Gabriella Marinaccio, a 28-year-old teacher from Norwalk, CT, says she was forever on the go. “Rush, rush, rush. Undergraduate degree, then master’s, got married, started my doctorate, bought a house, bing, bam, boom!” She was a full-time teacher of English as a second language (ESL) while working on her doctorate, and still found time to socialize with her husband and their many friends. Then, in January 2014, her busy but idyllic life hit a large and unexpected speed bump.
“I woke up and thought I had the flu. I was achy and sick for about a week,” she recalls. When the severe diarrhea that accompanied the illness didn’t go away, her primary care doctor ordered a battery of tests, but couldn’t find anything wrong. She referred Marinaccio to a gastroenterologist, who ordered more blood work and did an endoscopy and colonoscopy, again without identifying an underlying cause. Finally, the gastroenterologist prescribed a course of antibiotics, and eventually her stomach settled down and the diarrhea stopped.
Then, in late September, Marinaccio tested positive for the flu, which was followed by a series of sinus, ear, and other minor viral infections—plus swollen lymph nodes in her neck, a sore throat, and achy muscles. By the end of October she was so unwell that it became impossible for her to continue teaching. By early November she had stopped working.
She saw several more doctors, including one specializing in infectious diseases and another in allergies and immunology. “They said there was nothing wrong with me. They did 50 pages of blood work and said everything was fine.”
A DIAGNOSIS AT LAST
But an appointment with Susan Levine, MD, an infectious disease and allergy and immunology specialist in New York City, finally provided some answers. Dr. Levine reviewed Marinaccio’s blood work and tests, examined her, and spent an hour listening to her. “Then she looked at me and said, ‘It’s chronic fatigue syndrome [CFS], and I think you also have active Epstein-Barr virus [the virus that causes mononucleosis].’” Dr. Levine drew blood to test for the virus and called one week later to confirm the diagnosis.
NO DIAGNOSTIC TESTS
A long, winding road to a CFS diagnosis is not unusual. There are no tests to identify and confirm biomarkers (indicators of a disease in the blood or body), and many doctors are unfamiliar with the clinical symptoms. A diagnosis is made based on symptoms, as well as a patient history and testing to rule out other conditions that may cause similar levels of fatigue, says Dr. Levine.
“Fatigue is a very common symptom with a wide variety of causes,” so ruling out other conditions is crucial, says Joseph R. Berger, MD, a professor of neurology at the Perelman School of Medicine of the University of Pennsylvania, an expert in neuro-immunology and neurovirology, and a Fellow of the American Academy of Neurology (FAAN). In a study published in the Multiple Sclerosis Journal in 2013, Dr. Berger reviewed the medical histories of thousands of people who were ultimately diagnosed with multiple sclerosis (MS) and found that one out of three was first diagnosed with CFS or general fatigue in the two to three years before they developed clinical MS. He believes that finding should serve as a warning to doctors against jumping to conclusions if they can’t find an immediate organic cause for a patient’s fatigue.
Many skeptics cite the fact that fatigue is a common symptom of many other conditions and the lack of clinical proof as evidence that CFS is primarily a psychological condition. “When I talk about chronic fatigue to other neurologists, up to half don’t believe it is a real medical entity,” says Thomas Sabin, MD, FAAN, vice chair of neurology at Tufts University School of Medicine.
Dr. Sabin understands the skepticism. For many years, he referred to himself as a “CFS agnostic,” but after decades of seeing patients and hearing similar stories of sudden symptoms, he is now convinced that the condition is real and devastating.
QUELLING THE CRITICS
To clarify the competing definitions and diagnostic criteria, the US Department of Health and Human Services and several other government agencies commissioned the non-profit Institute of Medicine (IOM) to evaluate the literature and recommend the best diagnostic criteria for doctors, based on the evidence.
The IOM panel, comprising 15 experts in clinical care, immunology, infectious diseases, pediatrics, neurology, and other relevant specialties, as well as people with CFS and their caregivers, held public hearings with advocates and researchers, opened an online portal for the public to add input, and considered more than 9,000 medical articles and studies on CFS written between 1950 and 2014.
As a result of its findings, the IOM panel proposed renaming the condition “systemic exertion intolerance disease,” or SEID, and defined it as a serious, chronic, complex, and systemic disease that frequently and dramatically limits the activities of those affected. In its final report, “Beyond Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: Redefining an Illness,” the panel concluded that CFS is, indeed, a “real” condition. (“Myalgic encephalomyelitis” means muscle pain or fatigue caused by inflammation in the brain and spinal cord.)
NEW PROPOSED DIAGNOSTIC CRITERIA
The panel identified five major symptoms: profound fatigue, exhaustion after exertion, unrefreshing sleep, cognitive impairment, and orthostatic intolerance (feeling lightheaded upon standing). For a diagnosis of CFS, patients must have the first three symptoms and at least one of the other two, according to the report.
1. Profound Fatigue
The first and most widely known symptom of CFS is debilitating fatigue. For a CFS diagnosis, this fatigue must come on suddenly, last for a minimum of six months, and go beyond a slight sleepiness or the temporary tiredness many feel after a busy week at work. “I call it ‘trimodal fatigue,’” says Dr. Sabin. “It’s the fatigue you feel when you miss a lot of sleep, combined with the mental fatigue after you play in a chess tournament and the physical fatigue after you exercise a lot. It’s all three types together.”
Marinaccio says her fatigue spills over into her social and family life, and she worries it may affect her relationships. She has often found herself physically unable to pick up the phone when a friend calls, and then cannot summon the mental energy to return the call. “Because I’m exhausted all the time, I have less patience. I don’t want to be that person who is moody and cranky all the time.”
Her fatigue is chronic but unpredictable in its intensity. Some days she can go to the supermarket to shop. Other days, she doesn’t even have the energy to make a sandwich.
2. Exhaustion After Exertion
People who have CFS describe the second core symptom, post-exertional malaise—a serious exacerbation of symptoms after mental, emotional, or physical exertion that may last anywhere from 24 hours to months—as a “crash” or “collapse.” “Their fatigue worsens with even minimal physical or mental exertion—sometimes only 10 minutes,” says Dr. Levine. “Other symptoms, such as cognitive abnormalities and sore throats and/or lymph node swelling, may flare up as well.”
Each person has a different fatigue threshold. For Marinaccio, a walk around the block is like running miles for an ordinary person; if she pushes herself beyond that point, she is affected for days.
“Post-exertional malaise is difficult to measure clinically because patients may be ‘normal’ in a resting state, and most doctors don’t have a treadmill or other equipment in their offices to test for it,” says Dr. Levine. Besides, “this symptom is variable, and [physicians] have to learn to ask the right questions.” She suggests doctors ask their patients how they feel the day after doing a strenuous activity.
Dr. Sabin says he regularly encourages his patients to do as much as they can but reminds them that overexertion may be counterproductive. Each person has to identify his or her own threshold and be active up to that point. Some evidence suggests that those who exert up to their threshold can improve, he says, and the threshold may even increase over time.
3. Unrefreshing Sleep
No matter how many hours they sleep, people with CFS universally report feeling unrested when they wake up. As with many symptoms of CFS, the intensity may vary. Initially, Marinaccio says she had difficulty staying asleep because her legs and arms felt achy. She would toss and turn, trying to stretch out. These days she sleeps soundly, but she feels no less tired or achy when she wakes up. As the day goes on, her symptoms lessen, and she feels most energetic in the evenings.
4. Cognitive Impairment
The IOM panel noted that many people who have CFS report that they can’t process information as quickly as they used to, and that they lack focus and are more forgetful. “The neurocognitive symptoms are slowed processing of new information, short-term memory problems, and diminished attentiveness, all of which worsen following exertion,” says Dr. Levine. This dulling of mental faculties can be as debilitating as the physical fatigue, but it is equally difficult to measure clinically, she says. And neurocognitive testing for the symptoms may not be covered by insurance.
Marinaccio, who used to love to read and discuss books, now can only concentrate long enough to listen to audio books in short bursts. Because of this, she has had to put her doctorate on hold for now.
5. Orthostatic Intolerance
The report also found that many people with CFS feel lightheaded or faint or have heart palpitations or other cardiac symptoms when they stand up or after standing for a long time. Once they sit or lie down, the symptoms diminish. This condition, called orthostatic intolerance, is normally diagnosed and treated by cardiologists—another example, Dr. Levine says, of how CFS cuts across medical specialties.
“It’s not clear whether orthostatic intolerance precedes CFS symptoms,” she says. “Patients may recall feeling lightheaded or having migraines or light sensitivity before they have symptoms of CFS, or these symptoms may be a consequence of the illness.”
A STEP IN THE RIGHT DIRECTION
Dr. Sabin says the IOM’s proposed diagnostic criteria is “a simplification [of the condition], perhaps,” but one that clarifies the core symptoms and makes it easier to diagnose. He also thinks the report will draw attention to CFS, and he is happy that it confirms that the syndrome causes real suffering and should not be dismissed by doctors.
As the chair of the US Federal Advisory Committee on CFS, which is responsible for evaluating and implementing the IOM report, Dr. Levine says there is still debate about whether other common symptoms of CFS, such as viral infections, muscle and joint pain, and swollen lymph glands, should be included as part of the diagnostic criteria. Otherwise, she thinks the panel’s proposed criteria are a good start.
Dr. Berger adds that he believes too many people whose only symptom is fatigue are diagnosed with CFS. He thinks that physicians should apply the new diagnostic criteria for CFS strictly, and if their patients don’t satisfy them in full, they should look elsewhere for underlying causes.
SEARCHING FOR A CAUSE
Since chronic fatigue was first reported in the 1930s, researchers have put forward theories about its cause, but no single virus or environmental trigger has been proven and no single mechanism has been found. A 1934 outbreak in a hospital in Los Angeles was thought to be a mutation of the poliovirus. An outbreak in 1955 in London’s Royal Free hospital, which affected many staff members, was considered highly contagious. Another episode in the 1980s near Lake Tahoe was thought to be a chronic form of the Epstein-Barr virus.
Recently, many viruses and infectious agents have been studied as potential causes or triggers for the condition, including the human herpesvirus 6, Candida albicans (a fungus that causes yeast infections), and bornaviruses (a family of viruses found in farm animals and birds that affect neurons). However, none has been shown to be the single or most likely cause of CFS. “So far, we have not been able to identify an infectious agent,” says Dr. Berger, who doesn’t believe a single agent is likely to be behind all cases of CFS and is not convinced that a chronic or lingering infection gives rise to the symptoms. “It’s certainly conceivable that in a subpopulation [of people with CFS] there has been some change in their immune function triggered by an infection and that proinflammatory cytokines [proteins that regulate the body’s response to infection and inflammation, which in this case make disease worse] are now affecting their brains and giving rise to their symptoms,” he adds.
The lack of a proven cause or mechanism adds to the amorphous quality of the condition. After an exhaustive analysis of the medical literature, the IOM committee could not come to any conclusions about what causes CFS, how it works within the body, or how to treat it. The literature offered no consensus on the process or natural progression of the syndrome.
A DYNAMIC CONDITION
Chronic fatigue syndrome morphs over time, says Dr. Levine. “Within the first year of someone getting ill, there are many abnormalities in the blood and inflammatory markers, but these fade as time goes on.” This may be one reason it has been so difficult to find a single biomarker.
However, Dr. Levine thinks researchers are getting closer to finding these biomarkers. Jose Montoya, MD, and his colleagues at the Stanford ME/CFS Initiative, for example, have found evidence of inflammation and structural abnormalities in the brains of people with CFS. But, Dr. Levine cautions, “it’s so complex, we’re only scratching the outer surface. It’s going to take a while.”
Dr. Sabin agrees. “Something triggers an immune response,” he says, but the research can’t yet describe or explain it.
TREATING SYMPTOMS
Because there is no recognized treatment for CFS, doctors can only treat individual symptoms like pain, difficulty sleeping, and opportunistic infections. Marinaccio still takes medications for acid reflux and irritable bowel syndrome, but her doctor is slowly weaning her off them. She also takes an antiviral drug prescribed by Dr. Levine for the active Epstein-Barr virus and to reduce any other potential viral load, as well as an antihistamine prescribed by her primary care doctor for her allergies, which worsened with her CFS. She has also changed her diet, avoiding processed foods, cutting back on meat, and eating more greens and berries.
Dr. Sabin shares strategies with his patients with CFS for adapting to the illness and maintaining productivity. “I tell my patients to consider and examine how they spend their time and try to think of ways to use what energy they have productively,” he says. To help them do that, he often recommends cognitive behavioral therapy, a form of therapy that teaches people how to counter negative or inaccurate thoughts and cope with challenging or stressful situations. It’s important to avoid making the disease a lifestyle, he says.
A MIXED PROGNOSIS
Some people with CFS are profoundly disabled, while others recover, says Dr. Sabin. In general, though, symptoms can persist for years, and most people never regain their original level of health or functioning.
Marinaccio cried when she was diagnosed with CFS, but Dr. Levine reassured her that because it was caught so early, she has a better chance of improving than most. “I think it’s fair to say that most patients improve about 30 to 50 percent. They do better if they are treated, stop working, or both within 18 months of becoming ill. The outcomes are so variable, and no one has done long-term studies [on the condition].”
Marinaccio says she feels slightly better since she was first diagnosed last Thanksgiving. “I’m managing my fatigue and learning how to pace myself.” Even small changes help: Instead of writing Christmas cards by hand, for example, she now sends e-cards. Instead of shopping at a store for every essential, she orders items like paper towels and cleaning products online in bulk. This allows her to use the energy she has for more important things like maintaining relationships and teaching her class.
She also believes she has learned a lesson from her diagnosis. “I was always go, go, go. Now I realize life is not all about doing and achieving. I have started to appreciate what I have.” She has started a blog to chronicle her condition and how she is dealing with it, in hopes of helping others in similar situations. And she wants people to seek treatment as early as they can—before they “dig themselves into a hole they can’t get out of.”
WEB EXTRA: For more information on myalgic encephalomyelitis/chronic fatigue syndrome, including a proposed name change, visit http://bit.ly/NN-chronicfatigue.
Resources for CFS
* The complete IOM report can be downloaded for free or purchased in hard copy: http://bit.ly/IOM-CFS-report
* The Chronic Fatigue Initiative at the Hutchins Family Foundation is committed to supporting and publicizing research into causes and possible treatments: http://cfinitiative.org
* The Stanford Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) Initiative is investigating the possibility that CFS may be caused or triggered by an infectious agent or the body’s immune response to an infection: http://bit.ly/Stanford-CFS
* The US Centers for Disease Control and Prevention offers a resource page: http://cdc.gov/cfs
* Phoenix Rising offers support, forums, and further resources: http://phoenixrising.me
* The Solve ME/CFS Initiative is dedicated to finding a cure for the syndrome through patient-centered research: http://solvecfs.org
* The End ME/CFS Project, part of the Open Medicine Foundation, supports the ME/CFS Severely Ill, Big Data Study, which hopes to find a clinically useful diagnostic biomarker: http://bit.ly/End-MECFS
