Physiology Research

Physiology of ME/CFS

Post-exertional malaise (PEM) is a hallmark symptom of ME/CFS.  PEM is an exacerbation of symptoms that emerge when a patient exerts physically, cognitively or even emotionally beyond a threshold intensity. PEM can occur during or soon after exertion, or within hours or even a couple of days after exertion in patients with ME/CFS.

To identify PEM and the physiological impact of PEM, a patient’s functional capacity or maximum capacity to produce work must first be determined. An objective measure of an individual’s capacity to do work is peak oxygen consumption, or the maximum volume of oxygen used to produce work (VO2peak or VO2max). VO2peak is measured during a cardiopulmonary exercise test (CPET), while the patient walks on a treadmill or cycles on a stationary cycle. During the CPET, the patient breathes through a mouthpiece (like a snorkel mouthpiece) or facemask while expired gases are collected and analyzed to determine VO2 throughout the CPET. The workload is increased gradually until the patient reaches maximum effort and can no longer perform the required work. This usually takes about 8-12 minutes of exercise. Throughout the CPET, heart function is monitored with an electrocardiogram, as well as blood pressure, and oxygen saturation using a small clip that fits on a finger. Data collected during the CPET indicates the maximum energy producing capacity of the patient (VO2peak), and also if the patient exhibited normal physiologic responses during the test.

The ability to do work, such as climbing stairs, cooking food, sitting in a chair, or running two miles, requires oxygen to produce energy to perform the work. Energy requirements for many forms of work are well established, and therefore, knowing a patient’s VO2peak allows us to determine what types and intensities of work can be sustained at maximum effort by a patient. However, because the ability of ME/CFS patients to perform work and recover normally is impaired, it is important to measure the threshold intensity under which a patient can function without exacerbating symptoms or causing PEM. This threshold can be determined during a CPET with gas exchange measures, and is called the ventilatory/anaerobic threshold, or VAT.

VAT is a threshold that is individual to each patient, and exceeding the intensity of effort at which VAT occurs exacerbates the ME/CFS symptom complex (PEM). By knowing a patient’s VAT, we can then provide objective guidelines for exertion to help the patient avoid PEM. However, when a patient does experience PEM, often the VAT decreases; which means the patient’s tolerance for exertion is further reduced due to PEM. This phenomenon is the foundation of exertion intolerance in ME/CFS, and is why traditional graded exercise therapy is not a viable strategy to improve function in these patients.

To characterize the magnitude of impairment in ME/CFS caused by PEM, two successive CPETs are performed, separated by 24 hours. The first CPET is used to measure VO2peak, and also provoke PEM. The second CPET measures the impact of PEM on the patient’s ability to do work. In this way, we can measure the patient’s baseline VO2peak and VAT with the first CPET, and the effects of PEM on VO2peak and VAT with the second CPET. Using a two-day CPET protocol to provide evidence for PEM was pioneered by Center participants Staci Stevens and colleagues at the Workwell Foundation Dr. Betsy Keller at Ithaca College has also been testing ME/CFS patients who wish to document their disability or to participate in a research study. Both groups use a two-day CPET protocol with a stationary cycle.

In healthy individuals, and patients with various diseases, CPET parameters are quite reproducible from one day to the next.  However, Dr. Keller and the Workwell Foundation have observed that most ME/CFS patients do not reproduce one or more of the objective parameters that the two-day CPET provides, despite giving maximum effort during both tests.  Some patients fail to reproduce VO2peak and/or VAT during the second CPET, indicating impaired recovery and reduced energy production due to PEM. Some patients also exhibit forms of autonomic dysfunction, that are documented during the two-day CPET, and also indicate abnormal responses to exertion.  Patients also may have a combination of two or more abnormalities; all of which provide objective evidence of reduced energy producing capacity due to impaired recovery following exertion.

Maureen Hanson’s group is currently seeking funding to measure changes in gene expression, signaling molecules, and metabolites in patients at baseline and following induction of post-exertional malaise through CPET testing.  The Hanson group has already collaborated with Dr. Keller to measure physiological and molecular responses to exercise by a healthy twin and his identical twin who has ME/CFS.

Relevant Scientific Articles:

Giloteaux L, Hanson MR, BA Keller. 2016.
A pair of identical twins discordant for Myalgic Encephalomyelitis/Chronic Fatigue Syndrome differ in physiological parameters and gut microbiome composition.
Am J Case Rep 17:720-729

Keller BA, Pryor JL, Giloteaux L. 2014.
Inability of myalgic encephalomyelitis/chronic fatigue syndrome patients to reproduce VO2peak indicates functional impairment.
J Transl Med.12:104.

Snell CR, Stevens SR, Davenport TE, Van Ness JM: 2013.
Discriminative validity of metabolic and workload measurements to identify individuals with chronic fatigue syndrome.
Phys Ther  93:1484-1492.

VanNess JM,  Snell CR, and S R Stevens.  2007.
Diminished cardiopulmonary capacity during post-exertional malaise.
J. Chronic Fatigue Syndrome 14:77-85