Diagnosing Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: The Experts Weigh In

Lucinda Bateman, MD: Hello, I am Dr Lucinda Bateman, Medical Director at the Bateman Horne Center in Salt Lake City, Utah. Welcome to this program titled Diagnosing Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: The Experts Weigh In.

Panelists

Dr Bateman: Joining me today are my colleagues, Dr Natalie Azar, a rheumatologist with the Department of Rheumatology and clinical assistant professor with the Department of Medicine at New York University Langone Medical Center in New York City; Dr Nancy Klimas, chair of the Department of Clinical Immunology and professor of medicine at the College of Osteopathic Medicine at Nova Southeastern University in Fort Lauderdale, Florida. She is also a professor emerita of the University of Miami Miller School of Medicine; and Dr José Montoya, professor of medicine in the Division of Infectious Diseases and Geographic Medicine, Stanford University School of Medicine in Stanford, California. Welcome.

José Montoya, MD: Thank you.

Dr Bateman: We are a multidisciplinary group. I am a general internist who practiced as a primary care provider for 10 years and then specialized as a clinical specialist in the diagnosis and management of myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS).

Natalie Azar, MD: I have been a practicing rheumatologist for many, many years and I came to understand ME/CFS through a little bit of an indirect route, but it was quite practice-changing when I did. The messaging that I would really like to get out there today is that a lot of doctors and healthcare providers in this country are seeing these patients, they just do not realize it. They do not know what questions to ask.

Dr Bateman: Nancy.

Nancy Klimas, MD: Yes, I echo that. I am a clinical immunologist and I saw these patients initially because they found me. I think that that is exactly what is still happening now, more than 30 years later -- that these patients are developing their own teams. Frequently, they remain undiagnosed. If there was some way to get out the message that each element of these teams -- sleep, pain, rheumatology, and so on pulled together -- defines a patient with ME/CFS, if they have these same core symptoms.

Dr Montoya: I think through my specialty in infectious diseases I was able to see the devastation that this disease brings to patients, and I believe that ME/CFS is the greatest scientific challenge in the 21st century. On one side, we have a complex disease that affects millions of people, and on the other side, we have new technology that has not been applied to the disease. It is very possible that we can at one time have a solution for this illness and a treatment for these patients.

ME/CFS: Burden of Disease^[1]

Dr Bateman: I am optimistic. Thank you. Myalgic encephalomyelitis/chronic fatigue syndrome, commonly referred to ME/CFS or systemic exertion-intolerance disease, is a serious, complex, chronic multisystem disorder characterized by profound fatigue, cognitive dysfunction, sleep abnormalities, pain, and other symptoms that worsen with exertion. Although ME/CFS severely affects patients' daily lives, it may not be diagnosed for years or, in many cases, ever.

In 2015 the Institute of Medicine (IOM) convened an expert committee to review the scientific data on ME/CFS and developed evidence-based recommendations for recognizing and diagnosing the illness.^[1] Today we will be discussing how to recognize symptoms of ME/CFS in adults and adolescents and how to diagnose the disease using the 2015 IOM criteria.

Epidemiology of ME/CFS in the United States^[1]

Dr Bateman: Nancy, can you tell us a little bit about the epidemiology of ME/CFS?

Dr Azar: Sure. It is an important clinical and public health problem. It is estimated in the United States to have a prevalence of 800,000 to 2.5 million people. Shockingly, 85% to 90% of these patients go undiagnosed, and the economic burden is thought to be between $17 and $24 billion a year.^[1] It typically affects adults and adolescents. The average age at onset is around 33 years, though it certainly occurs in children. It is rare in children younger than 11 years.

Approximately 3 times as many cases occur in women than men, but it is not considered a women's disease.^[1] There is no cure, but spontaneously patients do improve and sometimes even resolve [their symptoms].

Etiology of ME/CFS: It Is Not a Psychosomatic Illness^[2,3]

Dr Bateman: José, what do we know about the causes of ME/CFS?

Dr Montoya: Although the causes of ME/CFS and the pathophysiology are still unknown,^[2] significant progress has been made. It is not a made-up illness. It is not a psychosomatic illness.^[3] Many theories [point to] multifactorial causes, including viral, bacterial, [or] parasitic infections as triggers or perpetrators of the illness.^[3] Other triggers or perpetrators include exposure to toxins, immune impairment, and inflammatory causes. A growing area of substantial evidence also suggests that the abnormalities are in the area of immune responses, the autonomic central nervous system (CNS [central nervous system]) function, and also significantly in the cellular energy production area.^[3] I believe that future research will provide the additional guidance that will lead to targeted treatments in this disease.

How Is ME/CFS Diagnosed?^[1,4]

Dr Bateman: Thank you. Natalie, can you explain how ME/CFS is diagnosed?

Dr Azar: Sure. There is no biomarker specific to the disease.^[1] There are no laboratory tests or imaging studies that you can order that can definitively make a diagnosis.^[1] It is predominantly a symptom-driven evaluation where a comprehensive history has to be taken and a physical examination is performed. Many different definitions of ME/CFS have been proposed regarding major symptoms.^[4] They do, however, vary in number of symptoms and exclusions.

IOM Diagnostic Criteria for ME/CFS^[1]

Dr Azar: To meet the IOM diagnostic criteria, patients must have the following 3 symptoms: a substantial reduction or impairment in the ability to engage in preillness levels of activities accompanied by fatigue, which is often profound, for greater than 6 months. They must experience the cardinal symptom, which is postexertional malaise, or PEM, as well as unrefreshing sleep.^[1] In addition to the core criteria, at least 1 of the following 2 is required: (1) cognitive impairment, and (2) orthostatic intolerance. Importantly, the frequency and severity of symptoms should be assessed. Postexertional malaise, unrefreshing sleep, or cognitive impairment should be present at least 50% of the time and be at least moderate to severe.^[1]

Can ME/CFS Be Diagnosed in Patients With Symptoms for <6 Months?^[1]

Dr Bateman: A provider can make a provisional diagnosis in patients who have had symptoms less than 6 months.^[1] Prolonged viral illness should arouse some suspicion as nonchronic infections rarely linger for longer than 6 weeks. During that first 6 months of symptoms, ongoing care, monitoring, and documentation are very important.

Postexertional Malaise: A Distinguishing Characteristic of ME/CFS^[1,5]

Dr Bateman: Nancy, can you explain PEM, or postexertional malaise, and how we know if patients have PEM?

Dr Klimas: Sure. PEM is an interesting term. It is an exacerbation of the ME/CFS symptoms. We are talking symptoms, not just fatigue, after a physical or cognitive exertion.^[1] It can occur immediately after exercise or exertion or it can occur hours or even days later. The critical issue here is that it increases the severity of the illness. It will often put people into bed. It can be very severe. It is not always observable in a clinic visit. In fact, patients sometimes rest up to be able to do a clinic visit. It can last for days or months after it has been triggered. By surveying patients with ME/CFS, you can see that fatigue is the most common symptom that is increased after physical or cognitive exertion or emotional stress.^[5] This is accompanied by other symptoms: flu-like illness, sore throat, tender lymph nodes. About 60% of patients describe these immune-like symptoms.

Percentage of ME/CFS Patients and Healthy Controls Reporting Immune-Related Symptoms of at Least Moderate Severity That Occurred at Least Half of the Time for the Past 6 Months^[1]

Dr Bateman: Let's explore immune symptoms a bit more. Patients with ME/CFS frequently report symptoms related to inflammation.^[1] Many describe it as feeling like a perpetual flu-like state. More specifically, patients report persistent or recurrent sore throats, tender/swollen cervical and/or axillary lymph nodes, muscle pain, achy joints without swelling or redness, headaches, chills, feverishness, and new or worsened sensitivities to certain foods, odors, or medications. It is not clear whether these symptoms associated with systemic inflammation have an infectious or inflammatory etiology. For example, one study cited by the IOM report found that compared with healthy persons, a far greater percentage of patients with ME/CFS report these immune-related symptoms with at least moderate severity, occurring at least half of the time for the past 6 months. The inflammatory symptoms can fluctuate and may be unmasked or exacerbated with physical or cognitive activity as part of the constellation of symptoms associated with PEM.

How Do You Determine If Your Patient Has PEM?: Questions to Ask^[5]

Dr. Klimas: So, it is important to ask the right kinds of questions to sort out if this is happening.^[5] For instance, patients [may report] waking up with about 30% of their charged battery and then crashing after exertion; triggers, so inquiring as to the kinds of things that trigger these events and the number and types of symptoms that occur, and the time course. All of this can help to identify PEM and assist with the ME/CFS diagnosis.

ME/CFS and Pain^[1]

Dr Bateman: In addition to those core criteria, there is an array of immune, neurologic, and autonomic symptoms and almost all patients report some type of pain, although it is highly variable and often occurs in pain as a consequence.^[1] Pain supports the diagnosis, but it is not specific to ME/CFS.

Percentage of ME/CFS Patients and Healthy Controls Reporting Pain Symptoms of at Least Moderate Severity That Occurred at Least Half of the Time for the Past 6 Months^[1]

Dr Bateman: Most patients with ME/CFS report pain, though there is wide variation in the types of pain reported. Research has shown that patients diagnosed with ME/CFS experience more pain compared with the general population. Another study cited by the IOM report found that compared with healthy persons, a greater percentage of patients with ME/CFS report pain symptoms of at least moderate severity, occurring at least half of the time during the past 6 months. While there is no consensus on the definition of chronic widespread pain in ME/CFS, all existing case definitions include muscle pain, joint pain, headaches, tender lymph nodes, and sore throat. In a multisite study conducted by the CDC [Centers for Disease Control and Prevention], muscle aches and pains were the most common pain complaint (reported by 72% to 79% of patients), followed by joint pain in 58% to 60% and headaches in 48% to 56%.^[6] Tender lymph nodes and abdominal pain were each reported in about one-third of patients, sore throat and eye pain in about one-quarter of patients, and chest pain in 15% of patients.^[6]

ME/CFS in Adolescents and Adults^[1]

Dr Bateman: Natalie, how do symptoms differ between adults and adolescents, and are there any assessment tools for ME/CFS

Dr Azar: Yes, there are some differences between adults and adolescents.^[1] Orthostatic intolerance is commonly a presenting symptom in adolescents. Manifestations of orthostatic intolerance include POTS, or postural orthostatic tachycardia syndrome; neurally mediated hypotension, which is typically a delayed presentation; as well as orthostatic hypotension.

Dr Bateman: Orthostatic intolerance testing might include orthostatic vital signs, a formal standing or lean test, which is a full 10-minute test measuring heart rate and blood pressure supine compared to standing, or a formal tilt table test. And much information can be gleaned from questionnaires about orthostatic intolerance, such as the COMPASS 31.^[1]

Common Orthostatic Intolerance Syndromes^[1]

Dr Bateman: There are a few important things about orthostatic intolerance to understand when assessing your patients. The most common forms of orthostatic intolerance are POTS, neurally mediated hypotension, and orthostatic hypotension.^[1] POTS is characterized by an increase in heart rate between the supine position and 10 minutes of standing. It is defined as an increase of more than 30 bpm [beats per minute] for adults or 40 bpm for adolescents, or a heart rate that reaches 120 bpm or higher during the first 10 minutes of upright posture in the absence of orthostatic hypotension. This change in heart rate must also be accompanied by characteristic orthostatic symptoms. Neurally mediated hypotension is a reflex drop in systolic blood pressure of at least 25 mm Hg during standing or upright tilt testing compared with supine systolic pressure. Typically, it is preceded by orthostatic symptoms of lightheadedness, nausea, pallor, and warmth, and it is accompanied by slowing of the heart rate. Orthostatic hypotension involves an immediate and sustained drop of at least 20 mm Hg in systolic pressure or 10 mm Hg in diastolic pressure in the first 3 minutes of standing or upright tilt. Although this is uncommon in ME/CFS, a delayed form has been reported in which blood pressure changes occur after 3 minutes upright.

Tools for Evaluation of Symptoms of ME/CFS^[1]

Dr Azar: Some other tools to evaluate for symptoms include the fibromyalgia impact questionnaire (FIQR).^[1] This is a good one for evaluating the impact of pain on function; it is available online and it is free. Additionally, there are the Multidimensional Fatigue Inventory-20, the CDC Symptom Inventory for CFS, and many others that are listed in the appendix to the IOM report; some of which are used clinically or for research.

Patient Case 1: 34-Year-Old Caucasian Woman

Dr Bateman: Let's discuss a patient case. A previously healthy 34-year-old Caucasian woman visits her PCP [primary care physician] for severe fatigue that started about 7 months prior to the visit. She works as a teacher and frequently calls in sick, and despite being exhausted she has trouble sleeping. She is taking a hormonal contraceptive and an occasional over-the-counter sleep aid. She drinks socially, but does not use drugs or smoke.

Percentage of ME/CFS Patients and Health Controls Reporting Sleep-Related Symptoms of at Least Moderate Severity That Occurred at Least Half of the Time During the Past 6 Months^[1]

Dr Bateman: As shown in the figure taken from the IOM report, sleep-related symptoms are very common. Nearly all patients with ME/CFS report some type of sleep dysfunction.^[1] They frequently experience sleep-related problems such as insomnia, sleep disturbances, and unrefreshing or nonrestorative sleep. Unrefreshing sleep -- or feeling as tired upon waking as before going to bed -- is among the most common symptoms. Research has shown that patients with ME/CFS are more likely than healthy controls to experience sleep-related symptoms of at least moderate severity, and occurring at least half of the time in the past 6 months.^[1] Although sleep-related symptoms are also reported by healthy persons and by chronically fatigued persons who do not fulfill criteria for ME/CFS diagnosis, a greater percentage of people who do meet the ME/CFS criteria report unrefreshing sleep, sleep disturbances, and difficulty falling asleep or waking up early in the morning.

ME/CFS: A Symptom-Based Diagnosis -- Tips for Taking a Good Patient History^[1]

Dr Bateman: José, what would you ask this patient to get a history of her symptoms?

Dr Montoya: It is key to note that ME/CFS is a symptom-based diagnosis. The history of impaired function and PEM, as my colleague Dr Azar has referred to as postexertional malaise, is key for the diagnosis. Many chronic illnesses involve fatigue, but patients with ME/CFS describe fatigue differently. Cognitive issues are often present and can complicate communication. It is important to ask the right questions. IOM compiled a list of suggested questions for symptoms and common responses from our patients.^[1] Examples include: What symptoms are keeping you from doing what you want or need to do? What makes the fatigue worse? What helps the most? What are you able to do now as opposed to before? Also, ask about other required symptoms: PEM and nonrefreshing sleep, cognitive impairment, orthostatic intolerance, hypersensitivity to sound or light, and cardiac, neurologic, and gastrointestinal symptoms.

Listen to What Patients Say About Their Symptoms

Dr Montoya: The kinds of answers you would expect to hear from patients include "achy," "exhausted," "like I never slept," "arms and legs feel heavy," "hard to think," "mentally or physically drained after the slightest activity." It is also important to ask about common symptoms of chronic pain, infection, and immune or neuroendocrine dysregulation.

History and Physical Examination

Dr Bateman: Natalie, what else would you look for?

Dr Azar: In addition to what Dr Montoya listed, we also would take a complete medical and social history. We want to know all prescription drugs, as well as over-the-counter medications, herbs, and supplements that the patient might be taking. We need to ask about their use of alcohol, as well as recreational drug use, if there have been any toxin exposures, or preceding viral or bacterial illnesses. The physical examination should include looking for signs of cardiopulmonary, neurologic, neuromuscular, or endocrine disease. Experts recommend a full 10 minutes of the standing or lean test to assess for orthostatic intolerance.^[1]

Sleep Assessment

Dr Bateman: In addition, sleep assessments should be made via questionnaire.

Patient Case 1: 34-Year-Old Caucasian Woman (cont)

Dr Bateman: Let's look at the patient history results. She has worse symptoms every time she does anything even mildly strenuous. It can take hours or days to resolve. It does not improve significantly with rest. She cannot sleep through the night without disruption. Unfortunately, she stopped going to the gym and she started missing a lot of work. She cannot think straight and loses track of conversations. She is not aware of any toxic exposure, but she did have a febrile illness approximately 1 year earlier with lingering symptoms. Nothing was found during physical examination, and no primary sleep disorder was identified.

The Role of Laboratory Tests in Diagnosing ME/CFS^[1]

Dr Bateman: Nancy, we mentioned earlier that there are no specific laboratory tests for ME/CFS. Are there any laboratory tests that can help with diagnosis?

Dr Klimas: Definitely. Labs tests are indicated in a case like this. First, to rule out other disorders with similar symptoms or presentations, including symptoms of fatigue; the common things: anemia, endocrine disorders, thyroid, Addison disease, diabetes, chronic infections, such as hepatitis or HIV. Patients should be evaluated for cardiovascular disease, pulmonary disease, and autoimmune diseases, which frequently present in a very similar way to ME/CFS. Celiac disease, lupus, and rheumatoid arthritis should also be ruled out.

There is no specific laboratory test that rules in the diagnosis of ME/CFS, though a common battery of tests might include a complete blood count, blood chemistry, thyroid test, erythrocyte sedimentation rate, and C-reactive protein level as screening tests to rule out ME/CFS.^[1] There are other tests you might consider, depending on what you find in your history and your physical exam. Those are our doctor skills. Because the symptoms affect so many systems, it sometimes takes multiple visits before you can arrive at the final diagnosis.

Patient Case Conclusion

Dr Bateman: I will tell you, the results of her [patient in case] laboratory tests are normal. Based on the IOM criteria, would you diagnose this patient with ME/CFS?

Dr Klimas: Yes, I would. I think it is a pretty typical case; a fairly acute onset of febrile illness with all the symptoms that make this case and excluding the other common illnesses that could present in the same way.

If ME/CFS Can't Be Treated, Why Is It Important to Diagnose It?

Dr Bateman: José, there are no specific treatments for ME/CFS, so why is it important to diagnose this condition?

Dr Montoya: It is key to do so because we reassure patients that help is available and to also reduce the risk of suicidal ideation that sometimes occurs in patients who are extremely ill. It also allows providers to formulate a management plan specific to ME/CFS; for example, restricting activity as opposed to encouraging activity, treating pain, and improving sleep. Misdiagnosis or no diagnosis can lead to incorrect advice, and a classic mistake that is made is to ask patients to exercise. This triggers PEM and is contraindicated in patients with ME/CFS. Diagnosis also facilitates tracking of the epidemiology of ME/CFS and the future development of clinical trials.

Patient Case 2: 38-Year-Old Caucasian Woman

Dr Bateman: Thank you so much. Let's look at another case. This one was one of yours, Natalie.

Dr Azar: This is a patient I had been following for years. She is a 38-year-old Caucasian female followed by me for multiple different diagnoses of fibromyalgia and undifferentiated connective tissue disease. During one of our visits she began to describe an unusual level of exhaustion: the inability to exercise or even maintain her work schedule due to brain fog, headaches, and sleep disturbances. Upon closer questioning, the patient described classic PEM when she stated that she could not get to the bus without needing to call her husband to pick her up, and she could not make it to work. It was one of the first times that the light bulb went off and I realized that there was an absence of mutual exclusivity of conventional rheumatic diseases in ME/CFS so that they can coexist. She was diagnosed with ME/CFS using the clinical criteria and, in fact, had very elevated Epstein-Barr virus titers indicative of reactivation [infection].

Management of ME/CFS

Dr Bateman: Nancy, we mentioned there are no specific treatments for ME/CFS. Is there anything clinicians can do for patients who are diagnosed with this disorder?

Dr Klimas: Certainly, it is important that we go beyond simple diagnosis. There is quite a bit we can do to help these patients. First, we can apply our expertise as physicians in assessing and managing the symptoms, including patients who have not had symptoms yet for 6 months, but who appear to be developing the classic criteria for ME/CFS.

Unique possibly to this illness is the importance of activity management to avoid severe or prolonged PEM. It is a primary intervention. It's hard for these patients to learn how to pace, but pacing is key to their ability to sustain a decent quality of life. The illness manifestations are all treatable: sleep, cognitive impairment, orthostatic intolerance. Again, we are using our doctor skills to treat these things, but they are often amenable to established treatments for conditions, such as volume expansion for orthostatic intolerance.

Dr Azar: For children, even while evaluation is ongoing, parents, guardians, and doctors can work with school staff and administrators to adjust school loads and schedules. Continuing social engagement is very important for the well-being of children.

Review of IOM Diagnostic Criteria^[1]

Dr Bateman: So let's review the IOM diagnostic criteria for ME/CFS. To meet the IOM diagnostic criteria, patients much have the following 3 core symptoms in order to make the diagnosis: a substantial reduction or impairment in the ability to engage in preillness levels of activity accompanied by fatigue (often profound), and it has lasted at least 6 months. Number 2 is PEM, a core presenting feature of the illness, and this is relapse after attempting to do cognitive or physical activity. Number 3 is unrefreshing sleep, as Nancy described. And at least 1 of the following 2 symptoms are required in order to make the diagnosis: cognitive impairment or orthostatic intolerance. The frequency and severity of symptoms should be assessed because PEM, unrefreshing sleep, and cognitive impairment should be present at least 50% of the time and be at least moderate to severe.

Proposed Approach to ME/CFS Diagnosis in Children and Adults^[7]

Dr Bateman: In this regard, let me finish with a review of the diagnostic algorithm developed by the Centers for Disease Control and Prevention (CDC) for use in patients who present with profound fatigue. The algorithm focuses on the core symptoms of impaired function, manifested as fatigue, postexertional malaise and unrefreshing sleep, plus either cognitive impairment or orthostatic intolerance, and these should generally be at least moderate to severe and present at least 50% of the time. Additional common, but not core, symptoms of ME/CFS include chronic pain, and immune or infection symptoms. To begin, ask the questions needed to determine if the patient has impaired function, gets worse after increasing physical or cognitive activity (postexertional malaise), reports unrefreshing sleep, and complains of either cognitive impairment or symptoms of orthostatic intolerance. If these core presenting features of ME/CFS are all present, obtain a thorough history, complete a full physical exam and mental health assessment, and order any tests needed to complete a differential diagnosis for the presenting symptoms. Treat all identifiable conditions and schedule periodic follow-up appointments. Manage symptoms supportively while continuing to investigate their origin. If the core features are still present at least 50% of the time and are moderate to severe after 6 months of illness (3 months for pediatric age group), diagnose ME/CFS and continue supportive management.

Concluding Remarks

Dr Bateman: In conclusion, ME/CFS is a real disease. It is easy to miss the diagnosis if you do not know what to ask. The IOM has developed new clinical diagnostic criteria to help providers identify patients with ME/CFS. It is important for providers to take a careful history and conduct a thorough physical examination, but also to ask the right questions, especially about impaired function and postexertional relapse symptoms, PEM. Be sure to rule out other illnesses that cause similar symptoms, and manage comorbidities. Patients and families benefit from having providers recognize what they are experiencing.

Thank you.

I'd like to thank you for joining me in this discussion, and I thank you for participating in this activity. Please continue on to answer the questions that follow and complete the evaluation.

This transcript has been edited for style and clarity.