Chronic Fatigue Syndrome: An Unfolding Story of Scientific Discoveries and Future Targeted Treatments
Presented by Jose Montoya, MD
Professor of Medicine, Infectious Diseases and Geographic Medicine
January 18, 2018
Five years ago, a young woman who had everything in life—flourishing career, happy marriage, and a taste for adventure—started to crash.
It began after one of her routine long hikes. First, she noticed skin bumps on her forehead. Within a few weeks, she was unable to walk even a few blocks without getting exhausted.
Gradually it became an ordeal to even take a shower. She had to lie down in bed to rest. She grew weak.
She saw doctors, going from one to another without getting a diagnosis. Eventually she was told her illness was the result of depression, and that she needed to get psychological help. She went to Mayo Clinic and got no answer, except that she didn’t have Lyme disease.
Finally, last year she came to Stanford, where her symptoms were recognized as chronic fatigue syndrome.
“This is the nightmare that many patients go through,” said Jose Montoya, MD, professor of medicine and a specialist in infectious diseases. “Some patients have gone with this issue for decades of not being diagnosed properly.”
More than one million Americans are estimated to have chronic fatigue syndrome (CFS). Its signature symptom is long-lasting fatigue so devastating that it can leave people unable to do the simplest tasks to take care of themselves.
“It’s a test of human compassion and kindness, because these patients go into such a desperate state that some of them take their lives,” Dr. Montoya said.
He added, “One of the biggest mistakes made by modern medicine is to have arrived at the conclusion that diseases like [chronic fatigue syndrome] …are a creation of the patient’s imagination,” said Dr. Montoya. “This historical mistake, made by many official government agencies and mainstream medical associations, has started to be mended.”
In 2015, the Institute of Medicine released a report recognizing the scientific validity of chronic fatigue syndrome as a biological illness not caused by psychological problems. The report began to reverse years of skepticism among many doctors, Dr. Montoya said.
Studies are finding evidence that the illness may be linked to an activation of the body’s immune system and inflammation. Researchers don’t yet have a clear answer to why that happens, although some clues are emerging.
Diagnosis at last
At least now doctors have a way to recognize the illness earlier. The Institute of Medicine report set out clear criteria for making a diagnosis:
- Deep long-term fatigue that limits someone’s ability to work, study, or socialize by at least 50 percent for more than 6 months.
- Lack of relief from rest or sleep, no matter how long the person sleeps. “When you listen to these patients, they will tell you they do not wake up refreshed,” Dr. Montoya said.
- Fatigue that gets even worse when the person tries to overcome symptoms to do even basic everyday activities.
“When they push beyond the threshold of what is too much effort, they crash,” Dr. Montoya said.
In addition to these 3 criteria, one of 2 other patterns should be present in a patient to reach a diagnosis of chronic fatigue syndrome:
- Decline in some cognitive abilities.
- Feeling weak or sick from merely standing up, rather than lying down. Doctors call this orthostatic intolerance.
No classic pattern
Often, symptoms differ dramatically from one CFS patient to another. That makes having a standard for diagnosing the syndrome all the more important.
“The patient will not present [symptoms] with any classic pattern,” Dr. Montoya said. Some patients will have one history of symptoms, while other patients will have a different history. “That could be one of the reasons why it’s been hard to conquer,” he said.
In the case of the young woman who came to Stanford last year, she was so weak she had to lie down to rest after taking a shower or walking to get groceries. As her illness got worse, if she tried to do even the simplest daily tasks, “she would get more exhausted and would crash even farther,” Dr. Montoya said.
Over time, the woman also gradually lost the ability to read, write emails, and remember some things.
After the diagnosis
While getting an early diagnosis is a great help to patients and doctors, it still falls short of a treatment to improve symptoms.
Since the 2015 report was released, momentum has grown for research on chronic fatigue syndrome. Major federal research agencies “have rallied behind the idea of getting this solved,” said Dr. Montoya.
It’s a big challenge.
“I haven’t seen any other disease that has humbled me the most, has terrified me the most and at the same time, has propelled me the most to try to find answers,” Dr. Montoya said.
He recalled seeing his first patient with chronic fatigue, in 2004. The patient had swollen lymph nodes and infections from herpesviruses. Dr. Montoya prescribed an antiviral drug—and months later, the patient said his fatigue was gone.
Intrigued, Dr. Montoya did a small study that found antiviral drugs eased symptoms of chronic fatigue in some patients. Funding to do larger studies has not come easily, however.
Since 2009, when he received an anonymous donation for more research, Dr. Montoya has worked to assemble a team of medical specialists in multiple fields–infectious diseases, immunology, neurology and other areas–to find what’s driving chronic fatigue syndrome.
In 2017, that work paid off: they found a link between high levels of 17 body proteins, called cytokines, and the severity of chronic fatigue syndrome. The higher the level of each of these 17 cytokines in a patient, the worse the symptoms of chronic fatigue were.
Cytokines are known to mediate the body’s immune system. When activated by an infection or other threat, the immune system response can lead to inflammation in parts of the body. While cytokines usually reduce inflammation, in some circumstances they can worsen it.
Among the 17 cytokines in the study, 13 were “pro-inflammatory”—meaning they caused inflammation of body tissues. That’s consistent with some of the symptoms of chronic fatigue syndrome.
A storm in the body
Very high levels of cytokines are called a “cytokine storm,” Dr. Montoya said. That can cause fever, pain, brain inflammation, confusion, and low oxygen supply to the body.
Still, Dr. Montoya stopped short of saying this causes chronic fatigue.
“You cannot necessarily say these cytokines are causing chronic fatigue syndrome,” he said. “Chronic fatigue syndrome might simply be the disease that is causing the increase in cytokines.”
But he added, “It’s very striking.”
The work has led him and others on the team to propose this idea: “Chronic fatigue syndrome is a cytokine storm that goes chronic.”
Triggered by infection
Other recent studies have also found evidence that the syndrome is linked to a reaction of the body’s immune system to threats including infection.
That fits the pattern of the young woman who came to Stanford. Five years earlier, just before she began to experience chronic fatigue, she showed symptoms of a virus infection: skin bumps on her forehead and scalp.
The bumps were a sign of herpes zoster, the virus that causes chickenpox and shingles. She was given an antiviral drug to take briefly and the bumps soon disappeared. Despite that, after a few weeks she began to feel fatigue.
Five years later, when she came to Stanford after years of full-blown chronic fatigue, her doctors decided to put her on a longer course of antiviral drugs. Since starting the drugs in September 2017, for the first time she’s starting to feel a slight improvement in her energy and mental abilities.
“She’s now able to write emails and read,” Dr. Montoya said.
It’s still not clear how many CFS patients can be helped with antiviral drugs. Dr. Montoya said it’s likely that the drugs should be taken for a long time to be effective against chronic fatigue.
“For CFS, you have to intervene for years, not weeks,” he said.
Other studies have also found a link between chronic fatigue syndrome and other events, beyond infection, that provoke an immune response: surgery, physical trauma, or pregnancy. In all of these situations, “it could be an immune response,” Dr. Montoya said.
Dr. Montoya’s team at Stanford is working on a larger study with Columbia University researchers to examine multiple key factors that may be involved in chronic fatigue syndrome. They will be looking at cytokines, inflammatory gene expression, antibodies, and other biological suspects.
Their team will also include medical experts in neurology, cardiology, brain imaging, nutrition, and the gut microbiome to explore what impact these areas may have on chronic fatigue syndrome.
With all this expertise, why haven’t doctors been able to find the cause of chronic fatigue syndrome yet? “This is a very tough disease,” Dr. Montoya said.
He and others feel the urgency to discover ways to help patients soon.
“We have lost, sadly, some of our patients when hope could not reach them,” he said. “It’s a serious issue.”
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