New Findings Elucidate Potentially Treatable Aspects of ME/CFS

Miriam E. Tucker

April 10, 2019

Bethesda, MD — New evidence of cardiopulmonary and nervous system abnormalities in people with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) yields clues to the etiology of their exercise intolerance and points to potential treatments.

The findings were presented during the 2-day Accelerating Research on ME/CFS Meeting sponsored by the National Institutes of Health (NIH) and held on its main campus. The meeting brought together researchers from a range of scientific and clinical disciplines along with patients and patient advocates.

Much of the focus on the clinical side centered around two key facets of the illness: postexertional malaise (PEM) and orthostatic intolerance (OI). According to the 2015 Institute (now Academy) of Medicine (IOM), definition of ME/CFS, PEM — described as a "crash" or worsening of all symptoms after even minor exertion — is required to make the diagnosis, along with at least 6 months of profound and disabling fatigue, and unrefreshing sleep. A fourth criterion is either OI or cognitive dysfunction.   

David M. Systrom, MD, a pulmonary and critical care medicine specialist and director of the Invasive Cardiopulmonary Laboratory at Brigham and Women’s Hospital (BWH), Boston, described results from invasive cardiopulmonary testing that show  that patients with ME/CFS have distinct defects in both ventricular filling pressure and oxygen extraction from the muscles.

Neither of those are features of deconditioning, in which the major defect is decreased stroke volume and cardiac output. In ME/CFS patients, he found supranormal pulmonary blood flow compared with VO2 max, indicating left-to-right shunting.

In addition, Systrom found that a large proportion of ME/CFS patients with these cardiopulmonary defects also have biopsy-demonstrated small fiber polyneuropathy, suggesting that PEM may be due to an underlying autonomic nervous system dysfunction.

Also at the meeting, Peter C. Rowe, MD, director of the Children's Center Chronic Fatigue Clinic and professor of pediatrics at Johns Hopkins University School of Medicine, Baltimore, presented his colleagues' findings showing that, in patients with ME/CFS who have OI, cerebral blood flow drops significantly compared with controls on tilt-table testing even without changes in heart rate or blood pressure. And this was true regardless of VO2 max or recorded steps, suggesting again that the phenomenon isn't simply due to illness-related inactivity. 

In an interview with Medscape Medical News, Lucinda Bateman, MD, founder and director of the Bateman Horne Center, Salt Lake City, Utah, called the new data "huge." And regarding OI, she said, "I honestly think it's one of the biggest, most missed clinical finding that's amenable to supportive treatment."

Systrom is now conducting a phase 3 clinical trial testing pyridostigmine bromide (Mestinon, Valeant Pharmaceuticals) in patients with ME/CFS. The drug is currently approved by the US Food and Drug Administration for the treatment of myasthenia gravis.

The rationale for using pyridostigmine in ME/CFS, Systrom said, is that enhancement of cholinergic stimulation of norepinephrine release at the postganglionic synapse may improve venoconstriction at the site of exercising muscles, leading to improved return of blood to the heart and better distribution of oxygenated blood to the skeletal muscle mitochondrion during exercise.

Both Rowe and Bateman have used pyridostigmine off-label in ME/CFS patients with some success. Rowe told Medscape Medical News in an interview, "For some of our patients it can be transformative, even if they have not responded to fludrocortisone, midodrine, or beta-blockers."

And Bateman, during a talk at the meeting, said that in her experience using pyridostigmine in patients with both ME/CFS and postural orthostatic tachycardia syndrome (POTS), "It's been an interesting and very effective intervention."

"Preload Failure" Characterizes Many With ME/CFS

At BWH, Systrom and colleagues developed an invasive cardiopulmonary exercise test (iCEPT) to investigate patients with exertional intolerance that's not explained by the usual less-invasive cardiopulmonary evaluations. The test involves placement of radial and pulmonary arterial catheters that allow for direct measurement of systemic and pulmonary vascular pressures, systemic and mixed venous oxygen, and cardiac output during 6-8 minutes of cycling.

The iCEPT was originally developed to detect early heart and heart-lung conditions, "but along the way what we found were patients with un- or under-explained exertional intolerance coming to us, many of them ending up with an ME/CFS clinical diagnosis. So I think we have something to offer with this test, which was initially developed to detect other diseases," Systrom said.

Indeed, for the past 3 to 4 years, about half of the 10 or so weekly iCEPT tests done at BWH have been for patients who meet the IOM criteria for ME/CFS, he noted.

During cycling, many ME/CFS patients will have relatively normal VO2 max levels but abnormally low filling pressure, particularly the right atrial pressure. That phenomenon, which Systrom and colleagues have called "preload failure," is seen in nearly all patients evaluated with iCEPT who meet ME/CFS criteria.

In a study Systrom and colleagues published in 2016 on 49 patients with this phenomenon, giving two saline boluses corrected the problem in most cases. The authors concluded that inadequate ventricular filling related to low venous pressure is a clinically relevant cause of exercise intolerance. "In retrospect, most of those patients had evidence of ME/CFS," he observed.

In addition, the difference between arterial and mixed venous oxygen content at peak exercise, a reflection of oxygen extraction in the periphery and the muscle, is abnormal in most ME/CFS patients. This could be a result of vascular dysregulation and peripheral left-to-right shunting, but also could be due to intrinsic mitochondrial dysfunction in the limb skeletal muscle, he speculated.

These two defects differ from the cardiac output abnormality normally seen in people who are merely deconditioned, he emphasized, noting that prior studies have suggested increased, rather than decreased, biventricular filling pressures in deconditioning. Other data suggest that impaired systemic oxygen extraction is mildly affected in deconditioning or not at all.

In a new, soon-to-be-published finding, 40% of 160 patients with ME/CFS and preload failure had evidence of small-fiber polyneuropathy on skin biopsy. That work was conducted with Anne Louise Oaklander, MD, PhD, a neurologist who directs the Nerve Unit and neurodiagnostic skin biopsy laboratory at Massachusetts General Hospital, Boston.

Oaklander also spoke at the NIH meeting about her findings with small-fiber polyneuropathy in fibromyalgia, which shares some features of ME/CFS and often co-occurs in patients. She'll be presenting new data on that at the upcoming American Academy of Neurology meeting.

Orthostatic Intolerance: A Major, Manageable Component of ME/CFS

Rowe has been investigating the relationship of OI to ME/CFS for over 20 years. In 1995, he and colleagues reported that an abnormal response to an upright 70-degree tilt-table test was seen in 22 of 23 patients with ME/CFS compared with just four of 14 controls.

In that study, the tilt-table test elicited nausea and lightheadedness in 22 of the 23 patients (96%), diaphoresis in 19 (83%), blurred vision and abdominal discomfort in 18 each (78%), and syncope/fainting in 10 (43%).

Other investigators have reported similar findings since, Rowe said. For example, a study published in 2012 demonstrated a link between increasing orthostatic stress and neurocognitive functioning in ME/CFS patients and POTS. As the level of tilt increased, subjects made more errors and had more delayed responses, typical of the so-called "brain fog" associated with ME/CFS.

Two phenomena appear to be contributing to the OI simultaneously, Rowe said: increased pooling of blood in the legs and decreased vasoconstriction, along with a decrease in circulating blood volume.

But in a new and potentially paradigm-shifting finding, van Campen and colleagues used transcranial Doppler echography of the internal carotid and vertebral arteries during the tilt-table test in over 400 ME/CFS patients. They displayed a greater than 20% reduction in cerebral blood flow compared with a 6% reduction found previously in healthy volunteers

"It was quite a profound change," Rowe said, noting, "Maybe we've been looking in the wrong place. If symptoms are due to decreasing cerebral blood flow, maybe that's where we should focus." 

The finding was seen even among the patients who did not demonstrate heart rate and blood pressure changes during the tilt test. And, arguing against the notion that the phenomenon is merely a result of deconditioning, the degree of cerebral blood flow decline was nearly identical between the 18 patients with VO2 max above 85% and the 59 with VO2 max below 85%, and didn't differ by the number of steps the patients took based on activity monitors.

"Upright posture consistently aggravates ME/CFS symptoms, even in the absence of heart rate and blood pressure changes, often for days, consistent with orthostatic stress being a cause of post-exertional malaise," Rowe said.

But, Rowe also noted, "OI is one of the most treatable problems in this illness."

Indeed, during the meeting, Bateman, whose center provides information on how to perform a lean test, shared her tips for managing OI. She recommends teaching patients to stay hydrated and increase their salt intake and prescribing medications such as fludrocortisone. Compression socks can be helpful, as can intravenous saline, if available.

She also prescribes low-dose beta-blockers and pyridostigmine to selected patients, and uses the 10-minute lean test to assess treatment efficacy.

"Orthostatic intolerance is the low-hanging fruit. It is diagnosable and treatable and we have a lot of literature about how to deal with it," Bateman said, noting that, although it isn't a cure for ME/CFS, "Improving OI improves symptoms and function and gives patients more control over activity intolerance."

Rowe has a financial interest in Vital Motion. Bateman has received research funding from Cortene and Lundbeck. Systrom has disclosed no relevant financial relationships.

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