Rainbow at shoreline

The Massachusetts ME/CFS & FM Association, a 501(c)3 founded in 1985, exists to meet the needs of patients with ME (Myalgic Encephalomyelitis), CFS (Chronic Fatigue Syndrome) or FM (Fibromyalgia), their families and loved ones. The Massachusetts ME/CFS & FM Association works to educate health-care providers and the general public regarding these severely-disabling physical illnesses. We also support patients and their families and advocate for more effective treatment and research.

Research articles

Dr. Gudrun Lange Reviews Neuropsychological Testing for CFS and FM

Dr. Gudrun Lange reviewed the process of neuropsychological testing for Chronic Fatigue Syndrome (CFS) and FM at the April 28, 2012 Educational Forum co-sponsored by the Massachusetts CFIDS/ME & FM Association (MassCFIDS) and the Massachusetts Department of Public Health.

Dr. Lange said that in the absence of objective biomarkers neuropsychological testing is "the silver bullet" when it comes to qualifying for disability. Cognitive testing is accepted as an objective measure of impairment in function by the Social Security Administration.

[Note: For some long-term disability policies, a finding of impaired cognitive function could lead to a limitation of benefits to two years. Read your policy!—Editor]

Gudrun Lange, Ph.D., is a Clinical Neuropsychologist with sixteen years of experience in the assessment and study of the cognitive and behavioral aspects of chronic pain and persistent fatigue. She has received federal grants for her work and most recently, received National Institutes of Health (NIH) funds for a pilot study to assess the tolerability and efficacy of vagus nerve stimulation (VNS) therapy in patients with severe Fibromyalgia (FM) pain.

Dr. Lange's approach

Dr. Lange uses a quantitative, individualized approach to neuropsychological testing that allows for detailed interpretation of the test data within the context of an individual's overall profile of cognitive strengths and weaknesses.

While individuals with Chronic Fatigue Syndrome (CFS) generally report that the cognitive problems they experience are of great impact on their lives and everyday function, quantitative, objective neuropsychological testing often reveals very subtle cognitive problems.

Many times the deficits found on objective testing do not rise to the level of an absolute impairment.

Dr. Lange argued that any deficits observed need to be interpreted relative to the individuals other strengths and weaknesses, otherwise it may lead to misleading findings.


Difference between focal or diffuse brain injury

Dr. Lange provided a brief overview of the developmental history of clinical neuropsychology. She mentioned that neuropsychological testing evolved to assess individuals with focal acquired brain injuries for diagnosis and management. She distinguished acquired brain injuries that occur after birth from those that an individual is born with, congenital or genetic brain conditions. Before the advances made in neuroimaging technology such as CAT and MRI scans, neuropsychology was used to pinpoint the area of dysfunction in the brain. However, damage to the brain is not always focal, but can be diffuse in nature. Dr. Lange explained that neuropsychological assessment of diffuse brain injuries, affecting many interconnecting areas of the brain, is difficult as the measures were developed to reveal dysfunction in specific brain regions. These conditions include Multiple Sclerosis, Parkinson's disease and Chronic Fatigue Syndrome.

She noted that appropriate interpretation of test data from individuals with these conditions requires a significant degree of interpretation and knowledge by the practitioner. If a neuropsychologist has not had the opportunity to deal with patients with an illness that affects the brain in a diffuse and subtle manner, such as CFS, they might not be sensitive to the type of cognitive dysfunctions seen in these patients. Patients need to find neuropsychologists who are sensitive and knowledgeable about these issues. When a patient is looking for a neuropsychologist, he or she must find someone who is knowledgeable about CFS and FM. Patients must interview neuropsychologists to determine the best candidate, because neuropsychological testing is expensive. CFS patients have deficits. A knowledgeable neuropsychologist must look at the numbers across the different cognitive domains for an appropriate reflection of the cognitive profile with its strengths and weaknesses.


Not less smart, just less fast

The brain is organized in a fashion where basic motor and sensory functions are well represented, allowing for a significant degree of redundancy. Therefore, if a problem occurs in one of these regions, the brain can adjust for it.

This is less true for cognitive functions that are considered "higher" functions, such as executive function, attention, working memory and information processing. Symptoms in CFS such as brain fog and memory impairments fall under these higher levels of brain function. Although many patients find ways to compensate and may not notice their full impairments all at once, it gets more exhaustive for the patient as they have to exert increased amounts of energy to do the same mental tasks.


Specific to CFS patients

It is not the case that patients with CFS become less intelligent. Many patients are concerned that they are "dementing." Dr. Lange stated that she has not seen a CFS patient with dementia. CFS is not a degenerative neurological disorder. I.Q. tests are divided between steady state functions, well-entrenched information firmly planted in the brain, and more transient functions. The steady state information does generally not decay in patients with CFS.

In Dr. Lange's experience, the major problem with CFS patients is the slowing down of information processing. It affects working memory, the ability to keep pieces of information in mind for immediate use. For instance, hearing a phone number and then being able to recall it five minutes later to make the call. For most CFS patients, that is impossible. The resulting frustration then makes the cognitive problem worse.

Dr. Denise Park has called this the "premature aging of the brain," meaning that the brain in a thirty-five-year-old fibromyalgia patient in Park's study (Park Dl et al, "Cognitive Function in Fibromyalgia Patients," Arthritis & Rheumatism 44, No. 9 (2001): 2125-2133) reflected the neuropsychological testing performance of a person 20 years older.


Neuropsychological testing for CFS

Dr. Lange described how she conducts neuropsychological testing. First, she conducts a thorough clinical interview, which lasts about two hours. After the clinical interview, patients receive a full I.Q. assessment.

After the I.Q. testing, she tests for memory, attention, visual, language, and motor function, and executive function including multi-tasking and decision-making. Language, visual and motor function are almost never affected, but attention and executive function are usually abnormal and often relatively impaired.

Overall, she spends a total of 20-25 hours on a case, first reviewing the medical records, then spending time with the patient in the initial interview, then hours of testing and scoring with several more hours for writing up the report.

If a patient is required to redo the testing for Social Security, Dr. Lange uses a screening tool and taps into the specific issues previously identified to keep the time and costs down. That usually takes 3-4 hours.


To test or not

If a patient is trying for Social Security disability, neuropsychological testing is the only objective test to show a dysfunction in the brain. MRI and SPECT scans are not standardized for CFS. Again, Dr. Lange pointed out that there are no focal injuries in CFS. It is a diffuse assault of the central nervous system in the brain, so static MRI scans are generally normal.

Dr. Lange urged patients to carefully think about undergoing neuropsychological testing before paying the expense of the testing procedures. She recommended discussing it with a patient's physician before moving forward to identify a clinical neuropsychologist with knowledge about cognitive function in CFS.

Dr. Lange also recommended patients proceed with integrative medicine because a CFS patient must approach the chronic condition in an integrative fashion. That includes pharmacological approaches, but also complementary alternative methods such as low impact physical modalities—tai chi and Qi Gong are two techniques that patients can do at their own pace. Dr. Lange underscored the importance of "coaching," an intervention that can help patients learn ways to gain a modicum of control back over their lives and ultimately, feel better.

Dr. Benjamin Natelson is 2012 keynote speaker at Mass CFIDS/ME & FM Association : Lumper or Splitter

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

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.

Subcategories

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.