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Dr. Benjamin Natelson is 2012 keynote speaker at Mass CFIDS/ME & FM Association : Lumper or Splitter
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- Last Updated: 23 November 2015 23 November 2015
Common symptoms and lumping chronic conditions together
In a lecture called "CFS Diagnosis: Are You a Lumper or a Splitter" co-sponsored by the Massachusetts CFIDS/ME & FM Association (MassCFIDS) and the Massachusetts Department of Public Health on April 28, 2012 Dr. Benjamin Natelson, Director of the Pain and Fatigue Center at Beth Israel Medical Center in New York City, presented twenty years of research and work with Chronic Fatigue Syndrome (CFS) patients. Dr. Natelson's wife, Dr. Gudrun Lange, Ph.D., a Clinical Neuropsychologist accompanied Dr. Natelson to Massachusetts, and in a surprise double-header, also spoke about the process of neuropsychological testing for CFS patients.
What's a syndrome?
Dr. Natelson explained that in CFS, as well as such other syndromes as Irritable Bowel Syndrome (IBS), Temporal Mandibular Joint Syndrome (TMJ), Migraine, Depression and Schizophrenia, there are common symptoms that seem similar and therefore, the medical professionals label it a syndrome. A syndrome is a cluster of symptoms that can have multiple causes. "We need to figure out ways to reduce the variability. CFS is the tip of the iceberg" he said. Fatigue can be related to many pain syndromes but whether the fatigue is a result of sleep problems or if the fatigue itself produces pain needs to be sorted out.
Fatigue is the most common symptom in medicine
There are many medical conditions and syndromes that are associated with severe fatigue. These conditions can include Chronic Fatigue Syndrome (CFS), Fibromyalgia (FM), Irritable Bowel Syndrome (IBS), heart failure, Multiple Sclerosis (MS) and Chronic Obstructive Pulmonary Disease (COPD). In fact, fatigue is the most common symptom in medicine, and there are multiple causes, including sleep disorders, infection or any number of other conditions. Dr. Natelson stressed that in CFS there is severe fatigue marked by a substantial decrease in activity.
Dr. Natelson presented statistics to drive his point home. A person has a 9% chance of developing CFS within 6 months after a bad infection, but not necessarily lasting for more than 6 months. About 15% of breast cancer survivors fulfill the criteria for CFS. Fatigue is often the first symptom in Multiple Sclerosis (MS), and many Parkinson's patients are often debilitated by fatigue.
Lumper's approach
The lumper's approach groups all chronic conditions, such as CFS or FM, in which a person has physical symptoms that involve more than one part of the body but seemingly without physical cause, as a somatization disorder. Doctors are inclined to diagnose pain and fatigue related syndromes, which currently have no diagnostic test, as Somatic Amplification, a tendency to psychologically perceive normal sensations as overly intense.
Dr. Natelson feels that Somatic Amplification has a derogatory connotation and should be replaced with Medically Unexplained Symptoms. In fact, the rate of somatic disorder reported in CFS patients depends entirely on whether the cause of the symptoms is interpreted as psychological or physical by the physician who is making the diagnosis.
Splitting patients into subgroups and looking for more ways to differentiate
The splitter's approach
When it comes to determining a cause for Chronic Fatigue Syndrome, is it better to lump CFS patients together with other chronic conditions causing pain and fatigue, or is it better to split patients into subgroups?
Dr. Natelson takes the splitter's approach and identifies patient subgroups in order to determine the cause, or causes, of Chronic Fatigue Syndrome. Dr. Natelson's research for biomarkers, a biological characteristic that can be objectively measured as an indicator of abnormal biological processes, has pointed in the direction of a brain dysfunction in a specific subset of CFS patients.
As there are most likely several causes for CFS, the subgroups help to narrow the pool of patients in order to determine specific causes. This process is called Stratification Strategy.
While FM is another way to split out a diagnosis, FM is tenfold more common than CFS because FM is a diagnosis that is made without any exclusions.
CFS is a diagnosis of exclusion, which requires ruling out all possibilities causing fatigue such as thyroid disease, MS, Lupus, diabetes, etc. and hoping the fatigue will be resolved.
The prevalence rate for FM is 3%, being mostly a women's health issue breaking down to 75% women to 25% men. The prevalence rate for CFS is 0.3%— again favoring women.
In a research paper Natelson published 10 years ago regarding sudden onset, it looks at CFS patients and charts the dates when they became ill. Looking at the chart shows the onset was not random because if random, the charted line would have been straight across. This line went up all around the same time, in winter, suggesting an infection-related trigger.
Stratification Strategy
Co-morbidity is the existence of another diagnosis along with CFS. Dr. Natelson looked at several ways of splitting CFS patients: CFS patients with and without Fibromyalgia; sudden or gradual onset of symptoms; severe or non-severe symptoms; cognitive impairment versus normal cognition; and patients with and without a psychiatric diagnosis—usually depression. About 35% of patients in Dr. Natelson's center reported a sudden onset of symptoms, while the balance report fatigue and symptoms that increased gradually.
Are CFS and FM the same?
In his clinical sample, Dr. Natelson compared CFS and FM to determine if they are the same condition. While overlaps do exist, there are medical differences as well.
About 40% of the CFS patients fulfill the criteria for FM. About 20% of FM patients had CFS. The spinal fluid of FM patients shows an elevation of Substance P (responsible for pain), but that is not the case in CFS patients.
Another study had shown that CFS was common in patients with obstructive sleep apnea, while FM was not. Also, FM pain responds to some anti-depressant medications, but CFS fatigue does not.
Natelson concluded that CFS and FM are not the same and therefore do not have the same causes, nor should they have the same treatments.
Twenty years of research shows possible brain dysfunction
In the past twenty years, Dr. Natelson has conducted a number of studies to determine the differences, and possibly determine the causes, for CFS as compared to other syndromes, such as FM, Sjögren's and post-Lyme.
In a recently published study looking at sleep, CFS-only patients have increased rates of REM to wakefulness (tends toward awake) while CFS-plus-FM patients tend to fall asleep, but their sleep is disrupted by transitions to wakefulness. These marked differences may prove helpful in determining treatment approaches.
In a study looking at the blood prolactin (a hormonal surrogate for brain serotonin neuron activity) response to a tryptophan infusion, CFS patients showed increased brain response to the tryptophan infusion but not those with CFS-plus-FM or healthy controls. Studies done with depressed patients show an under-response to tryptophan infusion.
His conclusion was that CFS and FM are not the same, as the lumpers believe, and patients may not respond in the same way to commonly prescribed treatments.
Natelson's hypothesis
Natelson's hypothesis is that some CFS patients, especially those that have no accompanying psychological disorders, have brain dysfunction or encephalopathy. Furthermore, Natelson believes that further study will identify biomarkers to accurately diagnose that subset of CFS patients.
In his first study, twenty years ago, Natelson compared the cognitive dysfunction in patients with CFS, MS and healthy patients. He found that CFS patients function worse than controls on timed complex attentional tasks, and that those with the most impairment could have an underlying encephalopathy, or brain dysfunction.
As an example, he offered that a CFS patient in a quiet room talking to one person would be ok, but in a room with four people talking at once, the CFS patient would have a problem.
Research, ongoing studies, and use of new technology
Research finding
He is now looking at the brain by studying spinal fluid—the fluid that bathes the brain—and using brain imaging techniques.
Brain MRIs showed more abnormalities in CFS subjects with no psychiatric disorder as compared to CFS with a psychiatric disorder or to healthy controls. This finding again points to encephalopathy, especially in CFS patients without a coexisting psychiatric disorder.
The study also found significantly more abnormalities in the frontal lobe of the brain, as well as a reduction of the brain blood flow than the other groups.
Spinal taps on forty-four CFS patients showed that 30% of those patients had spinal fluid outside the norm, including elevated protein and increased white blood cells. Again, there were more spinal fluid abnormalities in patients without psychiatric comorbidities and 27% of the normal spinal fluid patients had depression.
While one-third of CFS patients experience a sudden flu-like onset of symptoms, Dr. Natelson looked for viral infections while studying the spinal fluid and found no convincing data for persistent viral infections. Only a small fraction of patients had shown evidence of reactivated Epstein Barr Virus (EBV).
He also found that Xenotropic Murine Leukemia Retrovirus (XMRV) was negative in the spinal fluid. Once an exciting possible cause for CFS, Natelson did not find the presence of the retrovirus in the spinal fluid. "That story is behind us," said Natelson.
He was also unsuccessful in replicating studies that showed immune activation, in which the immune system is turned on by a virus and then keeps running in CFS patients.
The search for biomarkers
Over time, reduced natural killer cells seem to be the only evidence of a reduced immune system that holds true across many studies. However, Natelson has found evidence for the opposite.
While the pro-inflammatory cytokines make you feel sick, he has found evidence that one of the anti-inflammatory cytokines, IL-10, was elevated and may contribute to disturbing sleep.
With today's technology, Dr. Natelson has come closer to finding biological abnormalities that could be used to unequivocally identify and diagnose Chronic Fatigue Syndrome in a specific subset of patients.
Using MRIs to look at chemicals in the brain, Natelson compared Ventricular Lactate in CFS and controls as a possible biomarker. He found that CFS patients without a coexisting psychiatric disorder had higher lactate, and he has now replicated this study.
Natelson also believes that 15% of CFS patients have an autoimmune disorder that is being missed.
He discussed Sjögren's Syndrome, another autoimmune illness, the main early symptoms of which are dry eyes and dry mouth but also include prolonged fatigue. A lip biopsy is the definitive way to diagnose Sjögren's, in which the body attacks its own tear and salivary glands.
In his small study, all the patients had a negative result to Sjögren's antibody blood test, but about half of the 25 patients reported dry eyes and mouth. Then the tear production was measured and it was found 10 of those 13 patients had abnormal tear production.
When lip biopsies were done on those patients, 1/3 were found to have an abnormal biopsy. Dr. Natelson thinks even though this was a small study, it may prove to be reliable in predicting autoimmune disease.
New technology
New technology now allows researchers to identify all the proteins in the spinal fluid. Through the use of mass spectrometry, an analyzer that separates proteins and breaks them down further and further than ever before, Natelson compared the proteins in spinal fluid between healthy controls, CFS patients and those with Post Lyme Fatigue Syndrome.
There are 305 proteins common to both CFS and Post-Lyme disease.
Natelson found 738 proteins unique to those with CFS. He is now working to identify three or four of those proteins that are specific to CFS to be used as a biomarker to diagnose at least a subset of CFS patients.
Findings so far
Some CFS patients have poorer neuropsychological test results, abnormal brain MRI imaging, poorer function in health related quality of life, wider reduction in brain blood flow, more abnormal spinal fluid results, and higher levels of ventricular lactate, all which point to a brain disease.
Ongoing studies
Natelson is looking to better define the subgroup with a neurological cause and develop specific treatments and medications for them. In order to complete this new study, the National Institutes of Health (NIH) has awarded him a grant to repeat all of his past studies, including neuroimaging, neuropsychology and spinal taps, but all on the same group of patients.
There is also a new grant from the CDC to find out if the diagnosis of CFS is the same across centers.
This has never been done. This study will compare how Dr. Natelson, a neurologist from NY, Dr. Nancy Klimas, an immunologist from Florida, and a leading CFS researcher/clinician, and another large group of practitioners expert in CFS make the CFS diagnosis.
There is a pharmaceutical industry study on using Milnacipran (brand name Savella) to see if it proves useful in reducing fibro-fog in FM patients. Milnacipran is a class of medications called selective serotonin and norepinephrine reuptake inhibitors.
Colleagues of Dr. Natelson's from Cornell have just recently received notice that a study to try to improve brain chemistry with an available food supplement will be funded.
Advice for treatment of chronic illness
Chronic illness treatment
Dr. Natelson's advice for treatment of any chronic illness has four components:
- education
- medication
- very gentle physical conditioning
- behavioral therapy, which can help the patient to learn new techniques to handle the illness.
He stressed that this last technique is difficult to do on your own and best learned from a professional.
If patients are interested in joining the studies described above, they will need to be off all medications that may alter brain chemistry or functioning. The study is also recruiting healthy controls and volunteers get a free work-up and are reimbursed for their time. The study is being conducted in New York City but the food study involves travel to Weill-Cornell's Imaging Center.
To participate in this momentous work, go to www.painandfatigue.com or call (212) 844-6747.
[2015 note: Both studies are still soliciting participants as of late 2015.]
Cytokines and CFS article on the CDC website
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- Last Updated: 23 November 2015 23 November 2015
Cytokines are immune system signaling molecules that encourage the blood cells of the immune system to move toward the site of inflammation.
The CDC has an article Cytokines and the Symptoms of CFS (Centers for Disease Control and Prevention, December 6, 2011) which describes research determining some symptoms of ME/CFS that can come from the release of cytokines. Most of the study centered on the effects of alpha-interferon.
Love and Fatigue in America
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- Last Updated: 21 January 2016 21 January 2016
Love and Fatigue in AmericaBy Roger King
University of Wisconsin, 254 pp., $26.95
Reviewed by Jean Zimmer
On April 23, 1991, at 8 p.m., a 40-year-old British economist, international consultant, novelist, and university instructor collapsed on the floor of the Sta-Fit gym in Spokane, Washington. He describes the moment:
It’s funny how the sitting down doesn’t end the going down—like gravity does not know where to stop, and its giant hand persists in pushing on my shoulders, insisting I go right through the floor, or failing that, to be flattened on it like paint. I cannot let this happen. It would look bad. It might attract attention. I concentrate on the countervailing force offered by friction, back pressed against the wall, feet pulled up and flat on the carpet. I stare with unseeing eyes—they are busy playing their own game of light and dark—a hint of a smile on my lips. Not ridiculous, I hope.
Thus begins the narrator’s 21-year journey with chronic illness. King’s just-released autobiographical novel is a heart-baring exploration of what it is to lose the classic measures of success—a thriving career, prospects of a family, and financial security—when they are supplanted by illness. In poignant parcels, the narrator describes his comic-tragic journey as he navigates, in faltering steps, the strange and unfamiliar landscape of our profit-driven healthcare system.
Occasional illness is a fact of life for most of us. As I write this, my teenage son lies in bed, red-nosed and sneezing, sequestered with a book and a box of Kleenex. He awaits, with full expectation of attainment, the return of health—in his ideal world, before his friends’ Frisbee game begins this afternoon.
Others don’t rebound so quickly or completely. My family practice physician once referred to them, not unkindly, as his “fat file” patients—the ones whose medical files overflow with test orders and memos from repeated office visits. Most of us have known a “fat file” person: the cousin diagnosed with multiple sclerosis; the teacher who left her job when she came down with Lyme; the guy up the street with diabetes and a gimp knee; or the coworker medicated for chronic depression. For these people, the problems don’t go away. Often, they seem to compound.
If we are decent (and most of us are), we feel sorry for them, in their pain or debilitation. We do what we can: We bring them supper, we drive them to doctor’s appointments, we rake leaves from their lawn, or we listen while they talk about their problems.
If their illness lingers, and especially if their complaints mount, our helping hands might falter. We lose patience. Could they be malingering? Nothing we do seems to help much. Perhaps their disability insurance runs out. Their stories of an uncaring healthcare system scare us. We may drift away, breathing excuses about our busy lives. We might run.
In Love and Fatigue in America, the narrator muses about the person he has become:
You look well/You are not dying/Your complaint is modest/You are going to be trouble for a long time/Your brain does not work/Your charm has gone with it/You are inconsistent/Sometimes perversely well./You are unreliable/You explain your unreliability/Which is like whining/You cannot explain your illness/You are inconvenient, thoughtless, boorish, charmless, witless/And don’t do your share/You are not yourself./There is no place for people who are not themselves/You are not good at being ill…
Prior to his “profound overturning,” the narrator is, by most contemporary measures, at the top of his game. He has risen from a blue-collar background in a London suburb to earn a Ph.D. in agricultural economics. His first career in Africa and Asia as a socio-economist and institutions expert is supplanted by a second career as an award-winning novelist. Fit, seemingly fearless, and 40, he has negotiated world continents, closed on impressive contracts, won at love, and acquired an impressive, supportive community of friends.
His metaphorical crash-landing, with symptoms of what first seems like a bone-crushing flu, upends his life and career. As his illness persists from weeks to months to years, his girlfriend, friends, and colleagues drop away, one by one, from his life. Ironically, those who don’t abandon him use him—prone, sick, silent, but also sympathetic—as a sounding board for their own stories of emotional and physical suffering.
After receiving a diagnosis of chronic fatigue syndrome (CFS), the narrator follows the advice of a parade of doctors and alternative health practitioners, many of whom are portrayed as comically incompetent. Who knew that a story of getting sick could be funny? King weaves humor through his novel.
Unflappable college students meet with the narrator during his academic office hours, offering threats, attempts at coercion, or intimate details of their sex lives. His alternative medical practitioner in Santa Fe drives a red BMW with crash damage, which he soon replaces with a second vehicle that soon shows up with crash damage. At one point, the narrator kisses a potential murderess, “but, hello, this is California.”
Many people afflicted with CFS express frustration that the descriptor “chronic fatigue” reduces the syndrome to an undeserved simplicity. Outside the U.S., CFS goes by the weightier name “myalgic encephalopathy.” Beyond incapacitating fatigue, classic symptoms of CFS include impaired concentration and memory; muscle and joint pain; sleep disturbances; tender lymph nodes; sore throat; headache; and worsening of health following physical or mental exertion. The syndrome crosses lines of education, affluence, race, and gender.
No one knows how people get CFS, but a brain-targeting virus, genetic susceptibility, and a compromised immune system are suspected contributors.
The narrator seeks a recovery that, for a while, he does not doubt. As years pass and his condition deteriorates, however, his bewilderment, humiliation, and suffering increase while his hope diminishes.
With each remission I am convinced that the recovery will be permanent, and each time I am proved wrong. This never changes. Health is unable to imagine being ill; illness cannot recall a state of health.
Although he is a world traveler accustomed to harsh conditions, the narrator finds himself at a loss when he faces the foreign and confusing landscape of illness in the United States. He compares the U.S. healthcare system with the nationalized medical system of his homeland, England—a system that requires of its patients much less paperwork, permissions, and payments.
You remember visits to the doctor as blithe affairs. The burden of management customary to Americans strikes you as astonishing—staggering—in its complexity, trickery, and venality. You wonder that such a situation could ever be taken as normal.
The narrator points out “the labor of being sick in America,” a country where the more a person is weak and compromised, the more he must advocate for himself. Because he is so ill that he is limited to his sofa, that is the site from which he conducts his business. He stashes medical bills and insurance receipts in cracks between cushions and on the floor beside him. Using a telephone balanced on his chest, he works daily, until sickness and exhaustion overwhelm him, to clarify, defend, and understand his condition and his health benefits.
The narrator struggles to keep his university job, but he has numerous setbacks, such teaching “a horrific class” during which his head falls onto his desk and will not come up.
Over time, the narrator learns to ration his energy. He learns to cope with his incredulous coworkers. He describes the paradox of trying to maintain his job and maintain an appearance of a normal life:
The intermittent need to prove to doctors that my illness is not in my mind-when clearly my mind is affected—and to prove to the company’s private investigators that I am not disabled—when every day is taken up by trying to seem not disabled—causes paroxysms of internal conflict.
Over time, quietness, solitude, and low-grade panic overtake him. “It’s hard not to blame yourself for illness,” he writes, in perhaps his closest admission of self-pity. His income and savings dwindle. He struggles to maintain his job. He longs for a home and family.
Remarkably, he achieves love, in noncontiguous chunks: tender affection for a woman and her daughter, sex for money, and a more tenacious love from his dog Arthur.
King’s book was written from within the bounds of his own illness, and the format might be taken as evidence for his labor in writing it. It is crafted as a series of dozens of short chapters, some as short as a single page. They include narrative, essays, lists, and poems. King’s narrator is an appealing character: His illness seems to have made him, patient, kind, and wise—he inhabits a shrunken world, yet he maintains a wide worldview.
The book is fiction, but King’s use of first-person captures a real man—one with authentic, flawed retrospective recall. The novel reads a little bit like a diary, including a few steamy love scenes and witty, observant notes on topics as diverse as strippers, military life, and ambition.
Although the book weighs in at 254 pages, it’s hard not to want a little more about the main character’s origins. Who were his barely-mentioned parents? What was life like in suburban London for an introspective child? What series of events turned a provincial lad into a globetrotting economist?
The story opens with an exuberant and hopeful narrator circling in a jet above the city of Spokane, Washington. It concludes in a small town in western Massachusetts, with the narrator contemplating the gains and losses of his quiet existence.
From his place of retreat, the former world traveller and international problem-solver describes his “horizontal life” as peaceful, with appreciation for small beauties and subtleties. In a section titled “Lost and Found,” he comments
I have had pressed on me by illness the eternal good sense and wisdom of being present in my body, and relaxing the self in something larger … the nature of CFS is an object lesson in oneness. Which is an object lesson in love. You are lost, yet you are found.
An account of being sick could be a hard sell in today’s book market. If the daily news itself can be a downer, why read a narrative about illness and disability?
Answer: Because fate is fickle. The book’s publication follows closely on the U.S. Supreme Court’s review of President Obama’s healthcare law. King’s well-crafted book raises important questions about how our society treats sick people. What happened to the narrator could happen to anyone. Perhaps the book could help inspire a remedy for a healthcare system that doesn’t seem very caring.
Roger King is the author of four previous novels: Horizontal Hotel, Written on a Stranger’s Map, Sea Level, and A Girl from Zanzibar. He lives in Leverett, Massachusetts.
Jean Zimmer is a freelance writer and editor based in western Massachusetts.
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Notice about names
The Massachusetts ME/CFS & FM Association would like to clarify the use of the various acronyms for Chronic Fatigue Syndrome (CFS), Chronic Fatigue & Immune Dysfunction Syndrome (CFIDS) and Myalgic Encephalomyelitis (ME) on this site. When we generate our own articles on the illness, we will refer to it as ME/CFS, the term now generally used in the United States. When we are reporting on someone else’s report, we will use the term they use. The National Institutes of Health (NIH) and other federal agencies, including the CDC, are currently using ME/CFS.
Massachusetts ME/CFS & FM Association changed its name in July, 2018, to reflect this consensus.