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East African Disease Informs Nath’s Search for the Cause of ME/CFS

Could a disease found in the remote villages of East Africa end up being a model for chronic fatigue syndrome (ME/CFS)?

Ugandan Village

Ugandan Village (from the NIH)

Dr. Avindra Nath – the leader of the NIH Intramural study on ME/CFS –  thinks perhaps so. He’s not daunted by mysterious diseases and nor should he be. Just a couple of years ago his NIH team was able – by bringing new technology to bear – to unravel a mysterious disease plaguing children in Africa. Using a much larger array of tests he’s hoping to do the same in ME/CFS.

Nath became acquainted with “nodding syndrome” at a meeting in Uganda in 2012. This strange and often devastating disease, found in the remote regions of Uganda, Tanzania and South Sudan, causes children’s heads to periodically nod  and can produce seizures, mild to severe cognitive impairment, muteness, gait problems, paralysis and often death. Brain scans have shown significant brain atrophy.

Studies suggested that the disease was linked to a parasite, Onchocerca volvulus, carried by the black fly, but numerous efforts to find the parasite in the brain or cerebral spinal fluid failed.  Attempts to tie it to immune factors including autoantibodies, as well as genetics, toxins, nutritional factors, and others came to naught as well.

Like ME/CFS the speculation regarding the cause of nodding syndrome has been rife with possible connections to autism spectrum disorder, Alzheimer’s, poor nutrition, PTSD and others being put forth. Ugandan psychiatrists have even proposed that the disease is a form of “Developmental Trauma Disorder” brought on by the war.

Enter Nath, Tory Johnson, a former postdoc fellow of his, and Thomas Nutman, a National Institute of Allergy and Infectious Disease (NIAID) researcher.  Suspecting the problem was autoimmunity, they brought out one of their big guns – a kind of protein chip technology that allowed them to screen for thousands of antibodies at once.

The results were tantalizing. The levels of four antibodies were 100 fold higher in the sick children compared to the healthy children.  Further testing revealed that two of these antibodies were more reactive or active in the sick children. They ended up focusing on one antibody found in both the blood and cerebral spinal fluid.

This antibody – which was linked to the leiomodin-1 protein  – reacted 33,000 times more strongly in the children with nodding syndrome.  Interestingly, both groups – the sick and the healthy children – carried the antibodies, but they were elevated in the sick children.

Leiomodin-1 staining neurons

Staining reveals Leiomodin-1 antibody (green) interacts with human neurons

After finding this link, they deepened their search. The leiomodin-1 protein had been found primarily in smooth muscle tissue and the thyroid, but if it was causing the neurodegenerative symptoms it had to be in the brain as well. Further testing, including immunostaining human neurons, indicated that protein was indeed found in parts of the brain imaging studies had indicated were associated with nodding syndrome.

Having established a putative link between the antibody and the disease (that it was found in and could potentially affect the brain) the next step was to demonstrate that the antibody could indeed be causing the disease. Subjecting cultured human neurons to the antibody showed that the antibodies could indeed be damaging the childrens’ neurons.

Getting at the source of the antibody was next. The authors hypothesized that an immune attack against the parasitic worm had gone awry and was attacking the ill childrens’ neurons. This could only happen, though, if the parasitic worm and human neurons shared genetic sequences that could cause the immune system to mistakenly attack human neurons. Studies confirmed that a very short sequence of the parasite’s tropomyosin gene was quite similar to a sequence expressed in human neurons.

autoimmune responses ME/CFS

Nath believes the infections may have triggered a variety of autoimmune responses targeting the brain in ME/CFS

With that, the circle was closed. They had identified an antibody, shown it was in the brains of the sick children, showed that it could do damage to the neurons that were damaged in the children, and demonstrated similar genetic sequences were present in the parasite and humans.

There was still the nagging issue of antibody prevalence, though.  Only slightly over 50% of the sick children had antibodies to leiomodin-1. If the antibody to leiomodin-1 was causing the disease in these children, what was causing the disease in the others?

Nath et al proposed that the parasite triggers a different immune response in different children.  Some of the children developed autoantibodies that damaged neurons in their CNS  – and produced nodding syndrome (which is now understood to be a form of autoimmune epilepsy).

This syndrome is likely not a disease mediated by a single immune specificity. We speculate that nodding syndrome may not be a single antibody syndrome.  Nath et al.

Citing test results which showed a range of elevated autoantibodies in the sick children, they suggested that some children with nodding syndrome have developed antibodies to  neuronal proteins other than leiomodin-1.

A Model for Chronic Fatigue Syndrome (ME/CFS)?

Nath reported that his approach to ME/CFS has been shaped by his experiences with nodding syndrome. He suspects the infectious onset that so many people with this disease experienced triggered their immune system to accidentally produce autoantibodies that are attacking their central nervous system or other parts of the body.

If suspect antibodies show up, future research efforts will presumably proceed down the same pathway as they did in Nodding Disease: first they will identify the proteins the antibodies are attacking, and then they will determine where those proteins are found, and demonstrate experimentally that the antibodies are likely doing damage.

Nath and his compatriots uncovered the antibody connection to nodding disease seven years ago – a long time in this age of fast moving medical technology. Nath reported he’ll be using a newer approach involving mass spectrometry, or phage display, in ME/CFS which will allow him to “probe almost infinite numbers of proteins/peptides”.

Seven years ago, extensive testing had failed to find a culprit leaving the cause of nodding syndrome a complete mystery. In 2017 Nath et. al. produced a clear pathway that explains about 50% of nodding syndrome victims.

Technology Paves the Way

Note that the breakthrough didn’t come from the slow accumulation of results over decades; –  it occurred very quickly and simply required the right technology being applied to the disease. When that happened, a cause of the disease became clear, and researchers simply proceeded down established pathways to prove  it.

Nath and the NIH are looking at much more than antibodies in their intramural study, and ME/CFS, with its multiplicity of triggers, is likely to be more complex than nodding syndrome. The same principle, though, – a variety of autoimmune processes produced by an infectious trigger – may apply.

Dr. Nath appears to have gotten at a cause of one mysterious disease. May he be as successful with this one.

Check out an interview with Dr. Nath

Dr Nath Talks on the ME/CFS NIH Intramural Study

The NIH’s Accelerating Research on ME/CFS Conference

Because of a death in the family, Brian Wallitt will be presenting in Dr. Nath’s place at the NIH conference. Dr. Nath reported that Wallit will present on the high rate of rare diseases found during the first half of the study and some other data but will not present statistical analyses. With just half of the projected participants having finished the first part of a two-part study, the lack of statistical analyses is not really a surprise.

Brian Wallitt will be presenting at 10:00 AM EST on April 5th (day two) of the Accelerating Research on ME/CFS conference – the first NIH sponsored research conference on the disease since 2011. Check out the agenda here.

Learn more about the NIH Conference below.

NIH Brings in New Faces and Looks to the Future in Accelerating ME/CFS Research Conference

A Former Doctor Goes Through the NIH’s ME/CFS Intramural Study

Robert’s Story

Robert, an MD, is board certified in internal medicine. After the worst flu-like illness he ever had, he ended up in the hospital.  A regular exerciser prior to becoming ill, his legs were so weak that he could hardly walk afterwards.

His path to a chronic fatigue syndrome (ME/CFS) diagnosis was rapid. Three months of testing left him no other conclusion – it was clear to him that he had ME/CFS.  He was able to work on and off for a few years, but his health has deteriorated. He’s been unable to work for the last three years.

ME/CFS diagnosis

Robert, a former MD, was able to rapidly diagnose himself but remains severely ill.

Thankfully, he had a wide array of doctor friends who knew him before he became ill and didn’t encounter the skepticism and invalidation so commonly experienced in our community. He noted that our current medical culture doesn’t offer much for the complex patient. Doctors are busy and often time-constrained and if you don’t fit into one of the medical pigeon-holes, they don’t have much to offer.

Rating his level of health on a scale of 1-10 at 2, he’s one of the sickest, if not the sickest, ME/CFS patient to participate in the grueling two-part intramural study at the NIH. He was the first patient to go through the second phase of the Intramural trial which involved, among other things, the exercise study and an extended stay in a metabolic chamber.

One theme – validation – cropped up several times during Robert’s week long stay at the NIH hospital in Maryland. It was clearly apparent from the gestures of sympathy from the occupational therapist during a test to assess functioning.  Given cards which identified an activity, Robert put them into two piles – activities he used to do and activities he still did. The occupational therapist – who has probably given this test hundreds if not thousands of times – registered dismay at the few cards left in his “still do” pile. Those few cards left made the extra level of devastation that ME/CFS is so good at causing clear. It’s rare for people who are not elderly to be so sick.

Given his abysmal level of functioning, Robert’s willingness to participate in a study that Dr. Nath thought few might be willing to undergo was a real testament to the courage and determination that so impressed Dr. Nath. Despite Robert’s low functional level (1-2 on a 10-point scale), he was disappointed that the NIH was not doing a two-day exercise test (!).

The second part of the study is centered around the exercise stressor. Participants do cognitive testing, blood tests, the Seahorse mitochondrial test, a functional MRI and transcranial magnetic stimulation before and after the maximal exercise test.  (The NIH communicated with the Workwell Foundation on doing the exercise test with ME/CFS patients).

Exercise is finally getting its due in ME/CFS, and over the next couple of years several large studies should tell us much. With its extensive blood draws and millions of data points, Dr. Klimas’s exercise studies have informed her models of ME/CFS and laid the foundations for her clinical trial.  With help from the Solve ME/CFS Initiative, David Systrom has added gene expression to his already complex invasive cardiopulmonary exercise testing.  Maureen Hanson has incorporated exercise into her large NIH Research Center studies at Cornell, as well.  None of these studies, though, can match the sheer breadth of this NIH exercise study with its brain scans, lumbar punctures, Seahorse data, blood draws, etc..

Metabolic Chamber

Robert spent about three days in the metabolic chamber – a sparse box containing a bed and a toilet that’s designed to produce precise measures of metabolic activity – before and after the exercise test.  (I will expand on the metabolic chamber).  He wore an EEG, blood pressure and Holter monitor, while in the chamber.

Only thirty metabolic chambers exist in the world, and three of them are at the NIH. With 400 metabolic chamber studies underway every year, they’re pretty much in use all the time. These airtight 11-by-11.5-foot rooms aren’t much to look at or stay in: they come with a bed, an exercise bike, a toilet, and nothing else. Precisely measured meals are delivered through a small, air-locked opening in the wall.

metabolic chamber NIH

An early metabolic chamber at the NIH in 1957

Metal pipes running along the ceiling that measure oxygen consumption and CO2 production allow researchers to precisely calculate an individual’s metabolic rate.  From the O2 and CO2 readings, researchers can calculate calories burned and what type of fuel (carbs/fats) was used to burn them. Urine is collected to assess protein oxidation.

Metabolic chamber studies have demonstrated how flexible the body is with respect to metabolism. One reporter wrote, for instance, that they’ve debunked the idea that ketogenic diets (high-fat/low-carb) cause the body to burn more fat than high-carb diets.

Energy is burned in our body in three ways. It turns out that simply staying alive is pretty energy intensive. Most of the calories we burn (65-80%) are used simply to keep our body running (basal metabolism). Digestion is no walk in the park either; digesting our food takes up about 10% of the calories we burn in a day, with physical activity accounting for the remainder (10-30%).

If ME/CFS patients’ metabolic production and ability to produce energy is altered by exercise – as Workwell’s and Dr. Keller’s tests suggest it is – that will hopefully be picked up by the metabolic chamber.

Robert noted that if they can pair the findings from the metabolic chamber – which is measuring the metabolic effects of exercise – with the Seahorse tests- which are measuring energy production on the cellular level, they may really be onto something.

Brain Scan

The functional MRI – which Robert said was combined with a cognitive test – will assess the impact of exercise on a) cognitive functioning and b) brain functioning. A similar study by the CDC suggested that exercise negatively impacted both cognitive and brain functioning.

People who do cognitive tests tend to improve the more they do them but not in this case – not in people with ME/CFS after exercise.  Familiarity did not breed more competence. Despite doing the tests multiple times, the people with ME/CFS did worse and worse on them after exercise and the brain scans indicated why. Exercise had knocked out one area of the brain devoted to sustained attention causing the brain – in a mostly futile attempt to compensate – to increase activity in other parts of the brain (devoted to executive functioning).

A Chronic Fatigue Syndrome Brain on Exercise – Not a Pretty Sight

The end result was that people with ME/CFS expended more effort during the cognitive test and yet did worse. By the end of the test they were making about double the errors of the healthy controls.

rTMS Test

motor cortex

The rTMS test appeared to be designed to stimulate Robert’s motor cortex to activate his muscles.

The repetitive transcranial magnetic stimulation (rTMS) test proved enormously interesting but physically draining.  Robert reported that in a process that took hours, data from a previous fMRI was used map the exact location of his motor cortex in order to stimulate the muscles of his right hand/fingers.  The goal was apparently to determine the speed at which the signal traveled from the brain to the muscle of his finger before and after exercise.  A time delay after exercise would presumably indicate that exercise had interfered with the ability of the motor cortex to activate the muscles.

A 2003 study, in fact, suggested that reduced muscle recruitment due to reduced motor cortex output was occurring in ME/CFS. The motor cortex, it turns out, plans our movements in advance. The study, titled “Deficit in motor performance correlates with changed corticospinal excitability in patients with chronic fatigue syndrome“ suggested that problems in the “motor preparatory areas of the brain” might be hampering physical movements in ME/CFS. It has never to my knowledge been followed up on.

rTMS has relieved pain in fibromyalgia but it had the opposite effects in Robert. He wasn’t clear whether it was the effects of the rTMS or the rigors of setting up the test itself or both which triggered for him what turned out to be an extraordinary bout of PEM (post exertional malaise). The 2 hours it took – sitting up – to get the electrodes correct was in itself draining. (He suggested that they use a reclining chair for future patients if possible.)

At the end of test Robert felt exhausted and experienced transient vertigo, auditory disturbance, headache and sensitivity to light and noises.  His nurse was shocked at how poorly he looked.  He’d mentioned the documentary Unrest to her the day before. After seeing the movie, she said she could better appreciate what he was going through. (Hopefully she knows that watching the film will get her continuing medical education (CME) credits)

The rTMS test proved immediately much more exhausting than the exercise test, the effects of which took a day to kick in. The rTMS specialist/researcher was surprised at the effect the test had on Robert and its cause is unknown. Was it the long preparatory period or the activity of the rTMS machine on the muscle activation pathways or both?  It’ll be fascinating to see how other patients fare.

Robert was also tested for small fiber neuropathy via skin biopsy, underwent a post exercise lumbar puncture and quadricep muscle biopsy.  The possibility of integrating the brain scan, cerebral spinal fluid, Seahorse and metabolic chamber results after exercise – not to mention the immune tests – is an enticing one for sure.

NIH intramural ME/CFS study data collection

The study, which is going to generate an enormous amount of data, is still several years away from completion.

Plus there are the muscle biopsy results. Robert’s experience of a rather hefty muscle biopsy suggests that the NIH is not stinting on this area – which Dr. Nath believes may tell us much about ME/CFS.

Plenty of rest periods were provided during the study but at times the testing was lengthy, and the study, predictably, ended up being a rather grueling seven days for this courageous but very disabled ME/CFS patient. Participating in it wasn’t easy but the fact that Robert, even with his abysmal level of functionality, made it through it and recovered, was a good sign. Robert said he was touched by a chaplain who stopped by to see how he was doing.

He’s stayed in touch with the investigators from time to time alerting them of developments in the ME/CFS field.

Participating in the Study

The NIH needs more participants. If you’re interested in helping to further ME/CFS research by participating in the study, check out the study criteria below.

All participants must be 18-60 years old and have at least a 7th grade education. People whose ME/CFS started after an episode of infection and who have severe symptoms lasting from 6 months to 5 years are eligible to participate in the study.

Find out how to participate here.

Learn more about the Intramural Study

Dr Nath Talks on the ME/CFS NIH Intramural Study

Dr Nath Talks on the ME/CFS NIH Intramural Study

It looked like we were going to be late … again. It was pouring cats and dogs as we eased the van around tangled web of streets that is the NIH campus scanning glumly at the rain-obscured buildings. Even our guide on the phone seemed to be lost.

It had been a wild 12 hours. The night before, reaching up to turn on the fan on my brother’s porch, I’d let loose a rather large bug which tumbled into my eye. Howling with pain I stumbled off to the bathroom where I managed to wash it out – leaving my eye reddened and swollen. The next morning, my eye still swollen, my partner insisted I see an eye doctor.

 

NIH

Getting to Dr Nath’s office proved to be a challenge

To our surprise we found somebody. The problem was was that his office was right in the heart of downtown Washington DC. – where parking is scarce and traffic cops take their jobs very seriously. Finding no parking we stopped in a loading zone across from the doctor’s office, hoping that the big yellow van with it’s solar panels, Nevada license plate and all would for the next 15 minutes be taken for a loading van –

After being assured the appointment would be short, I dashed inside where I was  bombarded by frantic calls from my partner (who does not drive the van). She had immediately been accosted by first one then another traffic cop.

After seeing the doctor who informed me (for $250 dollars) that insects in the eyes almost never cause problems (but who did give me drops) I dashed back out to the van to find my now none-too happy partner.

We sped off in the rain – still seemingly on time for the appointment with Dr. Nath. Hauling up to the NIH we tried no less than three entrances – only to be turned away at each them (our oversize vehicle thwarting one attempt) – and directed to the next. Finally, as our appointment time came and went, we found the right entrance – for, ironically, delivery vehicles.

After going through an extensive (and time-consuming) security check we headed off into the labyrinth that is the NIH clutching small hard to decipher maps and immediately got lost. The  minutes continued to tick by and rain strengthened into a deluge and eventually we managed to steer onto the right street. Our guide, still on the phone, told us to stop, we jumped out of the car and looked up, rain pouring down, at a steep, muddy climb.

Five minutes later – 45 minutes late for our hour appointment, we strode, soaked and bedraggled into Dr. Nath’s office. He immediately set us at ease, and with his next appointment running late stayed overtime with us. We were there to talk about the NIH Intramural ME/CFS study.

The NIH Intramural ME/CFS Study

Dr. Nath informed us that the applications to be in the NIH Intramural ME/CFS study have been gratifyingly robust.  Dr. Nath noted that it was entirely possible that this is the most rigorously examined patient group ever assembled for a study.

Dr. Nath

Dr. Nath is leading the study. He has been around. He received his MD degree from Christian Medical College in India in 1981, completed a residency in Neurology from The University of Texas Health Science Center in Houston, did a fellowship in Multiple Sclerosis and Neurovirology at the same institution, and then another fellowship in Neuro-AIDS at NINDS.

Then it was up to Canada, where he held a faculty position at the University of Manitoba (1990-97), and then he was at The University of Kentucky (1997-02). In 2002, he became Professor of Neurology and Director of the Division of Neuroimmunology and Neurological Infections at Johns Hopkins.

in 2011, he became the Clinical Director of NINDS, the Director of the Translational Neuroscience Center, and Chief of the Section of Infections of the Nervous System. His research focuses on understanding the pathophysiology of nervous system infections and their outcomes, and the development of new diagnostic and therapeutic approaches for these diseases. He’s heavily involved in HIV research, the role endogenous retroviruses play in neurological diseases, and “undiagnosed neuroimmune and neuroinfectious diseases”.

He recently wrote a paper on Herpes Viruses, Alzheimer’s Disease, and Related Dementias: Unifying or Confusing Hypothesis?, which examined what role herpesviruses might be playing in dementia.

The NIH Intramural Chronic Fatigue Syndrome Study

The study takes place in two parts: a one week part which further assesses the potential participant and another one week section which measures a wide variety of parameters before and after an exercise test.

Requirements for entry are high, however, and not often met. You might say that many have been called – or rather have called – but few have been chosen. That was OK with Dr. Nath. “We need,” he explained, “to make sure that we’re studying the right population. That’s the best way to get to the answer, and then it’ll be broadly applicable.”

The response has been excellent.  Many people are traveling to participate, and they’re coming from all over. The NIH is even getting interest from people in other countries.

As of Dec. last year, 337 people had inquired about the study. One hundred and seventy-three were quickly screened out, and 164 participated in phone interviews. One hundred and twenty-seven made it to the medical record assessment stage.

Multiple reasons thwarted would-be participants from participating in the study.  The study required onset within 5 years which was triggered by infection. One-third had had the disease for too long, 20% had no evidence of infectious process (doctor’s records are required), 9% were too sick to travel, and just 3% were unwilling to have a lumbar puncture.

community ME/CFS

Nath noted that the ME/CFS community was very motivated to be in the study

The researchers were surprised at the last two figures. They expected, based on their experience from past studies, much higher percentages of people who were too sick to travel or unwilling to have a lumbar puncture. Dr. Nath well knows how difficult it can be to get people to participate in a study, but that’s not a problem here. Calling the numbers “very good”, Dr. Nath said the ME/CFS community was clearly “very motivated to participate in the study”.

It is not an easy study! It’s a two-part, two-week plus study on a population, which studies suggest, has the lowest functionality of any disease. The study includes a lumbar puncture, a maximal exercise test, several nights in a metal box (metabolic chamber), tilt table test, muscle biopsy, brain scans, lengthy neuropsychological tests and scads of blood tests. Every part of you is going to be probed.

Plus, you have to provide your entire medical history, get interviewed several times, and then, most likely travel.

Dr. Nath said he looked at the study – which is clearly larger and more intensive than most  – and said, “who is going to enroll in this study?” Laughing, he joked that, “I wouldn’t volunteer on my own study!” He was afraid no one was going to show up!  Instead he said the patients were very willing to undergo all the tests and are grateful for it.

Recruitment has been good, but as with any study, Dr. Nath said, it was high at first, and now it’s tailed off. As of March of this year, 19 ME/CFS patients and 21 healthy controls had completed the first phase of the study, and six people with ME/CFS and 7 controls had completed phase II.

Thus far, then, about half the projected participants (n=40 ME/CFS; 40 healthy controls) have gone through the first week of the study and about 15% have completed the entire study.

Quite a few people with autoimmune disorders have shown up during the filtering out process. Nath suggested that could be an interesting cohort to study on its own.  He’s also found quite a bit of head injury and loss of consciousness – which makes MRI and brain scans difficult to assess – and people with seizures and strokes. Interestingly, bnly one person had had a diagnosis of major depression….

High Percentage of Rare Diseases 

It’s a small sample set but it’s remarkable how many people participating in the first week were diagnosed with a rare disease. In something of a testament to the thoroughness of the study, almost third of week one participants (6/19) were found to have a rare disorder which the researchers believed was probably causing their symptoms and dismissed from the study. One appeared to have Parkinson’s Disease, another a neurological disease and I’m unsure of the others.

The study was designed to catch these people.  In fact because ME/CFS is something of a wastebasket diagnosis it went to extra lengths to ensure it was really studying ME/CFS.  Plus Dr. Nath reported that neurological diseases are inherently hard to diagnose anyway.  It is not unusual for people with multiple sclerosis, Parkinson’s, etc to be misdiagnosed with some other disease initially.  Plus, the opposite can happen (and has happened in ME/CFS) with some patients being misdiagnosed with M.S. for many years only to find later that they have some other immune disorder.

Big Data

They are gathering lots and lots of data – which brings its own problem. The study includes two different brain scans, blood, saliva, urine and stool samples, exercise data, tilt table data, spinal taps, Seahorse data, metabolic room data, cognitive testing, muscle and skin biopsies, and I’m probably missing some. I asked Nath, how will they able to integrate all this disparate data?

rare disorder chronic fatigue

Rare disorders are popping up at a high rate in the study group

Nath agreed that it was a challenge, but noted that that kind of challenge is a pretty common challenge now. Some of the really big Alzheimer’s and Parkinson’s studies contain thousands of individuals, each of whom has done thousands of tests. Computational biology has become a major part of medical research.

Google, not surprisingly, is collaborating with the NIH to create better ways to analyze data. Many of the discoveries in medicine today, Nath said, actually occur as breakthroughs in physics; MRI and CT scans, for example – came from physics.

Their general hypothesis is that an infection triggers brain and immune system issues (ranging from persistent immune activation to immune dysregulation) that stay stuck.  They don’t believe the nature of the infection is particularly important.

Check out a disease Nath believes could prove a model for ME/CFS

East African Disease Informs Nath’s Search for the Cause of ME/CFS

No Preliminary Findings Yet

Nath was unable to give me any preliminary findings. One reason is that they are storing samples so they can run them all at the same time. Another is that, echoing Ron and Mark Davis’s thoughts, they don’t want to even try to come up with hypotheses yet. They simply want to gather more and more data.

Making a conclusion on the basis of small samples is, Nath said, the kiss the death. They will not even try to interpret their findings until about half the study is done.

If, when they get to the end of the study, they see trends but don’t quite have a significant result, they’ll do sample size calculations to determine how many more patients they’ll need to see to get to statistical significance. If the calculation says do another 10 patients, they’ll probably expand the study to do 12 more. If the calculation says do another 100 patients, that’s too much.

They’re preventing another kind of bias by recoding the samples, so the analyst doesn’t know which are from patients and which are from controls.

The Study

Brian Vastag’s visit raised the issue of mitochondrial problems. Nath believes studying the muscle itself may be more important than assessing mitochondrial problems using the blood, and added muscle biopsies to the study. The muscle biopsies will be tested for DNA analysis, structural issues, and staining for various kinds of cells.

The Open Medicine Foundation and Ron Davis apparently believe likewise. They’ve pumped a million dollars into an ME/CFS Collaborative Research Center at Harvard lead by Ron Tompkins which will focus on figuring out what is going on in the muscles.

muscles ME/CFS

Dr. Nath believes the muscles could tell us much about ME/CFS

Because lots of patients have autonomic symptoms, the NIH is doing tilt table tests. Once those turn out positive, Nath said, the next question is why the autonomic nervous system problems are present. They’re doing small fiber neuropathy skin tests and examining the heart, peripheral nerves, adrenal glands, and sympathetic nervous system functioning.

I asked him if there were any surprises, and there were.  As Robert’s story will show, the NIH doesn’t seem to be prepared for the level of devastation ME/CFS can wreak in a relatively young group of patients.

Nath said his personal contact with the patients has led him to develop a real appreciation for the disease. These patients, he said, “are devastated”. Whether or not this study finds a cause, the reality, Nath said, is that the lives of the study patients are “totally messed up.” Then he made an important point.  Seeing the patients in the flesh naturally causes him and other researchers to develop additional empathy for them and “another level of appreciation” for them and their disease.

It was clear that just by being there and exposing the researchers and doctors at the NIH to this disease, the participants in the study are making a difference.  The lengths to which some patients are going to participate in this study are amply illustrated by Robert’s story.

Participating in the Study

The NIH needs more participants. If you’re interested in helping to further ME/CFS research by participating in the study, check out the study criteria below.

All participants must be 18-60 years old and have at least a 7th grade education. People whose ME/CFS started after an episode of infection and who have severe symptoms lasting from 6 months to 5 years are eligible to participate in the study.

Find out more here.

A former doctor on his experience going through the NIH’s intramural study

A Former Doctor Goes Through the NIH’s ME/CFS Intramural Study

The Brainstem, Vagus Nerve, Neuroinflammation and Chronic Fatigue Syndrome: The VanElzakker Way

In 2013, Michael VanElzakker produced one of the most intriguing hypotheses to date in ME/CFS. His Vagus Nerve Hypothesis proposed that an infection/inflammation near the vagus nerve was causing it to send an unending stream of messages to the brain, telling it to essentially shut the body down by producing fatigue, pain and other symptoms. Since then, he’s been particularly interested in the connection between the vagus nerve, the brainstem and the ME/CFS.

He’s not the only one interested in the brainstem. In 2019 once his brainstem compression was alleviated, Jeff completely recovered from his severe ME/CFS, POTS and MCAS. Since he published his story over a dozen people have been diagnosed with craniocervical instability – a condition which compresses the brainstem.

In this critical review paper, VanElzakker et. al. pick apart some of the research done and provide a guide to successfully getting at the brainstem and other regions of the brain. It’s called a “Critical Review” and is critical, indeed. It finds many past ME/CFS studies wanting, but then points a way to a better possible future. If brainstem problems play a role in ME/CFS these researchers demonstrate how to get at them.

One Theory To Explain Them All? The Vagus Nerve Infection Hypothesis for Chronic Fatigue Syndrome

Neuroinflammation and Cytokines in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS): A Critical Review of Research Methods.  Michael B. VanElzakker, Sydney A. Brumfield and Paula S. Lara Mejia. Front. Neurol., 10 January 2019 https://doi.org/10.3389/fneur.2018.01033 https://www.frontiersin.org/articles/10.3389/fneur.2018.01033/full

First, VanElzakker et. al. examines one of the sacred cows in the chronic fatigue syndrome (ME/CFS) community – the preferred term for so many: myalgic encephalomyelitis (ME), which refers to muscle pain (myalgia) related to central nervous system inflammation (encephalomyelitis).

While muscle pain is common, it’s not universal. Even people with severe ME may not report pain.

Still, the core part of the definition deals with central nervous system inflammation – a description that, with the emergence of the 2015 Yakatomi and the 2019 Younger studies, seems more and more likely to stick. (A 2018 PET scan study also found neuroinflammation in fibromyalgia as well.)

The idea that inflammation plays a key role in this illness makes sense, given the infectious trigger so commonly (but not universally) found. The authors are just a few among many (Avindra Nath, Jarred Younger, Andrew Lloyd and others) who believe that an infectious event has triggered changes in the brain that are producing fatigue, pain and other problems in ME/CFS.

They point to three ways an infectious trigger could produce central nervous system inflammation in ME/CFS:

A) immune factors (e.g. cytokines) triggered by the infection could get transported across the blood-brain barrier (BBB) that protects the brain. The normally taut blood–brain barrier makes blood-borne infections of the brain rare, but it can, like the gut, become leaky in inflammatory states, allowing immune factors and pathogens entry. Once in the central nervous system, they could trigger a large inflammatory response, or

B) High concentrations of immune factors could allow pathogens to passively diffuse across the BBB, or

C) Immune factors in the blood could trigger the vagus nerve to send signals to the brainstem and brain, which then sparks an inflammatory response.

It’s the last option that primarily concerns these authors. VanElzakker is the author of the Vagus Nerve Hypothesis, which proposes that an infection/inflammation near the vagus nerve is causing it to send an unrelenting stream of signals to the brain, telling it to produce the flu-like symptoms that constitute “sickness behavior” (withdrawal to bed), which isolates infected people from the community and keeps them from spreading an infection.

The largest nerve in the body, the vagus nerve transmits sensory, autonomic, immune and other signals to the brainstem – making it potentially a key player in a possible neuroinflammatory disease like ME/CFS.

Studies indicate that inflammation in the periphery tends to produce a mirror inflammatory response from the immune cells (the glia) in the brain. Even small levels of cytokines in the periphery or body have the potential to activate the chemoreceptors in the vagus nerve, which then activate the immune system in the brain.

That brain activation, interestingly, tends to occur in regions (basal ganglia, limbic system organs (amygdala, hippocampus and hypothalamus), anterior cingulate cortex, prefrontal cortex, and thalamus), which studies suggest are also involved in ME/CFS.

The Brainstem

brainstem

The brainstem regulates many vital functions in the body

The authors believe the brainstem (which, as it name implies, is found at the very base of the brain, above the termination of the spinal cord), could play a key role in chronic fatigue syndrome (ME/CFS) for four reasons:

  1. Immune signals from the vagus nerve to the brain travel through the brainstem.
  2. The brainstem is dense with mast cells, and mast cell activation syndrome (MCAS) appears to be common in ME/CFS.
  3. The brainstem regulates autonomic nervous system functioning – a common trouble area for ME/CFS and related disorders.
  4. The brainstem also regulates immune functioning; in particular, it triggers an anti-inflammatory response that should limit the inflammatory response.

Whether caused by a structural problem (as in Jeff’s case), inflammation or an infection, the brainstem is a centrally placed brain component that produces many of the issues in ME/CFS.

Could Craniocervical Instability Be Causing ME/CFS, Fibromyalgia & POTS? Pt I – The Brainstem Series

Seeing the Brainstem in Chronic Fatigue Syndrome (ME/CFS)

Consistent inflammation of the brainstem has not, however, been found in ME/CFS. The authors argue, though, that researchers have rarely used the right kind of imaging needed to investigate this.

The most commonly used method for measuring inflammation in the brain involves measuring the 18kD translocator protein (TSPO) with a PET scan. This protein is produced when the immune cells of the brain – the microglia – become activated. Because the microglia are the chief producers of inflammation in the brain, the TSPO provides a reliable way to indirectly measure neuroinflammation and its effects.

The Nakatomi Study

Nakotomi’s small ME/CFS study using TSPO made a big splash in 2014.   Tony Komaroff called the finding of central nervous system inflammation the most important study in decades. Five years later, Van Elzakker et. al. called it “important” and potentially “groundbreaking”. The study used TSPO imaging to find widespread neuroinflammation, particularly in the areas leading from the brainstem to the thalamus.

While the authors regard Nakatomi’s study as potentially groundbreaking, the study is not without significant issues. The authors, in fact, seemed a bit shocked that Nakatomi found as many effects as he did, given the techniques used.

The neuroimaging techniques Nakatomi used (and which most researchers use) were not designed to address brainstem inflammation. Nakatomi used a spatial “registration” technique that aligns the image on the neocortex or upper part of the brain. This kind of alignment is typically done because researchers tend to focus on the upper, “higher” functioning areas of the brain. It can, however, impair the sensitivity of imaging done on the lower, more densely packed, primitive areas of the brain, such as the brainstem, and lead to false negatives.

The PK-1195 tracer

Nakatomi also used an older tracer (PK-11195) which does not penetrate deeply into the brain and can bind to unintended elements in the brain. Differences in blood-brain barrier permeability between the ME/CFS patients and healthy controls – a distinct possibility – could have confounded the results, as well. Nakatomi’s use of the cerebellum as a kind of baseline measure could have introduced further issues if problems with the cerebellum (another possibility) exist in ME/CFS.

Plus, the hypometabolism believed present in ME/CFS could have resulted in lower amounts of the tracer being metabolized than usual – causing higher amounts of the tracer to reach the brain – and producing a false positive. Because exercise may affect how much of the tracer is taken up into the cells, Nakatomi’s use of healthy, non-sedentary controls instead of sedentary controls introduced another issue.

Finally, because the brainstem actually pulses with every heartbeat, that movement needs to be accounted for – and usually isn’t in ME/CFS studies.  The very small but important nuclei in the brainstem are also often not picked up with the standard imaging techniques used in ME/CFS research.

Nakatomi’s study results make sense given what we know, and were given a sort of validation by Jarred Younger’s recent results using thermal mapping – a new technology – but we need more validation.

The takeaway is that the brainstem – because of the role it plays in autonomic nervous system functioning, immune regulation and the transmission of motor signals – could play a major role in ME/CFS, but is essentially, according to these authors, still something of a black box.

Barnden’s Brainstem – the Australian Study

It’s not completely a black box, though. Researchers using other techniques have found evidence of brainstem problems in ME/CFS. Barndem in Australia, in particular, has done a series of MRI studies which have found striking brainstem issues in ME/CFS.

(During his talk at the 2019 Emerge conference, Barnden noted how he had to shift his MRI to avoid the alignment problem (that VanElzakker mentioned) which prevented him from getting a good image of the brainstem. )

One study found that reduced brainstem grey matter volume – suggesting that damage to the neurons in the brainstem had occurred – was correlated with autonomic nervous system problems in ME/CFS.

Barnden brainstem damage ME_CFS

Using the right imaging approach Barnden found extensive evidence of damage to the neurons (myelin) in the brainstem. (From the 2019 Emerge Conference Livestream)

Another study finding of impaired communication from the brainstem nuclei to other nuclei in the brain suggested the same, and found increased signs of myelination in the sensorimotor cortex of the brain.  Barnden proposed that decreased signaling from a damaged brainstem provoked a compensatory increase in myelination in the sensorimotor region as it bulked up to try to understand the limited signaling coming from the brainstem. The impaired brainstem-sensorimotor connection might be, Barnden thought, impacting motor functioning in ME; i.e. the ability to carry out physical activity.

Signals to move muscles pass from the motor cortex to the sensorimotor cortex down to the thalamus and then through the brainstem to the muscles. (Signals from the muscles to the brain pass up through the same pathways.) Barnden proposed that the movement problems in ME/CFS could start with the brainstem’s inability to properly relay signals to the motor cortex to activate the muscles.

Barnden’s most recent brainstem study validated the idea that inadequate communication between the brainstem nuclei and other nuclei in the brain, including the vasomotor region, hypothalamus and prefrontal cortex, was affecting autonomic nervous system functioning in ME/CFS.

Other Kinds of Brain Scans

Other kinds of brain scans, such as magnetic resonance spectroscopy (MRS), can pick up signs of neuroinflammation. Although almost 10 MRS studies of the brain in ME/CFS have been done, VanElzakker et. al. report that a clear and consistent picture of metabolite alterations in the brain has yet to emerge.

They believe that’s due largely to a common theme in medical research, found in this disease in particular – lack of standardization. Different diagnostic criteria, different types of healthy controls, different brain regions examined, and different metabolites targeted make it difficult to present a clear picture of the metabolic alterations in the brains of people with ME/CFS.

The Japanese Take

The Japanese probably couldn’t agree with Barnden more. Their studies indicate that, as the healthy controls became more fatigued, two core regions – both of which communicate with the brainstem ( the prefrontal cortex and the anterior cingulate cortex) – shut down.

As these regions begin to shut down, control of autonomic functioning becomes lost.  In particular, the ability to activate the parasympathetic nervous system (i.e. the vagus nerve) and tone down the sympathetic nervous system activity, is lost.

The Japanese believe a breakdown in what they call the facilitation system in the brain has occurred.  As we become fatigued, the facilitation system jumps in to increase the signals coming from the primary motor cortex to the muscles. This increased “drive” from the motor cortex prompts the muscles to work harder and activates more and more of them so that activity can proceed.

Fatigue – the Japanese Way: A Chronic Fatigue Syndrome Perspective

So long as new, fresh muscle fibers remain to be recruited, the activity can continue.  If no muscle fibers are left to be recruited or if the brain has a problem recruiting new muscle fibers, fatigue sets in.

A 2003 study suggested that reduced muscle recruitment due to reduced motor cortex output was indeed occurring in ME/CFS. That study suggested that, “… changing motor deficits in CFS has a neurophysiological basis [which] … supports the notion of a deficit in motor preparatory areas of the brain”.  That study titled, “Deficit in motor performance correlates with changed corticospinal excitability in patients with chronic fatigue syndrome“, to my knowledge was never followed up on.

Fatigue Explained? Japanese Assert Brain Damage Causes Fatigue in Chronic Fatigue Syndrome

Conclusion

Several studies suggest significant brainstem issues may be present in ME/CFS. Problems with the brainstem could produce everything from autonomic nervous system problems to immune issues to problems with movement.

The authors critique past brain imaging studies and provide a “how to” guide to assess the brainstem in ME/CFS. Barnden’s Australian brainstem studies suggest that when done correctly, MRI imaging studies may indeed find extensive damage is present in ME/CFS including evidence of brainstem neuron demyelination, a compensatory remyelination in parts of the brain the brainstem connects with, and lastly, a reduced connectivity between these regions.

VanELzakker et. al.  assert that future imaging studies that focus on the specific functional connectivity pathways in the brain which are activated by inflammatory processes should be able to capture the neuroinflammatory processes occurring in ME/CFS.  (Two of the three pathways they cite include the brainstem.) The thalamus’s role in sensory stimuli activity presents another fruitful pathway to assess.  Lastly, the authors suggest that researchers target the nucleus of the solitary tract (NTS) where the vagus nerve enters the brainstem.

With help from an ME/CFS donor, VanElzakker has been employing brain imagining techniques to assess the brainstem in chronic fatigue syndrome (ME/CFS). He will be speaking at the NIH ME/CFS Conference in Baltimore in April.

One Theory To Explain Them All? The Vagus Nerve Infection Hypothesis for Chronic Fatigue Syndrome

Could the Gut Cure Neuroinflammation? An MS and ME/CFS/FM Inquiry

Gut Neuroinflammation Connection Revealed

“There is something very critical about how the gut and brain are connected, and we’re starting to unravel the molecular threads behind that clinical observation. It’s a great example of how fast science can move.” Jen Gommerman – co-author

Limiting our attention solely to chronic fatigue syndrome (ME/CFS), fibromyalgia (FM) and allied disorders might be a mistake. Recent studies indicate that ME/CFS and FM fit into the broad category of neuroinflammatory disorders which include multiple sclerosis (MS), Parkinson’s disease and others.

ME/CFS and FM neuroinflammatory

ME/CFS and FM may fit into a broad spectrum of neuroinflammatory disorders.

The same parts of the brain may not be affected in each disease, but it’s possible that each is undergirded by a similar inflammatory milieu. If the goal is to reduce neuroinflammation, then an approach that works in one disease could work in another.

The immense amount of research being devoted to these other neuroinflammatory disorders suggests they could provide critical insights into ME/CFS and FM as well.

A recent multiple sclerosis gut study provided a prime example of how progress in one neuroinflammatory disease may benefit others. It underscored the gut’s long reach and illuminated a potential treatment approach – not just for MS, but possibly also for other neuroinflammatory diseases.

It raised the possibility that manipulating one’s gut bacteria may at some point become an effective treatment approach in the fight against neuroinflammation.

Cell. 2018 Dec 21. pii: S0092-8674(18)31560-5. doi: 10.1016/j.cell.2018.11.035. [Epub ahead of print] Recirculating Intestinal IgA-Producing Cells Regulate Neuroinflammation via IL-10. Rojas OL1, Pröbstel AK2, Porfilio EA1, Wang AA1, Charabati M3, Sun T1, Lee DSW1, Galicia G1, Ramaglia V1, Ward LA1, Leung LYT1, Najafi G1, Khaleghi K1, Garcillán B4, Li A5, Besla R6, Naouar I1, Cao EY1, Chiaranunt P1, Burrows K1, Robinson HG7, Allanach JR7, Yam J1, Luck H5, Campbell DJ8, Allman D9, Brooks DG10, Tomura M11, Baumann R2, Zamvil SS12, Bar-Or A13, Horwitz MS14, Winer DA6, Mortha A1, Mackay F4, Prat A3, Osborne LC7, Robbins C15, Baranzini SE16, Gommerman JL17.

Their study started in the head and moved downwards. Researchers wondered where the heck the plasma cells (IgA antibody producing B-cells) showing up in the central nervous systems of MS patients were coming from. It turned out they were coming from the gut.  They found that B-cells were making their way to the gut where gut bacteria where flipping their switch – and turning them into IgA producing plasma cells. Now their one and only goal was to produce IgA antibodies.

IgA antibody gut chronic fatigue

IgA antibody producing cells that are formed in the gut appear to play a major role in tamping down inflammation in the brain

Eventually they made their way up the body to the brain, where (in the presence of IL-10) they were tamping down inflammation. Interestingly, the guts of the mouse model for MS were deficient in these cells. These plasma B-cells were so effective at reducing brain inflammation that boosting their levels in the mice’s guts returned them to health.

The levels of these plasma cells are also reduced in the guts of humans during MS relapses – presumably because they’re being recruited to the brain to fight the inflammation.

This finding cleared up a conundrum – why knocking out B-cells tended to help people with MS while knocking out only the IgA-producing cells made them worse. B-cells were believed to promote neuroinflammation and autoimmunity and they do. The B-cell inhibitors used are believed to reduce T-cell activation and suppress autoantibody production.

No one suspected, though, that specialized B-cells might also play a critical role in suppressing inflammation. Knocking those cells out resulted in the patients getting worse.

Gut Modification

“Showing that IgA-producing B cells can travel from the gut to the brain opens a new page in the book of neuroinflammatory diseases and could be the first step towards producing novel treatments to modulate or stop MS and related neurological disorders.” Sergio Baranzini – co-author

The next steps seem clear: find a way to increase the number of IgA-producing plasma cells in the guts of people with neuroinflammatory disorders in the hope that they will knock down inflammation in the brain. Because some bacteria – which ones is unknown at the moment – trigger B-cells in the gut to change to IgA producing plasma B-cells, the next step is to identify that microbe and find a way to increase its numbers.  In other words, find a way for the gut to naturally reduce inflammation in the brain.

“If we can understand what these cells are reacting to, we can potentially treat MS by modulating our gut commensals. That might be easier than getting drugs into the brain, which is a strategy that hasn’t always worked in MS.” Gommerman – senior author

Potential Relevance to Chronic Fatigue Syndrome (ME/CFS), Fibromyalgia, etc.

“As a clinician-scientist, it is exciting that our experiments linking preclinical animal models to the biology we see in real MS patients may have uncovered a general mechanism for how the immune system counteracts inflammation.” Pröbstel – co-author

Chronic fatigue syndrome (ME/CFS) is not MS but the two diseases might be more closely related than one might think. Having mononucleosis/glandular fever increases the risk of coming down with either ME/CFS or MS and infections often trigger relapses in both diseases. The most disabling symptom in MS tends to be fatigue and both diseases mostly affect women. Plus pregnancy often brings a (temporary) respite in both diseases.

A Simmaron Research Foundation sponsored spinal fluid study found similar levels of immune alterations in ME/CFS and MS, and pointed to a major, almost MS-like, alteration of immune factors in ME/CFS.

Simmaron’s Spinal Fluid Study Finds Dramatic Differences in Chronic Fatigue Syndrome

Jarred Younger, who knows neuroinflammation as well as anyone in this field, believes that MS and ME/CFS could turn out to be close cousins. Younger believes the neuroinflammation present in both diseases may be similar, with the notable distinction that the immune cells in MS have been tweaked to attack the neurons, while those in ME/CFS, thankfully, have not. (Younger has begun a low dose naltrexone trial in early stage MS patients to see if he can stop the neuroinflammation before it has irrevocably damaged the nerves.)

 

Jarred Younger III : Treatments – A Better LDN and the Hunt for Microglia Inhibitors

What works in MS could work in ME/CFS and it already has – at least in two cases. A MS drug called Copaxone was very effective in two ME/CFS patients who’d been misdiagnosed with MS. In fact, it was much more effective in those patients – resulting in significant reductions in fatigue –  than it ever was in MS.

The really exciting thing about this study is its potential relatability to other diseases.  These researchers appeared to have stumbled upon a basic gut induced anti-inflammatory pathway that may help with other neuroinflammatory diseases including, who knows, perhaps ME/CFS and FM.

It’s clear that we can’t view MS as strictly a brain disease. Yes, the overt physical damage occurs in the brain, but gut issues play a role as well. In fact, this study suggests the possibility that gut damage – in the form of a dysregulated microbiome – might even play a critical role in allowing MS to progress.

Could the Gut Be a Potential Drug Factory?

Given the possibility that harnessing an as yet unknown microbe in the gut could reduce inflammation in the brain, one has to wonder if the gut, with its trillions of microbes, is a potential reservoir of drugs.  Could we tweak the microbes in the gut to provide other factors that reduce disease? Will gut manipulation ultimately play an important role in treating chronic diseases?