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Article Where Exactly does ME/CFS Research Stand in 2021? Dr. Komaroff Explains

Where Exactly does ME/CFS Research Stand in 2021?
Dr. Komaroff Explains

From the central nervous system to Long COVID to energy impairment, Dr. Anthony Komaroff provides his perspective on over 30 years of scientific research into myalgic encephalomyelitis/ chronic fatigue syndrome (ME/CFS) and post-acute viral illnesses.


For over 30 years, Dr. Anthony Komaroff has been closely following the science behind myalgic encephalomyelitis/ chronic fatigue syndrome (ME/CFS) and post-acute viral illnesses. Image courtesy of Dr. Anthony Komaroff.

Versión en españolVersion française

By Bronc and Eric Pyrrhus
Dr. Anthony Komaroff is really on a roll. For a sometimes reserved academic, he's been speaking out more and more lately. What has he been talking about, and why now? Phoenix Rising spoke with the good doctor, and summarizes some of his recent publications and interviews here.

For those who may be unfamiliar with him, Dr. Komaroff is a distinguished Professor of Medicine at Harvard Medical School and Senior Physician at Brigham and Women's Hospital in Boston. He has published over 230 research articles and two books.

He has been publishing research papers on ME/CFS since the late 1980s, and currently serves on the U.S. National Institutes of Health’s advisory body for research into ME/CFS.

"Since the resurgence of interest in ME/CFS 35 years ago, whole new technologies have become available that allow physicians and biomedical scientists to study human biology in ways that previously were not possible," explained Dr. Komaroff in a recent commentary.

"In fact, these and other technologies have revealed things that the standard laboratory tests cannot — abnormalities that previously were invisible to doctors."

When we asked him which new developments in ME/CFS research stood out for him, he answered:

"The underlying biological abnormalities in ME that seem to me the most well established involve the brain and autonomic nervous system, chronic activation and exhaustion of parts of the immune system, defects in energy metabolism and a general hypometabolic state, and abnormalities of the gut microbiome. I think it is likely that they are all real, and all connected to one another. To me, the most important research agenda is to understand how these abnormalities are connected to each other."

—Dr. Anthony Komaroff

The brain and autonomic nervous system

In a recent review he authored with Dr. Ian Lipkin, Dr. Komaroff explained that "a wide variety of objective central nervous system (CNS) and autonomic nervous system abnormalities have been reported in ME/CFS. Although the literature contains some contradictory reports, the preponderance of the published evidence has identified [certain abnormalities.]"

One of those abnormalities, first noted 30 years ago, can be seen with magnetic resonance imaging (MRI) of the brain of patients. What were originally referred to as "unidentified bright objects" are now known as "white matter abnormalities" or "T2 hyper-intensities."

Even after 30 years, the exact nature of these abnormalities remains elusive. "Unless a researcher has an autopsy specimen to correlate with MRI findings, what is causing the MRI findings often is speculation," Komaroff explained to Phoenix Rising.

"As for the cause of T2 hyper-intensities, dilated perivascular spaces are one definite possibility as are small areas of demyelination."

Another brain abnormality, however, happens to be entirely invisible on MRI images: neuroinflammation. Unlike classical inflammation, which involves immune cells that normally reside in the blood, neuroinflammation involves immune cells that only live in the brain. Since activation of these "tissue-resident" immune cells do not result in any swelling, MRI images of neuroinflammation appear entirely normal.

When we asked Dr. Komaroff about progress in the study of neuroinflammation, his response was brief and circumspect. "Michael VanElzakker and colleagues are conducting studies of neuroinflammation in [people with ME], but the results are preliminary."

However, in his recent review with Dr. Lipkin, he explained further.

"Several studies have reported widespread activation of both astrocytes and microglia in people with ME/CFS. Cognitive dysfunction (‘brain fog’) may reflect cytokines produced by immune activation (either peripherally or in the CNS) that are known to cause fatigue and cognitive and mood disorders. [...] Because this has been well documented for cytokines detected in the circulation, it is at least as likely when cytokines are generated in the brain by neuroinflammation."

What if neuroinflammation is indeed confirmed to occur in the brain and spinal cord? Does this mean that the term "encephalomyelitis" would accurately describe ME/CFS? When one of us posed this question to Dr. Komaroff in 2014, his answer raised more than a few eyebrows.

"Yes. If it were confirmed by multiple other investigators it would, for me, say there is a low-grade, chronic encephalitis in these patients. That the image we, as clinicians, have of encephalitis as an acute and often dramatic clinical presentation that can even be fatal, may have blinded us to the possibility that there may have been an entity of long-lasting (many years long), cyclic, chronic neuroinflammation and that that is underlying the symptoms of this illness."


"We do have theories, theories that are based on pretty substantial evidence — I think most people in this field think that [in] both ME/CFS and Long COVID the symptoms are caused primarily by brain abnormalities, that include an activation of the immune system inside the brain — or neuroinflammation — auto-antibodies or an auto-immune disease that [attacks] targets in the brain — decreased blood flow to the brain caused by abnormalities of the autonomic nervous system, [...] and then finally by an abnormality and a failure of the cells in the brain to produce enough energy molecules to meet the needs of the brain. All of those things have been documented in ME/CFS and are likely to apply to Long COVID as well."​

—Dr. Anthony Komaroff

The coronavirus pandemic has changed a lot of things. And yet, the more things change, the more they seem to stay the same.

"Long COVID is very much like the illness called ME/CFS," asserted Dr. Komaroff in a recent interview with Solve ME.

"That's an illness that was first described in the 19th century, maybe even earlier than that. [...] It often follows an infectious illness of some sort. [...] It's very similar to what's seen in Long COVID. [...] It's likely that, following a number of different infections, the same lingering post-infectious [...] illness can occur."

Long COVID is undoubtedly a public health emergency. Millions of previously healthy people were leading perfectly productive lives before the pandemic, but are now hit with debilitating symptoms and a profound disbelief at the reactions of friends, family, and doctors.

Some are also hit with a decidedly uneasy feeling whenever someone tries to compare Long COVID to ME/CFS, which is perfectly understandable.

"In the United States, we estimated last summer that the pandemic might produce 2.5 million cases of Long COVID. That was based on pretty conservative assumptions. I'm afraid that now, in early 2021, they look too conservative. [...] So, I think that 2.5 million is probably a bottom-case estimate," Dr. Komaroff warned in the interview.

"In the US, before the COVID pandemic, there were about 2.5 million people with ME/CFS. So, if the conservative projections of another 2.5 million cases of Long COVID prove to be true, that means that the population of people with these lingering post-infectious illnesses is going to double in the next year or two, in the United States."

But Dr. Komaroff sees very real reason for hope.

"Fortunately, the COVID relief bill that was passed in December includes a lot of funding for research. [...] The research questions to pursue, in my mind — [...] What's going on in the brain — with the immune system of the brain, with the autonomic nervous system, with energy metabolism, that may be causing the symptoms of the illness. When we understand that, we're going to have therapeutic targets that I think will make people better."

Of course, no one knows exactly what the future holds. But Long COVID may indeed turn out to be the tipping-point for post-acute viral illnesses — the point where the sheer scale of the problem leads more people like Dr. Komaroff to speak out with urgency, more research funds to become available, and more smart people to step up and figure out how to fix the problem.

Impaired energy metabolism

In his recent review with Dr. Lipkin, Dr. Komaroff also highlighted the findings of impaired energy metabolism. "ME/CFS is characterized by a generalized impairment in energy production, a general hypo-metabolic state, and [oxidative stress] that may contribute to the pathogenesis of fatigue."

Since recent hypotheses have considered the possibility that mitochondrial dysfunction might be behind the impaired energy metabolism, we asked him about any recent advances in our understanding of mitochondrial dysfunction.

"There’s increasing evidence of impairment in producing energy molecules (ATP) from all of the necessary sources: oxygen, glucose, fatty acids and amino acids. But as to what is causing this impaired energy production, that remains obscure," he responded.

If the impaired energy metabolism is not due to mitochondrial dysfunction, what else might be behind it?

Findings from recent studies of metabolomics (the study of all the molecules in the body that are involved in cellular nutrition) may provide some clues.

"[Metabolomics] studies have found evidence of [...] a general hypo-metabolic state characterized by depressed levels of most [cellular nutrients and by-products,]" Dr. Komaroff highlighted in the recent review.

If low levels of cellular nutrients are indeed behind the impaired energy production, then what's behind the low levels of cellular nutrients?

One possibility is oxidative stress — a cellular condition where nutrients might become depleted by the chemical process of oxidation. Specifically, the review notes that studies have found "increased levels of pro-oxidants [...] correlating with severity of symptoms" and "decreased levels of anti-oxidants [...] that correlate with severity of symptoms."

In addition, "brain magnetic resonance imaging (MRI) has shown elevated levels of ventricular lactic acid consistent with oxidative stress."

So if oxidative stress can degrade cellular nutrients, resulting in impaired energy metabolism, then what is behind the oxidative stress itself?

In the field of medicine, the usual suspect in oxidative stress is chronic inflammation. "The [oxidative stress] that is a central feature of ME/CFS may be a marker for [...] inflammation in response to infection or injury," the review noted.

However, Dr. Komaroff and Dr. Lipkin emphasized in the review that the sequence of events is far from clear:

"In addition to defining individual components in the pathogenesis of ME/CFS — chronic inflammation, [oxidative stress], defective energy metabolism — we also need to understand how these components interact. Several are bidirectionally related. For example, inflammation can create [oxidative stress] that, in turn, can damage mitochondrial DNA and membranes. Conversely, mitochondrial dysfunction can generate inflammation, as can [oxidative stress] sufficient to damage tissue."

—Dr. Anthony Komaroff and Dr. Ian Lipkin

PEM, sleep, and biomarkers

What about all the other research that is being conducted? Research that tries to objectively understand the nature of post-exertional malaise (PEM) or characterize sleep abnormalities? And are we any closer to a biomarker that could finally lead to a diagnostic test?

Post-exertional Malaise:

When we asked Dr. Komaroff about any advances that have been made in our understanding of post-exertional malaise (PEM), he responded "I think the most relevant advance is the growing recognition that the 2-day cardiopulmonary exercise test (CPET) produces physiological abnormalities that could well explain the symptoms of post-exertional malaise."

"Post-exertion neuromuscular studies reveal reduced anaerobic threshold and peak work, particularly after a second exercise challenge 24 hours later, as well as increased lactic acid in muscle and the need to recruit additional brain regions to respond to cognitive challenges (as demonstrated by functional MRI)," he clarified in his recent review with Dr. Lipkin.


Unfortunately, many people with ME/CFS are intimately familiar with chronic insomnia and/or non-refreshing sleep. So we asked Dr. Komaroff if there had been any progress in our understanding of sleep.

"There is evidence going back 25 years that people with ME have reduced time in deep, restorative sleep each night, and a tendency to wake up as they are slipping into deep sleep. But I don’t think anyone knows why this is. It is just another manifestation of something wrong with the function of the brain," he replied.


A key obstacle to patients receiving a timely diagnosis of their illness is the lack of an effective diagnostic test for the illness. So we asked the good doctor about biomarkers, and whether we are any closer to a real diagnostic test for ME/CFS.

"Quite a number of tests are showing promise at distinguishing [people with ME] from healthy control subjects of the same age and gender. More research is needed to see how these tests perform in people with other illnesses that cause fatigue such as multiple sclerosis, systemic lupus erythematosus, depression, narcolepsy, congestive heart failure, etc."

When pressed to identify a promising biomarker, he replied "there are so many of them that I can’t give an answer off the top of my head. [...] At least you’ve motivated me to consider doing it right, and transforming the answer into a scientific review article."

And a few short weeks later, an article arrived. In a commentary entitled "Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: When Suffering Is Multiplied," Dr. Komaroff pulled no punches in noting the abundance of potential biomarkers and their significance:

"Routine laboratory test results often are normal, raising the question of whether there are any underlying objective abnormalities. In the past 20 years, however, new research technologies have uncovered a series of biological abnormalities in people with ME/CFS. [...] Unfortunately, the normal results of “standard” laboratory tests led some physicians to [...] conclude that there were no underlying biological abnormalities causing the symptoms. [...] The normal results [...] were enough for them to render a judgment. It was a harsh judgment: “There is nothing wrong with you.” For these physicians, it was an efficient solution: it transformed what had been their problem — the lack of a diagnosis they were expected to make — into their patient’s problem. When the patients were told, implicitly or explicitly, that their symptoms were imaginary, it multiplied the suffering."
—Dr. Anthony Komaroff

Bronc is a former historian who is active in his local ME support group. He enjoys interviewing scientists involved in ME research to help himself and others better understand their illness.

Eric Pyrrhus is a scientist with an interest in flaviviruses, coronaviruses, and imaging technology. With undergraduate training at Columbia University and the University of Pennsylvania, and graduate training at U.C. Berkeley and UCSF Medical School, he has studied biomedical sciences, bioinformatics, biomedical imaging, biosensors, computer science, artificial intelligence, and business administration.
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A question: Where is the best place to send the spinal cord & brain after autopsy to help scientists unravel this condition? I told my husband I wanted that done, but his question is legitimate. Where does he send it?
Yours, Lenora.

I believe there is some good information in this discussion:

Autopsy Options

You may need to confirm some of the information there, as it may be a bit outdated.

I know that researcher Maureen Hanson has said that she is interested in studying more tissues...
Boy, this is getting harder all the time! I'm happy to donate my spinal cord and brain to any organization that will put it to the proper use. Therein, lies the problem....how does someone determine the "proper use."

I'll ask my neurologist when I see him at my next appt., he may have some suggestions as he knows my specific neurological illnesses, ME, FM as well as other issues that I face. As much as anything, I'd like an autopsy that could help as many of these problems as possible. Nancy Klimas is a good start for info, but I'll have to find out where she is at the moment. Many places in FL. are possibilities, including some university research units that I know of. It is getting far more complicated than I first thought and I would like to do it properly and give proper directions to my family.

If/when I get a reply, I'll be sure to give everyone the latest info for those interested in an autopsy themselves. There are so many ways of approaching this....it's complicated. Yours, Lenora.
I believe there is some good information in this discussion:

Autopsy Options

You may need to confirm some of the information there, as it may be a bit outdated.

I know that researcher Maureen Hanson has said that she is interested in studying more tissues...

@Pyrrhus....Hi! I didn't see this earlier, but did find out about the Brain Donor Project just yesterday. There may one with the same name in the UK, I haven't checked. This sends samples to multiple research groups, which can definitely be used in my case. Why not help as many illnesses (diseases, we're still not recognized though) as possible. Answers are needed and this is one free and certain way we can all help. Arrangements can be made beforehand.

Thanks for the above info, Pyrrhus, but I just didn't see it in time. I don't always check here. Sorry & thanks for your time. Yours, Lenora.
"Post-exertion neuromuscular studies reveal reduced anaerobic threshold and peak work, particularly after a second exercise challenge 24 hours later, as well as increased lactic acid in muscle

I wonder whether these measured changes in muscles and blood can be the result of neurological dysfunction: the brain isn't responding properly to signals and not producing the right levels of hormones, nutrient transport, etc needed to make muscles work properly.
Excellent article/interview. Many thanks for taking the time and interest to pursue and compile such information. Do you mind if I share with my physician? He has taken it upon himself of late to involve himself in deeper and more complete research into ME/CFS, in order that he might better understand how to assist me and his other afflicted patients.
Links between the different findings are keys to understand ME/CFS.

Here a 2022 study about ePVS (enlarged perivascular spaces), WMHs (white matter hyperdensity lesions) and some intellectual quotient index WMI and PSI (Working Memory index and Processing Speed Index)
3.4 Risk factors associated with the presence of WMHs and ePVS

After adjusting covariates such as gender and age, the presence of WMHs was significantly increased with age (odd ratio [OR] per standard error, 0.91; 95% CI: 0.86 to 0.97) and was more prevalent in subjects with higher QRISK3 score (OR, 0.65; 95% CI: 0.48 to 0.88).

WMHs also associated with cardio-cerebrovascular risk factors such as hypertension and an increased in systolic blood pressure (SBP) (see Table 3).

The presence of ePVS is also associated with age (OR, 0.95; 95% CI: 0.89 to 0.99), QRISK3 score (OR, 0.75; 95% CI: 0.58 to 0.98), and other cardio-cerebrovascular disease risk factors (i.e., family history of cardiocerebrovascular disease, hypertension, higher SBP, and higher body mass index [BMI]).

The prevalence of ePVS was found in much younger subjects compared to WMHs, indicating that ePVS can appear in much younger age compared to WMHs.

However, WMHs was not associated with family history of cardiocerebrovascular disease and BMI.

We found that, gender, ethnicity, smoking status, and education level were not associated with both WMHs and ePVS.

Moreover, we found that WMHs, specifically deep MWHs, was significantly associated with average volume of globus pallidum (GP) but not with CN, putamen, hippocampus (standardized ββ coefficients, 0.67 [95% CI: 0.001 to 0.003], p << 0.05).

In addition, subjects with both WMHs and ePVS (i.e., combined lesion) had higher mean age (49.00 ±± 11.80 yrs); mean SBP (146.00 ±± 12.01 mmHg), BMI (26.67 ±± 3.43 kg/m22), and QRISK3 score (7.99 ±± 7.33%) compared to subjects with WMHs or ePVS alone. However, the differences were not statistically significant.

3.5 Relationship between proportions of WMHs and ePVS with the risk factors and neurocognitive profiles

However, we found that PSI had a linear relationship with age (standardized ββ coefficients, –0.55 [95% CI: –0.94 to –0.38], p << 0.05) and QRISK3 (standardized ββ coefficients, –0.37 [95% CI: –1.91 to –0.34], p << 0.05), respectively.

Hence, aging, and individual with higher QRISK3 score had lower processing speed performance (see contour plot in Fig. 3).

Based on Table 3, the presence of WMHs and ePVS was not associated with odds of reduction in neurocognitive performance, except that ePVS was significantly associated with reduced PSI (p << 0.05).

Moreover, subjects with combined lesion had lower mean PRI score (99.83 ±± 10.81), WMI score (106.58 ±± 14.82), and PSI score (95.08 ±± 12.41) compared to single lesion (i.e., either WMHs or ePVS alone), although the difference was not statisticaly significant.

Additionally, the presence of combined lesion was also significantly associated with PSI (OR, 1.09; 95% CI: 1.00 to 1.18, p = 0.04 <<0.05). Therefore, subjects with ePVS lesion (either combined with WMHs or not) seem likely to have lower speed of processing performance.

Additionally, in subjects with WMHs–the volume of WMHs had a linear association with age and QRISK3 score, whereby the number of WMHs was associated with QRISK3 score (Table 4).

The volume and number of WMHs was not associated with cardiocerebrovascular risk factors (i.e., hypertension, SBP, family history, and BMI) and subjects’ neurocognitive performances.

On the other hand, subjects with ePVS showed a reduced average volume of CN, GP, putamen, and hippocampus were associated with increase age and QRISK3.
Moreover, reduced average volume of hippocampus also associated with a reduced subject working memory (WMI)
(standardized ββ coefficients, –0.46 [95% CI: 0.46 to 12.1], p << 0.05).

Subjects with ePVS lesion in their hippocampus may have reduced working memory performance.

The average volumes of putamen and hippocampus were also associated with subject BMI (see Table 4).

4. Discussion

We sought to determine the interrelations between the prevalence and proportions of WMHs and ePVS with the cardiocerebrovascular risk factors and neurocognitive profiles among asymptomatic individuals.

Interestingly, out of 54 neurological asymptomatic and economically active middle-aged individuals, we found 33.3% and 48.1% with an incidental WMHs and ePVS from the MRI brain, respectively, with the severity ranging from 1 to 2, based on Fazekas scale.

Moreover, ePVS was found mostly in subcortical white matter (i.e., centrum semiovale [92.3%]), basal ganglia including caudate nucleus (CN, 7.7%), globus pallidum (GP, 19.2%), and putamen (26.9%).

Among subjects with ePVS, 30.7% had ePVS in hippocampus. Of note, 12 subjects had both WMHs and ePVS (combined lesion).

Multiple studies had supported the finding that WMHs and ePVS are associated with aging and higher cardiocerebrovascular disease risk (i.e., hypertension and high SBP) and supported the notion that both of CSVD manifestation are particularly common in the world’s population including Caucasian [51], Afro-American and Afro-Caribbean [51, 52], and Asian populations such as Malays and Chinese Singaporeans [53, 54], Chinese populations [55], and Japanese populations [56]. Alarmingly, the prevalence of both CSVD manifestations have been reported to be higher in Asian population compared to western world [57].

The pathomechanism of WMHs and ePVS is still a subject in active research. However, it is well accepted that the pathological changes related to CSVD, and its manifestation are closely linked to the disrupted cerebral microcirculation [33] and characterized by occlusion of cerebral small vessel by age-related microvascular pathology (i.e., arteriolar tortuosity and venous collagenosis, age-related demyelination and loss of glial cells [41, 58, 59, 60]. Alongside several cardiocerebrovascular risk factors such as hypertension, obesity, and type-2 diabetes which in turn lead to decreased cerebral blood flow (cBF) and blood brain barrier (BBB) disruption in CSVD patients [61, 62].

In addition, the disturbance of interstitial fluid (ISF) drainage (i.e., due to waste product accumulation alongside the cerebral perforating arteries) and disrupted CSF-ISF exchange in glymphatic system (i.e., glympopathy) has been associated with the pathomechanism of WMHs and ePVS especially in subcortical region in asymptomatic individuals [32, 63, 64, 65, 66].

We also found that subjects with WMHs and ePVS had lower neurocognitive performance (from WAIS-IV indices) compared with individuals without WMHs and ePVS. Alarmingly, subjects with combined lesion had much lower processing speed performance.

Besides, reduced hippocampal volume in ePVS subjects is also associated with reduced working memory performance based on the WAIS-IV WMI scores. Additionally, we found that aging and QRISK3 was associated with reduced WAIS-IV PSI scores.

etc etc cf article link

5. Conclusions

Albeit from a single center in the suburban east coast peninsular Malaysia, the present study is the first from the region to evaluate the presence and proportion of WMHs and ePVS in asymptomatic, economically active working-aged individuals using neuroimaging and neurocognitive profiling, stratified as low-to-moderate QRISK3 scores.
The study showed interrelationship between occult CVSD manifestations (ie., WMHs and ePVS) with age, QRISK3 and neurocognitive function.

Although WMHs did not influence the subjects’ neurocognitive performance overall, presence of ePVS did influence subjects’ processing speed and working memory (in particular, with hippocampal ePVS and reduced hippocampal volume).

Presence of enlarged perivascular spaces is associated with reduced processing speed in asymptomatic, working-aged adults (imrpress.com)