symptoms – American ME and CFS Society

Dr. Bell on ME/CFS Symptom Variation: Illness or Host?

ProHealth.com
by David S Bell, MD, FAAP
March 7, 2012

This information is excerpted from the Nov 1999 issue of the Lyndonville Journal – a bi-monthly newsletter from Dr. Bell’s medical office that preceded the Lyndonville News. It is reproduced here with kind permission,* and offers still-relevant insights, as research to identify proper case definitions, potential ME/CFS subsets, and causes continues.

Reprinted with the kind permission of ProHealth: 3/7/12

Symptom Variation: Illness or Host?

Roughly 70% of the persons I see in the office have a pattern of symptoms that is “typical of” chronic fatigue syndrome (CFS). The remaining 30% have variations where doubt can be raised as to the diagnosis. This variation in symptoms is the main reason that researchers may see CFS as a variety of differing illnesses that produce fatigue as a symptom…. But I feel that the vast majority have a single illness, rather than CFS being a mish-mash of different illnesses. The issue here is the debate of illness versus host.

What exactly comes from the cause, and what comes from the host response? To look at this conflict, let us look at chicken pox.

Chicken pox is an everyday, run of the mill, simple illness. Every clinician makes the diagnosis with ease. You seen one chicken pox, you have seen a thousand. It is simple and it is one single illness. That is because it is an illness that affects a distant target organ – the skin. A five-year-old comes in with a fever and little blisters that look like a “dew drop on a rose petal.” And that is exactly what a perfect chicken pox looks like. (I have no idea where the chicken part comes in.)

There may be some minor variations. A child may have 30 pox or 300. Some pox (or poxes?) may get infected or scabbed over. Big deal, it is still chicken pox, one illness. The host (or person with the illness) does not affect it much.

But wait. In some cases the host is critical and the illness can be different. Some people have chicken pox without a rash, or have a pneumonia, or worse yet, have a neurologic complication. Is it still chicken pox? Yes, because we are able to culture the virus from the lung or brain, and it is the same as the regular chicken pox in the skin.

In CFS we do not have this luxury. The situation is different.

Whatever CFS is, it affects a very central mechanism within the body, not an end organ like the skin. And this central mechanism, probably the brain, can manifest the symptoms of an insult very differently. With the brain, the same injury or illness causes a variety of symptoms. (Brain tumors, for example. The symptoms of a one-inch area of brain injury depend entirely upon the location of this injury. In one area, there may be minor if any symptoms. In another it might cause arm weakness, in another area, behavior or emotional symptoms.)

Let us suppose for one minute that a single neurotropic virus – one that affects brain tissue – causes CFS. If this virus affects only a small part of the brain, the symptoms will be uniform (post-encephalitic Parkinson’s). But if it affects more than one area, then a multitude of symptoms may result, with clear variations from person to person (Post polio syndrome). The issue is the competition between agent specificity and how the host responds to it (host versus illness).

The enormous complexity of both genetic and environmental factors makes people different. By itself, this is an interesting discussion, and probably a good thing. But science would be easier if we were all clones. (We would probably get along better as well.) The complexity of host response, differences in immunity, emotional vulnerability, and environment makes it so that the same injury may cause a variety of responses, particularly if that injury is to a central or primitive part of the brain.

In CFS, we can trace the symptoms to this primitive part of the brain where hormones are produced, where sleep and alertness are regulated, where blood pressure and heart rate are controlled, where pain is modified.

One person with CFS may have asthenia [lack of energy and strength] as the worst symptom. In another, pain is the worse symptom. Are these two illnesses, or are they the same?

The answer is seen not by looking at one or two symptoms, but by examining the entire symptom pattern. For now, it is reasonable to define CFS broadly without being picky. A clinical, symptom-based diagnosis is appropriate, with the understanding that other fatigue-causing illnesses have been excluded. The pattern of symptoms rather than the specific worst symptom defines the diagnosis. And this pattern may vary from person to person. I do not see this variation as due to differing illnesses. Rather I see the same illness having differing host responses.

The roots of my bias are easy to spot.

In Lyndonville, many persons developed severe fatigue and other symptoms due to something. Because this took place in an isolated rural community, I feel that it must have been a single event. [The 1985 ‘Lyndonville outbreak’ of CFS affected 210 persons, 60 of whom were children, a patient group that Dr. Bell continues to track.(1)] I do not think that 15 different cause of CFS hit all at the same time. For this reason, the variation of symptom severity and even emphasis must be due to host responses rather than cause.

Two children in the same family become ill: One has acute onset, one gradual; one with fatigue as the worst symptom, one with headache. But it is too much of a coincidence that these would be different illnesses within the same family at the same time.

As an aside the CFC has stated that CFS does not run in families. This is because all may not fit the CDC research criteria. But most clinicians feel that there is a clear familial component. If three family members develop chronic fatigue at the same time, host response is more likely to explain the differences in symptoms than the possiblity of separate illnesses.

At the time of the CFS ‘outbreak’ in Lyndonville, there were those with viral infections that caused two months of fatigue. Lucky individuals. And there were siblings who got full-blown CFS. My hunch is that it is the same initiating event expressing itself differently in separate individuals.

We will know the answer to host versus illness only when an an underlying cause is known in a few persons. Then we can see if the others have evidence of the same underlying cause. This was the case with HIV infection. Some persons would have cancer, some bad pneumonias. Only when a specific initiating event was found was it possible to understand the full spectrum of HIV infection.

So now we have to wait. We can create a definition, and start from there. It is my hunch that we will soon define appropriate subgroups of CFS. And it remains to be seen whether these subgroups are artificial or will accurately define different causes of CFS.

But until this occurs, persons with CFS should not be denied appropriate diagnosis, treatment, or disability benefits if warranted. The definition of CFS now must be broad. Whether due to host response or initiating cause will be answered eventually with research.

I am going to put my money on:

• A few different initiating events,

• Causing a specific physiological injury,

• In persons with varying host response.

And I keep wondering why I am broke.

– Dr. David S Bell, MD, FAAP, Nov 1999

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1. See Dr. Bell’s presentation on his tracking of the Lyndonville outbreak patients (“25 Year Follow-up on Chronic Fatigue Syndrome: Rising Incapacity,”), delivered Apr 16, 2011 as part of the Massachusetts CFIDS/ME & FM Association’s lecture series. (Allow ample time for the video download.) He discusses symptom variation, and theorizes that ‘fibromyalgia’ is a term people use when they’re able to be up and around, but their pain is considerable.

“The Fruitcake Factor”: Dr. Bell on the Neurologic Nature of ME/CFS

by Dr. David S Bell, MD, FAAP*

This ME/CFS patient case history is one of 10 that Dr. David Bell included in his book Faces of CFS – Case Histories of Chronic Fatigue Syndrome, published in August, 2000. Each case illustrates a different aspect of the illness that he has studied in patients affected by the ‘Lyndonville Outbreak’ over the years.

Reprinted with the kind permission of Prohealth: 3/2/11

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THE FRUITCAKE FACTOR

“Neurologic symptoms appear to me to be the most direct window into the heart of this illness; they both define and explain CFS.” – David S Bell

When I was a child, I lay in a field one sunny day, puzzling over something that was brand new. Staring at the sky, I noticed what seemed to be an object of unknown identity hovering in my left field of vision. When I turned my head in its direction, however, it seemed to slide away and disappear. I realized I could also see a similar strange shape in my right field of vision. If I directed my gaze ever so slightly away, it might remain still for a moment, delicately balanced, but it slid away, too, when I turned my head to focus on it. They were shy, transparent objects, and they were not really in the sky. I studied the problem for an hour or so, then I fell asleep.

During my medical training, I learned that these curious objects are called “floaters” by neurologists and eye specialists. They are white cells that have collected in the anterior chamber of the eye. Almost everyone will notice them from time to time.

I have decided that floaters are very like CFS since, whenever you try to look directly at them, they skitter off to the periphery and then disappear. If you pretend not to really look at them, they may hold still just long enough for you to get some sense of their shape and size. Certainly, the illness I study in Lyndonville is like that. The harder you look at a specific aspect of CFS, the more whole disease slides off to one periphery or another, hiding itself just beyond your line of sight.

Let me give you an example. Nearly 80% of people suffering from CFS will have joint pain at some point in their disease, and many will have it as a chronic symptom. Yet, this pain is by no means a true arthritis.

When these painful joints are subjected to X-rays, the image looks normal; there is no joint damage or deterioration. I am able to rule out rheumatoid arthritis, a more severe disease than the common osteoarthritis, in CFS patients, as well, because the blood tests used to diagnose rheumatoid arthritis are negative.

I have noticed that the typical rheumatologist seeing a CFS patient may end up – as I did once as a child studying curious objects in the sky – falling asleep before the patient even comes to the end of his symptom list. Whatever the root cause of CFS, joint pain is some distance away from it.

Still, there are a few symptoms a doctor notices in CFS sufferers that I believe are crucial to understanding the disease.

Amanda Lewis was nearly 40 when I first saw her, and she had been ill with CFS for years. She had all the typical symptoms: unending fatigue, joint and muscle aches, headaches, trouble concentrating.

As her years of illness wore on, she had learned ways to cope with these unpleasant sensations, but there were a whole category of symptoms, which came under the heading of “neurologic,” from which she rarely found relief or escape, nor could she hide them from others.

• Lights hurt her eyes, and certain high pitched noises caused her to experience pain just behind her ears.

• Sometimes her fingers hurt when she touched objects.

• Amanda also described a burning sensation in her arms, as if they were in flames, and occasional episodes of either numbness, or tingling, in her arms.

• On occasion, she would also experience tremors in her upper arms, which would shake and begin to rise involuntarily. If Amanda had lost consciousness at such times, one could say she was suffering a seizure, but these were not true seizures because she was fully conscious throughout the ordeal.

• Amanda discovered, too, that on occasion her arm and hand muscles were so weak objects like empty coffee cups would just slip out of her hand.

Most distressing to her, Amanda’s intellectual capabilities seemed to have been shattered.

Sometimes she got lost – in her house. When she cooked, she sat by the oven until her food was ready in order to make sure she remembered to turn off the burners. She was utterly helpless when it came to managing two simple tasks simultaneously; she simply lacked the ability to concentrate.

She felt her brain’s gears had gone rusty.

I was hardly the first doctor Amanda had consulted. Among those few doctors who took her complaints seriously, a few had suggested her intellectual difficulties were the natural result of aging, a worrisome suggestion, as she was young.

In addition, although all the symptoms she described to these doctors could be huddled together under the umbrella of neurologic disease, they had been unable to find evidence of muscle wasting or atrophy, nor had they been able to measure any abnormal degree of weakness, using standard neurological tests. (They did detect a slight tremor in her arms and hands, however.)

In addition, Amanda failed what’s known in medicine as the Romberg test, named after its inventor. When she stood in a relaxed stance with her arms outstretched, she wobbled and usually fell backward and to the right.

When Amanda came to see me and described these problems, I decided to test her reflexes.

Everyone who has ever had a physical exam remembers the doctor tapping a rubber hammer on their knee, and watching their lower leg jerk forward. That’s a normal reflex.

When doctors test reflexes, they are checking a “reflex arc,” a nerve circuit or pathway that travels from a tendon in the leg to the spinal cord and back to the leg muscles. Diseases that interfere with the nerves of the leg will suppress that reflex to kick your doctor in the groin.

I was startled when I tapped Amanda’s kneecap tendon. She didn’t kick me – her whole body shook.- In fact, she almost jumped off the table. I then tested her vibratory sense with a tuning fork, the ability of her leg nerves to detect vibration. Her reaction was more muted, but similar to the first response by being exaggerated. It seemed to me as if Amanda was very much like a set mousetrap that was ready to trip given the tiniest nudge. I think this was the first time I was worried about hurting someone by tapping a tendon with a rubber hammer.

• I sent Amanda to a specialist, a neurologist. His diagnosis: Huntington’s chorea, a fatal disease of the central nervous system. Amanda was hardly cheered by the news, and I was dubious because her tremor was unlike the jerking motions of “chorea.”

• I arranged for another neurologist to see her in an effort to get a second opinion. The second neurologist suggested that Amanda might have multiple sclerosis, but seemed unwilling to test his own hypothesis by conducting the standard diagnostic tests for the disease.

• A third neurologist insisted that all of Amanda’s symptoms could be ascribed to depression. He prescribed antidepressants.

When I asked him, in a telephone conversation afterward, about Amanda’s remarkable response to tendon tapping, he assured me that her response was phony. Nobody jumps off the table when you tap their reflexes, he noted with a degree of confidence I found chilling.

I realized he was telegraphing to me some basic information he believed I needed to know: Amanda was a fruitcake. Amanda’s exaggerated reflex response became “the fruitcake factor.”

Neurologic symptoms appear to me to be the most direct window into the heart of this illness; they both define and explain CFS.

The reluctance of neurologists to be interested in CFS mystifies me. Perhaps it is too difficult; perhaps it is because they prefer the classic symptoms of seizure, isolated headache, and the shaking of Parkinson’s disease.

CFS is a unique blend of numerous neurologic symptoms, none of which are well understood today.

• The fatigue (not tiredness) must be generated somewhere in the primitive midbrain;

• The sleep center is nearby and clearly does not work correctly.

• Cognitive problems, pain, and headache are clearly neurologic.

• Even the immune system problems of CFS may be neurologic as we know that brain injured patients display immune system abnormalities.

But right now it is too complicated. Physicians can be very interested and scientific when it regards any other organ of the body, but the thing that sits atop the shoulders remains the “black box” of medicine and is largely ignored.

I have no problem with not understanding the exact mechanism of the symptoms of CFS. I was never good in the two week neuroanatomy class in medical school. I do have a problem with the lack of respect given patients with poorly understood neurologic disease.

Science has created a false aura of mastery, and if there is an area where mastery does not apply, it is an area to be disregarded, ignored, and even ridiculed. And this injury by the medical profession and society hurt almost as much as the symptoms of CFS.

I routinely see patients with CFS who are disappointed when an MRI scan does not find a nice big brain tumor. At least that is real. Ultimately, the neurologic symptoms of CFS will gain a foothold in the thinking of neurologists and garner respect. The brain is the Rodney Dangerfield of medicine.

It was a colleague who first described to me a possible mechanism for the fruitcake factor in CFS. Paradoxically, this symptom is prominent in only a small minority CFS sufferers, always the most severely ill; it may even be the medical marker for the degree of severity.

When I look for it, however, I can see traces of it, or at least very subtle myoclonus, in up to half of all patients.

And here I will reveal my hunch: The fruitcake factor not only represents a fundamental process of the disease, it probably exists in every patient to some degree, however minor, and expresses itself as pain.

Amanda’s violent reaction to tendon tapping was a manifestation of what doctors call “myoclonus.” Neurologists define myoclonus as a sudden and generalized jerking contraction of the muscles. You may have noticed your sleeping partner in the early stages of sleep either jump or jerk, sometimes kicking you quite fiercely without once offering an admission of guilt or regret.

So called “sleep myoclonus” is sometimes violent enough to wake you just as you’re falling asleep. Sleep myoclonus is perfectly normal, but – with few exceptions – it is the only kind of myoclonus that is normal.

Sadly, although myoclonus is a markedly abnormal finding, it is also the ultimate humiliation for the patient with CFS. Although this finding may be one of the most important signs of neurologic disease during any clinical exam, doctors most typically dismiss it as “hysterical” when they are examining CFS sufferers. What they mean by this is that the patient is going for dramatic effect.

In my view, this is like calling an epileptic patient a drama queen when he has a seizure.

Epilepsy is not due to “evil humors,” as seventeenth century healers once decreed, and the fruitcake factor – myoclonus – is not hypochondria.

Of course, muscle tension can cause the tendon reflex to be increased, and anxiety certainly increases muscle tension. But an abnormal reflex due to mere muscle tension would never cause someone to jump off the examining table.

This response is due to the fact that the reflex travels up the spinal cord, not just the isolated arc back down the leg.

Anxiety could not possibly explain Amanda’s reaction. Some experts on the subject consider myoclonus to be a form of epilepsy, because it originates in the brain. But whether myoclonus is a seizure or not, in a sane world, the neurologists Amanda visited should have recognized her abnormal response to their sensory stimulation for what it was: a highly abnormal neurologic sign.

Amanda had seen three neurologists over a one month period. She has been told:

• That she will either die soon, maybe in a while,

• And that she was a fruitcake and will probably never die.

She is in a bit of a dilemma; and I, as her doctor, am also in a bit of a spot. As primary care physicians, we suggest specialty examinations to offer patients the “real doctors”, who will solve their problem, perhaps verifying an opinion to instill confidence. However, as a first line clinician, one who sees the patients who walk off the street, I am now in a bad spot. I admit to bafflement at this juncture.

My patient was diagnosed with Huntington’s chorea, but if the neurologist who announced that dramatic news had really believed his own diagnosis, he should have conducted additional tests to confirm the diagnosis, as well as offered genetic counseling, since the disease is passed from generation to generation within families.

My patient was then diagnosed with multiple sclerosis, but if the neurologist who rendered that diagnosis had really believed Amanda had MS, he should have offered to perform the standard tests that MS experts use to confirm the presence of the disease, and told Amanda about some of the new MS drugs on the market, which are considered most effective when prescribed early in the disease.

My patient was then diagnosed as an hysteric, but if that doctor really believed his diagnosis, he should have written me a collegial letter explaining his theory about Amanda’s myoclonus response.

I guess few self-respecting neurologists, especially if they thought she was seriously ill, would call Amanda’s disease by its absurdly trivial and unscientific name: ‘chronic fatigue syndrome’.

As it turns out, this name not only debases the patient who suffers from it, this name also seems to chip away at the self-esteem of the doctor, especially if he is a highly paid specialist with a reputation to protect. I suspect that’s why people suffering from CFS are showered with myriad vaguely outlined diagnoses, or no diagnosis at all, despite having prominent abnormalities during examinations and on a number of lab tests.

Very few medical schools teach young doctors about this illness, and as medical students move into specialty training, their opportunities to learn about CFS from senior doctors who have actually studied the disease become even more rare. Publishing scientific papers about CFS has become so difficult in the last decade, a group of researchers decided in 1995 to establish a journal specifically for the disease, one that would afford clinicians and scientists a forum in which to report on developments in the field. [The Journal of Chronic Fatigue Syndrome, now discontinued, but succeeded by the Bulletin of the IACFS/ME.]

I sat down with Amanda in my office soon after the third specialist rendered his opinion. We had been offered a less than appealing choice by these men, all of whom were well respected: Either Amanda was going to die, or she was a great actress.

I suggested to Amanda that rather than arbitrarily choosing one of these diagnoses out of a hat, or choosing the one we liked best, that we throw them all out.

• I told her that her central nervous system symptoms were part of a disease that none of these highly regarded specialists really knew anything about.

• I told her she had CFS.

Over the next few years, that diagnosis has proven correct. Her symptoms abated somewhat except for a marked worsening when we tried a mild stimulant drug because of the fatigue. At that time the myoclonus became worse, but, fortunately quieted down when the drug was stopped.

She has not gone on to develop Huntington’s chorea nor has she developed the typical findings of MS. The symptoms persist; she has good years and bad years. So that means that she has either CFS or is a consistent fruitcake.

How do you go about diagnosing someone as a fruitcake; what, exactly, are the diagnostic markers?

Actually, while I know that many of my colleagues consider my patients fruitcakes, I am not really sure what a fruitcake is, exactly. It is a sweet pastry filled with nuts. Neurosis was defined by Carl Sandberg as the denial of legitimate suffering, and therefore most of my patients are surely neurotic as hell. But fruitcakes?

It turns out there is a diagnostic test for the diagnosis of fruitcake: time.

I have now known Amanda for several years. I have seen her during crises and during relatively good times, and the symptoms and signs persist. I have shared her sadness and anger – normal, healthy emotions that anyone should have. And as time passed I have come to admire her courage to get by despite the illness and the society’s contempt. And I respect her wishes not to be referred for further neurologic opinions.

– Dr. David S Bell, MD, Lyndonville, New York, August 15, 2000
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This article is excerpted with kind permission from Dr. Bell’s classic book Faces of CFS – Case Histories of Chronic Fatigue Syndrome; © David S Bell, MD, 2000,

“Andrea’s Revolver”: When ME/CFS Includes Pain

This case history of a CFS patient whose symptoms include chronic pain is excerpted from Dr. Bell’s book Faces of CFS – Case Histories of Chronic Fatigue Syndrome, published in August, 2000. “Andrea’s Revolver” illustrates one aspect of cases he has followed since the mid-1980s.

Reprinted here with the kind permission of ProHealth: 1/21/11

ANDREA’S REVOLVER

Pain is a common problem in CFS, but it is also symbolic of the enormous challenge this illness presents to doctors and to patients. Patients can’t prove it, and doctors usually fail to treat it.

Despite the fact that pain occupies nearly all of their working day, doctors have a very poor understanding of it. Although we now have in our arsenal good medicines to relieve pain, we nevertheless try to avoid prescribing them.

• When a person who has just shoveled the snow off a long driveway complains of back pain, his doctor is likely to prescribe the same pain medications you can readily buy at your local Seven-11.

• If the snow shoveler’s back pain doesn’t abate in a few weeks, then the doctor realizes the problem might be worse than suspected. He refers the patient to a back specialist, which gets rid of the problem – for the doctor.

Most practitioners tell patients who have unexplained pain to seek help elsewhere.

Doctors are, as a rule, genuinely concerned about doing harm to the patient. This concern merges with another worry: losing one’s medical license by prescribing too many narcotics.

By law in New York state, doctors are required to write prescriptions in triplicate for narcotics and other potentially addictive drugs, a category of pharmaceuticals that just happen to be the most effective drugs for pain. These triplicate prescriptions help insure that powerful drugs won’t be over-prescribed, but the law is both time consuming and expensive – a nuisance for busy doctors.

More importantly, we doctors secretly suspect that someone spends their days counting the number of prescriptions we write, and worry that we could lose our medical licenses if there are too many carbons in our waste bins.

Aspirin presents none of these anxieties for us.

We never get into trouble from state regulators for offering aspirin to our patients in pain. The great irony is that aspirin may be more likely to kill the patient by causing a bleeding ulcer. But, ignoring that, we urge our patients to try aspirin or acetaminophen or ibuprofen. And if all of these fail, we usually suggest another mild medication, preferably one that the patient has never heard of.

Cancer pain, of course, is dire, and it is hardly surprising that oncologists (doctors who care exclusively for cancer patients) tend to have the most sophisticated understanding of, and compassion for, pain. They also do the best job of treating pain. When a cancer patient complains of pain, for the most part, the doctor opens his medical chest and says, in effect, take what you need to help with your pain.

Three weeks ago I had a toothache.

Like most men, I find this difficult to confess: My toothache hurt. By Friday, two days after it began, my toothache really hurt. On Saturday, it was unbearable. As I hobbled around my house holding my jaw, I found myself thinking, as if silently reciting a mantra: So this is pain…. so this is pain.

A friend gave me some serious pain medication, the kind that requires a prescription written in triplicate, and I was able to fall asleep at last. Even with the narcotic, however, the weekend was horrible. On Monday, I underwent the most wonderful root canal and my pain vanished.

The experience was an important lesson for me. I was reminded of the vast gulf between the subjective complaints of the patient and the objective doctor who listens to these complaints, the difference between hearing about someone else’s pain, their toothache, and my own.

Most important, I was reminded of the gulf many CFS patients must navigate every day.

I was able to see the end of my pain, even when the pain was at its height. I knew that on Monday my dentist would help me, not only because I can afford a dentist and have always paid my bills on time, but because my dentist understood completely that my particular condition was a painful one, and he had been nicely trained to alleviate it.

I see patients with pain every day in my practice. Pain steals in under many guises: the twisted ankle, the stomach ulcer, the spread of a malignant tumor. I try to respond given my best estimation of the severity of the pain.

I have studied CFS for years, and I still am unsure precisely where CFS fits along the spectrum of pain.

• Some of my colleagues accept as bona fide the pain that often accompanies the disease, and try their best to relieve it with medication.

• Sadly, most of them tell their patients that CFS is a minor illness; they advise them to get used to the pain until either the pain or the illness goes away. They may suggest aspirin.

Despite the fact that pain can be a prominent and even disabling aspect of CFS, it is the rare CFS sufferer who receives adequate treatment for it.

Andrea Thompson had pain, pain that surpassed virtually anything that I had seen before in my practice.

By the time Andrea walked into my clinic, she had already seen over 30 doctors. Her story was typical of most of the CFS patients who end up in the village of Lyndonville: Each of the doctors she had consulted over the long years of her illness were mystified when she recounted her symptoms, inexcusable now that CFS has been studied in this country for so many years.

Some of them performed studies and offered a multitude of conflicting diagnoses, from the common thyroid disease, which causes fatigue, to the more arcane reflex sympathetic dystrophy, an extremely rare and famously painful nerve disease. All of these diagnoses were wrong, since Andrea had the other symptoms as well: sore throat, headache, numbness and tingling in her legs and arms, as well as a kind of intellectual fogginess that made her feel perpetually “out of it.”

As months turned into years, and her doctors found it increasingly difficult to support their original diagnoses given Andrea’s wide array of symptoms, several of them began to suspect Andrea was a junkie who wanted pain medication to get high.

Talking to Andrea for ten minutes displayed the absurdity of these suspicions. Con artists have a certain talent, but Andrea was hardly a con artist. She was in pain.

Andrea was 37 when I saw her for the first time. Before falling ill in 1988, she had worked as an executive in a brokerage firm in New York state. Her education had been top-notch, and she had a Masters degree in business administration. She was married, had three children, and a nice house in the suburbs. Andrea and her family had been living the American dream – even if they didn’t have a Beamer.

Two years after her symptoms began, Andrea’s husband was promoted and transferred to Boston. Andrea was looking forward to taking a few months off work to rest, and to settle into her new home in Boston, after which she planned to look for a new job.

Once the move was complete, however, Andrea seemed to fall apart completely. In the beginning, at a loss to explain the problem, she and her husband blamed her rapid decline on stress. Yet, the move had been relatively stress-free; her husband’s company paid for the packing and unpacking of their possessions, for example.

Andrea’s dominant and most crippling symptom was pain, though she was hard pressed to pin-point its source.

Pain seemed to migrate through her limbs and even her face. But there were other symptoms, too.

• She had migraine headaches that were impervious to medication.

• She became hypersensitive to light, and took to wearing sunglasses even when she was inside her house.

• Curiously, odors of any kind made her feel nauseous.

• Mere sound, too, was often too much to bear. Andrea was an avid R & B fan and had a large library of recordings dating to the 1940s, but she could barely tolerate even the softest music.

It was as if every sense she possessed was too finely wired for life on planet earth.

Her first encounter with a Boston doctor ended as badly as her numerous encounters with doctors in New York. Andrea hadn’t expected a miracle – she just wanted something to take away the pain. Wearing sunglasses and asking for pain medication at the same time apparently made a poor impression.

She downplayed her pain when she met with a second doctor, with the result that he gave her a complete physical exam, ordered several laboratory tests and an MRI scan of her brain and neck, and performed nerve conduction studies. The lab tests were normal, and he prescribed mild pain medications and suggested meditation

The drugs didn’t touch the pain she felt, however, and Andrea was unable to meditate while in so much pain. She soon gave up trying.

She found some relief when a dentist prescribed codeine after she complained of facial pain, but he denied her additional prescriptions for the drug on the grounds that she might develop an addiction to it.

Doctors at a famous Boston pain clinic prescribed exercise and antidepressants, two therapies that simply ended up causing more pain. After two agonizing weeks, Andrea checked out of the clinic.

She had always been an attractive woman, but now Andrea looked ragged. She pleaded with several Boston doctors for more powerful pain killers, but her need for pain relief was proportionate to the degree of skepticism she encountered.

In fact, by now, no one she consulted believed she was in pain at all.

Her life was little more than misery compounded by the skepticism of the medical establishment and her friends. Not surprisingly, she began to doubt her own sanity.

• She became disheveled; her weight plummeted to 89 pounds. She had begun to look like a junkie, even to herself.

• She felt as if she barely knew her children anymore; they spent much of their time in day-care facilities.

• Her once-loyal husband began to display frustration and skepticism about her condition.

And always the pain – pain that doctors refused to treat. Worst of all, pain with no end in sight.

One day, Andrea loaded her husband’s revolver and put it in her mouth.

To this day, she has no explanation for why she didn’t simply pull the trigger.

The following day, she entered a psychiatric unit of a Boston hospital, where she remained for three weeks. The psychiatrists talked to her about “relocation stress,” childhood traumas, and “displaced” anger.

Andrea felt she was the only person who saw the problem clearly: Get rid of the pain, she kept telling the psychiatrists, and she would be okay.

Finally, her pleas were heard.

The psychiatrists prescribed methadone, a synthetic form of morphine that is used to manage morphine addiction, but has the same pain-deadening effects as morphine. The drug worked. Slowly, Andrea began to reconstruct her life.

What was causing Andrea Thompson’s extraordinary pain?

Usually, pain is associated with tissue damage from injury. The pain sensation serves as a warning, preventing further damage to the victim. This sensation travels on nerve pathways from the injured tissue to the brain.

Sometimes, pain is due to damage in the pain receiving areas of the brain itself. In this case, the disease is to the actual pain processing centers, even though the body mistakenly interprets the sensation of pain as if it were coming from somewhere else.

Malignancies involving the thalamus, a part of the brain that helps to process sensory impulses, can cause this kind of pain. But Andrea Thompson had no malignancies, and the MRI scan I ordered of her brain proved to be normal.

A third cause of pain is known as “sympathetically mediated” pain – pain that derives from damage to the autonomic nervous system. The autonomic nervous system controls our breathing, body temperature, blood flow, and heart rate – all those functions we can’t control by sheer will; body functions we barely even notice.

One of the diseases associated with this kind of pain, “reflex sympathetic dystrophy,” was the nerve ailment proposed by at least one doctor as the cause of Andrea’s pain.

Usually, “RSD” is the a result of an injury to a leg or an arm, or even a single nerve in that extremity. What is most curious about RSD is that the pain may be delayed for months or years, long after the specific injury had healed.

RSD is often accompanied by changes in blood flow, sweating, and, curiously, atrophy of the fingers. In 1988, I heard Dr. Paul Cheney, who had studied CFS among Nevada patients, describe what he called the “disappearing fingerprints” of CFS sufferers. The surface of his patient’s fingertips had grown completely smooth, entirely lacking the normal, distinctive whorls.

Dr. Cheney, a true disease detective, even remanded a few of these patients to a police station to find out whether they could be fingerprinted, but their fingerprints left no distinctive pattern.

When I heard about this bizarre discovery, I wondered whether it was possible to experience RSD as a body-wide disease instead of one confined to an extremity.

Though it remains controversial, some doctors believe that sympathetically mediated pain can be eliminated by blocking the nerve pathways, or even severing the nerve itself. In truth, doctors argue about the causes – and the treatment – of sympathetically mediated pain every day. Some of my colleagues believe it to be a psychological condition, although new research suggests otherwise.

I began to learn about the relationship between CFS and another puzzling condition called orthostatic hypotension, a failure of the body to adequately pump blood while standing in the upright position, from Dr. Peter Rowe and colleagues at Johns Hopkins.

Soon afterward I began working with Dr. David Streeten, an endocrinologist who had worked extensively with “orthostatic intolerance” – the inability of the body to tolerate the upright position.

There are only a few truly great doctors who stand out from the thousands of ordinary ones; they are the true masters of medicine. [The late] David Streeten was one of these masters. He had both a brilliant scientific mind and the perception and intuition of a superb clinician. If I were 30 years younger and fresh from medical school, I would have become his intern and really learned medicine.

But working with a master has its drawbacks. When I sent my CFS patients to see him for a consultation, they returned to my clinic with the news that he was much nicer to them than I ever was.

I met Dr. Streeten for the first time in February 1994 when I accompanied Andrea Thompson to his offices in order to observe his evaluation of her first hand. Until this experience, I was under the mistaken perception that I understood CFS. Dr. Streeten proceeded to teach me some of the basics that I had overlooked for 15 years.

I had always viewed chronic fatigue as the result of the chemicals released by a viral infection, and had concentrated solely upon looking for the infection that might have caused the condition.

Now I was seeing what could be the mechanism, regardless of cause, which might be causing the symptoms to persist.

The myriad of symptoms revolving around exhaustion, weakness, lightheadedness, and inability to concentrate were likely due to the inability of the body to circulate blood to the brain when standing, or sometimes even sitting.

When the CFS patient is lying down, the symptoms are improved, although not gone entirely. The disability of CFS has to do with the fact that we spend our non-sleeping lives in the upright position.

Dr. Streeten utilized MAST trousers in his experiments. The acronym stands for Military AntiShock Trousers. These inflatable pants can be blown up like an inner tube in order to create a veritable body cast from the toes all the way to the mid-chest. When paramedics need to transfer trauma patients suffering from fractured legs, MAST trousers are very handy because they become an instant cast and compress the lower body.

Dr. Streeten performed a deceptively simple experiment with his patients.

He bid them don deflated MAST trousers, then asked them to stand next to a wall of his examining room. As they stood upright in these somewhat peculiar circumstances, he monitored the patient’s blood pressure and pulse. When the CFS patient would become ill during standing, he would inflate their MAST trousers.

Upon meeting Andrea, Dr. Streeten measured the amount of blood in circulating in Andrea’s body and discovered that the level was strikingly low. Next, he tested Andrea’s blood pressure and pulse for 10 minutes while she was lying down, and they were normal. Blood tests drawn at that time for adrenaline and other “catecholamines” were drawn and later shown to be normal.

Then Andrea stood quietly with the plastic MAST trousers around her body but not inflated. Then the problems began. Within minutes she began to feel ill, her pulse began to climb, and the pain began to grow. By 10 minutes of standing her speech was slurred and she appeared a little drunk, swaying back and forth and her feet began to look purple. Her blood pressure dropped and heart rate increased.

Then the pain really kicked in.

She was confused. All she could do was to say over and over, “The pain…the pain…” While still standing, a second sample of blood was drawn from the line in her arm, again tested for adrenaline.

At that point, while Andrea was still standing, Dr. Streeten inflated the MAST trousers, causing symmetrical pressure around her legs, thighs and abdomen. I had often seen Andrea in this state before, a state where she looked as if she had been on a binge for days. But my teeth nearly fell out when seven seconds later she straightened up and looked around and said with a clear voice, “What happened? The pain is gone.”

I was as astonished as Andrea. Even Dr. Streeten was surprised by the magnitude of this response. He hypothesized that the pressure on Andrea’s legs and abdomen by the MAST trousers had forced a more vigorous blood flow through Andrea’s brain, and that this increased blood flow stopped the pain.

Andrea wanted to buy a pair of MAST trousers for home use. (Later on we actually tried this, but it turns out to be impossible to walk around with these things on which sort of cancels out the purpose.)

Dr. Streeten was suitably impressed by Andrea’s case. He submitted his MAST trouser experiment on Andrea and about 20 other CFS patients to a scientific journal. The editors rejected the paper, initially, because the patient was not sufficiently “blinded” in this experiment. In the world of science, of course, it is optimum for patients in experiments to be ignorant of the researcher’s modus operandi.

My question to the journal editors is this: How could we sneak Andrea into a pair of MAST trousers without her finding out about it? I can think of only one way: Render her unconscious with a general anesthetic. The problem with that, of course, is that it is very difficult for people to describe their pain, or lack of it, while unconscious. Sometimes modern medicine is bewildering.

The temporary stoppage of Andrea’s pain in Dr. Streeten’s office that day offers up no simple explanations or conclusions, just theories.

One simplistic theory is that because Andrea had too little blood circulating in her body, her blood pressure dropped dramatically when she was forced to stand for any length of time. When her blood pressure dropped, so did the flow of blood to her brain, which houses the mechanism that mediates both the sensation of pain and blood flow: the autonomic nervous system.

By inflating Andrea’s MAST trousers, Streeten was able to rescue, so to speak, blood that was trapped in her legs, and send more to her brain.

Still, the theory has by no means been proven. In the time that has elapsed since Andrea’s visit with Dr. Streeten, however, it has become apparent to me and to other doctors who study CFS that problems with blood flow to the brain, and the regulator of that flow – the autonomic nervous system – is responsible for both the exhaustion and the migrating pain of the disease.

Of course, myriad questions remain. Might the cause of pain in CFS be a result of a decreased blood flow through the thalamus? Is there an inherent abnormality of the blood vessels that causes the decreased blood flow through the brain?

A different theory of CFS pain centers on hormones. Studies have demonstrated that a number of different hormones are in insufficient supply in CFS patients. One of these is called growth hormone. The pituitary gland of the brain produces this particular hormone, and besides its primary job of making children grow, it has numerous functions in the body.

Scientists have discovered that there is also a second hormone, called vasopressin, that is deficient in CFS patients.

This hormone is essential to regulate the concentration of water in the body, as well as to regulate the size, or diameter, of the blood vessels. I had already determined that Andrea had levels of vasopressin that were much too low to be considered normal. A deficiency of vasopressin could predictably cause excessive thirst as well as an insufficient supply of circulating blood in the body.

As things have turned out, many patients with CFS experience both of these problems.

And this is where the trail leads us to endorphins, hormones produced by healthy people that act as the natural pain killers for the body. Interestingly, vasopressin is a substance that reflects the production of the natural pain-killing endorphins.

Could it be that CFS patients have low levels of the endorphins, explaining in part, why they experience so much pain?

The fact remains: Regardless of why it exists, or what causes it, pain that is both intense and chronic is a daily fact of life for a great many patients who suffer from CFS.

I began testing CFS patients in my office for changes in pulse and blood pressure when they stand quietly, and found that the vast majority have abnormalities. This is the reason that people with CFS may look healthy to outsiders, but they are unable to stand at the check-out counter of the grocery store. In fact, on occasion, some of them faint, or come very close to fainting, presumably because they cannot maintain good blood flow to the brain.

One day, I showed the blood pressure graphs to one of my best friends, David Lieberman, a substance abuse counselor. I pointed out to him that in addition to their blood pressure abnormalities, these patients often experience a racing pulse. David made the observation that these physiological signs are picture identical to the body’s reaction during withdrawal from narcotics.

Could it be that CFS sufferers are in a constant state of ‘narcotic withdrawal’ because they fail to produce enough of the body’s natural pain killers, the endorphins?

I remember a patient with CFS that I had seen almost 15 years ago. This woman had taken doses of codeine three times a day, every day, for nearly 20 years. She told me it boosted her energy, and provided relief from her symptoms of muscle and joint pain, headache, and trouble thinking. Although she had never increased her dose, I privately suspected she was addicted to codeine.

To see if she was addicted, I asked her to stop taking codeine for a period of two months, and for reasons I will never understand, she actually agreed to do so upon my request. During those two months, her symptoms of pain and fatigue were prominent and troublesome, but she bravely stuck it out.

What fascinates me, in retrospect, is that after 20 years of taking codeine, this particular patient displayed absolutely no signs of withdrawal or even a craving for the drug. She never developed tolerance to codeine, where it would become ineffective without increasing the dose.

Could it be that for these 20 years she was replacing her own body’s deficient endorphins with daily codeine?

Many scientists would tend to dismiss this particular observation. The skeptics among them would probably assume that the woman was sneaking codeine on the side without my knowledge, and, frankly, I would be unable to prove otherwise, since I did not perform regular tests on this woman for the presence of codeine in her system. But, after years of practice, I believe that there is one factor in clinical medicine to which scientists rarely give credence: the bond of trust between doctor and patient. I tend to believe what my patients tell me. I may just be gullible.

Andrea has been taking methadone for four years now, and the synthetic morphine provides her with relief from her pain.

Curiously, she, too, has not required any increase in her dose, which typically occurs when people take drugs like morphine and methadone over the long haul. David Lieberman and I often talk about the possibility that CFS patients require narcotic drugs the way a diabetic needs insulin. The myriad symptoms of diabetes are caused, after all, by a deficiency of insulin, a natural substance that healthy people produce in adequate amounts.

I have wondered, as well, if blood volumes that are far too low are a clue to the cause of the major symptoms of CFS, particularly pain.

I frankly consider it embarrassing that so little research has been done on blood volume, blood flow, endorphins and other brain hormones in patients with CFS. If one tenth of the money that has been applied to psychological studies of people suffering from CFS had been used to study endorphins instead, we would have seen some progress in understanding this terrible disease.

One problem, of course, is that CFS continues to be so controversial throughout medicine that earnest investigators eager to study it are often stymied by the failure of government granting agencies to help.

This phenomenon is particularly unfortunate when one considers how many CFS patients are in pain each day. According to some researchers, more people in this country have CFS than all the people with AIDS, lung and breast cancer combined.

Currently, the disease is approximately 15 times more prevalent than paralytic polio was at the height of the polio epidemic of the late 1940s.

Research barriers have not only impeded my colleagues from understanding the disease, these barriers have prevented doctors from taking a hard look at the pain CFS patients experience, and from treating that pain appropriately.

Eventually, some patients just give up. The foundation of the Hippocratic oath is, “First, do no harm.”

By failing to treat her pain, doctors caused Andrea Thompson to spend half an hour with a loaded revolver in her mouth.

– Dr. David S Bell, MD, Lyndonville, New York, August 15, 2000
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* This article is excerpted with kind permission from Dr. Bell’s classic book Faces of CFS – Case Histories of Chronic Fatigue Syndrome; © David S Bell, MD, 2000. This information has not been evaluated by the FDA. It is general information only and is not meant to prevent, diagnose treat or cure any condition, illness or disease. It is very important that you make no change in your healthcare plan or health support regimen without researching and reviewing it in collaboration with your professional healthcare team.

Epigenome-wide profiling identifies distinct DNA methylation architecture underlying ME/CFS and fibromyalgia symptom burden

Abstract:

Background: Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) and fibromyalgia are overlapping chronic disorders characterized by fatigue, pain, cognitive dysfunction, sleep disturbance, and multisystem symptoms. Whether peripheral blood DNA methylation reflects diagnostic categories, quantitative symptom burden, or both remains unclear. We aimed to identify DNA methylation axes associated with diagnosis, symptom dimensions, and clinical differences between these conditions.

Methods: This cross-sectional study included 188 women: 73 healthy controls, 71 with ME/CFS, and 44 with fibromyalgia. DNA methylation was profiled in peripheral blood mononuclear cells using the Illumina MethylationEPIC v2 array. Principal component analysis identified latent methylation axes. Linear models adjusted for age, body mass index, and estimated immune-cell composition tested associations with diagnostic group and clinical measures. Region-level methylation analyses, functional enrichment, bootstrap resampling, permutation testing, leave-one-out analyses, and medication/comorbidity sensitivity analyses were performed.

Results: Both patient groups had greater symptom burden than healthy controls but differed clinically. Fibromyalgia showed greater widespread pain, pain catastrophizing, central sensitization inventory scores, and temporal summation, whereas ME/CFS showed greater post-exertional malaise, cognitive symptoms, and lower physical activity. Two methylation axes showed clinically relevant associations. PC5 differentiated ME/CFS from fibromyalgia and healthy controls and was associated mainly with post-exertional malaise and cognitive symptoms. PC6 separated both patient groups from healthy controls but not from each other, and was associated with broader symptom burden, including widespread pain, pain impact, sleep disturbance, visceral symptoms, and temporal summation. The temporal summation association, together with higher widespread pain and temporal summation in fibromyalgia, suggests that PC6 includes a pain-related component extending to experimentally assessed nociceptive summation. Region-level analyses identified 591 PC5-associated and 54 PC6-associated high-confidence differentially methylated regions. Enrichment implicated neuroimmune, metabolic, cytokine, NF-κB, JAK-STAT, TGF-β, and immune-regulatory pathways. Sensitivity analyses supported the stability of the main associations.

Conclusions: Peripheral blood DNA methylation profiles identified partly distinct but overlapping DNA methylation axes in ME/CFS and fibromyalgia. PC5 was aligned with post-exertional malaise and cognitive symptoms, whereas PC6 was aligned with broader pain-related multisystem burden. Independent replication and longitudinal studies are needed to establish clinical utility.

Source: Polli A, Hendrix J, Wyns A, Van Campenhout J, Allard S, Aerts JL, Laeremans T, Xiong H, Buntinx Y, Michiels J, Ben Amar J, Godderis L, Thienpont B, Nijs J. Epigenome-wide profiling identifies distinct DNA methylation architecture underlying ME/CFS and fibromyalgia symptom burden. J Transl Med. 2026 Aug 22;24(1):1222. doi: 10.1186/s12967-026-08824-5. PMID: 42811334. https://link.springer.com/article/10.1186/s12967-026-08824-5 (Full text)

Muscle symptoms and a latent physiological symptom-dysregulation factor in ME/CFS: exploratory analyses by sex and age-defined menopausal-status proxy group

Abstract:

Background: Muscle-related symptoms are among the most disabling manifestations of myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), yet their position within the broader symptom architecture of the disease remains unclear. We hypothesized that muscle symptoms may represent a candidate integrative symptom within a broader shared symptom-dysregulation structure and their symptom associations differ according to sex and menopausal status.

Methods: Cross-sectional data from 736 individuals with physician-diagnosed ME/CFS enrolled in the APAV-ME/CFS registry were analysed. Muscle problems served as the primary outcome variable. Associations with 14 symptom domains were examined using multivariable logistic regression. Pearson and tetrachoric correlations, exploratory factor analysis, and structural equation modeling (SEM) were used to identify latent symptom structures. Exploratory analyses were stratified by sex, menopausal status, and disease duration.

Results: In the full multivariable model (non-robust estimates), breathing problems (OR 2.49 [95% Conf. Interval: 1.42-4.38], p = 0.001), flu-like symptoms (OR 1.97 [1.14-3.42], p = 0.015), and temperature-regulation disorders (OR 1.97 [1.10-3.51], p = 0.021) independently predicted muscle problems. A reduced physiological model (not-robust estimates) additionally identified cardiovascular symptoms (OR 1.87 [1.09-3.24], p = 0.024) as a significant predictor. Tetrachoric correlations demonstrated substantial latent associations between muscle problems and breathing difficulties (ρ = 0.52), cardiovascular symptoms (ρ = 0.49), temperature-regulation disorders (ρ = 0.49), visual disturbances (ρ = 0.39), and flu-like symptoms (ρ = 0.39). Factor analysis and SEM supported a single latent physiological dysregulation factor with good model fit (RMSEA = 0.046, CFI = 0.971, TLI = 0.952, SRMR = 0.026).

The sex-stratified analyses revealed differences in the pattern of statistically significant symptom associations across the subgroups. However, the overall test of the symptom-by-sex interaction terms did not provide evidence for a statistically established difference in the symptom associations by sex. Thus, the subgroup-specific patterns should primarily be interpreted as descriptive and exploratory. At the individual symptom level, the association between breathing-related symptoms and muscle problems showed a statistically significant interaction with sex, suggesting that this association may differ between women and men. However, this finding should be interpreted cautiously given the non-significant overall interaction test and the wide confidence interval of the interaction estimate.

In women, all five physiological symptoms independently predicted muscle problems, whereas in men only breathing problems and temperature-regulation disorders remained significant. Women classified as premenopausal and postmenopausal based on an age-defined proxy showed different patterns of symptom associations with muscle problems in subgroup-specific analyses. Women in the premenopausal age-proxy group showed significant associations with cardiovascular symptoms, visual disturbances, and temperature-regulation disorders, whereas women classified as postmenopausal showed significant associations with breathing difficulties and flu-like symptoms. However, the overall menopausal-by-symptom interaction was not statistically significant (Wald χ² (5)=5.96, p = 0.310).

The specified latent physiological factor showed statistical comparability across the cross-sectional disease-duration groups. Gastrointestinal complaints loaded substantially on the latent factor despite lacking an independent association with muscle problems in multivariable regression. Urogenital symptoms also showed a smaller but significant association with the latent factor and substantial item-specific variance.

Conclusions: Muscle symptoms may represent a candidate integrative symptom within a latent physiological symptom-dysregulation factor encompassing respiratory, cardiovascular, thermoregulatory, visual, and flu-like symptoms in this ME/CFS sample. Secondary analyses suggested that gastrointestinal complaints were also part of the broader physiological symptom pattern, although they were not independently associated with muscle problems. The specified latent physiological factor showed no overall statistical evidence of measurement differences across the cross-sectional disease-duration groups. However, subgroup-specific symptom patterns differed descriptively by sex and age-defined menopausal-status proxy group.

Women classified as premenopausal were characterized primarily by cardiovascular, visual, and thermoregulatory symptom associations, whereas women classified as postmenopausal and men showed greater prominence of breathing-related symptoms. Flu-like symptoms were independently associated with muscle problems in the postmenopausal subgroup but not in the premenopausal subgroup. Because the corresponding interaction term was not statistically significant, this subgroup contrast should be interpreted as an exploratory difference in association rather than as evidence of a menopause-specific effect. More broadly, the findings are compatible with the hypothesis that the latent symptom-dysregulation factor may reflect a chronic PEM-associated multisystem response.

Whether this symptom-dysregulation factor corresponds to interacting autonomic, vascular, immunological, and metabolic processes remains to be determined by longitudinal and biomarker-based studies. ME/CFS phenotyping may improve patient stratification and facilitate the development of mechanism-based therapeutic approaches.

Source: Habermann-Horstmeier L, Horstmeier LM. Muscle symptoms and a latent physiological symptom-dysregulation factor in ME/CFS: exploratory analyses by sex and age-defined menopausal-status proxy group. J Transl Med. 2026 Sep 28;24(1):1216. doi: 10.1186/s12967-026-09018-9. PMID: 42806383. https://link.springer.com/article/10.1186/s12967-026-09018-9 (Full text)

Sex- and menopause-related differences in immune and gastrointestinal symptom architecture in ME/CFS: evidence from factor analysis and structural equation modeling

Abstract:

Background: Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a multisystem disorder characterized by neuroimmune, autonomic, and gastrointestinal dysfunction. Previous studies identified coherent symptom domains involving Brain, Autonomic, Gut, and Immune manifestations and demonstrated pronounced sex-specific differences in neurocognitive-sensory and autonomic symptom organization. However, whether immune-related and gastrointestinal symptoms form distinct or integrated latent structures in women and men with ME/CFS remains unclear. In addition, the potential influence of menopausal status on these symptom domains has not been systematically investigated.

Methods: Data from 748 adults with a medical diagnosis of ME/CFS were included in this cross-sectional analysis (608 women, 137 men, and 3 non-binary participants). Sex-stratified analyses were restricted to women and men. Symptoms were coded dichotomously. Sex-stratified analyses included cross-tabulations, Cramér’s V, tetrachoric correlations, logistic and linear regression models, exploratory factor analysis, and structural equation modeling (SEM). Additional subgroup analyses compared pre- and postmenopausal women. Model robustness was evaluated using a stratified training dataset.

Results: In women, Immune (flu-like symptoms, susceptibility to infections) and Gut (gastrointestinal complaints, food intolerances) symptoms formed two distinct but related clusters, characterized by moderate within-cluster correlations (tetrachoric ρ = 0.47-0.60) and weaker cross-cluster associations (ρ = 0.30-0.35). Exploratory factor analysis (EFA) supported a two-factor solution. Consistent with this result, the alternative one-factor SEM showed comparatively poor fit (CFI = 0.913; RMSEA = 0.119), whereas the specified two-factor model was just-identified and therefore not suitable for global fit evaluation. In men, all four symptoms loaded onto a single integrated Gut/Immune factor, with within- and cross-domain tetrachoric correlations ranging from 0.43 to 0.68. SEM confirmed excellent fit for a one-factor model (CFI = 0.981; RMSEA = 0.074). Susceptibility to infections emerged as the dominant predictor in regression analyses. Among women, menopausal status selectively affected immune-related symptoms. Women classified as premenopausal reported flu-like symptoms more frequently than women classified as postmenopausal, whereas gastrointestinal symptoms and food intolerances remained stable across groups. These findings suggest differential hormonal sensitivity of immune versus gastrointestinal symptom trajectories.

Conclusions: Immune and gastrointestinal symptoms in ME/CFS exhibit sex-specific latent structures. Women demonstrate two partially separable but related symptom domains, whereas men show a more integrated immune-gastrointestinal architecture. Furthermore, menopausal status appears to selectively modulate immune-related symptom expression while leaving gastrointestinal symptom patterns comparatively stable. Taken together, these results provide an exploratory framework that supports the concept of sex-dependent neuroimmune-autonomic mechanisms in ME/CFS and aligns with a dynamic, hormonally modulated immune component as well as a more persistent, gut-related process. The results highlight the importance of sex- and hormone-sensitive approaches to phenotyping, mechanistic research, and therapeutic stratification in ME/CFS.

Source: Habermann-Horstmeier L, Horstmeier LM. Sex- and menopause-related differences in immune and gastrointestinal symptom architecture in ME/CFS: evidence from factor analysis and structural equation modeling. J Transl Med. 2026 Jul 27;24(1):970. doi: 10.1186/s12967-026-08699-6. PMID: 42522006. https://link.springer.com/article/10.1186/s12967-026-08699-6 (Full text)

Gastrointestinal symptoms correlate with core clinical features and systemic inflammation in myalgic encephalomyelitis/chronic fatigue syndrome

Abstract:

Background: Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a debilitating multisystem illness marked by fatigue, cognitive impairment, and post-exertional malaise. Gastrointestinal (GI) symptoms are frequently reported, yet their relationship to central features of the illness and biological correlates remains poorly understood.

Objectives: We aimed to characterize GI symptom burden in ME/CFS and evaluate its associations with core clinical features and specific immune and inflammatory markers, with attention to potential gut-related contributions to disease expression.

Methods: GI symptoms and 49 additional symptoms across nine domains were assessed in 116 ME/CFS patients and 80 matched controls. Plasma C-reactive protein (CRP) and antibodies against dietary and microbial antigens were measured as indicators of systemic inflammation and putative gut-derived antigen exposure.

Results: ME/CFS patients reported significantly elevated GI symptom frequency and severity compared with controls, with 53% of ME/CFS patients versus 8% of controls reporting a prior diagnosis of irritable bowel syndrome. GI symptom burden correlated with fatigue, cognitive difficulties, flu-like symptoms, pain, sleep disturbances, neurological complaints, and sensory sensitivities, independent of illness duration. CRP levels were higher in patients with greater GI symptoms and correlated with GI, fatigue, musculoskeletal pain, and flu-like symptom burden. Patients with greater flu-like symptom expression exhibited higher IgM responses to dietary gliadin and bacterial lipopolysaccharide. These associations were not detected in controls.

Conclusions: GI symptoms are a prominent, clinically relevant dimension of ME/CFS, associated with broader symptom burden and inflammatory heterogeneity. These findings highlight the relevance of gut-related and immune processes in ME/CFS and underscore the value of incorporating GI symptom assessment in translational studies to help refine mechanistic understanding and improve therapeutic stratification. https://link.springer.com/article/10.1186/s12967-026-08442-1 (Full text available as PDF file)

Chronic stress and cognitive dysfunction in myalgic encephalomyelitis/chronic fatigue syndrome: HPA axis dysregulation and hippocampal plasticity

Abstract:

Cognitive dysfunction is a common and disabling clinical feature of myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), often described by patients as “brain fog.” These symptoms typically manifest as difficulties in attention, memory, and concentration. Chronic stress has been proposed as an important contributing factor in ME/CFS.

The hypothalamic-pituitary-adrenal (HPA) axis plays a central role in the stress response, and prolonged adverse stress may contribute to HPA axis dysregulation, including altered cortisol rhythmicity and impaired negative feedback regulation. Such dysregulation may be associated with cognitive dysfunction in ME/CFS through mechanisms involving neuroinflammatory responses, oxidative stress, and disturbances in neurotransmitter homeostasis. Studies suggest that these alterations may affect hippocampal structure and function, thereby contributing to impaired learning and memory processes.

As a key brain region involved in cognition and stress regulation, the hippocampus may be implicated in the neurobiological mechanisms underlying cognitive dysfunction in ME/CFS. This review integrates current evidence on the potential role of HPA axis dysregulation and related neurobiological alterations in chronic stress-associated cognitive dysfunction in ME/CFS, with the aim of providing a theoretical basis for identifying potential intervention targets and informing strategies centered on HPA axis regulation.

Source: Kang H, Shao T, Shi Y, Wang S, Xiong H, Jin X, Ren J. Chronic stress and cognitive dysfunction in myalgic encephalomyelitis/chronic fatigue syndrome: HPA axis dysregulation and hippocampal plasticity. Front Neurosci. 2026 Apr 22;20:1814098. doi: 10.3389/fnins.2026.1814098. PMID: 42100733; PMCID: PMC13144083. https://pmc.ncbi.nlm.nih.gov/articles/PMC13144083/ (Full text)

Symptom clusters in ME/CFS reflect distinct neuroimmune and autonomic pathophysiological mechanisms: a translational model

Abstract:

Background: Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a debilitating multisystem disease characterized by heterogeneous symptom patterns. Previous work suggested that specific symptoms tend to co‑occur, pointing toward underlying biological mechanisms. This study aimed to empirically validate literature‑based, hypothesis‑driven symptom clusters and assess whether they reflect distinct neuroimmune and autonomic pathophysiological pathways.

Methods: Symptom data from 748 adults with ME/CFS (≥20 years) participating in the APAV‑ME/CFS study were analyzed. Symptoms were assigned to predefined mechanistic groups informed by current pathophysiological hypotheses. Exploratory and Confirmatory Factor Analyses, followed by Structural Equation Modeling (SEM), evaluated the coherence, distinctiveness, and hierarchical structure of each cluster. Robustness was tested using a stratified, randomized training dataset.

Results: A coherent Brain factor (brain fog, sensory hypersensitivity, visual disturbances, sleep disturbances, headaches) showed excellent fit (RMSEA = 0.021; CFI = 0.996). Gastrointestinal symptoms demonstrated stronger internal consistency than Immune symptoms, and model comparisons supported a two‑factor Gut–Immune structure. Across all analyses, symptom groups emerged as internally consistent and statistically distinct. A higher‑order SEM including a common latent factor yielded excellent fit for the Autonomic symptom complex.

Conclusions: The findings support ME/CFS as a complex neuroimmune–autonomic multisystem disorder and suggest that symptom clusters align with functional biological systems. Mechanism-aligned symptom subgrouping may enable pathophysiology-guided diagnostics, patient stratification, and targeted therapeutic development. The proposed interpretations of underlying mechanisms derive from the integration of existing literature and were not directly measured in this study. The identified clusters therefore indicate mechanistic alignment rather than direct mechanistic validation.

Source: Habermann-Horstmeier L, Horstmeier LM. Symptom clusters in ME/CFS reflect distinct neuroimmune and autonomic pathophysiological mechanisms: a translational model. J Transl Med. 2026 Apr 28;24(1):606. doi: 10.1186/s12967-026-08159-1. PMID: 42050709; PMCID: PMC13126800. https://pmc.ncbi.nlm.nih.gov/articles/PMC13126800/ (Full text)

Assessment of symptoms in myalgic encephalomyelitis/chronic fatigue syndrome: a comparative study of existing scales

Abstract:

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a multifaceted disorder characterized by persistent fatigue, post-exertional malaise (PEM), cognitive dysfunction, sleep disturbance, pain, psychological distress, orthostatic intolerance, and impaired multidimensional health status and functioning. In the absence of reliable biomarkers, standardized symptom assessment is essential for accurate diagnosis and comparability across studies.

This narrative literature review synthesized studies identified through PubMed and Web of Science up to June 2024, covering assessment instruments across major ME/CFS symptom domains. Tools were evaluated for their psychometric validity, clinical applicability, and key limitations.

Overall, existing scales demonstrate acceptable reliability but vary in sensitivity and disease specificity. Harmonized, multidimensional, and digitally or objectively validated measures are needed to improve diagnostic precision, longitudinal monitoring, and clinical translation in ME/CFS.

Source: Lu J, Sun W, Li S, Qu Y, Liu T, Guo S, Feng C, Yang T. Assessment of symptoms in myalgic encephalomyelitis/chronic fatigue syndrome: a comparative study of existing scales. Front Neurol. 2025 Nov 18;16:1618272. doi: 10.3389/fneur.2025.1618272. PMID: 41341517; PMCID: PMC12668935. https://pmc.ncbi.nlm.nih.gov/articles/PMC12668935/ (Full text)