Brain imaging reveals clues about chronic fatigue syndrome

A brain imaging study shows that patients with chronic fatigue syndrome may have reduced responses, compared with healthy controls, in a region of the brain connected with fatigue. The findings suggest that chronic fatigue syndrome is associated with changes in the brain involving brain circuits that regulate motor activity and motivation.

Compared with healthy controls, patients with chronic fatigue syndrome had less activation of the basal ganglia, as measured by fMRI (functional magnetic resonance imaging). This reduction of basal ganglia activity was also linked with the severity of fatigue symptoms.

According to the Centers for Disease Control and Prevention, chronic fatigue syndrome is a debilitating and complex disorder characterized by intense fatigue that is not improved by bed rest and that may be worsened by exercise or mental stress.

The results are scheduled for publication in the journal PLOS One.

“We chose the basal ganglia because they are primary targets of inflammation in the brain,” says lead author Andrew Miller, MD. “Results from a number of previous studies suggest that increased inflammation may be a contributing factor to fatigue in CFS patients, and may even be the cause in some patients.”

Miller is William P. Timmie professor of psychiatry and behavioral sciences at Emory University School of Medicine. The study was a collaboration among researchers at Emory University School of Medicine, the CDC’s Chronic Viral Diseases Branch, and the University of Modena and Reggio Emilia in Italy. The study was funded by the CDC.

The basal ganglia are structures deep within the brain, thought to be responsible for control of movements and responses to rewards as well as cognitive functions. Several neurological disorders involve dysfunction of the basal ganglia, including Parkinson’s disease and Huntington’s disease, for example.

In previous published studies by Emory researchers, people taking interferon alpha as a treatment for hepatitis C, which can induce severe fatigue, also show reduced activity in the basal ganglia. Interferon alpha is a protein naturally produced by the body, as part of the inflammatory response to viral infection. Inflammation has also been linked to fatigue in other groups such as breast cancer survivors.

“A number of previous studies have suggested that responses to viruses may underlie some cases of CFS,” Miller says. “Our data supports the idea that the body’s immune response to viruses could be associated with fatigue by affecting the brain through inflammation. We are continuing to study how inflammation affects the basal ganglia and what effects that has on other brain regions and brain function. These future studies could help inform new treatments.”

Treatment implications might include the potential utility of medications to alter the body’s immune response by blocking inflammation, or providing drugs that enhance basal ganglia function, he says.

The researchers compared 18 patients diagnosed with chronic fatigue syndrome with 41 healthy volunteers. The 18 patients were recruited [not referred] based on an initial telephone survey followed by extensive clinical evaluations. The clinical evaluations, which came in two phases, were completed by hundreds of Georgia residents. People with major depression or who were taking antidepressants were excluded from the imaging study, although those with anxiety disorders were not.

For the brain imaging portion of the study, participants were told they’d win a dollar if they correctly guessed whether a preselected card was red or black. After they made a guess, the color of the card was revealed, and at that point researchers measured blood flow to the basal ganglia.

The key measurement was: how big is the difference in activity between a win or a loss? Participants’ scores on a survey gauging their levels of fatigue were tied to the difference in basal ganglia activity between winning and losing. Those with the most fatigue had the smallest changes, especially in the right caudate and the right globus pallidus, both parts of the basal ganglia.

Ongoing studies at Emory are further investigating the impact of inflammation on the basal ganglia, including studies using anti-inflammatory treatments to reduce fatigue and loss of motivation in patients with depression and other disorders with inflammation including cancer.

 

Source: Emory Health Sciences. “Brain imaging reveals clues about chronic fatigue syndrome.” ScienceDaily. ScienceDaily, 23 May 2014. https://www.sciencedaily.com/releases/2014/05/140523192427.htm

 

Chronic fatigue syndrome: System under stress

Australian researchers have discovered for the first time that reduced heart rate variability — or changes in heart beat timing — best predicts cognitive disturbances, such as concentration difficulties commonly reported by people with chronic fatigue syndrome (CFS). This adds to the growing body of evidence linking autonomic nervous system imbalance to symptoms of this poorly understood disorder.

The findings are reported in the journal PLOS ONE.

Chronic fatigue syndrome is characterised by medically unexplained, disabling fatigue and neuropsychiatric symptoms of at least six months’ duration. The disturbance underlying the symptoms in CFS is still poorly understood.

“We have studied autonomic function in CFS for some time and our findings clearly indicate a loss of integrity in stress-responsive neural and physiological systems in CFS. Patients with this condition are hyper-responsive to challenges arising both from within the body and from the environment,” says lead researcher, Associate Professor Ute Vollmer-Conna of the University of New South Wales in Sydney, Australia.

“Even when they sleep, their stress-responsive neural systems are on high alert, signalling that it is not safe to relax. I think this condition may be understood by analogy to post-traumatic stress disorder, just that in CFS the original trauma is most likely a physiological, internal one, such as a severe infection.”

In a study of 30 patients with CFS and 40 healthy individuals, UNSW researchers recorded the heart beats of participants (via ECG) and analysed cardiac responses to cognitive challenges, and associations with mental performance outcomes.

The patients with CFS performed with similar accuracy, but they took significantly longer to complete the tests than people without the condition. They also had greater heart rate reactivity; low and unresponsive heart rate variability; and prolonged heart rate-recovery after the cognitive challenge.

Resting heart rate variability (an index of vagus nerve activity) was identified as the only significant predictor of cognitive outcomes, while current levels of fatigue and other symptoms did not relate to cognitive performance.

“This is the first demonstration of an association between reduced cardiac vagal tone and cognitive impairment in CFS. Our findings confirm previous reports of a significant loss of vagal modulation, which becomes particularly apparent when dealing with challenging tasks. The current results are consistent with the notion that CFS represents a ‘system under stress’,” Associate Professor Vollmer-Conna says.

The findings could lead to new ways to improve cognitive difficulties in people with CFS, including biofeedback assisted retraining of autonomic functioning, the researchers say.

Journal Reference: Alison Beaumont, Alexander R. Burton, Jim Lemon, Barbara K. Bennett, Andrew Lloyd, Uté Vollmer-Conna. Reduced Cardiac Vagal Modulation Impacts on Cognitive Performance in Chronic Fatigue Syndrome. PLoS ONE, 2012; 7 (11): e49518 DOI: 10.1371/journal.pone.0049518

 

Source: University of New South Wales. “Chronic fatigue syndrome: System under stress.” ScienceDaily. ScienceDaily, 15 November 2012. https://www.sciencedaily.com/releases/2012/11/121115133806.htm

 

Chronic fatigue syndrome patients need an effective therapeutic, leading expert argues

Ampligen, the first drug ever seeking approval to treat chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME), recently hit another roadblock with the U.S. Food and Drug Administration (FDA). In its long quest to treat 1 million Americans suffering from this debilitating illness, the FDA advisory panel did not recommend the drug to be sold on the market, largely because CFS/ME doesn’t have clear biomarkers such as blood tests to define patients who most likely to respond to the drug. Data from clinical trials of Ampligen has not convinced the FDA so far.

Nancy Klimas, M.D., one of the world’s leading researchers and clinicians in chronic fatigue syndrome/myalgic encepahalomyelitis (CFS/ME), is the director the NSU Institute for Neuro Immune Medicine. “The real loser is not Ampligen, but CFS/ME patients whose daily suffering continues to be unabated,” she says. “CFS/ME feels like you’ve been run over by a truck — pain, inflammation, utter exhaustion and trouble concentrating.”

Klimas has been caring for patients with CFS/ME for 26 years now. “It’s heartbreaking seeing them struggle and suffer from this serious illness that has been trivialized by science and society. One of the early controversies quickly disproven suggested that CFS/ME is a form of depression. This led to enduring public policies that allowed insurance companies to limit coverage to CFS/ME to either mental health or exercise therapy, neither get to the root cause of CFS/ME,” she explains.

“CFS/ME researchers, including myself, have seen major advances in our understanding of the biology of CFS/ME. It seems to resemble an illness we know how to treat like multiple sclerosis (MS), chronic viral diseases and autoimmune diseases.”

Around since the late 1980s, this drug is not new to science and medicine. Two phase 3 clinical studies have been completed. The data shows that a subgroup of CFS/ME patients showed marked improvement, even recovery on the drug.

“Yet, that’s not enough evidence for the FDA advisory committee to approve because they would like to see a conclusive biomarker,” notes Klimas. “As a physician, I could live with this decision if I had other effective therapies to treat my CFS/ME patients. But I do not. Moreover, it defies common logic in used in drug approval for other complex immune mediated diseases.”

Take for example, MS: Its earliest approved treatments had opposite immune effects. One interferon increased immune activity and a second interferon quieted immune activity. In the studies that led to approval, MS drugs, like Ampligen, had about a 40 percent success rate.

Clinical research for these early MS drugs produced no biomarkers other than a patient’s successful response to therapy, such as the case of Ampligen. The biomarker the FDA relied on for approval of MS — seeing if the lesions in a patient’s brain decreased — had no correlation to the patient’s improvement.

Why would the FDA approve MS drugs before there were concrete biomarkers to determine success? The answer is simple, Klimas says. The advisory panel saw MS as a serious disease that required interventions ASAP, and were willing to accept that clinicians would better understand where to use the first drugs with more experience using them. Now there are seven approved drugs for MS that have significantly improved quality of life for patients. But they are not willing to use the same logic for Ampligen.

“With or without a biomarker, the FDA should recognize the seriousness of CFS/ME and approve Ampligen, and open the door for other targeted therapies now,” she says.

 

Source: Nova Southeastern University. “Chronic fatigue syndrome patients need an effective therapeutic, leading expert argues.” ScienceDaily. ScienceDaily, 24 January 2013. https://www.sciencedaily.com/releases/2013/01/130124183448.htm

 

Why exercise magnifies exhaustion for chronic fatigue syndrome patients

The mechanism that causes high-performance athletes to “feel the burn” turns out to be the culprit in what makes people with chronic fatigue syndrome feel exhausted by the most common daily activities, new University of Florida Health research shows.

Published in the February issue of the journal Pain, the study shows that the neural pathways that transmit feelings of fatigue to the brain might be to blame. In those with chronic fatigue syndrome, the pathways do their job too well.

The findings also provide evidence for the first time that peripheral tissues such as muscles contribute to feelings of fatigue. Determining the origins of fatigue could help researchers develop therapies or identify targets for those therapies.

Researchers focused on the role of muscle metabolites, including lactic acid and adenosine triphosphate, or ATP, in the disease. The study has demonstrated for the first time that these substances, released when a person exercises his or her muscles, seem to activate these neural pathways. Also, UF Health researchers have shown that these pathways seem to be much more sensitive in patients with chronic fatigue syndrome than in patients without the disease, something that hasn’t been studied before.

Chronic fatigue syndrome, which the Institute of Medicine recently renamed systemic exertion intolerance disease, or SEID, is characterized by extreme chronic fatigue. Because its chief symptom — fatigue — is often associated with many other diseases, it can be difficult to diagnose SEID for the more than 1 million people who actually have the disease, according to the Centers for Disease Control and Prevention. The disease has no root medical cause, and researchers don’t know what triggers it. But they are studying aspects of the disease to figure out ways to treat it.

“What we have shown now, that has never been shown before in humans, is that muscle metabolites can induce fatigue in healthy people as well as patients who already have fatigue,” said Dr. Roland Staud, a professor of rheumatology and clinical immunology in the UF College of Medicine and the paper’s lead author.

During exercise, muscles produce metabolites, which are sensed by metaboreceptors that transmit information via fatigue pathways to the brain, according to the researchers. But in patients with SEID, these fatigue pathways have become highly sensitive to metabolites and can trigger excessive feelings of fatigue.

“For most of us, at the end of strenuous exertion we feel exhausted and need to stop — but we will recover rapidly,” Staud said. “However, these individuals tire much more rapidly and sometimes just after moving across a room, they are fully exhausted. This takes a toll on their lives.”

Staud and co-author Michael E. Robinson, a professor in the department of clinical and health psychology in the UF College of Public Health and Health Professions, recruited a group of 39 patients with SEID and 29 participants without the disease. The researchers asked the participants to don a blood pressure cuff just above their elbows on their dominant side, pick up a spring-loaded device and squeeze it to 100 percent of their maximum capacity, which was measured by a dial.

With research assistants encouraging them, the study participants then squeezed the device so that the dial showed they were gripping at 50 percent of their maximum capacity for as long as they could.

At the end of the hand-grip exercise, the blood pressure cuff on the participant’s arm was inflated, almost instantly trapping the metabolites generated by the exercise within the forearm muscles. This allowed the metabolites to collect in the forearm tissue without being cleared by the circulatory system. There, the metabolites continued to activate fatigue pathways, sending messages of fatigue to the brain and allowing researchers to measure how much fatigue and pain may occur because of the trapped metabolites.

With the blood pressure cuff still inflated, the participants rated fatigue and then pain in their forearms every 30 seconds. Both patients with SEID and patients without the disease reported increasing fatigue, but patients with the disease recorded much higher levels of fatigue and pain.

“We found that the fatigued individuals reported more fatigue than the non-fatigued individuals during the exercise, and also found that they had more pain compared to the non-fatigued individuals,” Staud said.

On the Fatigue Visual Analog Scale used to measure participants’ fatigue, patients with SEID rated their fatigue at approximately 5.5 on a scale of 0 to 10 after the hand-grip exercise while wearing the inflated blood pressure cuff, whereas participants without the disease rated their fatigue at approximately 1.5.

After 30 minutes, the participants repeated the exercise, but with the opposite arm and without the cinching blood pressure cuff so the metabolites could be cleared from the arm. Both sets of participants experienced fatigue, but the feeling of fatigue in those with the disease was much lower than when the metabolites were trapped with the blood pressure cuff.

“This suggests that hypersensitive fatigue pathways play an important role for the often pronounced exercise-related fatigue of patients with the disease,” Staud said.

Next, Staud plans to explore treatment interventions and to conduct brain-imaging studies of patients with SEID.

“The take-home message here is, like many of the pain studies we have conducted, there are both peripheral and central nervous system factors at play in these complex syndromes,” said Robinson, who is also the director of the UF Center for Pain Research and Behavioral Health. “Our study seems to highlight the important role of these peripheral tissues.”

Journal Reference: Roland Staud, Meriem Mokthech, Donald D. Price, Michael E. Robinson. Evidence for sensitized fatigue pathways in patients with chronic fatigue syndrome. Pain, 2015; 156 (4): 750 DOI: 10.1097/j.pain.0000000000000110

 

Source: University of Florida. “Why exercise magnifies exhaustion for chronic fatigue syndrome patients.” ScienceDaily. ScienceDaily, 12 March 2015. https://www.sciencedaily.com/releases/2015/03/150312154135.htm

 

Toward a clearer diagnosis of chronic fatigue syndrome

Researchers at the RIKEN Center for Life Science Technologies, in collaboration with Osaka City University and Kansai University of Welfare Sciences, have used functional PET imaging to show that levels of neuroinflammation, or inflammation of the nervous system, are higher in patients with chronic fatigue syndrome than in healthy people.

Chronic fatigue syndrome, which is also known as myalgic encephalomyelitis, is a debilitating condition characterized by chronic, profound, and disabling fatigue. Unfortunately, the causes are not well understood.

Neuroinflammation — the inflammation of nerve cells — has been hypothesized to be a cause of the condition, but no clear evidence has been put forth to support this idea. Now, in this clinically important study, published in The Journal of Nuclear Medicine, the researchers found that indeed the levels of neuroinflammation markers are elevated in CFS/ME patients compared to the healthy controls.

The researchers performed PET scanning on nine people diagnosed with CFS/ME and ten healthy people, and asked them to complete a questionnaire describing their levels of fatigue, cognitive impairment, pain, and depression. For the PET scan they used a protein that is expressed by microglia and astrocyte cells, which are known to be active in neuroinflammation.

The researchers found that neuroinflammation is higher in CFS/ME patients than in healthy people. They also found that inflammation in certain areas of the brain — the cingulate cortex, hippocampus, amygdala, thalamus, midbrain, and pons — was elevated in a way that correlated with the symptoms, so that for instance, patients who reported impaired cognition tended to demonstrate neuroinflammation in the amygdala, which is known to be involved in cognition. This provides clear evidence of the association between neuroinflammation and the symptoms experienced by patients with CFS/ME.

Though the study was a small one, confirmation of the concept that PET scanning could be used as an objective test for CFS/ME could lead to better diagnosis and ultimately to the development of new therapies to provide relief to the many people around the world afflicted by this condition.

Dr. Yasuyoshi Watanabe, who led the study at RIKEN, stated, “We plan to continue research following this exciting discovery in order to develop objective tests for CFS/ME and ultimately ways to cure and prevent this debilitating disease.”

Journal Reference: Y. Nakatomi, K. Mizuno, A. Ishii, Y. Wada, M. Tanaka, S. Tazawa, K. Onoe, S. Fukuda, J. Kawabe, K. Takahashi, Y. Kataoka, S. Shiomi, K. Yamaguti, M. Inaba, H. Kuratsune, Y. Watanabe. Neuroinflammation in Patients with Chronic Fatigue Syndrome/Myalgic Encephalomyelitis: An 11C-(R)-PK11195 PET Study. Journal of Nuclear Medicine, 2014; DOI:10.2967/jnumed.113.131045

 

Source: RIKEN. “Toward a clearer diagnosis of chronic fatigue syndrome.” ScienceDaily. ScienceDaily, 4 April 2014. https://www.sciencedaily.com/releases/2014/04/140404085538.htm

 

Link between early menopause, chronic fatigue syndrome discovered

A newfound link between chronic fatigue syndrome (CFS) and early menopause was reported online today in Menopause, the journal of The North American Menopause Society (NAMS). This link, as well as links with other gynecologic problems and with pelvic pain, may help explain why CFS is two to four times more common in women than in men and is most prevalent in women in their 40s. Staying alert to these problems may also help healthcare providers take better care of women who may be at risk for CFS, say the authors of this population-based, case-control study.

Based on a long-term study of CFS and fatiguing illnesses in Georgia, this analysis from Centers for Disease Control scientists included 84 women with CFS and 73 healthy control women who completed detailed gynecologic history questionnaires. Striking differences emerged from the comparison between those groups.

The women with CFS were some 12 times more likely to have pelvic pain that wasn’t related to menstruation (such as pelvic floor dysfunction, interstitial cystitis/painful bladder syndrome or IC/PBS, and irritable bowel syndrome) than the control women. The women with CFS also reported excessive bleeding (74% vs 42%) much more often as well as significantly more bleeding between periods (49% vs 23%) and missing periods (38% vs 22%). In addition, they used hormones for purposes other than contraception (such as to treat irregular periods, menopausal symptoms or bone loss) much more often (57% vs 26%).

Also striking, most women with CFS–66%–had undergone at least one gynecologic surgery, compared with only 32% of controls, most commonly hysterectomy (55% versus 19%). Women with CFS underwent menopause early (at or before age 45) because of hysterectomy much more often (62% vs 33%). (Surgical menopause occurs immediately when both ovaries are removed at hysterectomy and often prematurely even when ovaries are preserved.) Bleeding as the reason for hysterectomy was significantly more common in the women with CFS. They also underwent natural menopause earlier, but the numbers were too small to show a significant difference.

Although CFS has previously been linked with pelvic pain and gynecologic conditions such as endometriosis, IC/PBS, polycystic ovaries, and menstrual abnormalities, this is the first study to show a link with early menopause. Sex hormone abnormalities or their early decrease or disappearance may underlie these links, and the authors called for more research to find out whether they do play a role in causing or perpetuating CFS in some women. But meanwhile, they emphasized, women’s healthcare providers need to stay alert for symptoms of CFS, such as sleep or memory problems, muscle and joint pain, and worse symptoms after exertion, developing in women who have these gynecologic or pelvic pain problems.

“CFS can take a tremendous toll on women’s lives at midlife and on our society and healthcare system. Being aware of the association of CFS and earlier menopause can help providers assist women in sorting out symptoms of CFS from symptoms of menopause,” says NAMS Executive Director Margery Gass, MD, NCMP. This paper also raises the chicken and egg question: Is early menopause the cause of later health problems or simply the result of earlier health problems not recognized as the cause of early menopause?

Journal Reference: Roumiana S. Boneva, Jin-Mann S. Lin, Elizabeth R. Unger. Early menopause and other gynecologic risk indicators for chronic fatigue syndrome in women. Menopause, 2015; 1 DOI: 10.1097/GME.0000000000000411

 

Source: The North American Menopause Society (NAMS). “Link between early menopause, chronic fatigue syndrome discovered.” ScienceDaily. ScienceDaily, 4 February 2015.  https://www.sciencedaily.com/releases/2015/02/150204075324.htm

 

Discovery could lead to faster diagnosis for some chronic fatigue syndrome cases

For the first time, researchers have landed on a potential diagnostic method to identify at least a subset of patients with chronic fatigue syndrome (CFS), a complex disorder with no known definitive cause or cure.

In a pilot study of six patients, scientists detected specific antibodies linked to latent Epstein-Barr virus reactivation in blood samples from people who had experienced classic CFS symptoms and responded to antiviral treatment. Control blood samples from 20 healthy people showed no such antibodies.

The research team, led by scientists from Ohio State University and Oakland University William Beaumont School of Medicine, acknowledges that the number of patients is small. But the researchers say the study’s power rests in their access to 16 months of blood samples for each patient — a collection allowing for an unprecedented longitudinal look at CFS.

The researchers plan to move forward with development of a clinical laboratory test that can detect these antibodies in blood samples.

The study is published in the Nov. 14 issue of the journal PLOS ONE.

The Epstein-Barr virus is a human herpes virus that causes infectious mononucleosis and several different types of tumors. An estimated 95 percent of Americans have been infected with the virus by adulthood, according to the Centers for Disease Control and Prevention (CDC), but fewer than half have experienced an active illness. Once a person is infected, the virus remains dormant in the body, and can be reactivated without causing symptoms of illness.

In these six patients, the study suggests that a latent Epstein-Barr virus had begun to reactivate, but that the newly awakened virus never reached its full potential to take over its host cells. That partial reactivation advanced enough to generate at least two viral proteins, DNA polymerase and dUTPase, and these patients produced antibodies specifically designed to identify and neutralize those proteins for more than a year.

The scientists theorize that even in the absence of a complete active infection, these viral proteins’ ability to induce inflammatory chemical signals causes enough immune system chaos to lead to CFS. The disorder’s main symptom is profound fatigue for at least six months that does not improve with rest, and is accompanied by problems that can include weakness, muscle pain, impaired memory and depression. Because the illness mimics many other disorders, diagnosis is difficult. An estimated 1 million Americans have CFS, but experts believe only 20 percent are diagnosed.

The study’s senior researchers agree that the work should be repeated in more patients “to confirm that these observations are real,” said virologist Ron Glaser, director of the Institute for Behavioral Medicine Research at Ohio State and a co-author of the study. “But finally, after more than 20 years, this is at least something to go on.”

Glaser’s primary collaborators on this work are Marshall Williams, professor of molecular virology, immunology and medical genetics at Ohio State, and A. Martin Lerner, a professor of internal medicine at Oakland University William Beaumont School of Medicine.

Ohio State and Lerner’s private practice, CFS LLC, have applied for a patent for the diagnostic method.

Glaser and Williams first published a paper in 1988 suggesting that these two viral proteins associated with partially reactivated Epstein-Barr virus could function as biomarkers for certain illnesses, including CFS. Meanwhile, Lerner became severely ill in 1986 and struggled for 10 years with CFS symptoms before treatment with antivirals dramatically improved his health.

Lerner, an infectious diseases specialist, runs his private CFS practice in Michigan, and his long-term tracking of patients’ characteristics and response to treatment made this longitudinal research possible.

The fact that CFS patients experience different symptoms and multiple types of viral and bacterial infections has led researchers to believe CFS potentially has numerous causes. That lack of uniformity also complicates the diagnostic process and development of treatments.

“Part of the problem in trying to identify an agent or biomarkers for chronic fatigue syndrome is the extreme variability among people who say they have CFS. How to sort that out has held the field back a lot of years,” said Glaser, who has studied the Epstein-Barr virus (EBV) for decades.

Lerner had long ago separated 142 of his patients into two groups: those who had tested positive for various antibodies against three types of herpes viruses and responded to months-long treatment with one of two types of antivirals, and a smaller group that had viral infections and a variety of co-infections who showed minimal response to antiviral treatment. As part of this tracking, he collected multiple blood serum samples for more than a year from each patient.

From those patients, he selected blood samples from six for this study. Five had been identified as an Epstein-Barr virus subset, and the sixth had Epstein-Barr virus and a bacterial co-infection. For comparison, researchers collected samples from 20 healthy people matched to the six CFS patients for age and sex.

Lerner, too, had independently hypothesized that CFS patients might be experiencing partial virus reactivation. Patients might test negative for the most active antibodies required to fight a virus, but could still recover from CFS after long-term antiviral treatment. One antiviral he uses is known to inhibit DNA polymerase, which would halt Epstein-Barr virus reactivation in its tracks.

With the CFS patients’ and control blood samples in hand, Williams used a highly sensitive laboratory method to detect whether they contained antibodies to the two target Epstein-Barr viral proteins, DNA polymerase and dUTPase, that are produced early in the process of viral reactivation.

Overall, 78.8 percent of the serum samples from the six CFS patients were positive for antibodies against DNA polymerase and 44.2 percent were positive for antibodies against dUTPase. No antibodies to these two proteins were detected in the 20 control samples.

“Every one of the six had antibodies to DNA polymerase or EBV dUTPase and those antibodies persisted over some 408 days,” Lerner said. “And the antibody levels were extraordinarily high.” High levels of antibodies circulating in the blood suggest long-term immune activation against those proteins.

Williams noted that the levels might be less significant than the antibodies being present in the first place.

“If you look at most healthy individuals, they wouldn’t have any reason to have an antibody against either of these proteins,” he said. “The antibodies alone are a good differentiator.”

This work was partially supported by the National Institutes of Health.

Additional co-authors include Maria Ariza of the Department of Molecular Virology, Immunology and Medical Genetics and Stanley Lemeshow, dean of the College of Public Health, both at Ohio State; Leonard Jason of DePaul University; Safedin Beqaj of Pathology Inc., in Torrance, Calif.; and James Fitzgerald of the University of Michigan School of Medicine.

Journal Reference: A. Martin Lerner, Maria E. Ariza, Marshall Williams, Leonard Jason, Safedin Beqaj, James T. Fitzgerald, Stanley Lemeshow, Ronald Glaser. Antibody to Epstein-Barr Virus Deoxyuridine Triphosphate Nucleotidohydrolase and Deoxyribonucleotide Polymerase in a Chronic Fatigue Syndrome Subset. PLoS ONE, 2012; 7 (11): e47891 DOI: 10.1371/journal.pone.0047891

 

Source: Ohio State University. “Discovery could lead to faster diagnosis for some chronic fatigue syndrome cases.” ScienceDaily. ScienceDaily, 14 November 2012. https://www.sciencedaily.com/releases/2012/11/121114171708.htm

 

Spinal fluid proteins distinguish Lyme disease from chronic fatigue syndrome

Patients who suffer from Neurologic Post Treatment Lyme disease (nPTLS) and those with the chronic fatigue syndrome report similar symptoms. However unique proteins discovered in spinal fluid can distinguish those two groups from one another and also from people in normal health, according to new research conducted by a team led by Steven E. Schutzer, MD, of the University of Medicine and Dentistry of New Jersey — New Jersey Medical School, and Richard D. Smith, Ph.D., of Pacific Northwest National Laboratory.

This finding, published in the journal PLoS ONE, also suggests that both conditions involve the central nervous system and that protein abnormalities in the central nervous system are causes and/or effects of both conditions.

The investigators analyzed spinal fluid from three groups of people. One group consisted of 43 patients who fulfilled the clinical criteria for chronic fatigue syndrome (CFS). The second group consisted of 25 patients who had been diagnosed with, and treated for, Lyme disease but did not completely recover. The third group consisted of 11 healthy control subjects. “Spinal fluid is like a liquid window to the brain,” says Dr. Schutzer. By studying the spinal fluid, the research team hoped to find abnormalities that could be used as markers of each condition and could lead to improvements in diagnosis and treatment.

Taking advantage of previously unavailable methods for detailed analysis of spinal fluid, the investigators analyzed the fluid by means of high powered mass spectrometry and special protein separation techniques. They found that each group had more than 2,500 detectable proteins. The research team discovered that there were 738 proteins that were identified only in CFS but not in either healthy normal controls or patients with nPTLS and 692 proteins found only in the nPTLS patients. Previously there had been no available candidate biomarkers to distinguish between the two syndromes, nor even strong evidence that the central nervous system is involved in those conditions.

This research represents the most comprehensive analysis of the complete CSF proteome (collection of proteins) to date for both Chronic Fatigue Syndrome and Neurologic Post Treatment Lyme disease (nPTLS). Prior to this study, many scientists believed that CFS was an umbrella category that included nPTLS. However these results call those previous suppositions into question.

According to Dr. Schutzer, spinal fluid proteins can likely be used as a marker of disease, and this study provides a starting point for research in that area. “One next step will be to find the best biomarkers that will give conclusive diagnostic results,” he says. “In addition, if a protein pathway is found to influence either disease, scientists could then develop treatments to target that particular pathway.”

“Newer techniques that are being developed by the team will allow researchers to dig even deeper and get more information for these and other neurologic diseases,” says Dr. Smith. “These exciting findings are the tip of our research iceberg”

Journal Reference: Steven E Schutzer, Thomas E Angel, Tao Liu, Athena A Schepmoes, Therese R Clauss, Joshua N Adkins, David G Camp, Bart K Holland, Jonas Bergquist, Patricia K Coyle, Richard D Smith, Brian A Fallon, Benjamin H Natelson. Distinct Cerebrospinal Fluid Proteomes Differentiate Post-Treatment Lyme Disease from Chronic Fatigue Syndrome. PLoS ONE, 23 Feb 2011 DOI: 10.1371/journal.pone.0017287

 

Source: Public Library of Science. “Spinal fluid proteins distinguish Lyme disease from chronic fatigue syndrome.” ScienceDaily. ScienceDaily, 23 February 2011. https://www.sciencedaily.com/releases/2011/02/110223171235.htm

 

Chronic Fatigue Syndrome Linked To Impaired Stress Response

Subtle alterations of a hormonal stress response system called the HPA axis may play a role in chronic fatigue syndrome, according to a study in the November/December issue of Psychosomatic Medicine.

A smoothly functioning hypothalamus-pituitary-adrenal, or HPA, axis helps the body remain stable under physiological and psychological stress through the actions of three hormones. First, the brain portion called the hypothalamus secretes a hormone that stimulates the pituitary gland to secrete a second hormone. This second hormone causes the adrenal glands to create cortisol.

Problems can occur at any point in this process and result in a variety of diseases. A research team led by Jens Gaab, Ph.D., of the Center for Psychobiological and Psychosomatic Research at the University of Trier in Trier, Germany; and the Institute of Psychology at the University of Zürich in Switzerland are proposing that chronic fatigue syndrome may be one of them.

Chronic fatigue syndrome is characterized by debilitating fatigue that can include including muscle aches, low-grade fever and sleep disturbances. Its cause is not understood.

Gaab and colleagues recruited approximately 40 study participants between the ages of 30 and 50. Half of the participants were chronic fatigue sufferers and the other half were healthy volunteers. All participants completed questionnaires measuring fatigue, depression and coping skills.

To examine the HPA axis in action, participants were given blood, cardiovascular and saliva tests before and after taking two stress tests. The first, a psychosocial stress test, involved preparing for a fake job interview and completing an arithmetic problem before an audience while under the impression they were being videotaped. The second test measured physical stress on a stationary bicycle.

Participants were also given a series of insulin injections known as the insulin tolerance test. “The ITT is considered the gold standard for testing the integrity of the entire HPA axis,” Gaab says.

The researchers found significantly lower response levels of one of the HPA hormones, called ACTH, among the chronic fatigue patients compared with the healthy volunteers, during both stress tests as well as the ITT test. In fact, the chronic fatigue patients had significantly lower levels of the hormone before the testing even began.

“These results suggest that on a central level, subtle dysregulations of the HPA axis exist” in chronic fatigue syndrome patients, Gaab says, adding that future studies should include repeated evaluation of the HPA axis over the course of the syndrome.

Gaab and colleagues note that the possible role of cortisol in chronic fatigue syndrome still merits investigation, as low doses of hydrocortisone have shown some positive results in chronic fatigue patients.

Source: Center For The Advancement Of Health. “Chronic Fatigue Syndrome Linked To Impaired Stress Response.” ScienceDaily. ScienceDaily, 27 November 2002. https://www.sciencedaily.com/releases/2002/11/021126202215.htm

Brain abnormalities found in chronic fatigue patients

An imaging study by Stanford University School of Medicine investigators has found distinct differences between the brains of patients with chronic fatigue syndrome and those of healthy people.

The findings could lead to more definitive diagnoses of the syndrome and may also point to an underlying mechanism in the disease process.

It’s not uncommon for CFS patients to face several mischaracterizations of their condition, or even suspicions of hypochondria, before receiving a diagnosis of CFS. The abnormalities identified in the study, to be published Oct. 29 in Radiology, may help to resolve those ambiguities, said lead author Michael Zeineh, MD, PhD, assistant professor of radiology.

“Using a trio of sophisticated imaging methodologies, we found that CFS patients’ brains diverge from those of healthy subjects in at least three distinct ways,” Zeineh said.

CFS affects between 1 million and 4 million individuals in the United States and millions more worldwide. Coming up with a more precise number of cases is tough because it’s difficult to actually diagnose the disease. While all CFS patients share a common symptom — crushing, unremitting fatigue that persists for six months or longer — the additional symptoms can vary from one patient to the next, and they often overlap with those of other conditions.

Scientific Challenge

“CFS is one of the greatest scientific and medical challenges of our time,” said the study’s senior author, Jose Montoya, MD, professor of infectious diseases and geographic medicine. “Its symptoms often include not only overwhelming fatigue but also joint and muscle pain, incapacitating headaches, food intolerance, sore throat, enlargement of the lymph nodes, gastrointestinal problems, abnormal blood-pressure and heart-rate events, and hypersensitivity to light, noise or other sensations.”

The combination of symptoms can devastate a patient’s life for 10, 20 or even 30 years, said Montoya, who has been following 200 CFS patients for several years in an effort to identify the syndrome’s underlying mechanisms. He hopes to accelerate the development of more-effective treatments than now exist. (A new Stanford Medicine magazine story describes the study in more detail.)

“In addition to potentially providing the CFS-specific diagnostic biomarker we’ve been desperately seeking for decades, these findings hold the promise of identifying the area or areas of the brain where the disease has hijacked the central nervous system,” Montoya said.

“If you don’t understand the disease, you’re throwing darts blindfolded,” said Zeineh. “We asked ourselves whether brain imaging could turn up something concrete that differs between CFS patients’ and healthy people’s brains. And, interestingly, it did.”

The Stanford investigators compared brain images of 15 CFS patients chosen from the group Montoya has been following to those of 14 age- and sex-matched healthy volunteers with no history of fatigue or other conditions causing symptoms similar to those of CFS.

Three Key Findings

The analysis yielded three noteworthy results, the researchers said. First, an MRI showed that overall white-matter content of CFS patients’ brains, compared with that of healthy subjects’ brains, was reduced. The term “white matter” largely denotes the long, cablelike nerve tracts carrying signals among broadly dispersed concentrations of “gray matter.” The latter areas specialize in processing information, and the former in conveying the information from one part of the brain to another.

That finding wasn’t entirely unexpected, Zeineh said. CFS is thought to involve chronic inflammation, quite possibly as a protracted immunological response to an as-yet unspecified viral infection. Inflammation, meanwhile, is known to take a particular toll on white matter.

But a second finding was entirely unexpected. Using an advanced imaging technique — diffusion-tensor imaging, which is especially suited to assessing the integrity of white matter — Zeineh and his colleagues identified a consistent abnormality in a particular part of a nerve tract in the right hemisphere of CFS patients’ brains. This tract, which connects two parts of the brain called the frontal lobe and temporal lobe, is called the right arcuate fasciculus, and in CFS patients it assumed an abnormal appearance.

Furthermore, there was a fairly strong correlation between the degree of abnormality in a CFS patient’s right arcuate fasciculus and the severity of the patient’s condition, as assessed by performance on a standard psychometric test used to evaluate fatigue.

Right vs. Left

Although the right arcuate fasciculus’s function is still somewhat mysterious, its counterpart in the brain’s left hemisphere has been extensively explored. The left arcuate fasciculus connects two critical language areas of the left side of the brain termed Wernicke’s and Broca’s areas, which are gray-matter structures several centimeters apart. These two structures are important to understanding and generating speech, respectively. Right-handed people almost always have language organized in this fashion exclusively in the left side of the brain, but the precise side (left or right) and location of speech production and comprehension are not so clear-cut in left-handed people. (It’s sometimes said that every left-hander’s brain is a natural experiment.) So, pooling left- and right-handed people’s brain images can be misleading. And, sure enough, the finding of an abnormality in the right arcuate fasciculus, pronounced among right-handers, was murky until the two left-handed patients and four left-handed control subjects’ images were exempted from the analysis.

Bolstering these observations was the third finding: a thickening of the gray matter at the two areas of the brain connected by the right arcuate fasciculus in CFS patients, compared with controls. Its correspondence with the observed abnormality in the white matter joining them makes it unlikely that the two were chance findings, Zeineh said.

Although these results were quite robust, he said, they will need to be confirmed. “This study was a start,” he said. “It shows us where to look.” The Stanford scientists are in the planning stages of a substantially larger study.

 

Source: Stanford University Medical Center. “Brain abnormalities found in chronic fatigue patients.” ScienceDaily. ScienceDaily, 29 October 2014.  https://www.sciencedaily.com/releases/2014/10/141029084118.htm