To Exercise or Not to Exercise: Understanding PEM in ME/CFS and the Potential Role of WBV
Chronic illness brings many challenges. For individuals who live with ME/CFS, there are many limitations that they face which create barriers to activity. This multisystem disease affects all aspects of life and often causes severe levels of disability. Symptoms such as widespread muscle and joint pain, low blood pressure, tachycardia, and severe fatigue are just some of the issues that interfere with an individual’s ability to exercise. Post-exertional malaise (PEM) can occur with minor levels of exertion and is often extremely debilitating. Its onset may occur fairly immediately after activity or may be delayed, lasting anywhere from one day to several weeks or even months. Keeping all of these factors in mind, an individual with ME/CFS must approach exercise with great care. Patients require the skill of competent healthcare professionals to determine what types of activity can be performed safely within the limitations associated with PEM. This can only be accomplished with a great deal of insight and attention to individual needs.
With so many complexities to consider, it seems that exercise would fall to the bottom of the priority list. Considering that movement is essential for good health and quality of life, it is important not to discount the possibility of exercise altogether. As patients with ME/CFS will require interventions for other illnesses or injuries at one time or another, it is crucial for all healthcare providers to understand the functional limitations associated with this disease. Designing an appropriate exercise program proves to be extremely challenging due to the occurrence of PEM and the many other symptoms that affect exercise tolerance. How can a patient with these issues realistically participate in an exercise program? Should exercise even be prescribed, and if so, what types are recommended? Before this topic can be addressed, it is necessary to develop a keen understanding of PEM.
Various entities, including the CDC, originally promoted graded exercise therapy (GET – an approach in which exercise is increased gradually on a daily basis) and cognitive behavioral therapy (CBT – a general term that describes psychological interventions that address how thoughts and beliefs are tied to behaviors) as two standards of care for patients diagnosed with ME/CFS. Following the advancement of research over the last decade, medical professionals concluded that GET is not helpful and may even be harmful to this patient population. The results of more recent studies suggest that short bouts of exercise are better tolerated than longer periods of activity. This conclusion has been drawn based on studies that have involved different physiological responses in muscle activity and oxygen consumption confirmed by cardiopulmonary exercise testing, changes in gene expression and distinct differences in brain activity compared to that of healthy controls.
Dr. Dane Cook, Ph.D., is an exercise physiology researcher whose studies have been funded by various governmental and advocacy organizations. As a clinical professor at the University of Wisconsin-Madison and as a member of the CFS Advisory Committee (CFSAC) at the Department of Health and Human Services through 2017, he has shared the results of his work which link the relationship between biology and its outward expression of ME/CFS. Through his investigations of PEM, he has been able to demonstrate the consequences of exercise as noted by the various manifestations including pain dysregulation, sleep dysfunction, cognitive decline, and changes in biological markers (cytokines, oxidative stress, natural killer cells). His research has also highlighted the presence of altered cardiopulmonary responses to submaximal exercise as well as functional changes in various regions of the brain, signifying the consequences of fatigue on physical performance and cognition.
The results of Dr. Cook’s studies have confirmed changes in executive processing, memory, and sustained attention due to altered function of different regions of the brain including the dorsal lateral prefrontal cortex, the hippocampus and anterior cingulate cortex. Through blood and stool samples analysis pre and post exercise, it has been noted that there is a sustained increase in adrenergic receptors (which are involved in energy production) and in cortisol receptors (NR23C1 receptors) up to 72 hours post exercise, which is in contrast to what is noted in healthy controls. He was able to confirm that patients whose fatigue was the most significant showed the greatest difference in the cortisol receptors. This research has reinforced that the symptoms associated with PEM encompass much more than fatigue.
The Institute of Medicine (IOM) report in 2015 reinforced the importance of understanding PEM as it relates to patients’ function. Exercise testing is one of the critical areas of investigation that has served an important purpose in shedding light on the physiological mechanisms that underlie PEM. Dr. David Systrom, a pulmonologist and critical care physician, has made great contributions to clinical research with a focus on cardiopulmonary exercise testing in the ME/CFS patient population. His main area of interest has focused on exercise intolerance. Through exercise testing that is conducted in the dyspnea clinic and the invasive cardiopulmonary exercise testing that is administered in the cardiac catheterization lab, results are analyzed to determine the patient’s exercise capacity in the context of physiological markers.
Blood gas analysis is done using blood taken from the pulmonary artery and the radial artery in order to assess the blood for oxygen content, carbon dioxide, pH and lactate as well as biomarkers to determine if there are certain identifiers at rest, every minute during exercise, at peak exercise and one hour after recovery. Blood pressures are also measured at several different levels of the pulmonary and radial arteries. A common finding in patients who have a clinical diagnosis of ME/CFS is something called internal preload failure – this refers to the inability of the vessels in the legs and abdomen to push blood upward into the right side of the heart. What has been found in most cases is that the right side of the heart exhibits inadequate filling pressures. In addition, an abnormality of systemic oxygen usage has been observed as the muscle does not take up oxygen normally. One mechanism behind this issue is thought to be due to mitochondrial dysfunction within the muscle tissue.
Another factor that affects the symptoms of PEM (which include increased pain, severe fatigue, shortness of breath and orthostatic intolerance) is the presence of small fiber polyneuropathy. Dr. Anne Louise Oaklander, a neuroimmunologist at Massachusetts General Hospital, created an FDA approved skin biopsy to diagnose small fiber polyneuropathy (SFPN). The small nerve fibers are responsible for mediating pain and their function is integrated with the autonomic nervous system. It is estimated that up to half of patients who are diagnosed with ME/CFS have SFPN; this issue is also commonly found in patients who are diagnosed with fibromyalgia and POTS. The new understanding of SFPN provides one more piece to the complicated puzzle of the physiological basis of ME/CFS. While there are many areas of research including the role of the gut microbiome, immune system function, brain function and gene expression, all are interrelated and require great attention to detail.
There have been many other pioneers who have become experts with regard to ME/CFS – too many to adequately credit in the context of this article. Some of the contributors include Dr. Anthony Komaroff, Dr. Susan Levine, Dr. Peter Rowe, Dr. Lily Chu and Dr. Sarah Myhill. Dr. Komaroff is a Professor of Medicine at Harvard Medical School and a practicing physician at Brigham and Women’s Hospital. He has devoted 35 years of his career to caring for patients with ME/CFS and his various research efforts have provided insight into many aspects of PEM. Testing has demonstrated that the neuroendocrine system, which influences how hormones work in the brain, functions differently in a patient with ME/CFS. These changes affect memory and attention and have also been tied to altered function of the autonomic system.
EEG studies have also shown marked differences in brain function which have allowed researchers to identify patients with ME/CFS compared to healthy subjects or even those who have been diagnosed with depression. Collectively, all of these changes in body system function undoubtedly contribute to PEM. In addition, studies have shown that acid accumulates in the muscles post exercise as noted by decreased pH. The excess lactic acid is associated with the shift to an anaerobic metabolic state at a much earlier stage in exercise compared to healthy controls, which is another component of PEM.
Dr. Susan Levine is a physician in New York City who specializes in the treatment of patients with ME/CFS. Her practice is centered around a compassionate approach which allows her to offer patients hope. The vast amount of knowledge that she has acquired about this disease has been developed over many years of study and practice, allowing her to provide comprehensive care. Her awareness of the importance of treating the various comorbidities associated with ME/CFS has drawn more attention to these issues. Disorders such as mast cell activation syndrome and autonomic conditions such as POTS (postural orthostatic tachycardia syndrome) are common in patients with ME/CFS and need to be addressed accordingly. Mast cells are inflammatory cells that are also present near the pain centers in the brain. The use of anti-inflammatory medications reduces their activity and subsequently has the potential to decrease pain. Dr. Levine has continued to merge her efforts with those of Dr. Ian Lipkin, a professor and Director of the Center for Infection & Immunity at Columbia University, to create a multi-site center for excellence.
The work of Dr. Peter Rowe has been well respected by the ME/CFS community. As a Professor of Pediatrics at the Johns Hopkins Children’s Center and the director of the CFS clinic for twenty years, he has elevated the clinical knowledge about PEM. Based on the results of a treadmill study by VanNess et al, he noted that it took over 50% of the subjects at least five days to recover back to baseline, as compared to healthy controls who reached this point within 24 hours post exercise. Furthermore, symptoms including fatigue were still present 24 hours post-exercise in 68% of the patients with ME/CFS as compared to only 4% of healthy controls. While none of the healthy patients experienced dizziness or lightheadedness 24 hours after the exercise test, 24% of the patients with ME/CFS experienced the persistence of these symptoms. Cognitive dysfunction such as difficulty concentrating was present immediately after exercise in 28% of patients with ME/CFS and was worse up to seven days after exercise. Compared to the absence of this problem in healthy controls, 48% of the patients with ME/CFS experienced this at any point after exercise. Finally, pain levels were actually worse after 48 hours in 56% of patients with ME/CFS in contrast to no pain in the healthy controls at this stage following the exercise test.
In his review of a study by Dr. Alan Light, Dr. Rowe emphasized the finding that white blood cells contain receptors that are also present in nerve and muscle. These are thought to be involved in the mechanisms that generate post-exercise pain and fatigue. The presence of biomarkers such as functional changes in adrenergic genes shed light on how the changes in gene expression affect blood flow to the muscles. These alterations in the genes that regulate immune responses may be related to the presence of flu-like symptoms in patients with ME/CFS. Dr. Rowe has also discussed the importance of understanding the effects of cognitive exertion on PEM. An older study from 1998 by LaManca et al involved implementing a cognitive assessment using a tool called the Stroop test, following an exhaustive treadmill test. Patients were asked to read the colors of several Xs on the sheet. Following this exercise, the patients had to read the color that the word was printed in (e.g. the word ‘black’ printed in red). The patients with CFS exhibited significantly different results from healthy controls, highlighting how exercise impacted their cognition 24 hours following activity.
Another important factor to acknowledge is how orthostatic intolerance affects PEM. The pooling of blood in the lower extremities causes less blood flow to the brain, which affects patients both from a physical and mental standpoint. In a study that he published in 1995, The Relationship Between Neurally Mediated Hypotension and Chronic Fatigue Syndrome, observed the effects of orthostatic problems in 23 patients (18 female) with an average age of 34 years. Ninety-six percent of the patients in the study reported dizziness and a very high percentage also reported sweating, blurred vision and abdominal discomfort, with 43% who had experienced prior episodes of fainting. The patients expressed that certain activities, such as taking a hot shower, prolonged standing and physical activity in general triggered PEM symptoms.
Tilt table testing was implemented and demonstrated how orthostatic issues act as a trigger for PEM in terms of producing acute changes – one patient demonstrated a loss of consciousness within fifteen minutes of being upright. Following the tilt table tests, patients expressed the same type of ‘crashes’ that they developed after traditional exercise testing. Although the administration of intravenous saline was implemented which mediated the symptoms, Dr. Rowe acknowledged that the researchers failed to randomize patients into a group that received saline and one that did not. In synthesizing all of this data, he has stressed that the degree and duration of PEM depends on the level of exertion as well as the severity of the illness. Simple activities such as prolonged sitting, standing or even reading, which an individual may have tolerated prior to the onset of the illness, can be enough to aggravate the symptoms of PEM. In order to design an appropriate exercise program, clinicians must appreciate the variability of triggers and the differences in presentation of PEM from one patient to another.
As Co-Vice President of the IACFS/ME (International Association for Chronic Fatigue Syndrome/Myalgic Encephalomyelitis) and a member of the Stanford University ME/CFS Community Advisory Board, Dr. Lily Chu has also shared her knowledge pertaining to PEM. In a 2015 webinar, she gave a detailed discussion about the history of clinical case definitions of ME/CFS and the patient experience of PEM. She emphasized that the symptoms of PEM manifest differently in different patients and are sometimes so severe that they affect the ability to perform self-care independently. She also noted that the triggers of PEM vary widely and may include anything from sleep disturbances to cognitive decline to emotional distress. It is important for clinicians to acknowledge how unpredictable PEM can be in order to be mindful of how exercise might affect a patient.
The official definition of PEM that was established by the Institute of Medicine (IOM) in 2015 which is included in the IOM Clinician Guide is as follows: ‘Worsening of a patient’s symptoms and function after exposure to physical or cognitive stressors that were normally tolerated before disease onset. Subjective reports of PEM and prolonged recovery are supported by objective evidence in the scientific literature, including failure to normally reproduce exercise test results (2 day cardiopulmonary exercise test and impaired cognitive function after exertion). Dr. Chu’s review of many different studies that investigated PEM and interrelated issues shed light on various topics. Examples include how mild activities such as walking can trigger delayed onset of PEM (Black et al, 2005), how the recovery period after exercise is significantly longer for patients with ME/CFS compared to that of healthy controls (VanNess et al, 2010), how the pain threshold changes post exercise for patients with ME/CFS (Nijs et al, 2010), and how exercise impacts sleep and fatigue levels (Togo et al, 2011).
In addition, she discussed studies that demonstrated the effects of cognitive exertion on mental fatigue and performance on informational processing tests (Cockshell et al, 2014; Capuron et al, 2006) and a review of four different studies pertaining to physiological findings associated with repeated cardiopulmonary exercise testing. Overall, she emphasized the point that it is important to consider sub-grouping patients based on the type and degree of their symptoms. She also touched on the fact that whether or not PEM is identified depends somewhat on which case definition is used within the context of the research studies.
It is important to mention Dr. Sarah Myhill’s contributions to the ME/CFS community as she has been committed to elevating the of medicine in an effort to develop better patient care. As an experienced physician in the United Kingdom, she has become a specialist in treating patients with this condition and has been at the forefront of educating other medical professionals about the physiological basis of the disease. In her book, It’s Mitochondria, Not Hypochondria, she describes in detail the physiological issues associated with ME/CFS and how to treat them. Dr. Myhill’s work emphasizes the need to balance energy stores with energy expenditures and stresses the protective function that fatigue serves as a prompt for activity modification.
More than two-thirds of our energy is devoted to maintaining our basic bodily functions. As the liver consumes 27% of our energy use, Dr. Myhill has pointed out that this is more than the brain and heart combined. The function of the liver is to detoxify the body, therefore, the liver works extremely hard in the presence of any disease. Due to the fact that mental and physical exertion take a higher toll on patients with ME/CFS, it is especially important to manage how energy is spent. A mitochondrial function test (also called an ATP Profile test, developed by Dr. John McClaren-Howard) can be administered to objectively document how efficiently the mitochondria recycle ATP (adenosine triphosphate – the cellular chemical that is involved in energy production in the cells). This blood test provides confirmation of the physiological deficits associated with energy production, which is an important component of diagnosing ME/CFS and understanding the nature of PEM.
Another very important point of discussion is the tendency of an early switch from aerobic to anaerobic metabolism in patients with ME/CFS. When this occurs, the body must generate more ATP per glucose molecule than it does during aerobic metabolism. Lactic acid builds up rapidly but is cleared slowly. Therefore, symptoms of PEM such as muscle pain and fatigue may persist for hours or even days. This is due to poor mitochondrial function which limits the amount of available ATP and affects the ability to clear lactic acid from the body quickly. Overall, patients with ME/CFS have poor cardiac output due lower than normal energy supply. As a result, atypical angina (chest pain) that does not resolve immediately with rest and cardiac dysrhythmias are common. There is an inordinate amount of stress on all of the body organs which is typically compounded by poor antioxidant levels, toxin buildup and chronic infections. These physiological changes can be identified through lab testing and treated accordingly.
Dr. Myhill has also highlighted the altered function of the immune system, seemingly connected to operational changes in the B-lymphocytes, a type of white blood cell which is responsible for the secretion of antibodies. Patients with ME/CFS often experience difficulty regulating temperature as circulation decreases to the skin in the body’s attempt to conserve energy. Fatigue is associated with lower cardiac output, gut dysfunction occurs in the form of digestive issues due to poor energy supply, and hormone synthesis is slowed which affects overall body function.
There is still debate about what types of exercise that patients with ME/CFS should perform, if any at all. Due to its high level of efficiency and effectiveness, WBV has emerged as a method that is worthy of further research to determine its potential applications for this patient population. Graded exercise therapy was proposed in the past as a viable approach for patients with ME/CFS and was later rejected as an appropriate method by various experts. It is critical to identify which exercises are the least detrimental in order to avoid reinforcing the notion that it is impossible or inappropriate for every single patient with this disease to exercise. While this may be the case for a subgroup of individuals with the most severe form of the disease, it is likely not the case for all individuals who have it. The challenge lies in figuring out approaches that do not trigger PEM. While PEM is impossible to avoid completely, it is possible to minimize its effects by designing a thoughtful exercise program. In order for this to be accomplished, healthcare professionals must have a very good understanding of what PEM is and its potential triggers.
In a 2006 study that employed a six-month WBV program during submaximal aerobic exercise with ten patients who were diagnosed with chronic fatigue syndrome, results were favorable. A pivotal unit (the Galileo 2000) was used to implement the WBV sessions with both males (4 patients) and females (6 patients). A frequency of 18 Hz was used for the first two months of the study, followed by a frequency of 22 Hz for the last four months. Subjects assumed four upright positions on the platform which included squats and partial lunges. The time that each position was maintained was increased to two minutes each, for a total of 8 minutes.
Prior to and after the sessions, patients received an assessment in which the muscles were tested using an algometer (a device which measures the level of pressure applied to the tissue to elicit a pain response) applied bilaterally to the quadriceps, trapezius, and deltoid muscles. In addition, muscle performance was analyzed as well as a physical and psychosocial assessment. Detailed answers were provided using a VAS (visual analog scale) pertaining to pain level, fatigue level, mood, quality of life and working activity. Researchers noted that the 6-month program resulted in an overall improvement in all areas, suggesting that WBV has the potential to be a useful exercise tool for this patient population. Considering the amount of new information that has emerged with regard to understanding ME/CFS, additional WBV studies would be very useful and should be designed with respect to different sub-groups of patients to facilitate more meaningful and clinically relevant data.
In order to effectively treat patients with ME/CFS, providers must have a keen understanding of how PEM presents in each individual in order to determine an appropriate exercise regimen. Approaching patients with compassion and recognizing their individuality are of great importance. Assisting these individuals in breaking the fear-avoidance cycle can only be accomplished by a well-informed clinician who is willing to become more educated about ME/CFS and the challenges associated with PEM. Above all, maintaining an open mind while being committed to learning are the keys to helping patients learn strategies to exercise and achieve successful outcomes.
References
Books:
Diagnosis and Treatment of Chronic Fatigue Syndrome and Myalgic Encephalomyelitis, 2nd Edition: It’s Mitochondria, Not Hypochondria (2018) by Dr. Sarah Myhill
Journal Articles & Online Publications:
A Neuroimmune Model of Myalgic Encephalomyelitis. Metabolic Brain Disease. Morris & Maes, 2013.
A Review on Cognitive Behavioral Therapy (CBT) and Graded Exercise Therapy (GET) in Myalgic Encephalomyelitis (ME)/Chronic Fatigue Syndrome (CFS): CBT/GET Is Not Only Ineffective and Not Evidence Based, but Also Potentially Harmful for Many Patients with ME/CFS. Neuroendocrinology Letters. Twisk & Maes, 2009.
Changes in Gut and Plasma Microbiome following Exercise Challenge in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome. PLOS One. Shukla et al, Dec 2015.
https://bmjopen.bmj.com/content/bmjopen/4/2/e003973.full.pdf
Chronic Fatigue Syndrome and Vibration Exercise (2013)
www.vibrationexercise.com/chronic-fatigue-syndrome-and-vibration-exercise/
Experiences of Daily Activity in Chronic Fatigue Syndrome/Myalgic Encephalomyelitis (CFS/ME) and Their Implications for Rehabilitation Programmes. Disability and Rehabilitation. Pemberton & Cox, 2013.
Hypothalamic-Pituitary-Adrenal Hypofunction in Myalgic Encephalomyelitis (ME)/Chronic Fatigue Syndrome (CFS) as Consequences of Activated Immune-Inflammatory and Oxidative and Nitrosative Pathways. Molecular Neurobiology. Morris et al, 2017.
Neural Consequences of Post-Exertion Malaise in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome. Elsevier. Cook et al, Feb 2017.
https://www.sciencedirect.com/science/article/pii/S088915911730051X
Unraveling the Nature of Post-Exertional Malaise in Myalgic Encephalomyelitis and Chronic Fatigue Syndrome: The Role of Elastase, Complement C4a and Interleukin-1 β. Journal of Internal Medicine. Nijs et al, 2010.
Submaximal Aerobic Exercise with Mechanical Vibrations Improves the Functional Status of Patients with Chronic Fatigue Syndrome. Saggini et al, 2006.
Interviews & Lectures:
Dane Cook (Ph.D., Clinical Professor at University of Wisconsin-Madison)
Deciphering Post-Exertion Malaise: The Intersection Between Biology and Behavior: (Nov 2015)
https://www.youtube.com/watch?v=vfmrPd4-rIE
Dr. Lily Chu (Co-Vice President of IACFS/ME, Stanford University ME/CFS Initiative Community Advisory Board member)
Post-Exertional Malaise: History, Characteristics, Evidence (June 2015)
https://www.youtube.com/watch?v=hxJPrkWHcBo
Dr. Anthony Komaroff (MD, Professor at Harvard Medical School, Senior Physician at Brigham and Women’s Hospital)
Hot Areas in ME/CFS Research (May 2018)
https://www.youtube.com/watch?v=VprqU9knS4Y
Dr. Susan Levine (Physician, Infectious Disease Specialist)
ME/CFS Alert Episode 101 (Sept 2018)
https://www.youtube.com/watch?v=SkGolvt0oSM
Dr. Sarah Myhill (Physician, ME/CFS Specialist – UK)
Chronic Fatigue Syndrome/ME: The Biological Basis of the Treatment of ME/CFS – It’s Mitochondria, Not Hypochondria (May 2014)
https://www.youtube.com/watch?v=BG_v6-U1a8g
Dr. Peter Rowe (Professor of Pediatrics, Director – Children’s Center Chronic Fatigue Clinic)
Inducing Post-Exertional Malaise in ME/CFS: A Look at the Research Evidence (July 2015)
https://www.youtube.com/watch?v=ux93w7yGQ5g&t=23s
Dr. David Systrom (Pulmonlogist, Brigham and Women’s Hospital, Boston, MA)
Advancements in ME/CFS Research – ME/CFS Alert (July 2018)
https://www.s4me.info/threads/dr-david-m-systrom-at-bwh-has-evidence-of-sfpn-in-some-patients.4855/
Resources:
American Myalgic Encephalomyelitis and Chronic Fatigue Syndrome Society: Exercise
https://ammes.org/exercise/
Dane Cook, PhD- research
https://me-pedia.org/wiki/Dane_Cook
Overview of ME/CFS Protocol by Dr. Myhill
https://www.drmyhill.co.uk/wiki/Overview_of_CFS/ME_protocol
