All posts tagged seahorse

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

The Big Fishing Expedition: Report From the NIH Intramural Study on ME/CFS

A Big, Deep Fishing ExpeditionNIH jpeg

“We’re throwing every known sophisticated technology at these patients.”

Avindra Nath, MD – Lead Investigator of NIH Intramural Study on Chronic Fatigue Syndrome

The NIH’s Intramural Study on ME/CFS now underway is almost certainly the most comprehensive chronic fatigue syndrome (ME/CFS) study ever done. In fact, it may be one of the more multi-faceted studies done in any disease. It’s breadth is astonishing. Besides the blood, urine, fecal matter and saliva gathered, participants will spend a night in a metabolic chamber, get their brains scanned, have their their immune systems transplanted into mice, and their neurons grown in a petri dish. After years of patient advocacy – at least in this one study – ME/CFS has abruptly transitioned from being one of the poorest studied diseases of all to getting an array of cutting-edge technologies thrown at it.

NIH intramural study net me/CFS

The NIH is casting a wide, wide net in its intramural ME/CFS study

Featuring top researchers at the NIH’s big research hospital its results are guaranteed to get noticed. This one study won’t solve ME/CFS – no one study can do that –  but it could and really should provide dramatic new insights into it, and, most importantly, provide the foundation for years and years of study into it.  Nath, for instance, recently suggested the study could produce the bio-signature we’ve been seeking for years.

The study is basically a huge fishing expedition, an anomaly for an institution known for its strict adherence to hypothesis testing. The NIH is looking (and building data) just about everywhere in patients.

We probably have NIH Director Francis Collins to thank for that. Collins has more control and discretion over the intramural site than any other part of the NIH and it shows. Collins got this study started before the NIH allocated money for the research centers. He wanted and got Avindra Nath – a highly prestigious researcher specializing in neuro-infectious diseases – to lead it and he got the NIH to bring out its fishing poles and fish.

Round One: The NIH’s “Deep Phenotyping Exercise”

Not only is the breadth of the study unusual, but the rigor with which it’s being run is unmatched. The first part of the study (participants come in for two rounds of testing) is partially being done to ensure that only one kind of patient participates. This is an important point since the ME/CFS disease population is very heterogeneous and mounting studies are identifying distinct subgroups.

In order to capture post-infectious ME/CFS patients, the study requires participants to have a sudden flu-like onset that’s been documented in a doctor’s files.  After taking questionnaire after questionnaire, a complete review of a patient’s medical records are being made by a panel of ME/CFS experts. Dr. Dan Peterson noted that one patient’s file ran to 191 pages (he said read every one). Dr. Peterson, longtime expert ME/CFS clinician and Simmaron Scientific Advisor, is reviewing patient selection for the NIH Intramural study.

Even the ME/CFS doctors reviewing the patient records have been taken aback at times with the strictness of the study. Dr. Peterson relayed one incident where Brian Walitt’s questioning of whether a patient should be included in the study raised eyebrows. (Walitt is the clinical lead investigator. Wallitt promptly dug into the Canadian Consensus Criteria to show the exact criteria the patient didn’t meet.)

Dr. Peterson noted that the reviewers have debated how “sudden” a sudden onset needs to be for someone to be included in the study. Does a patient have to remember the exact date they became ill or is something more general sufficient?

Another interesting twist concerns the rigor with which prospective patients have been tested. ME/CFS doctors that do more testing that others are more likely to find something that could kick a patient out of the study. That same patient coming from an ME/CFS doctor that doesn’t do a lot of testing might get into the study.

The first part of the study is apparently an attempt to level the playing field. Test after test after test is being done during the nine days a) to gather data and b) to ensure that nothing other than ME/CFS (and specified co-morbid diseases) is going on in these patients. At least in these early stages anything that looks off is being investigated. The NIH is calling the visit a “deep phenotyping” exercise.

An ME/CFS Patient Reports: Brian Vastag on Round One of the Intramural Study

It was fitting that Brian Vastag be one of the first ME/CFS patients to go through the first part of the study. He did after all, play a role in getting it started.

Vastag’s  “Dear Dr. Collins: I’m Disabled. Can the N.I.H. Spare a Few Dimes?” piece effectively used Vastag’s personal story to highlight the devastating funding problem and, importantly, provide a way out of the problem that was probably very appealing to Collins. (The dark humor in the piece didn’t hurt either.)

Francis Collins - Brian Vastag

Francis Collins, the Director of the NIH stops by for a visit. Vastag pushed for more ME/CFS funding and asked for ME/CFS to be assigned to a single institute

Vastag used to work for the NIH; in fact, Vastag worked with John Burklow, Francis Collins’ right hand man for communications for years. Vastag also worked with the Journal of American Medical Association (JAMA), and then reported for the Washington Post on science and medical issues. He knows the NIH well and used his personal connection to Collins to lobby for more funding.

He got in the study the old-fashioned way – by emailing the study recruiter.  In the months leading up to his stay, Vastag reported he had several conversations with the lead clinical investigator, Dr. Brian Wallitt, provided his medical records, was fully informed what he was in for and was provided several opportunities to bow out if he chose.

Thus far the reviews of Dr. Walitt from two people (Dr. Peterson, Vastag) participating with him have been positive.  Dr. Peterson said he found him attentive and interested, and Vastag, who said he spent a lot of time with him, found him available and dedicated.

Vastag spent five or six hours relaying his medical history to Dr. Walitt and nine full days in the NIH hospital. The history, he said, was very detailed.

Some people have worried that the ME/CFS patients well enough to participate in the NIH’s intramural aren’t sick enough to get results. Brian Vastag is exhibit number one why that hopefully is not the case.

When Vastag got sick he got really sick. At one point, he was 98% bedbound.  On his eighth or nineth doctor journey, Vastag saw neurologists and got checked out at a multiple sclerosis clinic.  Now he’s probably moderately ill for an ME/CFS patient and has to limit his walking to about 2 blocks a day; e.g. Vastag cant work at all, and he’s functionally very limited.

My guess is that if you can only walk two blocks a day without getting whacked there is something seriously, seriously wrong with you. Ditto with work; if you can’t work without getting hammered you have something seriously wrong with you that should be discoverable.

Having moderately ill people (by ME/CFS standards) participate in a study may not get the sickest patients in the study but it also brings with it the bonus that researchers don’t have to worry about the confounding factors that severe deconditioning brings. If there’s something to find in the testing the NIH is doing it should be found in these patients.

Cutting-Edge Technology

“I can’t believe they are letting us do all this stuff”.

Brian Walitt, MD MPH

The NIH is after all, throwing a lot of new technology at this disease. Vastag was told the intramural researchers have the green light to do a deep exploration of this disease and to let the evidence take them where it will.  They also have carte blanche to add to the study if the need arises.

Nath-Vastag-NIH

Avindra Nath stops by. Vastag said Nath had a great sense of humor. (Photo by Beth Mazur)

The head of Clinical Neurology at the Intramural Center, Avindra (Avi) Nath, heads the study. Nath has co-authored hundreds of journal articles and is on the editorial board of several journals. His main research focus – on the effects of infection on the brain – couldn’t be better suited to ME/CFS.

His latest paper on the cerebral spinal fluid in the survivors of the Ebola epidemic is exactly the kind of post-infectious work he’s been tasked with doing in ME/CFS. His 2016 review of Ebola survivors highlighted the functional declines seen in those who survived the outbreak. The study also noted that joint and muscle pains were “persistent problems” in more than half the 200 plus survivors assessed.

“Tellingly, the survivors reported a functional decline when compared with before the EVD outbreak. In comparison with the household contacts, the survivors were more likely to report a decline in both overall health (70% vs 18%) and ability to work (70% vs 7%).”

Nath told Dr. Peterson, after Peterson’s NIH talk on epidemic presentations of ME/CFS, that the Incline Village outbreak was probably an infectious encephalitis type of outbreak but that the technology at the time wasn’t up to diagnosing it. Nath has also collaborated often with Dr. Ian Lipkin on infectious diseases, and we know Lipkin’s work in ME/CFS is refining our understanding of immunity in the disease. Nath’s 2015 review paper demonstrated that the HIV virus may be able to survive in reservoirs in the brain indefinitely.

Nath will oversee a huge amount of work and do some cutting-edge work of his own. Using a new technique developed in his lab, Nath will knock out the immune systems of transgenic mice and give them the immune systems of ME/CFS patients.  He’ll also turn white blood cells from ME/CFS patients into “brains in a dish” neurons grown in the lab that Nath can then test. This technique, pioneered by Nath for other neurological diseases, can point highlight certain types of cellular problems.

A ton of data is being gathered in the first part of the study.  Besides his half a day of questionnaires, Vastag had standard labs done, provided his spinal fluid, did a sleep study, got 3.4 billion white blood cells drawn for Nath’s experimental studies, had his blood drawn for the Sea horse (mitochondria/energy production) study, had an EMG done to rule out muscle myopathy, did a tilt table test( positive for POTS), an MRI, and gave samples for the metabolomics part of the study. Just about every “tissue” possible, from blood, to urine, to cheek swabs to cerebral spinal fluid was gathered.

Seahorse-Vastag-chronic-fatigue

Rebekah Feng is studying the mitochondria in ME/CFS

Some results may already be showing up.  The Seahorse study results from just three patients were unusual enough that the intramural mitochondrial expert came down to Brian’s room and chatted with him.

Part II of the study will require a week’s stay and include an exercise test on a stationary bicycle, sleeping in a metabolic chamber, cognitive testing, and more blood and other tests.

The study’s only down-side appears to be its size and the time it is taking. Vastag reported that Nath expressed regret that the study was taking so long and told him that he was trying to speed things up. A couple of months ago, Vastag said he was the fourth patient to go through the study. At the NIH Telebriefing Nath said ten people have now gone through the first part of the study and one will start the second part at the end of July. Since the second part of the study was originally slated to begin in fall, it appears that Nath may indeed have speed things up.

Some researchers and doctors have expressed concern about the study’s forty-patient size, but Nath is convinced he can peel off any subsets with the patient group he has to work with.

 

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