JAMA Network by Quinn Eastman, 15 March 2024
In the eyes of the medical community, myalgic encephalomyelitis/chronic fatigue syndrome, or ME/CFS, has had a legitimacy deficit for decades. Now, a team of 75 multidisciplinary scientists and clinicians from across the National Institutes of Health (NIH) and collaborators have completed an extensive inpatient study of a carefully selected group of people with post-infectious ME/CFS, published in Nature Communications.
Led by neurologist Avindra Nath, MD, clinical director for the NIH’s National Institute of Neurological Disorders and Stroke (NINDS), the researchers report several physiological differences between people with ME/CFS and healthy volunteers. Nath said in an interview with JAMA:
“Overall, what we show is that ME/CFS is unambiguously biological, with multiple organ systems affected. It’s a systemic disease, and the people living with it deserve to have their experiences taken seriously.”
Article extracts
The Backstory
Throughout the 20th century, ME/CFS appeared under various names in medical literature, a 2015 Institute of Medicine (IOM, now the National Academy of Medicine) report noted. With outbreaks in Nevada and New York in the 1980s, chronic fatigue syndrome—a name chosen by the US Centers for Disease Control and Prevention (CDC)—attracted national attention. The term myalgic encephalomyelitis has been more frequently used in the UK and other countries outside the US.
For patients, a point of frustration is the word fatigue, which is a temporary experience for most people but is chronic in ME/CFS. This often leads physicians, as well as friends and family, to discount the severity of the symptoms. Individuals’ complaints are often interpreted as having a psychological basis, the IOM report acknowledged.
“The word fatigue warped mainstream medicine’s understanding of ME/CFS for decades, these are people who can’t function.”
Liz Burlingame, leader of the Georgia chapter of ME Action
The IOM expert panel wrote in their 2015 report that “the health care community generally still doubts the existence or seriousness of this disease.” Since then, ME/CFS has seen an increase in attention from the NIH and an acceleration of research, both in the US and other countries.
The COVID-19 pandemic added millions to the number of people around the world with ME/CFS. Among people with post–COVID-19 condition, also known as long COVID, about half meet the duration and symptom severity criteria for ME/CFS.
Nath and his coauthors say that a better understanding of ME/CFS pathophysiology, and perhaps a diagnostic biomarker, will be critical for future research. In April, the NINDS is scheduled to release an ME/CFS Research Roadmap. Experts think the field may be ready for the initiation of clinical trials with repurposed drugs, based on existing knowledge.
“It’s exciting to see what’s happening now,” Burlingame said of the roadmap. “It’s a shame that they didn’t do it 30 years ago.”
Study design
For the new study, more than 200 people with possible ME/CFS went through a detailed case review, including telephone interviews and a review of medical records. The most common reasons for exclusion in the study were:
• disease onset more than 5 years ago.
• no documentation of an initial infection.
• diagnosis with other diseases, including Lyme disease.
• being too sick to travel.
Out of this group, 27 people came to the NIH Clinical Center for an in-person research evaluation. A panel of 5 clinical ME/CFS experts unanimously determined that 17 of the individuals had postinfectious ME/CFS. These participants then went through a thorough set of physiological and neurocognitive tests, along with brain imaging and biochemical; microbiological; and immunological analyses of blood, cerebrospinal fluid, muscle, and stool.
The Findings
• Immune system differences.
• Fecal microbiome changes.
• Reduced neurotransmitter metabolism.
• Autonomic nervous system dysfunction.
• Impaired cardiorespiratory performance.
• Alteration of “effort preference.”
• Differences in performance on handgrip tests.
The authors attributed ME-CFS participants’ fatigue “to dysfunction of integrative brain regions that drive the motor cortex,” such as the temporal-parietal junction. They noted that “psychiatric disorders were not a major feature in this cohort and did not account for the severity of their symptoms.”
The Mechanisms
Based on the findings, the researchers suggest how an infection could “create a cascade of physiological alterations” that lead to what’s experienced in post-infection ME/CFS. They hypothesize that an infection causes lasting changes in the immune system and gut microbiome, possibly driven by the pathogen’s persistence in the body. These changes affect the brain, leading to a decrease in neurotransmitters that alters the autonomic nervous system and, ultimately, reduces cardiopulmonary capacity. Hypothalamic function is altered in this cascade, decreasing brain activity during motor tasks.
“This decreased brain activity is experienced as physical and psychological symptoms and impacts effort preferences,” the authors write, “leading to decreased engagement of the motor system and decreases in maintaining force output during motor tasks.”
They posit that in post-infection ME/CFS, physical activity is reduced by both autonomic and central motor dysfunction and that, over time, this leads to physical deconditioning and functional disability.
What the ME/CFS Community says
Burlingame said that members of the ME/CFS community have been waiting to see the results of the NIH study for years. The publication has gotten some negative feedback.
- Among other issues, the use of the term effort preference to describe the basis for fatigue in ME/CFS has been criticized by some experts in the field as unnecessary, considering that autonomic nervous system and metabolic dysfunction could account for fatigue.
- The small number of participants was another limitation noted by some. The study began in 2016. Because of restrictions imposed by the COVID-19 pandemic, the cohort ended up smaller than organizers originally intended.
- Moreover, not including people who were sick for more than 5 years or were too sick to travel may have skewed the picture researchers obtained, because a substantial fraction—at least a quarter—of people with ME/CFS are housebound or bedbound.
- Partly because of concerns about harming participants through overwork, researchers did not conduct 2-day cardiopulmonary exercise tests, despite previous reports that such tests could offer a way to capture postexertional malaise, a central feature of the disease.
The Clinical Takeaway
According to Nath, the study has several instructive messages for clinicians seeing people who report symptoms consistent with ME/CFS. The first is that these patients should not be dismissed or told that their symptoms have a psychological basis.
He noted that even if the origin and pathophysiology for ME/CFS remain unclear, people with ME/CFS can be treated for their symptoms. Nath recommended referrals to multidisciplinary clinics, such as those that specialize in complex chronic illnesses or the long COVID clinics that many medical centers established during the COVID-19 pandemic. Depending on their symptoms, people with ME/CFS may need to see a neurologist, a psychiatrist, a cardiologist (for autonomic nervous system symptoms such as orthostatic hypotension), or a pain management specialist, he said.
“The most important message arising from this paper is that people with ME/CFS show significant objective changes across multiple systems, it shows to nonbelievers that people with ME/CFS have a real problem—but we still have a lot to learn.”
Hector Bonilla, MD, Director of Stanford’s ME/CFS clinic