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0:00
DR. PARKER: This morning, really excited to have a wonderful speaker for you all, this is Dr. Anthony L. Komaroff. He is the Simcox-Clifford-Higby Distinguished Professor of Medicine at Harvard Medical School, and a senior physician at Brigham and Women's Hospital. He holds several leadership positions including Director of the Division of General Medicine and Primary Care within the Department of Medicine at Brigham and Women's, Harvard Medical School. He's a founding
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editor of the New England Journal of Medicine Journal Watch General Medicine, which is the publication of Medical Society in New England Journal of Medicine, he is the editor-in-chief for all Harvard Medical School's consumer health publications, and author of ongoing series of articles about the impact of basic biological research on medical practice, and he has published over 270 research articles, and book chapters and 2 full books. In the past 30 years his publications
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have been focused on myalgic encephalomyelitis/ chronic fatigue syndrome, ME/CFS, so you'll hear us say ME/CFS a lot this morning, and the biology and clinical consequences of infection with Human Herpes Virus 6A 6B. He served on multiple committees of the Department of Health and Human Services, the NIH, the CDC and National Academy of Sciences. He's a project PI on one of the NIH-funded ME/CFS research centers, so we are so happy to have you here today,
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one of the things COVID has done is opened up our Zoom lectures to some stellar presentations, and you are one of them, Dr. Komaroff. So today we're going to learn all about the pathophysiology of ME/CFS, and I will let you take the floor, Doctor. DR. KOMAROFF: Thank you so much, Dr. Parker, and thanks to everyone for inviting me. My goals today are to describe the clinical presentation and case definition of ME/CFS, to review the underlying
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pathophysiology, very briefly, to describe treatment alternatives, and finally to discuss similarities between ME/CFS and what is being called Long Covid, lingering symptoms after Covid-19. So the first question that one often hears, less needs these days than 20-30 years ago, is: 'is ME/CFS real?' Meaning are there objective biological markers that are abnormal in ME/CFS, and do we understand the pathogenesis of ME/CFS? My answers to those two questions are 'yes,' and 'no.' First, let's put
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ME/CFS in context. Any of us are who are in or have been in primary care know that the presenting complaint of fatigue is very common, one of the top 10% presenting complaints according to the National Center of Health Statistics. And many studies of what is the underlying cause of fatigue as a complaint in primary care have been done, and they generally agree that of all of the people with a presenting complaint of fatigue,
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many are suffering from major depression as probably the factor causing the fatigue. Fewer studies had formerly examined overwork, but those studies that have indicate that overwork is, that the work week in America, for men and particularly women, has been increasing over the last 40, 50 years, and is a cause of chronic fatigue. Occasionally, well-recognized organic diseases: an occult malignancy, anemia, hypothyroidism, are the underlying cause of the presenting complaint of fatigue,
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but it's not very common, and occasionally, ME/CFS is the cause of the presenting complaint of fatigue, but that also is much less common than depression and overwork. So since depression is a common cause of fatigue as a presenting complaint, why isn't ME/CFS 'just' depression? Well, there are four general reasons. One is that a variety of neuroendocrine studies have been done that show quite different responses in people with ME/CFS from those with depression.
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Second, treatment trials, randomized trials of SSRI's have not been able to cure ME/CFS. Third, several nervous system and immunologic findings distinguish ME/CFS from depression, and then finally and most directly, formal psychiatric assessment finds that fewer than half of patients with that ME/CFS have ever suffered, in their lifetime, an episode of major depression. ME/CFS is a problem of considerable scope and seriousness. In 2015, the Institute of
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Medicine of the National Academy of Sciences published a book basically, a very long report, in which they cited CDC data that the estimate is that between 800,000 and 2.5 million Americans have them ME/CFS. The direct and indirect economic costs of this annually range from $17-$24 billion dollars. They've described ME/CFS as "a serious, chronic, complex, systemic disease that often can profoundly affect the lives of patients,"
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and not, as many clinicians believe, a psychological problem. How is ME/CFS defined? There are several case definitions, the most recent, and probably now the most widely used, was created by the Institute of Medicine, and it's shown here. The criteria are: substantial impairments in the ability to function, at home or at work, lasting for more than 6 months, and accompanied by profound fatigue of new or definite
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onset, not lifelong, that is not substantially alleviated by rest, so that's, that's for openers. And then in addition to that, there is a state of post-exertional malaise. This is a condition in which people following, typically, physical exertion, or sometimes cognitive exertion, may feel good, may even feel exhilarated while they're doing it, but the next day, feel like they were hit by a truck:
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they have much worse fatigue, more trouble with concentration and cognition, more pain, sometimes fevers. That post-exertional malaise is a cardinal feature of ME/CFS, and we'll come back to that in a minute. Third, unrefreshing sleep, virtually every night. All of us wake up sometimes feeling unrefreshed, but with this illness, virtually every morning, even in people who think they slept well, they feel unrefreshed on waking.
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Plus, at least, documented cognitive impairments or orthostatic intolerance. These are the cardinal features of ME/CFS, by this most widely used case definition. Who are these patients? First of all, there is a difference between patients who seek care in a primary care practice or specialty practice for their symptoms, and those who don't, and there's a surprising number of people who community
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surveys show have this illness, but have never sought care. We don't know as much about them, obviously as we do about those who have sought care, but the ones who have sought care, in my experience over 35 years and that of my colleagues around the world, they tend to be young adults in their mid-thirties when the illness starts, although it can begin in childhood and it can begin later in life. 65% roughly
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are female, but there's a substantial minority who are males. They're typically middle-class, and indeed the illness is more common among African-American and Latino minority populations when you do community outreach surveys. Of those seeking practice, 50% are college graduates-- Can I ask folks who are listening in to mute? Because we're getting some background noise. [inaudible] Thank you. 50% of college graduates in office-based samples, uh, 50% *are* college graduates
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in office-based samples, 50% are intermittently bedridden or shut-in, and the average duration, the last time we measured it in the population of people we see, was 14 years. The thing that first attracted my attention about this illness, made me think that was an illness that I hadn't read about in textbooks was this: that in the majority of patients, not all of them, but the majority, people say, I was perfectly healthy, I was fine,
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and then one day I came down with, they might say a flu, a virus, a bad cold an infectious-like illness, not very different from infectious-like illness they had in the past characterized by respiratory, gut, other symptoms, fever, but was different was, they feel they never got over this acute infectious-like illness, and now it's months or years later and they're still hobbled. That I hadn't heard before, and that you hear from
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the majority of patients. We talked about post-exertional malaise as a cardinal feature of ME/CFS. What are the objective correlates of that? First, let's look at fatigue levels itself. This is a study of, [coughs] pardon me, an exercise study in ME/CFS patients in red, and healthy controls in blue, measuring the levels of fatigue pre-exercise, immediately post-exercise, 48, and 72 hours after exercise. Look first at the healthy
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controls. Immediately following exercise, in blue, you can see the fatigue level rise as you would expect. But, 48 and 72 hours later, fatigue level, if anything is lower than it was pre-exercise, probably the experience most of us have with regular exercise. In ME/CFS, however, the level of fatigue pre-exercise, not surprisingly, is higher than a healthy controls, goes up post exercise, but then it stays up, at 48 and 72 hours, very different from in the healthy controls.
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What about the impact of exercise on cognition? This is, let me walk you through this slide, again, the ME/CFS patients to are in red the controls in this case are gray, what's being plotted on the y-axis is the number of errors in formal cognitive testing. The test is repeated 3 times, pre-exercised, and then repeated three times post-exercise. Let's look first at the healthy controls. When the test was repeated pre-exercise, each time to test was
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repeated, the number of errors dropped. It was a learning effect: they were taking the same test repeatedly, getting a little better at it, and then when they took the same test post-exercise, the number of errors dropped or continued to drop. But in the ME/CFS patients, each time they were cognitively challenged, the number of errors kept going up, pre-exercise, and then post-exercise, very different pattern. So, we have an illness with the whole group of symptoms,
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including cognitive symptoms, what do we know about what's wrong in the brain? There have been now, probably over 1,000 peer reviewed published studies, looking the brain in different ways in people with ME/CFS, and there is robust evidence of neuroendocrine dysfunction, that is impairment of multiple limbic-hypothalamic-pituitary axes, and of the serotonin system. There are formal tests of cognition with shown impairments in cognition, particularly information processing speed,
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memory, and attention, that are not explained by any concomitant psychiatric disorders that some patients may have. There is autonomic dysfunction, both impaired sympathetic and parasympathetic function, in 30%-80% of people. MRI abnormalities of multiple types, SPECT abnormalities, PET abnormalities, I'll show you some of those, and EEG abnormalities, an increase in the number of sharp spike waves, and the distinctive spectral coherence pattern
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that almost perfectly people with ME/CFS from healthy and from major depression patients. Here is a noninvasive measurement of lactate in the spinal fluid in people with ME/CFS, and in people with generalized anxiety disorder, and healthy controls. A clear difference that indicates a shift to anaerobic metabolism in the brain, and we'll come back to that momentarily. Neuroinflammation looks like it's an important component of the underlying biology of ME/CFS. By neuroinflammation I
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mean activation of both the innate and adaptive immune systems in the brain, by stimuli, either in the brain, or from outside the brain, I'll describe that in a second. Here is a formal test of neuroinflammation, been very hard until the last 5-10 years, to measure neuroinflammation non-invasively in humans, but now PET techniques exist to measure the activation of glial cells in the brain, the main immune cells of the brain, and what it showed in this study was a clear increase in markers of
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neuroinflammation in the ME/CFS patients compared with the matched healthy controls. Small study, needs to be replicated, and has been replicated in- by a couple of other small studies but I'd like to see a larger study before I became confident in this. Interestingly, similar evidence using PET scans of neuroinflammation has also recently been reported in people with fibromyalgia, a clinical condition with a lot of clinical
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similarity to ME/CFS. This is a study from MGH and The Karolinska Institute. Just looking at the left, you can see that the ME/CFS patients in red have higher levels of inflammation than the control patients. I said earlier that there is autonomic dysfunction, and that's been demonstrated in a wide variety of autonomic tests. Here's just one, and let me focus you just on the left part of this slide. These are people who were subjected to a tilt table
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test, and when the table was tilted upright, in the healthy controls, there was a small drop in cerebral blood flow, but in a ME/CFS patients, there was a much more dramatic drop in cerebral blood flow. A, at least, temporary failure of the local sympathetic system to adequately perfuse the brain. There's a state, also, of chronic immune activation, as demonstrated by many different markers of inflammation in hundreds of studies: increased levels of circulating
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immune complexes, increased levels of IGG, decreased levels of certain IGG subsets, increased levels, or increased numbers, rather, of the activated CD8 cytotoxis T cell, poorer function of natural killer cells, important cells in antiviral defence, and increased blood levels of, and lymphocyte production of, cytokines particularly pro-inflammatory cytokines. Here's the largest, and in the my opinion, best study of cytokines in ME/CFS patients. This
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is a study from the laboratory of Mark Davis at Stanford, one of the world's most honored immunologists, a study of nearly 200 ME/CFS patients, and nearly 400 healthy controls, in which 51 different cytokines were measured in the same sample of blood, and the level of the cytokine correlated with level, or the severity, of the Chronic Fatigue Syndrome. Here just to take one of the 17 of the 51 cytokines
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of which which a strong correlation was observed, you see that as the level of the cytokine goes up, the severity of the illness goes up, and that's entirely plausible, because we know from therapies using a variety of cytokines, interleukins, interferons, for typically treatments of malignancy, sometimes other disorders, that when the infusion of the cytokine starts, people often develop, temporarily, a symptom complex that's very much like
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ME/CFS, and when the infusion is turned off, the symptom complex goes away, so could the symptoms of this illness reflect an increased production of cytokines, certain kinds of cytokines, in the brain? There's also many studies now showing a variety of autoantibodies in ME/CFS, increased numbers of B cells, anti-nuclear antibodies, anti-cardiolipin antibodies, and a variety of antibodies that target the central or autonomic nervous system. What about studies of infectious agents?
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I've said that a majority, but not all, patients with ME/CFS say it all begins with a flu-like illness. What do we know about the relationship between the acute infections and chronic fatiguing illnesses? Well in fact, there's a huge literature on a variety of post-infectious fatigue syndromes, some of it, just like a ME/CFS, infectious-like illness has been which typically no attempt has been made to document the infectious agent because it was assumed to be a transient, typical
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infection, not worth documenting. But following well-documented other viral illnesses, a wide variety of very different types of viruses, Epstein-Barr virus, Ross River virus, West Nile, SARS, and bacteria: Lyme Disease, an odd bacteria like coxiella burnetti and mycoplasma, and even parasites like giardia lamblia. Infection, at least of certain types, well-documented, has been followed in some people, typically a small
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minority, by a chronic, debilitating illness, raising the question: do all of these illness share some common underlying pathophysiology, and do they share it with the ME/CFS? Abnormal energy metabolism. Early on in this illness, someone puts forward a hypothesis that, at least I thought, was pretty simplistic, which was that, if the organism, the human, experiences the lack of energy, perhaps there is a defect in energy metabolism at
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the cellular level. While that seemed pretty simplistic to me, there is now an abundant literature that is consistent with that hypothesis. We now have, really in the last 10 years, technology has developed that makes it possible in a single sample of blood or spinal fluid, whatever, the ability to measure simultaneously hundreds, even thousands, of molecules of different types:
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small molecules like metabolites, large proteins, and what those studies are showing is that the levels of most metabolites are lower in people with ME/CFS. This is a pattern that is seen in hibernating animals. There are abnormalities that incriminate the impairment of cellular energy production, including impaired oxidative phosphorylation, as I'll show you, and there is one study not yet,
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no attempt to replicate it yet, I'm aware of, of the defects in one critical enzyme in energy metabolism: pyruvate dehydrogenase. But what strikes me is that there appears not to be single focal defect, but, in fact, a general pattern of downregulation of pathways that generate energy from sugars, from lipids, from amino acids, and from oxygen. As if the body has been instructed to throttle down energy production. Oxidative phosphorylation is considerably different
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in people with ME/CFS than in matched healthy controls. What about another big area that was off everyone's radar screen in human health even ten years ago, and now is really at the center of many studies of human health: the microbiome? As I think you have heard, we've known for close to 200 years that there are trillions of microbes living on us, and in us but we had thought, for most of that 200 years, that they were virtually all just freeloaders, they were- they were
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there for the ride, they were there for our- the heat of our body and for the nutrients we would provide them, and they were just innocent bystanders doing nothing to affect our health, but in the last 10 years, when it's been possible to identify how many of these microbes there are there, are and what their genes are, and what their genes do, we have discovered that these microbes make molecules that not only affect microphysiology, but that also affect human physiology. In ME/CFS, a number of
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studies now have shown that there is a dysbiosis, an imbalance in various species of gut microbior- micro-organisms, that leads to gut inflammation, that leads to increased permeability of the gut wall, which leads to gut to become leaky, allowing bacterial products like- like polysaccharide and full bacteria to enter the circulation, which activates the body's systemic inflammatory response, and may, this is less well-documented, trigger autoimmunity,
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which leads to a leaky blood-brain barrier, which leads to humoral signals getting into the brain that activate the innate immune system of the brain, and also, by the way, the gut inflammation sends retrograde signals up the vagus nerve, directly into the brain that also activates the innate immune system of the brain, so inflammation inside the brain, or outside the brain, can signal the brain's inflammatory system to turn on. So I've said a group of abnormalities have been documented in
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ME/CFS, brain abnormalities of wide variety, autonomic abnormalities, chronic immune activation, post-infectious onset, often, impaired energy metabolism, abnormal gut microbiome, I would say- you know, all of those things are now pretty solidly documented. The question, and the unanswered question now is: how are they all connected to each other? Because if they're all part of one big pathophysologic process,
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they have to be connected to each other, and how do they lead to the symptoms of this illness? So now I want to talk a little speculatively about that. In a review article published that I just published in August with colleagues Bindu Paul and Solomon Snyder from Johns Hopkins, we pointed out the evidence for all of these different abnormalities in ME/CFS, and pointed out in
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particular, how these abnormalities influence each other: how oxidative and stress, for instance, triggers chronic inflammation, and likewise, chronic inflammation triggers oxidative stress. How oxidative stress triggers mitochondrial dysfunction, and likewise mitochondrial dysfunction triggers oxidative stress. All of these cardinal elements that are seen in ME/CFS talk to each other in both directions, there is the potential for a whole series of pathophysiologic vicious
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circles that exist in people with ME/CFS. But why the symptoms? What causes the symptoms in ME/CFS? Well, let's begin- I'll present a hypothesis that many people think is plausible and worth pursuing, I'm one of them, I'm not saying it's proven, but I am saying there's a fair amount of empirical evidence in support of it. So what do we feel like when we get sick? We've all gotten the flu or some similar illness, what do you feel like?
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You know what the symptoms are: it's pretty characteristic, and, in fact, from one infectious-like illness to another, while there may be certain specific symptoms like gross diarrhea in one and not in another, there are shared, complex symptoms that are almost stereotyped. Why do we feel that way when we get sick, when it's a virus or microbe enters our body, for instance? It's well-documented in the biological literature that there is, in most animals, a hardwired
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system, a hunkering down mechanism, a temporary acute response to injury or to infection, in which the brain generates a series of symptoms that leads to a reduction in energy consuming activities, so we become lethargic, and we- we have social withdrawal, we're achy, we don't want to move around very much, we're sleepy, we don't want to move around very much, there's a loss of libido, difficulty thinking, depression, reduced appetite, we don't want to digest very much.
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why are all of these activities that consume energy throttled down by this set of symptoms, so as to conserve the body's available energy stores to fight the infection, or heal the injury? And when that infection or injury is healed, that behavior is turned off, that happens in every one of us when we become seriously injured or infected. The question in this illness is: can that temporary mechanism, somehow, for some reason, become stuck, become chronic,
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become not turned off when it should be? That's the question, our question to study, but we know that we see this sickness symptoms syndrome in most animals, even in invertebrates, and in fact if you think about it, you can tell when your pets are sick by the way they look, by the way they behave. Animals behave like we do when they get sick. So it is- the theory I'm putting forward is that the symptoms of sickness are generated by neuroinflammation, and that your neuroinflammation
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is the cause of the fatigue, the cognitive problems, and the group of other symptoms that one sees. What's the evidence for that? I've already shown you several studies, only a few of the studies I could have shown, of neuroinflammation in ME/CFS. Is neuroinflammation a cause of fatigue? I don't have time to show you several studies from MS patients, in which it's pretty clearly shown that the degree of neuroinflammation in the brain is what correlates
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with the degree of fatigue the MS patients suffer, much more so than the number of plaques, for instance, or the extent of neurological damage. Now let's turn to Long Covid. To a similar chronic debilitating illness that appears to be developing in people following acute Covid-19. What do we know about this illness? Well, first of all how common is it? This is a study from- a massive study from the United Kingdom. Of all of the 67 million people in the United Kingdom, this is *all* people,
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not all people infected with Covid, all people, 1.6% now record persistent symptoms that are not otherwise explained, that remain symptomatic one year later when they've had Covid, that are adversely affecting their daily activities and greatly limiting those activities, and the symptoms that are mentioned most often are fatigue, similar to ME/CFS, dyspnea, not common in ME/CFS, myalgias, difficulty concentrating, again overlapped with ME/CFS.
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And the prevalence of these self-reported Long Covid symptoms is greater, appears to be greater, in people who became ill with Covid, between the ages of 35 and 69, a little bit greater in females than males, a little bit greater in people from lower socio-economic groups, and in those who had pre-existing health conditions. What do we know about associated abnormalities,
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biological abnormalities in people with Long Covid? Well, as you might expect there's not a lot of studies about it yet, but there are quite a number, and they show persistent endothelial dyfunction, with an associated coagulopathy, dysautonomia, just like in ME/CFS, small fiber neuropathy, as has been mentioned that has been shown in ME/CFS, a hypometabolic state in the brain on PET scanning, as I said existed in ME/CFS,
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and persisting cognitive deficits by several studies, typically deficits in attention and concentration as are seen in ME/CFS So the way I put together the very preliminary evidence so far on Long Covid, is there probably is a post-Covid form of ME/CFS, but what we don't know is how common it is, how long it lasts, and what the diagnostic tests and treatments should be in this illness, and what we don't know is whether it really is-
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shares the same underlying pathophysiology as ME/CFS, but fortunately the NIH is set to invest close to a billion dollars to studying the various chronic illnesses that follow in the wake of acute Covid-19, and hopefully those studies will offer answers that apply not only to Long Covid but also to ME/CFS. Let me turn back to ME/CFS and talk about, briefly about diagnostic tests. I want to make one point, that I think
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it is often confused. There are, now, many different objective biological tests that are able to distinguish patients with ME/CFS, as a group, from healthy controls in some studies, that distinguish them from depressed controls. But there are none, none of these studies have sufficient sensitivity, and sensitivity, even though they are there statistically significantly able to distinguish people with ME/CFS than healthy and sometimes depressed controls
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to constitute a diagnostic test. Some of them that do have sufficient sensitivity and specificity haven't yet been tested for their specificity in people with other fatiguing illnesses like MS, like lupus, for instance, so we still can't stay there are good diagnostic tests, but there's a lot of work going on to try to make them good diagnostic tests. So the diagnostic tests that are used in ME/CFS are really tests used
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to try to rule out other fatiguing illnesses like ME/CFS, pardon me, like MS, or like lupus. What about treatments? There's no treatment that has been shown conclusively, by large, lengthy, replicated randomized trials to have long-term effectiveness in ME/CFS. There is a lot of anecdotal experience, however, that finds that, as has been demonstrated with randomized trials in fibromyalgia, very low doses of tricyclics,
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very low doses, help improve the sleep disorder that is associated with ME/CFS. The same is true of Doxepin and Trazodone. Non-steroidals can be helpful for the pain that's associated with ME/CFS in many patients. Jury is still out on a lot of other treatments that have been studied, some of them in small, randomized trials with not slam-dunk results, in my opinion. Cognitive behavioral therapy and gradual exercise, graduated exercise, have been studied in
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randomized trials and shown to be beneficial, but those trials have been shown, in my opinion, to have serious flaws, so I don't take those trials as strong evidence of the value of these treatments. Prognosis, what do we know? A systematic review of 14 studies of prognosis ME/CFS patients found that full recovery occurred only in about 5% of patients. Improvement over time in about 40% of patients, and a return to work in only a minority of patients.
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Now I would say the quality of the studies included in the systematic review were not all great, and not all of them really followed patients for a long enough period of time to say much about the long-term prognosis, but in my own experience, following some patients for close to 30 years, I can- there are many patients unfortunately we remain ill all of that 30 year period. So, in summary, ME/CFS is not an imaginary illness. It has underlying biological
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causes, it's often triggered by an inherent infectious-like illness, it is is characterized by chronic immune activation and neuroinflammation, the presence of a variety of autoantibodies, many of them targeting the nervous system, oxidative stress, defective energy metabolism, autonomic abnormalities, pro-inflammatory gut microbiome. These abnormalities are all connected, in biology in general, and probably in people ME/CFS specifically, and they reinforce each other.
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they are probably the cause of the chronic sickness symptoms, although to prove that you would have to intercept them, stop them, demonstrating reduction in symptoms, and intervening in that hugely complicated set of interconnected abnormalities is not something we've been clever enough yet to figure out how to do. So, in summary, ME/CFS is an illness that, for many years, was
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somewhat controversial and for good reason, because for many years there wasn't much evidence, *objective* evidence of underlying biological abnormalities. That now, I think, should be put to rest. This is a biologically-based illness, it has similarities to Long Covid, it hasn't yet been if they share the same pathophysiology, but my bet is that the- underlying biology of the two illnesses will prove to be similar, and that the lessons learned in studying one will prove to apply to the other.
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Thanks very much for your attention, I'm happy to take any questions.
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