“We believe these are virtually the same disease, although there are some differences, and they should be managed and studied in multidisciplinary clinics focused on post-infectious syndromes.” Avindra Nath, MD, FAAN, clinical director of the National Institute of Neurological Disorders and Stroke (NINDS).
Neurology Today, by Gina Shaw, 18 April 2024
A new “deep dive” study of a small, carefully selected population of individuals with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) adds weight to the growing evidence characterizing this long-misunderstood disease as a neuroimmunologic disorder.
- Read more about the research: NIH Study of ME/CFS points to immune dysfunction and brain abnormalities | 21 February 2024
Article extracts
The findings reported Feb. 21 in Nature Communication point to a phenotype for ME/CFS that involves autonomic dysfunction, immunologic abnormalities, and microbiome alterations, which are influenced by sex variabilities and genetic components.
It also indicates an overlap between ME/CFS and long COVID, debilitating symptoms including chronic pain, brain fog, shortness of breath, and intense fatigue that can persist for months or longer after an initial acute SARS-CoV-2 infection.
“We believe these are virtually the same disease, although there are some differences, and they should be managed and studied in multidisciplinary clinics focused on post-infectious syndromes,” said lead author Avindra Nath, MD, FAAN, clinical director of the National Institute of Neurological Disorders and Stroke (NINDS), director of the Translational Neuroscience Center, and chief of the section of infections of the nervous system.
The study involved 17 patients with ME/CFS and 21 healthy controls. “We know that the majority of patients with ME/CFS report that they had some kind of infection and never really got better, so we decided to focus on only that subset of individuals,” Dr. Nath said. “We also limited our study to individuals who had symptoms for no longer than five years. If you have a disease that has prevented you from being mobile over an extended period of time, you will ultimately also develop secondary complications that could confound our results.”
“This is a more extensive set of biological measurements in people with post-infectious ME/CFS than any previous study,” said Dr. Nath. “It reveals that there is an absolute biological basis for this disease, involving clear immune system abnormalities.”
The investigators characterized the phenotype of post-infection ME/CFS this way:
“Exposure to an infection leads to concomitant and persistent immune dysfunction and changes in gut microbiome. Immune dysfunction affects both innate and adaptive immune systems that are sex-dependent. We hypothesize that these changes are driven by antigen persistence of the infectious pathogen,” they wrote.
“These immune and microbial alterations impact the brain, leading to decreased concentrations of metabolites which impacts brain function. The catecholamine nuclei release lower levels of catechols, which impacts the autonomic nervous system and manifests with decreased heart rate variability and decreased baroreflex cardiovascular function, with downstream effects on cardiopulmonary capacity.”
“Using functional brain imaging, we also found that the temporoparietal junction was hypoactive during motor tasks in the ME/CFS group,” said Dr. Nath. “This is not the kind of weakness that you see in patients with strokes—if the person is forced to do so, they can exert full strength. But the hypoactivity of the temporoparietal junction limits the brain from exerting that complete effort because too much effort, either cognitive or motor, wipes them out.”
“This is the first time we have seen such comprehensive objective findings documented and reported in ME/CFS.
“Previously, we were primarily talking about clinical symptoms established by different groups. Yes, this is a small number of individuals with ME/CFS, but it is a select group with a deep analysis.
“Next, we need to go deeper to identify potential biomarkers that will allow us to test therapeutics to approach the pathobiology they have identified here.”
Hector Bonilla, MD, clinical associate professor of medicine at Stanford University and co-director of Stanford's ME/CFS and Post-Acute COVID-19 Syndrome Clinic.
“In the history of neurology, we've had a lot of diseases that were difficult to explain and would often be characterized as ‘malingering’ or ‘hysteria,’ such as epilepsy and dystonia.
“As our science has gotten more sophisticated, we have begun to understand that these are true brain-driven diseases that can be treated, and no one dismisses them anymore. ME/CFS has faced that same skepticism.”
Lead author Avindra Nath, MD, FAAN, clinical director of the National Institute of Neurological Disorders and Stroke (NINDS).
“Today, newer imaging methodologies show ongoing and continuing inflammation in the brain and have been able to give concrete evidence that ME/CFS is a physiological disease, not something that is simply psychiatric or psychological.
“Unfortunately, many clinicians are still not informed about ME/CFS and other post-infection syndromes.”
Vicky Whittemore, PhD, program director for the division of neuroscience at NINDS.
“This is an ambitious and thorough study that is a good start, reaffirming the pathophysiologic mechanisms in ME/CFS that have been demonstrated in prior studies over the years.
“While a lot of good testing was done, I would have liked to see the additional tests, including supine and standing transcranial dopplers to assess for cerebral perfusion; complete autonomic function testing, including quantitative sudomotor axon reflex test; and a two-day cardiopulmonary test. These tests have shown significant difference between patients with ME/CFS and healthy controls in prior studies.”
“Nonetheless, the NIH study clearly shows how much is altered in these individuals, with respect to neurologic, metabolic, autonomic, and hormonal pathophysiology.”
“Based on their data, ME/CFS is clearly a central nervous system disorder, and the associated fatigue is defined by autonomic dysfunction unrelated to psychological or psychiatric causes.”
Svetlana Blitshteyn, MD, director of the dysautonomia clinic and clinical associate professor of neurology at the University of Buffalo Jacobs School of Medicine and Biomedical Sciences.
The relationship to Long Covid
After the emergence of Long Covid, some experts argued that this is not really a new condition but a new name for an old one: ME/CFS. In other words, an acute COVID-19 infection may trigger ME/CFS much the same way that other infections do. (As of mid-2023, the Centers for Disease Control and Prevention estimated the prevalence of long COVID in the adult population at around 6 percent.)
“The emerging concept is that COVID-19 and other acute infections can trigger a chronic post-infection disease in the form of ME/CFS.
“A great deal of investigation is going on now to look across these infectious disease states to see what is going on with the immune and nervous system that is perpetuating the disease.
“Is persistent virus stored somewhere in the body that keeps reactivating? Or does the initial infection, whatever it is, reactivate other viruses that have been harbored in the body and remained dormant until some sort of trigger?”
Vicky Whittemore, PhD, program director for the division of neuroscience at NINDS.
“When Long Covid entered the picture, it demonstrated that ME/CFS is relevant.
“Look at the outbreaks of SARS in China in 2002 and MERs in the Arabian Peninsula in 2012; these were also coronavirus infections, and people who recovered from those illnesses have similar symptoms that we see now in Long Covid and have seen with ME/CFS for years.
“These are the same conditions, or very similar and related conditions. The impact now with COVID is so big that we cannot keep ignoring it, and the implications for the economy are huge, representing a major opportunity and imperative to study these persistent post-viral illnesses better.”
Hector Bonilla, MD, clinical associate professor of medicine at Stanford University and co-director of Stanford's ME/CFS and Post-Acute COVID-19 Syndrome Clinic.
“Long Covid has convinced the medical community that a horrible infection can yield chronic fatigue syndrome. In our population of individuals with Long Covid, as many as half of them fulfill the case criteria for ME/CFS.
“These people are a very important population, in that we know two things about them: they were well previously and became ill following infection with the SARS-CoV-2 virus, and their illness has been relatively short compared with individuals who have had ME/CFS for many years.
“We ought to be able to learn more from them about immune dysfunction and brain neuroinflammation in these syndromes than from individuals who have been sick for many years.”
Benjamin H. Natelson, MD, director of the Pain & Fatigue Study Center and professor of neurology at the Icahn School of Medicine at Mount Sinai.
Research towards therapeutics
Therapeutic trials will require the development of biomarkers that objectively point to the dysfunction ME/CFS causes:
“The disease is very heterogeneous; some people have very significant gastrointestinal [GI] issues, where others don't. Some have very severe dysautonomia, including orthostatic intolerance, while others don't. That makes it very challenging to come up with a single biomarker.
“From what we have seen in collaborative research we have funded, it is likely that there will be multiple biomarkers rather than one single one, such as markers of immune dysfunction and cardiovascular dysfunction.”
Vicky Whittemore, PhD, program director for the division of neuroscience at NINDS.
For example, she cites research on post-exertional malaise published in 2023 by Maureen Hanson, PhD, an endowed professor in the department of molecular biology and genetics at Cornell University and director of the Cornell Center for Enervating NeuroImmune Disease. The research shows that individuals with ME/CFS took an average of about two weeks to recover from two cardiopulmonary exercise tests (CPET) separated by 24 hours, whereas sedentary controls needed only two days:
“They took biospecimens before and after each day of testing and found some pretty significant changes from baseline day one to baseline day two and again after the exercise challenge, showing that the system can't function normally.
“If you look at baseline, those markers in the individuals with ME/CFS were not all that different from normal healthy controls, but when given an exercise challenge, you can begin to see some of these metabolic changes showing that the immune, nervous, and cardiovascular systems do not compensate in the same way.”
Dr. Blitshteyn would like to see larger controlled trials of therapies including immunotherapy, such as intravenous or subcutaneous immunoglobulin (IgG) and plasmapheresis. In 2022, she and her team published a case series in the Journal of Neurology on subcutaneous IG (SCIG) and plasmapheresis (PLEX) in people with severe postural orthostatic tachycardia syndrome (POTS), many of whom also fit the criteria for ME/CFS:
“These seven individuals were mostly bedbound and housebound and very sick despite medications for autonomic disorders.”
“Five received SCIG, and two received PLEX. They all experienced significant functional improvement; six patients were able to discontinue or reduce oral medications, and five reported being able to return to work or school, with no serious adverse events.”
Dr. Nath's group has begun recruiting study participants for a clinical trial of intravenous IG (IVIG) in Long Covid:
“In order to bring treatments to people with ME/CFS quickly, we need to do trials in Long Covid, because there are so many of them, they are closer to the infectious process, and we know exactly what the infectious process was.”
The multidisciplinary clinics built around Long Covid are an essential approach to all of these disorders, Dr. Nath said:
“One medical specialty cannot handle these conditions. It requires neurology, infectious disease, GI, rheumatology, psychiatry, physical therapy, and a wide range of disciplines.
“Many of these syndromes have been given different names because they started with different infectious initiating events, but instead of creating separate clinics for all of them, we should be studying them in a more unified approach as post-infection syndromes.”