Patients with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) have long argued that their disease has been ignored. Two years ago, they staged a worldwide protest demanding more money for research and stronger accountability from government agencies.

Fast-forward to 2018: Avindra Nath, MD, clinical director for the National Institute of Neurological Disorders and Stroke (NINDS), is now principal investigator of the first in-house study of ME/CFS.

Nath said he's learned a lot just in talking to patients about their illness.

"For a little while, I didn't understand all the aspects of malaise and fatigue ... there are all these aspects of ME/CFS that sometimes get missed in the use of the term 'fatigue' in the English language because what you experience you have no expressive words to truly embody that feeling," he told MedPage Today in a phone interview.

The study is focusing on ME/CFS that emerges following infection. It will include 80 individuals: 40 with ME/CFS that started after an infection, 20 treated for Lyme disease who had no subsequent fatigue symptoms, and 20 healthy controls. It will involve a slew of tests including metabolomic and proteomic analyses (including cerebrospinal fluid sampling) and sleep studies.

Some responses have been edited for brevity and clarity.

What is the purpose of your study?

Nath: People have been studying this disease, a little bit here a little bit there, and haven't really come up with anything consistent yet as far as understanding the pathophysiology of the illness.

This study is a hypothesis-generating study that involves a small number of patients, but studies them in-depth. It's an opportunity to really look at the disease in a different way with new tests that are available -- to study the brain and the immune system, and metabolic abnormalities and the microbiome -- all kinds of things that you couldn't study just a few years ago.

The goal is to identify a a subset of abnormalities that are worth pursuing further. Then you can narrow down the tests and use a much larger sample size.

What does the study look like to an outside observer?

Nath: The first phase of the study is the screening/phenotyping visit. You've got to make sure there's no other disease that could be accounting for the patient's symptoms. If a patient complains of malaise and fatigue maybe you have underlying cancer, or a muscle disorder.

A committee takes all the information from those tests to make sure that the patient meets the criteria for post-infection ME/CFS. Then we bring those patients who meet the criteria back for a second visit and again do extensive testing to really study the disease.

How are patients chosen for the study?

Nath: Our study is very narrow in terms of criteria. Patients have to be adults, have to have had post-infection ME/CFS for at least 6 months, but not longer than 5 years, and they they have to be ambulatory. We have 200 people who have been screened, and a larger number that were quickly told this wasn't the right protocol for them. Of the 200, about 20 people were eligible for the initial screening visit.

What aspect of this study do you find the most difficult?

Nath: To me, the most challenging aspect is defining the patient population correctly. I always worry, "Am I really studying a well- defined population or am I studying a mixed bag of diseases?"

The second challenge is that the clinical parameters are largely subjective.

It's not like a patient with Parkinson's disease, where even though there is no diagnostic test, an astute neurologist will see a patient and say, "You've got Parkinson's." The features are so darn typical you're 99% right every time.

So, for a neurologist, that is frustrating because you can see the patients, and examine them, but you have to somehow make a gestalt as to whether to believe this aspect of the history or not.

With migraines, you have to believe what the patient tells you about the history of their headaches.

That's true for all pain related syndromes, but we've made big mistakes there. You have the whole opioid crisis.

The last thing you want to do is to treat patients for the wrong thing or give a name to their disease that they don't really have. You can end up causing more harm.

Why did you choose people who've recovered from Lyme disease as a comparison group?

Nath: We wanted a control population where they develop an infection but they did not develop a syndrome. So the post-Lyme was a convenient population for us, because there is a study ongoing here at NIH.

Will your study help examine the physiological basis of fatigue?

Nath: We'll be looking at mitochondrial function and metabolism and that will give us some idea about fatigue. And we may understand some things about the the fundamental aspects of fatigue and malaise that would be helpful beyond this disease itself, for example in cancer and in multiple sclerosis.

I noticed you are also looking at patients' genes. Do you believe ME/CFS could be heritable?

Nath: From what has been been published, there doesn't seem to be a strong genetic link. A weak genetic link, that would be hard for us to figure out with the sample size that we have. I don't think we're going to find any genetic basis for the disease, but we're collecting that kind of data.

The patient community has at times been critical of the scientists studying ME/CFS and the way the study was designed. Is it challenging to work with this community?

Nath: Some patients are angry and upset for good reason, and there's nothing bad about voicing your concerns.

As a physician you don't always learn patient care from books and textbook and literature, you really learn medicine from your patients.

Those physicians who really listen to their patients will make a huge difference in trying to advance our understanding of diseases, and provide better care than those who just take the history take notes on the computer and fill out forms.

I've really benefitted from talking with the patients about their own disease. For a little while, I didn't understand all the aspects of malaise and fatigue, and why patients were trying to differentiate that so much and what they meant when they use the word "fatigue."

So, there are all these aspects of ME/CFS that sometimes get missed in the use of the term "fatigue" in the English language because what you experience you have no expressive words to truly embody that feeling. That is an aspect you learn.

As a scientist, you've made clear that you also have other research priorities outside ME/CFS. When your work on ME/CFS is complete, what do you hope other researchers will learn from this study?

Nath: It's not that I'm not interested in the disease. The limitation that I have is that we can only study small sample sizes. We don't have the ability to do a multi-site study or a large clinical trial.

Once we make our observations, I think they'll need to be translated to larger sample sizes. If there are certain questions that we still need to answer in small sample sizes then we will continue that research. But as soon as our observations need to be to translated to a larger site then the best thing for us to do is to let it out into the community and provide opportunities for people to follow-up on our observations.