additional oxygen to the blood. The heart also works harder to get more blood to the muscles as exertion increases, and the veins return more blood to the right side of the heart.

The iCPET looks at all of these cardiopulmonary processes in a patient and collects data about how they might deviate from the norm. As the patient cycles to exhaustion on a stationary bike, a mouth piece collects the breath-by-breath exchange of gases and measures oxygen uptake; a 12-lead electrocardiogram measures heart function; and two catheters, one inserted at the neck and the other at the wrist, measure pressure and pull blood samples to detect changes in blood oxygen content in the veins and arteries.

Systrom and his colleagues developed the iCPET to help spot heart failure and pulmonary hypertension in their initial stages, when the subtle signs are hard to detect in a person at rest. But soon Systrom and his team began using iCPET to test people with ME/CFS, and those patients now account for almost half of iCPET testing at Brigham and Women’s. Almost all of them show specific patterns of cardiovascular dysfunction distinct from other heart and lung conditions.

For some reason, in these test subjects, the large veins in the lower body fail to constrict effectively during exercise. This results in less blood being pushed up to the right atrium. Systrom calls this phenomenon “preload failure,” a condition that is particularly pronounced when exercising in an upright position, suggesting it may also be related to the common ME/CFS symptom of orthostatic intolerance, in which problems become worse when sitting or standing.

In many of those same patients, Systrom has also found abnormalities in a measurement of how well muscles extract oxygen from the blood—an indication that their mitochondria-rich muscle fibers aren’t getting sufficient oxygen. That adds to the problems of preload failure and clearly distinguishes ME/CFS patients from others whose muscles have lost conditioning because of inactivity.


FOR PATIENTS SUCH AS Katie Hart, whose iCPET results showed preload failure, this kind of objective finding can be reassuring. “When we show them their abnormal physiology in the exercise lab—when we can give them reasonably hard data that this is a real illness—they are so relieved,” Systrom says.

Spurred by these discoveries, Systrom teamed up with Anne Louise Oaklander, a neurologist who directs the nerve unit at Massachusetts General Hospital. Oaklander specializes in small fiber neuropathy (SFN), in which small nerve fibers are damaged and misfire. SFN is characterized by chronic pain but also chronic fatigue and other symptoms often shared by patients with ME/CFS. Oaklander and Systrom began to look into whether the ME/CFS patients he was testing with iCPET might also have SFN. In about 40% of those who showed preload failure in the iCPET, they found a positive match.

The tiny nerve fibers involved in SFN are found everywhere and may affect the proper functioning of the autonomic nervous system, which regulates blood pressure, breathing, digestion and other automatic body processes. Systrom and Oaklander suspect that the physiological problems Systrom documents with his test—preload failure and poor oxygen extraction in muscles—may, in some patients, be caused by an autonomic nervous system that is out of whack because of SFN. “We’re marrying the physiology to the neuroanatomy,” Systrom says.

While the researchers don’t yet know for sure what causes SFN, they suspect that inflammation, perhaps brought on by infection or another trigger, might set off an autoimmune process that then attacks the small nerve fibers. “We know there is a large overlap with autoimmunity and inflammation,” Systrom says. And patients with some autoimmune conditions—particularly SjÖgren’s syndrome, which attacks tear and salivary glands—also have a high prevalence of SFN. Now Systrom and Oaklander are analyzing biomarkers to explore possible connections.

Even before the physiology of these conditions is fully mapped out, Systrom is looking at possible treatments. A drug called pyridostigmine, approved by the U.S. Food and Drug Administration to treat myasthenia gravis, an autoimmune disorder, prevents the breakdown of the neurotransmitter acetylcholine. Increasing the effectiveness of acetylcholine appears to improve the functioning of nerves that interact with slow-twitch muscle fibers—the same fibers that, in Systrom’s exercising patients, aren’t getting enough oxygen. Pyridostigmine also promotes constriction of veins, helping pump more blood back to the heart during peak exercise. Benefits may also come from the drug’s anti-inflammatory and immune system effects, although Systrom doesn’t yet understand exactly how that might happen. Systrom has treated about 300 ME/CFS patients with good results and has recently launched a phase 3 trial.


BETTER IMAGING COULD HELP scientists understand more about the role of inflammation in ME/CFS. Michael VanElzakker, a neuroscientist at the Martinos Center for Biomedical Imaging at MGH, is using functional magnetic resonance imaging (fMRI) to study the brains of these patients both at rest and after they’ve undergone Systrom’s exercise test. VanElzakker’s work is centered on the function of the vagus nerve, a key nerve in the autonomic nervous system that has acetylcholine as its primary neurotransmitter. He hopes his research will help researchers see what happens when patients experience post-exertional malaise and how that may be related to problems with the autonomic nervous system. Another study with positron emission tomography, which uses radioactive substances that bind to certain proteins, will help them see whether and where neuroinflammation may exist in the brain.

In other work, Jose Montoya, an infectious disease specialist at Stanford Medical School, used MRIs of patients with ME/CFS to discover an abnormal thickening of the right arcuate fasciculus, which connects the brain’s frontal lobe with its temporal lobe. Although the function of the arcuate fasciculus isn’t fully understood, the researchers were intrigued to find that the patients in which it was thickest also had the most severe symptoms.

Images also show another possible result of inflammation—abnormally low levels of white matter, the long, myelin-coated, cable-like tracts of nerves that carry signals between the widely dispersed “gray matter” in the brain. And in this case too, there seemed to be a correlation between the extent of the abnormality and the severity of symptoms, a way of sorting data that Montoya is convinced will lead to significant clues about the processes at work in ME/CFS.

Jarred Younger, a clinical researcher and director of the Neuroinflammation, Pain and Fatigue Laboratory at the University of Alabama in Tuscaloosa used MRIs to map brain temperatures and found that patients with ME/CFS had warmer brains than healthy people. The brain areas most affected were known to cause feelings of malaise, fatigue and depressed mood. But those higher temperatures were found in only about a third of patients, who may represent a subgroup with unusually high levels of neuroinflammation. Younger believes that these patients may have highly active microglia, immune cells in the brain, which release small proteins called cytokines that produce inflammation and may cause some symptoms of ME/CFS.

Yet even the hypothesis that neuroinflammation is a core part of ME/CFS doesn’t point to a specific cause for the disease. Montoya says he believes that in many cases of ME/CFS, a viral infection such as Epstein-Barr or human herpesvirus 6 has altered the immune system, which overreacts, gets stuck in overdrive and can’t reset itself to proper functioning. Some of Montoya’s ME/CFS patients who have tested positive for chronic viral infections have improved or recovered by taking antiviral medications.

Younger suspects that there are multiple subgroups of people with ME/CFS—some who have an infection with a chronic pathogen such as Epstein-Barr, and some who don’t have a chronic infection but do have an abnormal immune response in the brain. In that second set of patients, microglia are likely to have become traumatized in some way, he suggests. “The microglia are on a hair trigger and it takes very little to set them off,” Younger says. “In these patients, things that most people encounter every day without a problem cause a cytokine release.” Younger is now testing treatments that could return the microglia to a resting state.

Montoya and other researchers are also looking for ME/CFS biomarkers in the immune system, and they’re especially interested in cytokines. In one study, Montoya measured 51 cytokines in several hundred patients with ME/CFS as well as in healthy subjects. His team found 17 cytokines that were significantly associated with ME/CFS severity, and 13 of those are known to cause inflammation. The higher patients’ cytokine levels were, the more intense their symptoms. “It’s exciting to see a clear correlation between symptoms and a biological signal,” Montoya says.

The fact that the disease affects so many body systems—the nervous system, the muscular system, the cardiovascular system and the immune system—may add to its complexity, and help explain why causes and mechanisms have taken so long to unravel. As specialists from each of these fields pin down some of the details, however, a clearer picture of ME/CFS is emerging. The next step requires these pieces to come together, as researchers collaborate and share research to finally get to the bottom of a disabling and long-neglected disease.